Allan L. Reiss

All Publications

• Longitudinal changes in functional neural activation and sensitization during face processing in fragile X syndrome. Biological psychiatry Gao, Y., Li, R., Ma, Q., Bartholomay, K. L., Lightbody, A. A., Reiss, A. L. 2024

  Abstract

  Fragile X syndrome (FXS) is a genetic condition associated with increased risk for social anxiety and avoidance. Using functional near-infrared spectroscopy (fNIRS), we previously demonstrated aberrant neural activity responding to faces in young girls with FXS cross-sectionally. Here, we tested the hypothesis that abnormalities in neural activation and sensitization would increase with age in 65 girls with FXS, ages 5-16 years, relative to an age-matched control group of 52 girls who had comparable cognitive function and clinical symptoms.Functional NIRS data were collected at two time points, 2.8±0.6 years apart during a face-processing task. Linear mixed-effects models examined longitudinal neural profiles in girls with FXS and control. Correlational analysis was performed to examine associations between neural sensitization (increasing neural response to repeated stimuli), and clinical ratings.In girls with FXS, 32 participants had one, and 24 had two fNIRS scans. In controls, 21 had one, and 29 had two fNIRS scans. Brain activations in the right middle and superior frontal gyri were higher in FXS than controls at both time points. Neural sensitization also increased in FXS at a higher rate than controls in the superior frontal gyrus when responding to upright faces. For the FXS group, sensitization in the superior frontal gyrus positively correlated with longitudinal increases in anxiety and social avoidance scores.Girls with FXS show increasingly abnormal neural activation and sensitization responding to faces over time. Aberrant neural sensitization in girls with FXS is associated with longitudinal changes in anxiety and social skills.

  View details for DOI 10.1016/j.biopsych.2024.06.020

  View details for PubMedID 38945386

• Association of Intrinsic Functional Brain Network and Longitudinal Development of Cognitive-Behavioral Symptoms in Young Girls with Fragile X Syndrome. Biological psychiatry Li, R., Lightbody, A. A., Lee, C. H., Bartholomay, K. L., Marzelli, M. J., Reiss, A. L. 2023

  Abstract

  BACKGROUND: Fragile X syndrome (FXS) is an X chromosome-linked, genetic disorder characterized by increased risk for behavioral, social, and neurocognitive deficits. Due to a more severe phenotype relative to females, research has focused largely on identifying neural abnormalities in all-male or mixed-sex participants with FXS. Therefore, very little is known about the neural alterations that contribute to cognitive-behavioral symptoms in females with FXS. This cross-sectional study aimed to elucidate the large-scale resting-state brain networks associated with the multi-domain cognitive-behavioral phenotype in girls with FXS.METHODS: We recruited 38 girls with full mutation FXS (11.58 ± 3.15 years) and 32 girls without FXS (11.66 ± 2.27 years). Both groups were matched on age, verbal IQ, and multi-domain cognitive-behavioral symptoms. Resting-state functional magnetic resonance imaging data were collected.RESULTS: Compared to the control group, girls with FXS showed significantly greater resting-state functional connectivity of the default mode network (DMN), lower nodal strength at the right middle temporal gyrus, stronger nodal strength at the left caudate, and higher global efficiency of DMN. These aberrant brain network characteristics map directly onto the cognitive-behavioral symptoms commonly observed in girls with FXS. An exploratory analysis suggested that brain network patterns at a prior time point (Time 1) were predictive of the longitudinal development of participants' multi-domain cognitive-behavioral symptoms.CONCLUSIONS: These findings represent the first examination of large-scale brain network alterations in a large sample of girls with FXS, expanding our knowledge of potential neural mechanisms underlying the development of cognitive-behavioral symptoms in girls with FXS.

  View details for DOI 10.1016/j.biopsych.2023.03.017

  View details for PubMedID 37004849

• Virtual (Zoom) Interactions Alter Conversational Behavior and Inter-Brain Coherence. The Journal of neuroscience : the official journal of the Society for Neuroscience Balters, S., Miller, J. G., Li, R., Hawthorne, G., Reiss, A. L. 2023

  Abstract

  A growing number of social interactions are taking place virtually on video conferencing platforms. Here, we explore potential effects of virtual interactions on observed behavior, subjective experience, and neural "single-brain" and "inter-brain" activity via functional near-infrared spectroscopy (fNIRS) neuroimaging. We scanned a total of 36 human dyads (72 participants, 36 males, 36 females) who engaged in three naturalistic tasks (i.e., problem-solving, creative-innovation, socio-emotional task), in either an in-person or virtual (Zoom®) condition. We also coded cooperative behavior from audio recordings. We observed reduced conversational turn-taking behavior during the virtual condition. Given that conversational turn-taking was associated with other metrics of positive social interaction (e.g., subjective cooperation and task performance), this measure may be an indicator of prosocial interaction. In addition, we observed altered patterns of averaged and dynamic inter-brain coherence in virtual interactions. Inter-brain coherence patterns that were characteristic of the virtual condition were associated with reduced conversational turn-taking. These insights can inform the design and engineering of the next generation of video conferencing technology.Significance StatementVideo conferencing has become an integral part of our lives. Whether this technology impacts behavior and neurobiology is not well understood. We explored potential effects of virtual interaction on social behavior, brain activity, and inter-brain coupling. We found that virtual interactions were characterized by patterns of inter-brain coupling that were negatively implicated in cooperation. Our findings are consistent with the perspective that video conferencing technology adversely affects individuals and dyads during social interaction. As virtual interactions become even more necessary, improving the design of video conferencing technology will be crucial for supporting effective communication.

  View details for DOI 10.1523/JNEUROSCI.1401-22.2023

  View details for PubMedID 36868852

• A Pilot randomized trial to examine effects of a hybrid closed-loop insulin delivery system on neurodevelopmental and cognitive outcomes in adolescents with type 1 diabetes. Nature communications Reiss, A. L., Jo, B., Arbelaez, A. M., Tsalikian, E., Buckingham, B., Weinzimer, S. A., Fox, L. A., Cato, A., White, N. H., Tansey, M., Aye, T., Tamborlane, W., Englert, K., Lum, J., Mazaika, P., Foland-Ross, L., Marzelli, M., Mauras, N. 2022; 13 (1): 4940

  Abstract

  Type 1 diabetes (T1D) is associated with lower scores on tests of cognitive and neuropsychological function and alterations in brain structure and function in children. This proof-of-concept pilot study (ClinicalTrials.gov Identifier NCT03428932) examined whether MRI-derived indices of brain development and function and standardized IQ scores in adolescents with T1D could be improved with better diabetes control using a hybrid closed-loop insulin delivery system. Eligibility criteria for participation in the study included age between 14 and 17 years and a diagnosis of T1D before 8 years of age. Randomization to either a hybrid closed-loop or standard diabetes care group was performed after pre-qualification, consent, enrollment, and collection of medical background information. Of 46 participants assessed for eligibility, 44 met criteria and were randomized. Two randomized participants failed to complete baseline assessments and were excluded from final analyses. Participant data were collected across five academic medical centers in the United States. Research staff scoring the cognitive assessments as well as those processing imaging data were blinded to group status though participants and their families were not. Forty-two adolescents, 21 per group, underwent cognitive assessment and multi-modal brain imaging before and after the six month study duration. HbA1c and sensor glucose downloads were obtained quarterly. Primary outcomes included metrics of gray matter (total and regional volumes, cortical surface area and thickness), white matter volume, and fractional anisotropy. Estimated power to detect the predicted treatment effect was 0.83 with two-tailed, α = 0.05. Adolescents in the hybrid closed-loop group showed significantly greater improvement in several primary outcomes indicative of neurotypical development during adolescence compared to the standard care group including cortical surface area, regional gray volumes, and fractional anisotropy. The two groups were not significantly different on total gray and white matter volumes or cortical thickness. The hybrid closed loop group also showed higher Perceptual Reasoning Index IQ scores and functional brain activity more indicative of neurotypical development relative to the standard care group (both secondary outcomes). No adverse effects associated with study participation were observed. These results suggest that alterations to the developing brain in T1D might be preventable or reversible with rigorous glucose control. Long term research in this area is needed.

  View details for DOI 10.1038/s41467-022-32289-x

  View details for PubMedID 36042217

• Dynamic Inter-Brain Synchrony in Real-life Inter-Personal Cooperation: A Functional Near-infrared Spectroscopy Hyperscanning Study. NeuroImage Li, R., Mayseless, N., Balters, S., Reiss, A. L. 2021: 118263

  Abstract

  How two brains communicate with each other during social interaction is highly dynamic and complex. Multi-person (i.e., hyperscanning) studies to date have focused on analyzing the entire time series of brain signals to reveal an overall pattern of inter-brain synchrony (IBS). However, this approach does not account for the dynamic nature of social interaction. In the present study, we propose a data-driven approach based on sliding windows and k-mean clustering to capture the dynamic modulation of IBS patterns during interactive cooperation tasks. We used a portable functional near-infrared spectroscopy (fNIRS) system to measure brain hemodynamic response between interacting partners (20 dyads) engaged in a creative design task and a 3D model building task. Results indicated that inter-personal communication during naturalistic cooperation generally presented with a series of dynamic IBS states along the tasks. Compared to the model building task, the creative design task appeared to involve more complex and active IBS between multiple regions in specific dynamic IBS states. In summary, the proposed approach stands as a promising tool to distill complex inter-brain dynamics associated with social interaction into a set of representative brain states with more fine-grained temporal resolution. This approach holds promise for advancing our current understanding of the dynamic nature of neurocognitive processes underlying social interaction.

  View details for DOI 10.1016/j.neuroimage.2021.118263

  View details for PubMedID 34126210

• Impact of Type 1 Diabetes in the Developing Brain in Children: A Longitudinal Study. Diabetes care Mauras, N., Buckingham, B., White, N. H., Tsalikian, E., Weinzimer, S. A., Jo, B., Cato, A., Fox, L. A., Aye, T., Arbelaez, A. M., Hershey, T., Tansey, M., Tamborlane, W., Foland-Ross, L. C., Shen, H., Englert, K., Mazaika, P., Marzelli, M., Reiss, A. L., Diabetes Research in Children Network (DirecNet) 2021

  Abstract

  OBJECTIVE: To assess whether previously observed brain and cognitive differences between children with type 1 diabetes and control subjects without diabetes persist, worsen, or improve as children grow into puberty and whether differences are associated with hyperglycemia.RESEARCH DESIGN AND METHODS: One hundred forty-four children with type 1 diabetes and 72 age-matched control subjects without diabetes (mean ± SD age at baseline 7.0 ± 1.7 years, 46% female) had unsedated MRI and cognitive testing up to four times over 6.4 ± 0.4 (range 5.3-7.8) years; HbA1c and continuous glucose monitoring were done quarterly. FreeSurfer-derived brain volumes and cognitive metrics assessed longitudinally were compared between groups using mixed-effects models at 6, 8, 10, and 12 years. Correlations with glycemia were performed.RESULTS: Total brain, gray, and white matter volumes and full-scale and verbal intelligence quotients (IQs) were lower in the diabetes group at 6, 8, 10, and 12 years, with estimated group differences in full-scale IQ of -4.15, -3.81, -3.46, -3.11, respectively (P < 0.05), and total brain volume differences of -15,410, -21,159, -25,548, -28,577 mm3 * 103 at 6, 8, 10, and 12 years, respectively (P < 0.05). Differences at baseline persisted or increased over time, and brain volumes and cognitive scores negatively correlated with a life-long HbA1c index and higher sensor glucose in diabetes.CONCLUSIONS: Detectable changes in brain volumes and cognitive scores persist over time in children with early-onset type 1 diabetes followed longitudinally; these differences are associated with metrics of hyperglycemia. Whether these changes can be reversed with scrupulous diabetes control requires further study. These longitudinal data support the hypothesis that the brain is a target of diabetes complications in young children.

  View details for DOI 10.2337/dc20-2125

  View details for PubMedID 33568403

• Aberrant Neural Response During Face Processing in Girls with Fragile X Syndrome: Defining Potential Brain Biomarkers for Treatment Studies. Biological psychiatry. Cognitive neuroscience and neuroimaging Li, R., Bruno, J. L., Jordan, T., Miller, J. G., Lee, C. H., Bartholomay, K. L., Marzelli, M. J., Piccirilli, A., Lightbody, A. A., Reiss, A. L. 2021

  Abstract

  Children and adolescents with fragile X syndrome (FXS) manifest significant symptoms of anxiety, particularly in response to face-to-face social interaction. In this study we used functional near-infrared spectroscopy (fNIRS) to reveal a specific pattern of brain activation and habituation in response to face stimuli in young girls with FXS, an important but understudied clinical population.Participants were 32 girls with FXS (age: 11.8 ± 2.9 years) and a control group of 28 girls without FXS (age: 10.5 ± 2.3 years) matched for age, general cognitive function and autism symptoms. Functional NIRS was used to assess brain activation during a face habituation task including repeated upright/inverted faces and greeble (nonface) objects.Compared to the control group, girls with FXS showed significant hyper-activation in the frontopolar and dorsal lateral prefrontal cortices in response to all face stimuli (upright + inverted). Lack of neural habituation (and significant sensitization) was also observed in the FXS group in the frontopolar cortex in response to upright face stimuli. Finally, aberrant frontopolar sensitization in response to upright faces in girls with FXS was significantly correlated with notable cognitive-behavioral and social-emotional outcomes relevant to this condition including executive function, autism symptoms, depression and anxiety.These findings strongly support a hypothesis of neural hyper-activation and accentuated sensitization during face processing in FXS, a phenomenon that could be developed as a biomarker endpoint for improving treatment trial evaluation in girls with this condition.

  View details for DOI 10.1016/j.bpsc.2021.09.003

  View details for PubMedID 34555563

• X-chromosome insufficiency alters receptive fields across the human early visual cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience Green, T., Hosseini, H., Piccirilli, A., Ishak, A., Grill-Spector, K., Reiss, A. L. 2019

  Abstract

  Here, we investigated processing by receptive fields, a fundamental property of neurons in the visual system, using fMRI and population receptive field (pRF) mapping in 20 human females with monosomic Turner syndrome (TS) (mean age, 10.3 ± 2.0) versus 22 age- and sex-matched controls (mean age, 10.4 ± 1.9). TS, caused by X-chromosome haploinsufficiency in females is associated with well-recognized effects on visual-spatial processing, parieto-occipital cortical anatomy, and parietal lobe function. However, it is unknown if these effects are related to altered brain structure and function in early visual areas (V1-V3) versus downstream parietal cortical regions. Results show that girls with TS have: (i) smaller volume of V1-V3, (ii) lower average pRF eccentricity in early visual areas, and (iii) sparser pRF coverage in the periphery of the visual field. Further, we examined whether the lower volume of early visual areas, defined using retinotopic mapping, in TS is due to smaller surface area or thinner cortex. Results show that girls with TS had a general reduction in surface area relative to controls in bilateral V1 and V2. Our data suggest the possibility that the smaller cortical surface area of early visual areas in girls with TS may be associated with a lower number of neurons which, in turn, leads to lesser coverage of the peripheral visual field compared to controls. These results indicate that X-chromosome haploinsufficiency associated with TS affects the functional neuroanatomy of early visual areas and suggest that investigating pRFs in TS may shed insights into their atypical visual-spatial processing.SIGNIFICANCE STATEMENTTurner syndrome is caused by the absence of one of the two X-chromosome in females. Using functional neuroimaging and population receptive field mapping, we find that chromosome dosage variation (X-monosomy) associated with Turner syndrome affects the functional neuroanatomy of the visual cortex. Specifically, girls with Turner syndrome have smaller early visual areas that provide lesser coverage of the peripheral visual field compared to healthy controls. Our observations provide compelling evidence that the X-chromosome affects not only parietal cortex, as described in previous studies, but also affects early visual areas. These findings suggest a paradigm change in understanding the effect of X-monosomy on the development of visual-spatial abilities in humans.

  View details for DOI 10.1523/JNEUROSCI.2745-18.2019

  View details for PubMedID 31434689

• Real-life creative problem solving in teams: fNIRS based hyperscanning study. NeuroImage Mayseless, N. n., Hawthorne, G. n., Reiss, A. L. 2019: 116161

  Abstract

  It is often assumed that groups of individuals can work together to achieve innovation and solve complex problems they are unable to solve on their own. One of the underlying assumptions is that a group can be more creative and innovative than single individuals. Previous research has begun to examine the process by which problem solving occurs in teams looking to achieve innovation. Despite this progress, a clear, brain-based model that informs how team interactivity contributes and impacts the outcome of an innovation event is lacking. Here we present a naturalistic study designed to examine creative problem solving involving team cooperation. We used functional near infrared spectroscopy (fNIRS) to measure inter-brain synchrony (IBS) between interacting partners engaged in a creative design task. Results implicate the involvement of cognitive control coupled with the mentalizing and mirror neuron networks in IBS. Post hoc behavioral and temporal analyses revealed an increase in cooperation over time in association with reduction in IBS. Our results demonstrate the importance of a naturalistic design for investigating the neural underpinnings of team interactions as well as suggest a possible mechanism for team creativity.

  View details for DOI 10.1016/j.neuroimage.2019.116161

  View details for PubMedID 31493532

• Brain Development in School-Age and Adolescent Girls: Effects of Turner Syndrome, Estrogen Therapy, and Genomic Imprinting. Biological psychiatry O'Donoghue, S. n., Green, T. n., Ross, J. L., Hallmayer, J. n., Lin, X. n., Jo, B. n., Huffman, L. C., Hong, D. S., Reiss, A. L. 2019

  Abstract

  The study of Turner syndrome (TS) offers a unique window of opportunity for advancing scientific knowledge of how X chromosome gene imprinting, epigenetic factors, hormonal milieu, and chronologic age affect brain development in females.We described brain growth trajectories in 55 girls with TS and 53 typically developing girls (258 magnetic resonance imaging datasets) spanning 5 years. Using novel nonparametric and mixed effects analytic approaches, we evaluated influences of X chromosome genomic imprinting and hormone replacement therapy on brain development.Parieto-occipital gray and white matter regions showed slower growth during typical pubertal timing in girls with TS relative to typically developing girls. In contrast, some basal ganglia, cerebellar, and limited cortical areas showed enhanced volume growth with peaks around 10 years of age.The parieto-occipital finding suggests that girls with TS may be particularly vulnerable to altered brain development during adolescence. Basal ganglia regions may be relatively preserved in TS owing to their maturational growth before or early in typical pubertal years. Taken together, our findings indicate that particular brain regions are more vulnerable to TS genetic and hormonal effects during puberty. These specific alterations in neurodevelopment may be more likely to affect long-term cognitive behavioral outcomes in young girls with this common genetic condition.

  View details for DOI 10.1016/j.biopsych.2019.07.032

  View details for PubMedID 31561860

• Towards a new approach to reveal dynamical organization of the brain using topological data analysis NATURE COMMUNICATIONS Saggar, M., Sporns, O., Gonzalez-Castillo, J., Bandettini, P. A., Carlsson, G., Glover, G., Reiss, A. L. 2018; 9: 1399

  Abstract

  Little is known about how our brains dynamically adapt for efficient functioning. Most previous work has focused on analyzing changes in co-fluctuations between a set of brain regions over several temporal segments of the data. We argue that by collapsing data in space or time, we stand to lose useful information about the brain's dynamical organization. Here we use Topological Data Analysis to reveal the overall organization of whole-brain activity maps at a single-participant level-as an interactive representation-without arbitrarily collapsing data in space or time. Using existing multitask fMRI datasets, with the known ground truth about the timing of transitions from one task-block to next, our approach tracks both within- and between-task transitions at a much faster time scale (~4-9 s) than before. The individual differences in the revealed dynamical organization predict task performance. In summary, our approach distills complex brain dynamics into interactive and behaviorally relevant representations.

  View details for PubMedID 29643350

• Longitudinal identification of clinically distinct neurophenotypes in young children with fragile X syndrome. Proceedings of the National Academy of Sciences of the United States of America Bruno, J. L., Romano, D. n., Mazaika, P. n., Lightbody, A. A., Hazlett, H. C., Piven, J. n., Reiss, A. L. 2017

  Abstract

  Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability. The cognitive, behavioral, and neurological phenotypes observed in affected individuals can vary considerably, making it difficult to predict outcomes and determine the need for interventions. We sought to examine early structural brain growth as a potential marker for identification of clinically meaningful subgroups. Participants included 42 very young boys with FXS who completed a T1-weighted anatomical MRI and cognitive/behavioral assessment at two longitudinal time points, with mean ages of 2.89 y and 4.91 y. Topological data analysis (TDA), an unsupervised approach to multivariate pattern analysis, was applied to the longitudinal anatomical data to identify coherent but heretofore unknown subgroups. TDA revealed two large subgroups within the study population based solely on longitudinal MRI data. Post hoc comparisons of cognition, adaptive functioning, and autism severity scores between these groups demonstrated that one group was consistently higher functioning on all measures at both time points, with pronounced and significant unidirectional differences (P < 0.05 for time point 1 and/or time point 2 for each measure). These results support the existence of two longitudinally defined, neuroanatomically distinct, and clinically relevant phenotypes among boys with FXS. If confirmed by additional analyses, such information may be used to predict outcomes and guide design of targeted therapies. Furthermore, TDA of longitudinal anatomical MRI data may represent a useful method for reliably and objectively defining subtypes within other neuropsychiatric disorders.

  View details for PubMedID 28923933

  View details for PubMedCentralID PMC5635864

• Changes in Brain Activation Associated with Spontaneous Improvization and Figural Creativity After Design-Thinking-Based Training: A Longitudinal fMRI Study. Cerebral cortex Saggar, M., Quintin, E., Bott, N. T., Kienitz, E., Chien, Y., Hong, D. W., Liu, N., Royalty, A., Hawthorne, G., Reiss, A. L. 2016

  Abstract

  Creativity is widely recognized as an essential skill for entrepreneurial success and adaptation to daily-life demands. However, we know little about the neural changes associated with creative capacity enhancement. For the first time, using a prospective, randomized control design, we examined longitudinal changes in brain activity associated with participating in a five-week design-thinking-based Creative Capacity Building Program (CCBP), when compared with Language Capacity Building Program (LCBP). Creativity, an elusive and multifaceted construct, is loosely defined as an ability to produce useful/appropriate and novel outcomes. Here, we focus on one of the facets of creative thinking-spontaneous improvization. Participants were assessed pre- and post-intervention for spontaneous improvization skills using a game-like figural Pictionary-based fMRI task. Whole-brain group-by-time interaction revealed reduced task-related activity in CCBP participants (compared with LCBP participants) after training in the right dorsolateral prefrontal cortex, anterior/paracingulate gyrus, supplementary motor area, and parietal regions. Further, greater cerebellar-cerebral connectivity was observed in CCBP participants at post-intervention when compared with LCBP participants. In sum, our results suggest that improvization-based creative capacity enhancement is associated with reduced engagement of executive functioning regions and increased involvement of spontaneous implicit processing.

  View details for PubMedID 27307467

• Specific effect of the fragile-X mental retardation-1 gene (FMR1) on white matter microstructure BRITISH JOURNAL OF PSYCHIATRY Green, T., Barnea-Goraly, N., Raman, M., Hall, S. S., Lightbody, A. A., Bruno, J. L., Quintin, E., Reiss, A. L. 2015; 207 (2): 143-148

  Abstract

  Background Fragile-X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability and neurobiological abnormalities including white matter microstructural differences. White matter differences have been found relative to neurotypical individuals. Aims To examine whether FXS white matter differences are related specifically to FXS or more generally to the presence of intellectual disability. Method We used voxel-based and tract-based analytic approaches to compare individuals with FXS (n = 40) with gender- and IQ-matched controls (n = 30). Results Individuals with FXS had increased fractional anisotropy and decreased radial diffusivity values compared with IQ-matched controls in the inferior longitudinal, inferior fronto-occipital and uncinate fasciculi. Conclusions The genetic variation associated with FXS affects white matter microstructure independently of overall IQ. White matter differences, found in FXS relative to IQ-matched controls, are distinct from reported differences relative to neurotypical controls. This underscores the need to consider cognitive ability differences when investigating white matter microstructure in neurodevelopmental disorders.

  View details for DOI 10.1192/bjp.bp.114.151654

  View details for Web of Science ID 000359180800009

  View details for PubMedID 25792692

• Longitudinal Assessment of Neuroanatomical and Cognitive Differences in Young Children With Type 1 Diabetes: Association With Hyperglycemia DIABETES Mauras, N., Mazaika, P., Buckingham, B., Weinzimer, S., White, N. H., Tsalikian, E., Hershey, T., Cato, A., Cheng, P., Kollman, C., Beck, R. W., Ruedy, K., Aye, T., Fox, L., Arbelaez, A. M., Wilson, D., Tansey, M., Tamborlane, W., Peng, D., Marzelli, M., Winer, K. K., Reiss, A. L. 2015; 64 (5): 1770-1779

  Abstract

  Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.

  View details for DOI 10.2337/db14-1445

  View details for PubMedID 25488901

• Pictionary-based fMRI paradigm to study the neural correlates of spontaneous improvisation and figural creativity. Scientific reports Saggar, M., Quintin, E., Kienitz, E., Bott, N. T., Sun, Z., Hong, W., Chien, Y., Liu, N., Dougherty, R. F., Royalty, A., Hawthorne, G., Reiss, A. L. 2015; 5: 10894-?

  Abstract

  A novel game-like and creativity-conducive fMRI paradigm is developed to assess the neural correlates of spontaneous improvisation and figural creativity in healthy adults. Participants were engaged in the word-guessing game of Pictionary(TM), using an MR-safe drawing tablet and no explicit instructions to be "creative". Using the primary contrast of drawing a given word versus drawing a control word (zigzag), we observed increased engagement of cerebellum, thalamus, left parietal cortex, right superior frontal, left prefrontal and paracingulate/cingulate regions, such that activation in the cingulate and left prefrontal cortices negatively influenced task performance. Further, using parametric fMRI analysis, increasing subjective difficulty ratings for drawing the word engaged higher activations in the left pre-frontal cortices, whereas higher expert-rated creative content in the drawings was associated with increased engagement of bilateral cerebellum. Altogether, our data suggest that cerebral-cerebellar interaction underlying implicit processing of mental representations has a facilitative effect on spontaneous improvisation and figural creativity.

  View details for DOI 10.1038/srep10894

  View details for PubMedID 26018874

• Cognitive and neurological aspects of sex chromosome aneuploidies LANCET NEUROLOGY Hong, D. S., Reiss, A. L. 2014; 13 (3): 306-318

  Abstract

  Sex chromosome aneuploidies are a common group of disorders that are characterised by an abnormal number of X or Y chromosomes. However, many individuals with these disorders are not diagnosed, despite established groups of core features that include aberrant brain development and function. Clinical presentations often include characteristic profiles of intellectual ability, motor impairments, and rates of neurological and psychiatric disorders that are higher than those of the general population. Advances in genetics and neuroimaging have substantially expanded knowledge of potential mechanisms that underlie these phenotypes, including a putative dose effect of sex chromosome genes on neuroanatomical structures and cognitive abilities. Continuing attention to emerging trends in research of sex chromosome aneuploidies is important for clinicians because it informs appropriate management of these common genetic disorders. Furthermore, improved understanding of underlying neurobiological processes has much potential to elucidate sex-related factors associated with neurological and psychiatric disease in general.

  View details for PubMedID 24556008

• Neuroanatomical correlates of dysglycemia in young children with type 1 diabetes. Diabetes Marzelli, M. J., Mazaika, P. K., Barnea-Goraly, N., Hershey, T., Tsalikian, E., Tamborlane, W., Mauras, N., White, N. H., Buckingham, B., Beck, R. W., Ruedy, K. J., Kollman, C., Cheng, P., Reiss, A. L. 2014; 63 (1): 343-353

  Abstract

  Studies of brain structure in type 1 diabetes (T1D) describe widespread neuroanatomical differences related to exposure to glycemic dysregulation in adults and adolescents. In this study, we investigate the neuroanatomical correlates of dysglycemia in very young children with early-onset T1D. Structural magnetic resonance images of the brain were acquired in 142 children with T1D and 68 age-matched control subjects (mean age 7.0 ± 1.7 years) on six identical scanners. Whole-brain volumetric analyses were conducted using voxel-based morphometry to detect regional differences between groups and to investigate correlations between regional brain volumes and measures of glycemic exposure (including data from continuous glucose monitoring). Relative to control subjects, the T1D group displayed decreased gray matter volume (GMV) in bilateral occipital and cerebellar regions (P < 0.001) and increased GMV in the left inferior prefrontal, insula, and temporal pole regions (P = 0.002). Within the T1D group, hyperglycemic exposure was associated with decreased GMV in medial frontal and temporal-occipital regions and increased GMV in lateral prefrontal regions. Cognitive correlations of intelligence quotient to GMV were found in cerebellar-occipital regions and medial prefrontal cortex for control subjects, as expected, but not for the T1D group. Thus, early-onset T1D affects regions of the brain that are associated with typical cognitive development.

  View details for DOI 10.2337/db13-0179

  View details for PubMedID 24170697

• SCIENCE AND SOCIETY The neural basis of humour processing NATURE REVIEWS NEUROSCIENCE Vrticka, P., Black, J. M., Reiss, A. L. 2013; 14 (12): 860-868

  Abstract

  Humour is a vital component of human socio-affective and cognitive functioning. Recent advances in neuroscience have enabled researchers to explore this human attribute in children and adults. Humour seems to engage a core network of cortical and subcortical structures, including temporo-occipito-parietal areas involved in detecting and resolving incongruity (mismatch between expected and presented stimuli); and the mesocorticolimbic dopaminergic system and the amygdala, key structures for reward and salience processing. Examining personality effects and sex differences in the neural correlates of humour may aid in understanding typical human behaviour and the neural mechanisms underlying neuropsychiatric disorders, which can have dramatic effects on the capacity to experience social reward.

  View details for DOI 10.1038/nrn3566

  View details for Web of Science ID 000327459000013

• The neural basis of humour processing. Nature reviews. Neuroscience Vrticka, P., Black, J. M., Reiss, A. L. 2013; 14 (12): 860-868

  Abstract

  Humour is a vital component of human socio-affective and cognitive functioning. Recent advances in neuroscience have enabled researchers to explore this human attribute in children and adults. Humour seems to engage a core network of cortical and subcortical structures, including temporo-occipito-parietal areas involved in detecting and resolving incongruity (mismatch between expected and presented stimuli); and the mesocorticolimbic dopaminergic system and the amygdala, key structures for reward and salience processing. Examining personality effects and sex differences in the neural correlates of humour may aid in understanding typical human behaviour and the neural mechanisms underlying neuropsychiatric disorders, which can have dramatic effects on the capacity to experience social reward.

  View details for DOI 10.1038/nrn3566

  View details for PubMedID 24169937

• Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Hoeft, F., Carter, J. C., Lightbody, A. A., Hazlett, H. C., Piven, J., Reiss, A. L. 2010; 107 (20): 9335-9339

  Abstract

  Longitudinal neuroimaging investigation of fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, provides an opportunity to study the influence of a specific genetic factor on neurodevelopment in the living human brain. We examined voxel-wise gray and white matter volumes (GMV, WMV) over a 2-year period in 1- to 3-year-old boys with FXS (n = 41) and compared these findings to age- and developmentally matched controls (n = 28). We found enlarged GMV in the caudate, thalamus, and fusiform gyri and reduced GMV in the cerebellar vermis in FXS at both timepoints, suggesting early, possibly prenatal, genetically mediated alterations in neurodevelopment. In contrast, regions in which initial GMV was similar, followed by an altered growth trajectory leading to increased size in FXS, such as the orbital gyri, basal forebrain, and thalamus, suggests delayed or otherwise disrupted synaptic pruning occurring postnatally. WMV of striatal-prefrontal regions was greater in FXS compared with controls, and group differences became more exaggerated over time, indicating the possibility that such WM abnormalities are the result of primary FMRP-deficiency-related axonal pathology, as opposed to secondary connectional dysregulation between morphologically atypical brain structures. Our results indicate that structural abnormalities of different brain regions in FXS evolve differently over time reflecting time-dependent effects of FMRP deficiency and provide insight into their neuropathologic underpinnings. The creation of an early and accurate human brain phenotype for FXS in humans will significantly improve our capability to detect whether new disease-specific treatments can "rescue" the FXS phenotype in affected individuals.

  View details for DOI 10.1073/pnas.1002762107

  View details for PubMedID 20439717

  View details for PubMedCentralID PMC2889103

• Genetic Influences on Sociability: Heightened Amygdala Reactivity and Event-Related Responses to Positive Social Stimuli in Williams Syndrome JOURNAL OF NEUROSCIENCE Haas, B. W., Mills, D., Yam, A., Hoeft, F., Bellugi, U., Reiss, A. 2009; 29 (4): 1132-1139

  Abstract

  Williams syndrome (WS) is a genetic disorder caused by a hemizygous microdeletion on chromosome 7q11.23. WS is associated with a compelling neurocognitive profile characterized by relative deficits in visuospatial function, relative strengths in face and language processing, and enhanced drive toward social engagement. We used a combined functional magnetic resonance imaging (fMRI) and event-related potential (ERP) approach to examine the neural basis of social responsiveness in WS participants to two types of social stimuli, negative (fearful) and positive (happy) emotional facial expressions. Here, we report a double dissociation consistent across both methods such that WS participants exhibited heightened amygdala reactivity to positive (happy) social stimuli and absent or attenuated amygdala reactivity to negative (fearful) social stimuli, compared with controls. The fMRI findings indicate that atypical social processing in WS may be rooted in altered development of disparate amygdalar nuclei that subserve different social functions. The ERP findings suggest that abnormal amygdala reactivity in WS may possibly function to increase attention to and encoding of happy expressions and to decrease arousal to fearful expressions. This study provides the first evidence that the genetic deletion associated with WS influences the function of the amygdala to be particularly responsive to socially appetitive stimuli.

  View details for DOI 10.1523/JNEUROSCI.5324-08.2009

  View details for Web of Science ID 000262859000025

  View details for PubMedID 19176822

  View details for PubMedCentralID PMC2754840

• Gender differences in the mesocorticolimbic system during computer game-play JOURNAL OF PSYCHIATRIC RESEARCH Hoeft, F., Watson, C. L., Kesler, S. R., Bettinger, K. E., Reiss, A. L. 2008; 42 (4): 253-258

  Abstract

  Little is known about the underlying neural processes of playing computer/video games, despite the high prevalence of its gaming behavior, especially in males. In a functional magnetic resonance imaging study contrasting a space-infringement game with a control task, males showed greater activation and functional connectivity compared to females in the mesocorticolimbic system. These findings may be attributable to higher motivational states in males, as well as gender differences in reward prediction, learning reward values and cognitive state during computer video games. These gender differences may help explain why males are more attracted to, and more likely to become "hooked" on video games than females.

  View details for DOI 10.1016/j.jpsychires.2007.11.010

  View details for Web of Science ID 000254137300001

  View details for PubMedID 18194807

• Sex differences in brain activation elicited by humor PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Azim, E., Mobbs, D., Jo, B., Menon, V., Reiss, A. L. 2005; 102 (45): 16496-16501

  Abstract

  With recent investigation beginning to reveal the cortical and subcortical neuroanatomical correlates of humor appreciation, the present event-related functional MRI (fMRI) study was designed to elucidate sex-specific recruitment of these humor related networks. Twenty healthy subjects (10 females) underwent fMRI scanning while subjectively rating 70 verbal and nonverbal achromatic cartoons as funny or unfunny. Data were analyzed by comparing blood oxygenation-level-dependent signal activation during funny and unfunny stimuli. Males and females share an extensive humor-response strategy as indicated by recruitment of similar brain regions: both activate the temporal-occipital junction and temporal pole, structures implicated in semantic knowledge and juxtaposition, and the inferior frontal gyrus, likely to be involved in language processing. Females, however, activate the left prefrontal cortex more than males, suggesting a greater degree of executive processing and language-based decoding. Females also exhibit greater activation of mesolimbic regions, including the nucleus accumbens, implying greater reward network response and possibly less reward expectation. These results indicate sex-specific differences in neural response to humor with implications for sex-based disparities in the integration of cognition and emotion.

  View details for DOI 10.1073/pnas.0408456102

  View details for Web of Science ID 000233283700066

  View details for PubMedID 16275931

  View details for PubMedCentralID PMC1277963

• COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome NATURE NEUROSCIENCE Gothelf, D., Eliez, S., Thompson, T., Hinard, C., Penniman, L., Feinstein, C., Kwon, H., Jin, S. T., Jo, B., Antonarakis, S. E., Morris, M. A., Reiss, A. L. 2005; 8 (11): 1500-1502

  Abstract

  Although schizophrenia is strongly hereditary, there are limited data regarding biological risk factors and pathophysiological processes. In this longitudinal study of adolescents with 22q11.2 deletion syndrome, we identified the catechol-O-methyltransferase low-activity allele (COMT(L)) as a risk factor for decline in prefrontal cortical volume and cognition, as well as for the consequent development of psychotic symptoms during adolescence. The 22q11.2 deletion syndrome is a promising model for identifying biomarkers related to the development of schizophrenia.

  View details for DOI 10.1038/nn1572

  View details for Web of Science ID 000232966600023

  View details for PubMedID 16234808

• Neuroanatomical alterations in young boys and adolescents with Klinefelter syndrome. Psychiatry research. Neuroimaging Foland-Ross, L. C., Jordan, T. L., Marzelli, M. J., Ross, J. L., Reiss, A. L. 2024; 346: 111929

  Abstract

  Klinefelter syndrome (KS, 47,XXY) is a common sex chromosome aneuploidy in males that is characterized by pubertal developmental delays and a wide range of alterations in cognitive, social and emotional functioning. The neural bases of these behavioral symptoms, however, are unclear. A total of 130 boys and adolescents, including 67 males with KS (11.5 ± 2.8 years) and 63 typically developing (TD; control) males (10.6 ± 2.8 years) underwent MRI scanning and pubertal assessment. Group differences in regional gray matter volume was examined using voxel-based morphometry while controlling for age at scan and total gray matter volume. Thresholded statistical significance maps indicated widespread reductions in frontal and temporal and cerebellar gray matter in males with KS relative to TD males, as well as increases in parietal and occipital gray matter. Secondary analyses explored potential associations between GMV in these regions and pubertal development. Lower testicular volume was a significant predictor of reduced GMV in frontal, temporal and cerebellar subregions, even after accounting for group status (KS, TD). Taken together, these findings add support for a neuroanatomical phenotype of KS and provide initial evidence for a role of pubertal development in KS-associated differences in gray matter structure. Future studies that examine the influence of testosterone supplementation on GMV in males with KS are warranted.

  View details for DOI 10.1016/j.pscychresns.2024.111929

  View details for PubMedID 39637706

• Alterations in cortical and subcortical neuroanatomy and associations with behavior in females with fragile X syndrome. Developmental medicine and child neurology Bartholomay, K. L., Jordan, T. L., Foland-Ross, L. C., Kendall, N., Lightbody, A. A., Reiss, A. L. 2024

  Abstract

  To address substantial gaps in the literature on neuroanatomical variations in females with fragile X syndrome (FXS).Surface-based modeling techniques were applied to the magnetic resonance imaging of 45 females with FXS (mean age = 10 years 9 months, range 6 years-16 years 4 months, SD = 2 years 9 months) and 33 age-matched and developmentally matched females without FXS to elucidate differences in cortical gray matter volume, surface area, and thickness. Gray matter volumes in subcortical regions were examined to ascertain differences in subcortical volume.In females with FXS, cortical volume was greater bilaterally in the occipital pole and smaller in the right postcentral gyrus. Seven regions demonstrated lower surface area in participants with FXS, while cortical thickness was significantly greater over the posterior and medial surfaces in the group with FXS. Subcortical region of interest analyses demonstrated greater volume in the caudate nucleus, globus pallidus, and nucleus accumbens in the group with FXS. Global gray matter volume, pial thickness, and surface area were associated with behavioral outcomes in the group with FXS but not in the comparison group.Females with FXS demonstrated unique cortical and subcortical gray matter anatomy relative to a matched comparison group. These findings may be relevant to the pathogenesis of the FXS behavioral phenotype and provide insights into behavioral interventions targeted to this population.

  View details for DOI 10.1111/dmcn.16081

  View details for PubMedID 39279261

• Cognitive and Social-Emotional Development in Girls With Fragile X Syndrome. Pediatrics Bartholomay, K. L., Lightbody, A. A., Ma, Q., Jo, B., Jordan, T. L., Reiss, A. L. 2024

  Abstract

  To evaluate the developmental trajectory of key cognitive, social, and emotional features in girls with fragile X syndrome (FXS).This longitudinal, parallel cohort study collected data between January 2018 and December 2022. Participants were evaluated 3 times with ∼12-18 months between visits. Participants included 65 girls with FXS, 6 to 16 years, and 52 age- and developmentally-matched girls without FXS. Participants' scores from direct assessment and caregiver report evaluated 3 cognitive domains (verbal abilities, nonverbal abilities, executive function) and 4 social-emotional domains (depression, general anxiety, social behavior, and social anxiety).Participants included 117 girls (mean [M] [SD] age at study entry: FXS M = 10.59 [3.00]; comparison M = 10.45 [2.40])). Omnibus tests showed 4 domains with significant group differences: Verbal (P < .0001, eg, Differential Abilities Scale-II(DAS-II), Picture Vocabulary (-6.25 [1.87])), nonverbal (P < .0001, eg, Kaufman Test of Educational Achievement, Third Edition, Brief Form, Math (-8.56 [2.90])), executive function (P < .0001, eg, NIH Toolbox List Sorting (-6.26 [1.48])), and social anxiety (P < .03, eg, Anxiety, Depression, and Mood Scale (ADAMS) Social Avoidance (1.50 [0.65])). Three domains had significant group by age interaction: Verbal (P < .04, eg, DAS-II, Word Definitions (-1.33 [0.55])), social behavior (P < .01, eg, Social Responsiveness Scale-2 Social Communication (1.57 [0.51])), and social anxiety (P < .01, eg, ADAMS Social Avoidance (0.46 [0.19])).These findings support the development of early, disorder specific interventions for girls with FXS targeting verbal and nonverbal skills, executive function, social behavior, and social anxiety.

  View details for DOI 10.1542/peds.2023-065145

  View details for PubMedID 39262346

• PUBERTAL DIFFERENCES IN BOYS WITH KLINEFELTER SYNDROME AND TYPICALLY DEVELOPING PEERS Ikomi, C., Reynolds, V., Foland-Ross, L., Kowal, K., Reiss, A. L., Ross, J. KARGER. 2024: 148-149

  View details for Web of Science ID 001315953400121

• Alterations in Neural Activation During Facial Emotion Processing in Adolescent Male Participants With Klinefelter Syndrome. Journal of developmental and behavioral pediatrics : JDBP Vreeland, A., Reiss, A. L., Ross, J., Foland-Ross, L. C. 2024

  Abstract

  Klinefelter syndrome (KS) is the most common sex-chromosome aneuploidy (47,XXY), affecting 1 in 500 male participants. The phenotype of male participants with KS includes both physical features, such as tall stature and testicular insufficiency, and behavioral alterations, including difficulties in social functioning, anxiety, and depression. Studies examining underlying neural alterations associated with the behavioral phenotype, however, are sparse. We aimed to address this gap in knowledge using functional magnetic resonance imaging in conjunction with an emotion processing paradigm.Functional magnetic resonance imaging was conducted on 38 children and adolescents with KS (Mage = 12.85, SD = 2.45) and 47 typical developing (control) boys (Mage = 12.04, SD = 1.82) as they completed a facial emotion processing task. Group differences in activation occurring during the processing of angry versus neutral faces were examined while controlling for age.The results indicated that relative to typically developing boys, boys with KS exhibited anomalous increases in activation of frontal, temporal, and occipital cortices. Within the KS group, secondary analyses indicated that greater activation in these regions was associated with more internalizing symptoms (e.g., anxiety, depression, withdrawn behaviors) and greater social impairments (e.g., social cognition, social communication, social motivation, social communication and interaction, functional communication).The findings from this study indicate a possible neural correlation for difficulties in social and emotional function in KS and add to a growing body of research aimed at increasing our understanding of neural biomarkers in this condition. Future studies that examine the influence of testosterone-replacement therapy on these differences are warranted.

  View details for DOI 10.1097/DBP.0000000000001279

  View details for PubMedID 38990140

• Associations between brain network, puberty, and behaviors in boys with Klinefelter syndrome. European child & adolescent psychiatry Li, R., Foland-Ross, L. C., Jordan, T., Marzelli, M. J., Ross, J. L., Reiss, A. L. 2024

  Abstract

  Klinefelter syndrome (KS), also referred to as XXY syndrome, is a significant but inadequately studied risk factor for neuropsychiatric disability. Whether alterations in functional brain connectivity or pubertal delays are associated with aberrant cognitive-behavioral outcomes in individuals with KS is largely unknown. In this observational study, we investigated KS-related alterations in the resting-state brain network, testosterone level, and cognitive-behavioral impairment in adolescents with Klinefelter syndrome.We recruited 46 boys with KS, ages 8 to 17 years, and 51 age-matched typically developing (TD) boys. All participants underwent resting-state functional magnetic resonance imaging scans, pubertal, and cognitive-behavioral assessments. Resting-state functional connectivity and regional brain activity of the participants were assessed.We found widespread alterations in global functional connectivity among the inferior frontal gyrus, temporal-parietal area, and hippocampus in boys with KS. Aberrant regional activities, including enhanced fALFF in the motor area and reduced ReHo in the caudate, were also found in the KS group compared to the TD children. Further, using machine learning methods, brain network alterations in these regions accurately differentiated boys with KS from TD controls. Finally, we showed that the alterations of brain network properties not only effectively predict cognitive-behavioral impairment in boys with KS, but also appear to mediate the association between total testosterone level and language ability, a cognitive domain at particular risk for dysfunction in this condition.Our results offer an informatic neurobiological foundation for understanding cognitive-behavioral impairments in individuals with KS and contribute to our understanding of the interplay between pubertal status, brain function, and cognitive-behavioral outcome in this population.

  View details for DOI 10.1007/s00787-024-02501-y

  View details for PubMedID 38904702

  View details for PubMedCentralID 6815760

• Childhood exposure to organophosphate pesticides: functional connectivity and working memory in adolescents. Neurotoxicology Gao, Y., Li, R., Ma, Q., Baker, J. M., Rauch, S., Gunier, R. B., Mora, A. M., Kogut, K., Bradman, A., Eskenazi, B., Reiss, A. L., Sagiv, S. K. 2024

  Abstract

  Early life exposure to organophosphate (OP) pesticides is linked with adverse neurodevelopment and brain function in children. However, we have limited knowledge of how these exposures affect functional connectivity, a measure of interaction between brain regions. To address this gap, we examined the association between early life OP pesticide exposure and functional connectivity in adolescents.We administered functional near-infrared spectroscopy (fNIRS) to 291 young adults with measured prenatal or childhood dialkylphosphates (DAPs) in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a longitudinal study of women recruited during pregnancy and their offspring. We measured DAPs in urinary samples collected from mothers during pregnancy (13 and 26 weeks) and children in early life (ages 6 months, 1, 2, 3, and 5 years). Youth underwent fNIRS while they performed executive function and semantic language tasks during their 18-year-old visit. We used covariate-adjusted regression models to estimate the associations of prenatal and childhood DAPs with functional connectivity between the frontal, temporal, and parietal regions, and a mediation model to examine the role of functional connectivity in the relationship between DAPs and task performance.We observed null associations of prenatal and childhood DAP concentrations and functional connectivity for the entire sample. However, when we looked for sex differences, we observed an association between childhood DAPs and functional connectivity for the right interior frontal and premotor cortex after correcting for the false discovery rate, among males, but not females. In addition, functional connectivity appeared to mediate an inverse association between DAPs and working memory accuracy among males.In CHAMACOS, a secondary analysis showed that adolescent males with elevated childhood OP pesticide exposure may have altered brain regional connectivity. This altered neurofunctional pattern in males may partially mediate working memory impairment associated with childhood DAP exposure.

  View details for DOI 10.1016/j.neuro.2024.06.011

  View details for PubMedID 38908438

• Prenatal and childhood exposure to organophosphate pesticides and functional brain imaging in young adults. Environmental research Sagiv, S. K., Baker, J. M., Rauch, S., Gao, Y., Gunier, R. B., Mora, A. M., Kogut, K., Bradman, A., Eskenazi, B., Reiss, A. L. 2023: 117756

  Abstract

  Early life exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment from infancy to adolescence. In our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort, we previously reported that residential proximity to OP use during pregnancy was associated with altered cortical activation using functional near infrared spectroscopy (fNIRS) in a small subset (n = 95) of participants at age 16 years.We administered fNIRS to 291 CHAMACOS young adults at the 18-year visit. Using covariate-adjusted regression models, we estimated associations of prenatal and childhood urinary dialkylphosphates (DAPs), non-specific OP metabolites, with cortical activation in the frontal, temporal, and parietal regions of the brain during tasks of executive function and semantic language.There were some suggestive associations for prenatal DAPs with altered activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during a task of cognitive flexibility (β per ten-fold increase in DAPs = 3.37; 95% CI: -0.02, 6.77 and β = 3.43; 95% CI: 0.64, 6.22, respectively) and the inferior and superior frontal pole/dorsolateral prefrontal cortex of the right hemisphere during the letter retrieval working memory task (β = -3.10; 95% CI: -6.43, 0.22 and β = -3.67; 95% CI: -7.94, 0.59, respectively). We did not observe alterations in cortical activation with prenatal DAPs during a semantic language task or with childhood DAPs during any task.We observed associations of prenatal OP concentrations with mild alterations in cortical activation during tasks of executive function. Associations with childhood exposure were null. This is reasonably consistent with studies of prenatal OPs and neuropsychological measures of attention and executive function found in CHAMACOS and other birth cohorts.

  View details for DOI 10.1016/j.envres.2023.117756

  View details for PubMedID 38016496

• Cognition, academic achievement, and adaptive behavior in school-aged girls with fragile X syndrome. Research in developmental disabilities Jordan, T. L., Bartholomay, K. L., Lee, C. H., Lightbody, A. A., Reiss, A. L. 2023; 143: 104622

  Abstract

  Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism in males and females. Females with FXS typically display a milder cognitive phenotype than males, despite experiencing significant developmental, behavioral, and social-emotional issues.To measure and distinguish the cognitive-behavioral profile of girls with FXS relative to verbal IQ-matched peers.Ninety-seven participants (NFXS=55, Ncomparison=42) six to 16 years of age completed assessments evaluating cognition, academic achievement, and adaptive behavior. The comparison group consisted of age-, sex-, and verbal IQ-matched peers.Consistent with previous studies, the FXS group demonstrated mean cognitive skills, academic achievement, and adaptive behavior in the borderline to low average range. On average, the FXS group showed poorer nonverbal reasoning, visual pattern recognition, verbal abstraction, math abilities, attention, inhibitory control, and working memory than the comparison group. There were no significant group differences in adaptive behavior. Different patterns of associations between cognition and selected outcomes emerged in each group.Results highlight the importance of identifying specific cognitive-behavioral profiles in girls with FXS to inform more targeted interventions for optimizing outcomes and quality of life in this population.

  View details for DOI 10.1016/j.ridd.2023.104622

  View details for PubMedID 37939495

• Neural responses to gender-based microaggressions in academic medicine. Journal of neuroscience research Balters, S., Foland-Ross, L. C., Bruno, J., Periyakoil, V. S., Valantine, H., Reiss, A. L. 2023

  Abstract

  Gender-based microaggressions have been associated with persistent disparities between women and men in academia. Little is known about the neural mechanisms underlying those often subtle and unintentional yet detrimental behaviors. Here, we assessed the neural responses to gender-based microaggressions in 28 early career faculty in medicine (N = 16 female, N = 12 male sex) using fMRI. Participants watched 33 videos of situations demonstrating gender-based microaggressions and control situations in academic medicine. Video topics had been previously identified through real-life anecdotes about microaggression from women faculty and were scripted and reenacted using professional actors. Primary voxel-wise analyses comparing group differences in activation elucidated a significant group by condition interaction in a right-lateralized cluster across the frontal (inferior and middle frontal gyri, frontal pole, precentral gyrus, postcentral gyrus) and parietal lobes (supramarginal gyrus, angular gyrus). Whereas women faculty exhibited reduced activation in these regions during the microaggression relative to the control condition, the opposite was true for men. Posthoc analyses showed that these patterns were significantly associated with the degree to which participants reported feeling judged for their gender in academic medicine. Lastly, secondary exploratory ROI analyses showed significant between-group differences in the right dorsolateral prefrontal cortex and inferior frontal gyrus. Women activated these two regions less in the microaggression condition compared to the control condition, whereas men did not. These findings indicate that the observation of gender-based microaggressions results in a specific pattern of neural reactivity in women early career faculty.

  View details for DOI 10.1002/jnr.25240

  View details for PubMedID 37654210

• Cognition, Academic Achievement, Adaptive Behavior, and Quality of Life in Child and Adolescent Boys with Klinefelter Syndrome. Journal of developmental and behavioral pediatrics : JDBP Jordan, T. L., Foland-Ross, L. C., Wun, V. L., Ross, J. L., Reiss, A. L. 2023; 44 (7): e476-e485

  Abstract

  Klinefelter syndrome (KS; 47, XXY), the most common sex chromosome aneuploidy in males, is characterized by testicular failure and testosterone deficiency as well as a variety of cognitive, social, and emotional challenges. In the current study, we aimed to clarify the cognitive-behavioral profile of peripubertal boys with KS using measures of cognition, academic achievement, adaptive behavior, and quality of life.We compared 47 boys with KS (7-16 years of age) with 55 performance IQ-matched boys without KS on measures of cognition (WISC-V), executive function (BRIEF-2), academic achievement (KTEA-3), adaptive behavior (Vineland-3), and quality of life (PROMIS). In exploratory analyses, we examined associations among these measures and potential associations with pubertal metrics.Boys with KS demonstrated a significantly different profile of cognition, behavioral ratings of executive function, academic achievement, adaptive behavior, and quality of life compared with their typically developing peers, with, on average, lower functioning. The groups showed significantly different correlations between cognition and aspects of quality of life. No associations were observed between behavior and pubertal development.Taken together, these findings indicated that boys with KS are at increased risk for cognitive difficulties, which may affect academic achievement, adaptive behavior, and quality of life. Although initial exploratory analyses indicated that the magnitude of these alterations was not correlated with severity of testicular failure, longitudinal analyses currently being conducted by our group may help clarify the trajectory of these difficulties through the pubertal transition and testosterone replacement.

  View details for DOI 10.1097/DBP.0000000000001201

  View details for PubMedID 37696031

• Executive dysfunction in Klinefelter syndrome: associations with brain activation and testicular failure. The Journal of clinical endocrinology and metabolism Foland-Ross, L. C., Ghasemi, E., Wun, V. L., Aye, T., Kowal, K., Ross, J., Reiss, A. L. 2023

  Abstract

  CONTEXT: Executive dysfunction is a well-recognized component of the cognitive phenotype of Klinefelter syndrome (KS), yet the neural basis of KS-associated cognitive weaknesses, and their association with testicular failure is unknown.OBJECTIVE: We investigated executive function, brain activation and pubertal development in adolescents with and without KS.METHODS: Forty-three adolescents with KS (mean age 12.3 ± 2.3 years) and 41 typically developing males (mean age 11.9 ± 1.8 years) underwent pubertal evaluation, behavioral assessment and completed functional magnetic resonance imaging (fMRI) as they performed an executive function task, the go/no-go task. Group differences in activation were examined. Associations among activation, executive function and pubertal development measures were tested in secondary analyses.RESULTS: Males with KS exhibited reduced executive function, as well as lower activation in brain regions subserving executive function, including the inferior frontal gyrus, anterior insula, dorsal anterior cingulate cortex and caudate nucleus. Secondary analyses indicated that the magnitude of activation differences in males with KS was associated with severity of pubertal developmental delay, as indexed by lower testosterone (t(36) = 2.285, p = 0.028) and lower testes volume (t(36) = 2.238, p = 0.031). Greater parent-reported attention difficulties were additionally associated with lower testicular volume (t(36) = -2.028, p = 0.050).CONCLUSION: These findings indicate a neural basis for executive dysfunction in KS and suggest alterations in pubertal development may contribute to increased severity of this cognitive weakness. Future studies that examine whether these patterns change with testosterone replacement therapy are warranted.

  View details for DOI 10.1210/clinem/dgad487

  View details for PubMedID 37595261

• Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities. Translational psychiatry Rai, B., Naylor, P. E., Siqueiros-Sanchez, M., Wintermark, M., Raman, M. M., Jo, B., Reiss, A. L., Green, T. 2023; 13 (1): 245

  Abstract

  The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: (1) How Ras-MAPK activating variants of PTPN11/SOS1 protein-coding genes affect brain anatomy. (2) The relationship between PTPN11 gene expression levels and brain anatomy, and (3) The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 (n = 30) or SOS1 (n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA), and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area (d's < -0.8), and extensive effects on SA (d's > |0.8|) and CT (d's > |0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for the effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

  View details for DOI 10.1038/s41398-023-02504-4

  View details for PubMedID 37407569

  View details for PubMedCentralID 4115674

• A Twin Study of Altered White Matter Heritability in Youth With Autism Spectrum Disorder. Journal of the American Academy of Child and Adolescent Psychiatry Hegarty, J. P., Monterrey, J. C., Tian, Q., Cleveland, S. C., Gong, X., Phillips, J. M., Wolke, O., McNab, J. A., Hallmayer, J., Reiss, A. L., Hardan, A. Y., Lazzeroni, L. C. 2023

  Abstract

  OBJECTIVE: White matter alterations are frequently reported in autism spectrum disorder (ASD), yet the etiology is currently unknown. The objective of this investigation was to examine, for the first time, the impact of genetic and environmental factors on white matter microstructure in twins with ASD compared to control twins without ASD.METHOD: Diffusion-weighted MRIs were obtained from same-sex twin pairs (aged 6-15 years) in which at least one twin was diagnosed with ASD or neither twin exhibited a history of neurological or psychiatric disorders. Fractional anisotropy (FA) and mean diffusivity (MD) were examined across different white matter tracts in the brain and statistical and twin modeling were completed to assess the proportion of variation associated with additive genetic (A) and common/shared (C) or unique (E) environmental factors. We also developed a new version of the twin-pair difference score analysis method that estimates the contribution of genetic and environmental factors to shared covariance between different brain and behavioral traits.RESULTS: Good quality data were available from 84 twin pairs, 50 ASD pairs [32 concordant for ASD (16 monozygotic; 16 dizygotic), 16 discordant for ASD (3 monozygotic; 13 dizygotic), and 2 pairs in which one twin had ASD and the other exhibited some subthreshold symptoms (1 monozygotic; 1 dizygotic)] and 34 control pairs (20 monozygotic; 14 dizygotic). Average FA and MD across the brain, respectively, were primarily genetically mediated in both control twins (A=0.80 [0.57,1.02]; A=0.80 [0.55,1.04]) and twins concordant for having ASD (A=0.71 [0.33,1.09]; A= 0.84 [0.32,1.36]). However, there were also significant tract-specific differences between groups. For instance, genetic effects on commissural fibers were primarily associated with differences in general cognitive abilities and perhaps some diagnostic differences for ASD, e.g., our new twin-pair difference-scores analysis indicated that genetic factors may have contributed to 40-50% of the covariation between IQ scores and FA of the corpus callosum. Conversely, the increased impact of environmental factors on some projection and association fibers were primarily associated with differences in symptom severity in twins with ASD, e.g., twin-pair difference-scores suggested that unique environmental factors may have contributed to 10-20% of the covariation between autism-related symptom severity and FA of the cerebellar peduncles and external capsule.CONCLUSION: White matter alterations in youth with ASD are associated with both genetic contributions and potentially increased vulnerability or responsivity to environmental influences.DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as living with a disability. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

  View details for DOI 10.1016/j.jaac.2023.05.030

  View details for PubMedID 37406770

• A PILOT TO INVESTIGATE RESTING STATE IN PATIENTS WITH SICKLE CELL DISEASE POST STEM CELL TRANSPLANT Alva, H., Marzelli, M., Foland-Ross, L., Porteus, M., Reiss, A. WILEY. 2023: S168

  View details for Web of Science ID 001042987300333

• Neuropsychiatric phenotypes in children with Noonan syndrome. Developmental medicine and child neurology Naylor, P. E., Bruno, J. L., Shrestha, S. B., Friedman, M., Jo, B., Reiss, A. L., Green, T. 2023

  Abstract

  AIM: We investigated neuropsychiatric outcomes in children with Noonan syndrome and addressed limitations in previous research with a focus on prepubertal children, comparison to typically developing children, comprehensive neuropsychiatric evaluation, and controlling for overall cognitive abilities.METHOD: Forty-five children with Noonan syndrome (mean=8years 6months, SD=2years 2months; 29 females) and 40 typically developing children (mean=8years 9months, SD=2years; 22 females) were evaluated with objective, parent-report, and psychiatric interview measures.RESULTS: Children with Noonan syndrome demonstrated elevated symptoms across attention-deficit/hyperactivity disorder (ADHD) (attention, hyperactivity, and inhibition), autism spectrum disorder (ASD) (maintaining social relationships, behavioral rigidity, and sensory sensitivity), and oppositional defiant disorder (ODD) (aggression) symptom clusters relative to typically developing children (all p<0.05). Group differences in nearly all parent-report measures were significant after accounting for variations in intellectual functioning, suggesting that increased neurodevelopmental symptoms are not simply driven by overall intelligence. Twenty out of 42 children with Noonan syndrome met criteria for ADHD, eight out of 42 for ODD, and 11 out of 43 demonstrated clinically significant symptoms seen in children with ASD.INTERPRETATION: Children with Noonan syndrome are at increased risk for a range of ADHD, ASD, and ODD associated symptoms. A dimensional approach reveals significant ASD symptoms in Noonan syndrome that do not emerge when using the currently accepted categorical diagnostic approach.

  View details for DOI 10.1111/dmcn.15627

  View details for PubMedID 37130201

• Adolescent brain development in girls with Turner syndrome. Human brain mapping Lozano Wun, V., Foland-Ross, L. C., Jo, B., Green, T., Hong, D., Ross, J. L., Reiss, A. L. 2023

  Abstract

  Turner syndrome (TS) is a common sex chromosome aneuploidy in females associated with various physical, cognitive, and socio-emotional phenotypes. However, few studies have examined TS-associated alterations in the development of cortical gray matter volume and the two components that comprise this measure-surface area and thickness. Moreover, the longitudinal direct (i.e., genetic) and indirect (i.e., hormonal) effects of X-monosomy on the brain are unclear. Brain structure was assessed in 61 girls with TS (11.3 ± 2.8 years) and 55 typically developing girls (10.8 ± 2.3 years) for up to 4 timepoints. Surface-based analyses of cortical gray matter volume, thickness, and surface area were conducted to examine the direct effects of X-monosomy present before pubertal onset and indirect hormonal effects of estrogen deficiency/X-monosomy emerging after pubertal onset. Longitudinal analyses revealed that, whereas typically developing girls exhibited normative declines in gray matter structure during adolescence, this pattern was reduced or inverted in TS. Further, girls with TS demonstrated smaller total surface area and larger average cortical thickness overall. Regionally, the TS group exhibited decreased volume and surface area in the pericalcarine, postcentral, and parietal regions relative to typically developing girls, as well as larger volume in the caudate, amygdala, and temporal lobe regions and increased thickness in parietal and temporal regions. Surface area alterations were predominant by age 8, while maturational differences in thickness emerged by age 10 or later. Taken together, these results suggest the involvement of both direct and indirect effects of X-chromosome haploinsufficiency on brain development in TS.

  View details for DOI 10.1002/hbm.26327

  View details for PubMedID 37126641

• Social gaze behavior and hyperarousal in young females with fragile X syndrome: A within-person approach DEVELOPMENT AND PSYCHOPATHOLOGY Miller, J. G., Sharifi, R., Piccirilli, A., Li, R., Lee, C. H., Bartholomay, K. L., Jordan, T. L., Marzelli, M. J., Bruno, J. L., Lightbody, A. A., Reiss, A. L. 2023

  View details for DOI 10.1017/S095457942300038X

  View details for Web of Science ID 000976684600001

• Social gaze behavior and hyperarousal in young females with fragile X syndrome: A within-person approach. Development and psychopathology Miller, J. G., Sharifi, R., Piccirilli, A., Li, R., Lee, C. H., Bartholomay, K. L., Jordan, T. L., Marzelli, M. J., Bruno, J. L., Lightbody, A. A., Reiss, A. L. 2023: 1-12

  Abstract

  Children with fragile X syndrome (FXS) often avoid eye contact, a behavior that is potentially related to hyperarousal. Prior studies, however, have focused on between-person associations rather than coupling of within-person changes in gaze behaviors and arousal. In addition, there is debate about whether prompts to maintain eye contact are beneficial for individuals with FXS. In a study of young females (ages 6-16), we used eye tracking to assess gaze behavior and pupil dilation during social interactions in a group with FXS (n = 32) and a developmentally similar comparison group (n = 23). Participants engaged in semi-structured conversations with a female examiner during blocks with and without verbal prompts to maintain eye contact. We identified a social-behavioral and psychophysiological profile that is specific to females with FXS; this group exhibited lower mean levels of eye contact, significantly increased mean pupil dilation during conversations that included prompts to maintain eye contact, and showed stronger positive coupling between eye contact and pupil dilation. Our findings strengthen support for the perspective that gaze aversion in FXS reflects negative reinforcement of social avoidance behavior. We also found that behavioral skills training may improve eye contact, but maintaining eye contact appears to be physiologically taxing for females with FXS.

  View details for DOI 10.1017/S095457942300038X

  View details for PubMedID 37185087

• Aerobic Exercise, Cognitive Performance, and Brain Activity in Adolescents with Attention-Deficit/Hyperactivity Disorder. Medicine and science in sports and exercise Van Riper, S. M., Tempest, G. D., Piccirilli, A., Ma, Q., Reiss, A. L. 2023

  Abstract

  INTRODUCTION: Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder for which behavioural treatments such as exercise are recommended as part of a multi-disciplinary treatment program. Exercise improves executive function in individuals with ADHD, but limited information exists regarding the mechanisms involved in the response. We examined task-evoked brain responses during exercise and seated rest in 38 adolescents (n = 15 ADHD; age = 13.6+/-1.9, male = 73.3%, n = 23 typically developing (TD; age = 13.3+/-2.1, male = 56.5%)).METHODS: Participants completed a working memory and inhibitory task while cycling at a moderate intensity for 25 minutes (i.e., exercise condition) and while seated on the bike without pedalling (i.e., control condition). Conditions were randomized and counter-balanced. Functional near-infrared spectroscopy measured relative changes in oxygenated hemoglobin concentration in 16 brain regions-of-interest. Brain activity for each cognitive task and condition was examined using linear mixed effects models with a false discovery rate correction (FDR).RESULTS: The ADHD group had slower response speeds for all tasks and lower response accuracy in the working memory task during exercise compared to the TD group (p < 0.05). For the inhibitory task, the ADHD group had lower brain activity in the inferior/superior parietal gyrus during exercise compared to the control condition, while the opposite was true for TD (FDRcorrected, p < 0.05). For the working memory task, higher brain activity during exercise was observed, regardless of group, in the middle and inferior frontal gyrus and the temporoparietal junction (FDRcorrected, p < 0.05).CONCLUSIONS: Dual-task performance is challenging for adolescents with ADHD and exercise may modulate neuronal resources in regions such as the temporoparietal junction and frontal areas known to be hypoactive in this population. Future research should examine how these relationships change over time.

  View details for DOI 10.1249/MSS.0000000000003159

  View details for PubMedID 36897828

• Expressing appreciation is linked to interpersonal closeness and inter-brain coherence, both in person and over Zoom. Cerebral cortex (New York, N.Y. : 1991) Balters, S., Miller, J. G., Reiss, A. L. 2023

  Abstract

  Expressing appreciation is essential for establishing interpersonal closeness, but virtual interactions are increasingly common and create social distance. Little is known about the neural and inter-brain correlates of expressing appreciation and the potential effects of virtual videoconferencing on this kind of interaction. Here, we assess inter-brain coherence with functional near-infrared spectroscopy while dyads expressed appreciation to one another. We scanned 36 dyads (72 participants) who interacted in either an in-person or virtual (Zoom) condition. Participants reported on their subjective experience of interpersonal closeness. As predicted, expressing appreciation increased interpersonal closeness between dyad partners. Relative to 3 other cooperation tasks (i.e. problem-solving task, creative-innovation task, socio-emotional task), we observed increased inter-brain coherence in socio-cognitive areas of the cortex (anterior frontopolar area, inferior frontal gyrus, premotor cortex, middle temporal gyrus, supramarginal gyrus, and visual association cortex) during the appreciation task. Increased inter-brain coherence in socio-cognitive areas during the appreciation task was associated with increased interpersonal closeness. These findings support the perspective that expressing appreciation, both in-person and virtually, increases subjective and neural metrics of interpersonal closeness.

  View details for DOI 10.1093/cercor/bhad032

  View details for PubMedID 36848244

• Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities. Research square Rai, B., Naylor, P., Sanchez, M. S., Wintermark, M., Raman, M., Jo, B., Reiss, A., Green, T. 2023

  Abstract

  The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: 1. How Ras-MAPK activating variants of PTPN11 / SOS1 protein-coding genes affect brain anatomy. 2. The relationship between PTPN11 gene expression levels and brain anatomy, and 3. The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 ( n  = 30) or SOS1 ( n  = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA) and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area ( d 's<-0.8), and extensive effects on SA ( d 's>|0.8|) and CT ( d 's>|0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

  View details for DOI 10.21203/rs.3.rs-2580911/v1

  View details for PubMedID 36865206

  View details for PubMedCentralID PMC9980214

• Longitudinal investigation of cognition, social competence, and anxiety in children and adolescents with Turner syndrome. Hormones and behavior Jordan, T. L., Klabunde, M., Green, T., Hong, D. S., Ross, J. L., Jo, B., Reiss, A. L. 2023; 149: 105300

  Abstract

  Turner syndrome (TS), a common neurogenetic disorder caused by complete or partial absence of an X chromosome in females, is characterized by distinct physical, cognitive, and social-emotional features. Girls with TS typically display average overall intellectual functioning with relative strength in verbal abilities and weaknesses in visuospatial processing, executive function (EF), and social cognition. This study was designed to better understand longitudinal trajectories of cognitive and social-emotional domains commonly affected in TS. Participants included 57 girls with monosomic 45,X TS and 55 age- and verbal-IQ matched girls who completed behavioral, child-report, and parent-report measures across four timepoints. Group differences in visuospatial processing, EF, social cognition, and anxiety were assessed longitudinally. Potential effects of estrogen replacement therapy (ERT) were assessed cross-sectionally on an exploratory basis. The TS group showed poorer performance on measures of visuospatial processing, EF, and social cognition, but not anxiety, compared to controls throughout childhood and adolescence. There were no significant group differences in the trajectory of skill development over time. Exploratory analyses within the TS group revealed that girls who were receiving ERT showed better performance on measures of overall IQ, expressive vocabulary, and visuospatial processing compared to those not receiving ERT. Consistent with existing literature, weaknesses in visuospatial processing, EF, and social competence among girls with TS persisted throughout childhood and adolescence. Exploratory analyses suggest that ERT may help improve some aspects of cognitive function in TS, although other pre-existing, nonhormonal differences between the two TS subgroups may alternatively explain these findings, given our study design. Future studies are needed to examine potential impacts of ERT on cognitive and social-emotional development in TS.

  View details for DOI 10.1016/j.yhbeh.2022.105300

  View details for PubMedID 36640638

• Current opinions on the present and future use of functional near-infrared spectroscopy in psychiatry. Neurophotonics Li, R., Hosseini, H., Saggar, M., Balters, S. C., Reiss, A. L. 2023; 10 (1): 013505

  Abstract

  Functional near-infrared spectroscopy (fNIRS) is an optical imaging technique for assessing human brain activity by noninvasively measuring the fluctuation of cerebral oxygenated- and deoxygenated-hemoglobin concentrations associated with neuronal activity. Owing to its superior mobility, low cost, and good tolerance for motion, the past few decades have witnessed a rapid increase in the research and clinical use of fNIRS in a variety of psychiatric disorders. In this perspective article, we first briefly summarize the state-of-the-art concerning fNIRS research in psychiatry. In particular, we highlight the diverse applications of fNIRS in psychiatric research, the advanced development of fNIRS instruments, and novel fNIRS study designs for exploring brain activity associated with psychiatric disorders. We then discuss some of the open challenges and share our perspectives on the future of fNIRS in psychiatric research and clinical practice. We conclude that fNIRS holds promise for becoming a useful tool in clinical psychiatric settings with respect to developing closed-loop systems and improving individualized treatments and diagnostics.

  View details for DOI 10.1117/1.NPh.10.1.013505

  View details for PubMedID 36777700

  View details for PubMedCentralID PMC9904322

• Design science and neuroscience: A systematic review of the emergent field of Design Neurocognition DESIGN STUDIES Balters, S., Weinstein, T., Mayseless, N., Auernhammer, J., Hawthorne, G., Steinert, M., Meinel, C., Leifer, L. J., Reiss, A. L. 2023; 84

  View details for DOI 10.1016/j.destud.2022.101148

  View details for Web of Science ID 000914428800002

• Anxiety, Depression, and Social Skills in Girls with Fragile X Syndrome: Understanding the Cycle to Improve Outcomes. Journal of developmental and behavioral pediatrics : JDBP Lightbody, A. A., Bartholomay, K. L., Jordan, T. L., Lee, C. H., Miller, J. G., Reiss, A. L. 2022

  Abstract

  OBJECTIVE: Female patients with fragile X syndrome (FXS), a genetic condition associated with a mutation in the FMR1 gene, are at significantly elevated risk for developing anxiety and depression. This study is designed to better understand these symptoms in school-age girls, particularly as they relate to age, social skills, and functional outcomes.METHODS: We compared 58 girls aged 6 to 16 years with FXS with 46 age-matched, sex-matched, and developmentally matched peers without FXS on measures of anxiety, depression, social skills, adaptive behavior, and quality of life.RESULTS: Girls with FXS 10.5 years and older demonstrated significantly higher levels of depression, withdrawal, and social avoidance than girls younger than 10.5 years with FXS (p-values < 0.01). Girls in the comparison group did not show any age-related differences on these measures. The older FXS cohort also showed associations between social communication and interaction skills, adaptive behavior, and measures of anxiety and depression (p-values < 0.05) not seen in the comparison group, regardless of age.CONCLUSION: We found that age seems to play an important role in the development of mood symptoms and that such symptoms are uniquely correlated with social communication and reciprocal social interaction behaviors and adaptive functioning in girls with FXS after puberty. These data suggest a critical window of intervention for girls with FXS in the improvement of social interaction skills and the prevention of social avoidance and symptoms of anxiety and depression, with the ultimate goal of improving quality of life and promoting greater independence.

  View details for DOI 10.1097/DBP.0000000000001128

  View details for PubMedID 36219483

• Pesticide exposure and cortical brain activation among farmworkers in Costa Rica. Neurotoxicology Mora, A. M., Baker, J. M., Hyland, C., Rodriguez-Zamora, M. G., Rojas-Valverde, D., Winkler, M. S., Staudacher, P., Palzes, V. A., Gutierrez-Vargas, R., Lindh, C., Reiss, A. L., Eskenazi, B., Fuhrimann, S., Sagiv, S. K. 2022

  Abstract

  BACKGROUND: Previous epidemiological studies have reported associations of pesticide exposure with poor cognitive function and behavioral problems. However, these findings have relied primarily on neuropsychological assessments. Questions remain about the neurobiological effects of pesticide exposure, specifically where in the brain pesticides exert their effects and whether compensatory mechanisms in the brain may have masked pesticide-related associations in studies that relied purely on neuropsychological measures.METHODS: We conducted a functional neuroimaging study in 48 farmworkers from Zarcero County, Costa Rica, in 2016. We measured concentrations of 13 insecticide, fungicide, or herbicide metabolites or parent compounds in urine samples collected during two study visits (approximately 3-5 weeks apart). We assessed cortical brain activation in the prefrontal cortex during tasks of working memory, attention, and cognitive flexibility using functional near-infrared spectroscopy (fNIRS). We estimated associations of pesticide exposure with cortical brain activation using multivariable linear regression models adjusted for age and education level.RESULTS: We found that higher concentrations of insecticide metabolites were associated with reduced activation in the prefrontal cortex during a working memory task. For example, 3,5,6-trichloro-2-pyridinol (TCPy; a metabolite of the organophosphate chlorpyrifos) was associated with reduced activation in the left dorsolateral prefrontal cortex (beta = -2.3; 95% CI: -3.9, -0.7 per two-fold increase in TCPy). Similarly, 3-phenoxybenzoic acid (3-PBA; a metabolite of pyrethroid insecticides) was associated with bilateral reduced activation in the dorsolateral prefrontal cortices (beta = -3.1; 95% CI: -5.0, -1.2 and -2.3; 95% CI: -4.5, -0.2 per two-fold increase in 3-PBA for left and right cortices, respectively). These associations were similar, though weaker, for the attention and cognitive flexibility tasks. We observed null associations of fungicide and herbicide biomarker concentrations with cortical brain activation during the three tasks that were administered.CONCLUSION: Our findings suggest that organophosphate and pyrethroid insecticides may impact cortical brain activation in the prefrontal cortex - neural dynamics that could potentially underlie previously reported associations with cognitive and behavioral function. Furthermore, our study demonstrates the feasibility and utility of fNIRS in epidemiological field studies.

  View details for DOI 10.1016/j.neuro.2022.10.004

  View details for PubMedID 36228750

• Cortical activation predicts posttraumatic improvement in youth treated with TF-CBT or CCT. Journal of psychiatric research Espil, F. M., Balters, S., Li, R., McCurdy, B. H., Kletter, H., Piccirilli, A., Cohen, J. A., Weems, C. F., Reiss, A. L., Carrion, V. G. 2022; 156: 25-35

  Abstract

  BACKGROUND: Identifying neural activation patterns that predict youths' treatment response may aid in the development of imaging-based assessment of emotion dysregulation following trauma and foster tailored intervention. Changes in cortical hemodynamic activity measured with functional near-infrared spectroscopy (fNIRS) may provide a time and cost-effective option for such work. We examined youths' PTSD symptom change following treatment and tested if previously identified activation patterns would predict treatment response.METHODS: Youth (N=73, mean age=12.97, SD=3.09 years) were randomly assigned to trauma-focused cognitive behavioral therapy (TF-CBT), cue-centered therapy (CCT), or treatment as usual (TAU). Parents and youth reported on youth's PTSD symptoms at pre-intervention, post-intervention, and follow-up. Neuroimaging data (N=31) assessed at pre-intervention were obtained while youth engaged in an emotion expression task. Treatment response slopes were calculated for youth's PTSD symptoms.RESULTS: Overall, PTSD symptoms decreased from pre-intervention through follow-up across conditions, with some evidence of relative benefit of TF-CBT and CCT over TAU but significant individual variation in treatment response. Cortical activation patterns were correlated with PTSD symptom improvement slopes (r=0.53). In particular, cortical responses to fearful and neutral facial stimuli in six fNIRS channels in the bilateral dlPFC were important predictors of PTSD symptom improvement.CONCLUSIONS: The use of fNIRS provides a method of monitoring and assessing cortical activation patterns in a relatively inexpensive and portable manner. Associations between functional activation and youths' PTSD symptoms improvement may be a promising avenue for understanding emotion dysregulation in clinical populations.

  View details for DOI 10.1016/j.jpsychires.2022.10.002

  View details for PubMedID 36228389

• Impact of dysglycemia and obesity on the brain in adolescents with and without type 2 diabetes: A pilot study. Pediatric diabetes Snyder, L. L., Foland-Ross, L. C., Cato, A., Reiss, A. L., Shah, C., Hossain, J., Elmufti, H., Nelly Mauras 2022

  Abstract

  OBJECTIVE: Both diabetes and obesity can affect the brain, yet their impact is not well characterized in children with type 2 (T2) diabetes and obesity. This pilot study aims to explore differences in brain function and cognition in adolescents with T2 diabetes and obesity and nondiabetic controls with obesity and lean controls.RESEARCH DESIGN AND METHODS: Participants were 12-17 years old (5 T2 diabetes with obesity [mean HgbA1C 10.9%], 6 nondiabetic controls with obesity and 10 lean controls). Functional MRI (FMRI) during hyperglycemic/euglycemic clamps was performed in the T2 diabetes group.RESULTS: When children with obesity, with and without diabetes, were grouped (mean BMI 98.8%), cognitive scores were lower than lean controls (BMI 58.4%) on verbal, full scale, and performance IQ, visual-spatial and executive function tests. Lower scores correlated with adiposity and insulin resistance but not HgbA1C. No significant brain activation differences during task based and resting state FMRI were noted between children with obesity (with or without diabetes) and lean controls, but a notable effect size for the visual-spatial working memory task and resting state was observed.CONCLUSIONS: In conclusion, our pilot study suggests that obesity, insulin resistance, and dysglycemia may contribute to relatively poorer cognitive function in adolescents with T2 diabetes and obesity. Further studies with larger sample size are needed to assess if cognitive decline in children with obesity, with and without T2 diabetes, can be prevented or reversed.

  View details for DOI 10.1111/pedi.13420

  View details for PubMedID 36131363

• Syndrome specific neuroanatomical phenotypes in girls with Turner and Noonan Syndromes. Biological psychiatry. Cognitive neuroscience and neuroimaging Sanchez, M. S., Rai, B., Chowdhury, S., Reiss, A. L., Green, T. 2022

  Abstract

  BACKGROUND: Turner syndrome (TS) and Noonan syndrome (NS) are distinct genetic conditions with highly similar physical and neurodevelopmental phenotypes. TS is caused by X-chromosome absence, whereas NS results from genetic mutations activating the Ras mitogen-activated protein kinase (RAS-MAPK) signaling pathway. Previous neuroimaging studies in TS and NS have shown neuroanatomical variations relative to typically developing (TD) individuals, a standard comparison group when initially examining a clinical group of interest. However, none of these studies included a second clinical comparison group, limiting their ability to identify syndrome-specific neuroanatomical phenotypes.METHODS: In this study, we compared the behavioral and brain phenotypes of 37 girls with TS, 26 girls with NS, and 37 TD girls, all 5-12 years of age, using univariate and multivariate data-driven analyses.RESULTS: We found divergent neuroanatomical phenotypes between groups, despite high behavioral similarities. TS was associated with smaller whole-brain cortical surface area (SA) (p=<0.0001) whereas NS was associated with smaller whole-brain cortical thickness (CT) (p=.013) relative to TD. TS was associated with larger subcortical volumes (left amygdala, p=0.002; right hippocampus, p=0.002) whereas NS was associated with smaller subcortical volumes (bilateral caudate, p≤0.003; putamen, p<0.001; pallidum, p<0.001; right hippocampus, p=0.015). Multivariate analyses also showed diverging brain phenotypes in terms of SA and CT, with SA outperforming CT at group separation.CONCLUSION: TS and NS have syndrome-specific brain phenotypes, despite their behavioral similarities. Our observations suggest that neuroanatomical phenotypes better reflect the different genetics etiologies of TS and NS and may be superior biomarkers relative to behavioral phenotypes.

  View details for DOI 10.1016/j.bpsc.2022.08.012

  View details for PubMedID 36084900

• Towards assessing subcortical "deep brain" biomarkers of PTSD with functional near-infrared spectroscopy. Cerebral cortex (New York, N.Y. : 1991) Balters, S., Schlichting, M. R., Foland-Ross, L., Brigadoi, S., Miller, J. G., Kochenderfer, M. J., Garrett, A. S., Reiss, A. L. 2022

  Abstract

  Assessment of brain function with functional near-infrared spectroscopy (fNIRS) is limited to the outer regions of the cortex. Previously, we demonstrated the feasibility of inferring activity in subcortical "deep brain" regions using cortical functional magnetic resonance imaging (fMRI) and fNIRS activity in healthy adults. Access to subcortical regions subserving emotion and arousal using affordable and portable fNIRS is likely to be transformative for clinical diagnostic and treatment planning. Here, we validate the feasibility of inferring activity in subcortical regions that are central to the pathophysiology of posttraumatic stress disorder (PTSD; i.e. amygdala and hippocampus) using cortical fMRI and simulated fNIRS activity in a sample of adolescents diagnosed with PTSD (N=20, mean age=15.3±1.9years) and age-matched healthy controls (N=20, mean age=14.5±2.0years) as they performed a facial expression task. We tested different prediction models, including linear regression, a multilayer perceptron neural network, and a k-nearest neighbors model. Inference of subcortical fMRI activity with cortical fMRI showed high prediction performance for the amygdala (r>0.91) and hippocampus (r>0.95) in both groups. Using fNIRS simulated data, relatively high prediction performance for deep brain regions was maintained in healthy controls (r>0.79), as well as in youths with PTSD (r>0.75). The linear regression and neural network models provided the best predictions.

  View details for DOI 10.1093/cercor/bhac320

  View details for PubMedID 36066436

• Concurrent fNIRS and EEG for Brain Function Investigation: A Systematic, Methodology-Focused Review. Sensors (Basel, Switzerland) Li, R., Yang, D., Fang, F., Hong, K. S., Reiss, A. L., Zhang, Y. 2022; 22 (15)

  Abstract

  Electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) stand as state-of-the-art techniques for non-invasive functional neuroimaging. On a unimodal basis, EEG has poor spatial resolution while presenting high temporal resolution. In contrast, fNIRS offers better spatial resolution, though it is constrained by its poor temporal resolution. One important merit shared by the EEG and fNIRS is that both modalities have favorable portability and could be integrated into a compatible experimental setup, providing a compelling ground for the development of a multimodal fNIRS-EEG integration analysis approach. Despite a growing number of studies using concurrent fNIRS-EEG designs reported in recent years, the methodological reference of past studies remains unclear. To fill this knowledge gap, this review critically summarizes the status of analysis methods currently used in concurrent fNIRS-EEG studies, providing an up-to-date overview and guideline for future projects to conduct concurrent fNIRS-EEG studies. A literature search was conducted using PubMed and Web of Science through 31 August 2021. After screening and qualification assessment, 92 studies involving concurrent fNIRS-EEG data recordings and analyses were included in the final methodological review. Specifically, three methodological categories of concurrent fNIRS-EEG data analyses, including EEG-informed fNIRS analyses, fNIRS-informed EEG analyses, and parallel fNIRS-EEG analyses, were identified and explained with detailed description. Finally, we highlighted current challenges and potential directions in concurrent fNIRS-EEG data analyses in future research.

  View details for DOI 10.3390/s22155865

  View details for PubMedID 35957421

• Aberrant brain network and eye gaze patterns during natural social interaction predict multi-domain social-cognitive behaviors in girls with fragile X syndrome. Molecular psychiatry Li, R., Bruno, J. L., Lee, C. H., Bartholomay, K. L., Sundstrom, J., Piccirilli, A., Jordan, T., Miller, J. G., Lightbody, A. A., Reiss, A. L. 2022

  Abstract

  Girls with fragile X syndrome (FXS) often manifest significant symptoms of avoidance, anxiety, and arousal, particularly in the context of social interaction. However, little is currently known about the associations among neurobiological, biobehavioral such as eye gaze pattern, and social-cognitive dysfunction in real-world settings. In this study, we sought to characterize brain network properties and eye gaze patterns in girls with FXS during natural social interaction. Participants included 42 girls with FXS and 31 age- and verbal IQ-matched girls (control). Portable functional near-infrared spectroscopy (fNIRS) and an eye gaze tracker were used to investigate brain network alterations and eye gaze patterns associated with social-cognitive dysfunction in girls with FXS during a structured face-to-face conversation. Compared to controls, girls with FXS showed significantly increased inter-regional functional connectivity and greater excitability within the prefrontal cortex (PFC), frontal eye field (FEF) and superior temporal gyrus (STG) during the conversation. Girls with FXS showed significantly less eye contact with their conversational partner and more unregulated eye gaze behavior compared to the control group. We also demonstrated that a machine learning approach based on multimodal data, including brain network properties and eye gaze patterns, was predictive of multiple domains of social-cognitive behaviors in girls with FXS. Our findings expand current knowledge of neural mechanisms and eye gaze behaviors underlying naturalistic social interaction in girls with FXS. These results could be further evaluated and developed as intermediate phenotypic endpoints for treatment trial evaluation in girls with FXS.

  View details for DOI 10.1038/s41380-022-01626-3

  View details for PubMedID 35595977

• Exposure to DDT and DDE and functional neuroimaging in adolescents from the CHAMACOS cohort. Environmental research Binter, A., Mora, A. M., Baker, J. M., Bruno, J. L., Kogut, K., Rauch, S., Reiss, A. L., Eskenazi, B., Sagiv, S. K. 2022: 113461

  Abstract

  BACKGROUND: Epidemiological studies suggest that exposure to p,p'-dichloro-diphenyl-trichloroethane (p,p'-DDT) is associated with poorer cognitive function in children and adolescents, but the neural mechanisms underlying this association remain unclear.OBJECTIVE: We investigated associations of prenatal and childhood exposure to p,p'-DDT and its metabolite p,p'-dichloro-diphenyl-dichloroethylene (p,p'-DDE) with cortical activation in adolescents using functional near-infrared spectroscopy (fNIRS).METHODS: We administered fNIRS to 95 adolescents from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) aged 15-17 years. We assessed cortical activity in the frontal, temporal, and parietal brain regions while participants completed tasks of executive function, language comprehension, and social cognition. We measured serum p,p'-DDT and -DDE concentrations at age 9 years and then estimated exposure-outcome associations using linear regression models adjusted for sociodemographic characteristics. In secondary analyses, we back-extrapolated prenatal concentrations using prediction models and examined their association with cortical activation.RESULTS: Median (P25-P75) p,p'-DDT and -DDE concentrations in childhood were 1.4 (1-2.3) and 141.5 (75.0-281.3) ng/g lipid, respectively. We found that childhood exposure to p,p'-DDT and -DDE was associated with altered patterns of brain activation during tasks of cognition and executive functions. For example, we observed increased activity in the left frontal lobe during a language comprehension task (beta per 10 ng/g lipid increase of serum p,p'-DDE at age 9 years = 3.4; 95% CI: 0.0, 6.9 in the left inferior frontal lobe; and beta = 4.2; 95% CI: 0.9, 7.5 in the left superior frontal lobe). We found no sex differences in the associations of childhood p,p'-DDT and -DDE concentrations with neural activity. Associations between prenatal p,p'-DDT and p,p'-DDE concentrations and brain activity were similar to those observed for child p,p'-DDT and -DDE concentrations.CONCLUSIONS: Childhood p,p'-DDT and -DDE exposure may impact cortical brain activation, which could be an underlying mechanism for its previously reported associations with poorer cognitive function.

  View details for DOI 10.1016/j.envres.2022.113461

  View details for PubMedID 35550812

• The Intriguing Role of Thalamic Structure and Function in Youth With and at Familial Risk for Bipolar Disorder Singh, M., Gorelik, A., Gorelik, M., Chang, K., Gotlib, I., Reiss, A., Nimarko, A. ELSEVIER SCIENCE INC. 2022: S38

  View details for Web of Science ID 000789022200095

• Altered canonical and striatal-frontal resting state functional connectivity in children with pathogenic variants in the Ras/mitogen-activated protein kinase pathway. Molecular psychiatry Bruno, J. L., Shrestha, S. B., Reiss, A. L., Saggar, M., Green, T. 2022

  Abstract

  Mounting evidence supports the role of the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway in neurodevelopmental disorders. Here, the authors used a genetics-first approach to examine how Ras/MAPK pathogenic variants affect the functional organization of the brain and cognitive phenotypes including weaknesses in attention and inhibition. Functional MRI was used to examine resting state functional connectivity (RSFC) in association with Ras/MAPK pathogenic variants in children with Noonan syndrome (NS). Participants (age 4-12 years) included 39 children with NS (mean age 8.44, SD = 2.20, 25 females) and 49 typically developing (TD) children (mean age 9.02, SD = 9.02, 33 females). Twenty-eight children in the NS group and 46 in the TD group had usable MRI data and were included in final analyses. The results indicated significant hyperconnectivity for the NS group within canonical visual, ventral attention, left frontoparietal and limbic networks (p < 0.05 FWE). Higher connectivity within canonical left frontoparietal and limbic networks positively correlated with cognitive function within the NS but not the TD group. Further, the NS group demonstrated significant group differences in seed-based striatal-frontal connectivity (Z > 2.6, p < 0.05 FWE). Hyperconnectivity within canonical brain networks may represent an intermediary phenotype between Ras/MAPK pathogenic variants and cognitive phenotypes, including weaknesses in attention and inhibition. Altered striatal-frontal connectivity corresponds with smaller striatal volume and altered white matter connectivity previously documented in children with NS. These results may indicate delayed maturation and compensatory mechanisms and they are important for understanding the pathophysiology underlying cognitive phenotypes in NS and in the broader population of children with neurodevelopmental disorders.

  View details for DOI 10.1038/s41380-021-01422-5

  View details for PubMedID 35087195

• Functional near-infrared spectroscopy brain imaging predicts symptom severity in youth exposed to traumatic stress. Journal of psychiatric research Balters, S., Li, R., Espil, F. M., Piccirilli, A., Liu, N., Gundran, A., Carrion, V. G., Weems, C. F., Cohen, J. A., Reiss, A. L. 2021; 144: 494-502

  Abstract

  Functional near-infrared spectroscopy (fNIRS) is a non-invasive neuroimaging technique with the potential to enable the assessment of posttraumatic stress disorder (PTSD) brain biomarkers in an affordable and portable manner. Consistent with biological models of PTSD, functional magnetic resonance imaging (fMRI) and fNIRS studies of adults with trauma exposure and PTSD symptoms suggest increased activation in the dorsolateral prefrontal cortex (dlPFC) and ventrolateral PFC (vlPFC) in response to negative emotion stimuli. We tested this theory with fNIRS assessment among youth exposed to traumatic stress and experiencing PTSD symptoms (PTSS). A portable fNIRS system collected hemodynamic responses from (N=57) youth with PTSS when engaging in a classic emotion expression task that included fearful and neutral faces stimuli. The General Linear Model was applied to identify cortical activations associated with the facial stimuli. Subsequently, a prediction model was established via a Support Vector Regression to determine whether PTSS severity could be predicted based on fNIRS-derived cortical response measures and individual demographic information. Results were consistent with findings from adult fMRI and fNIRS studies of PTSS showing increased activation in the dlPFC and vlPFC in response to negative emotion stimuli. Subsequent prediction analysis revealed ten features (i.e., cortical responses from eight frontocortical fNIRS channels, age and sex) strongly correlated with PTSS severity (r=0.65, p<.001). Our findings suggest the potential utility of fNIRS as a portable tool for the detection of putative PTSS brain biomarkers.

  View details for DOI 10.1016/j.jpsychires.2021.10.020

  View details for PubMedID 34768071

• Neuroanatomical Profile of Young Females with Fragile X Syndrome: A Voxel-Based Morphometry Analysis. Cerebral cortex (New York, N.Y. : 1991) Lee, C. H., Bartholomay, K. L., Marzelli, M. J., Miller, J. G., Bruno, J. L., Lightbody, A. A., Reiss, A. L. 2021

  Abstract

  Fragile X syndrome is a genetic condition associated with alterations in brain and subsequent cognitive development. However, due to a milder phenotype relative to males, females with fragile X syndrome are underrepresented in research studies. In the current study, we investigate neuroanatomical differences in young females (age range: 6.03-16.32years) with fragile X syndrome (N=46) as compared to age-, sex-, and verbal abilities-matched participants (comparison group; N=35). Between-group analyses of whole-brain and regional brain volumes were assessed using voxel-based morphometry. Results demonstrate significantly larger total gray and white matter volumes in girls with fragile X syndrome compared to a matched comparison group (Ps<0.001). In addition, the fragile X group showed significantly larger gray matter volume in a bilateral parieto-occipital cluster and a right parieto-occipital cluster (Ps<0.001). Conversely, the fragile X group showed significantly smaller gray matter volume in the bilateral gyrus rectus (P<0.03). Associations between these regional brain volumes and key socio-emotional variables provide insight into gene-brain-behavior relationships underlying the fragile X syndrome phenotype in females. These findings represent the first characterization of a neuroanatomical phenotype in a large sample of girls with fragile X syndrome and expand our knowledge about potential neurodevelopmental mechanisms underlying cognitive-behavioral outcomes in this condition.

  View details for DOI 10.1093/cercor/bhab319

  View details for PubMedID 34546362

• Effect of sex chromosome number variation on attention-deficit/hyperactivity disorder symptoms, executive function, and processing speed. Developmental medicine and child neurology Green, T., Flash, S., Shankar, G., Bade Shrestha, S., Jo, B., Klabunde, M., Hong, D. S., Reiss, A. L. 2021

  Abstract

  AIM: To study sex differences in attention-deficit/hyperactivity disorder (ADHD) symptoms, we explored whether X chromosome absence or excess is independently associated with deficits in attention and hyperactivity, executive function, and processing speed.METHOD: We assessed 116 children (ages 3y 10mo-11y 11mo, mean 8y 5mo, SD 1y 11mo) with a variable number of sex chromosomes: 36 females with Turner syndrome (45, X0), 20 males with Klinefelter syndrome (47, XXY), 37 typically developing females (XX), and 23 typically developing males (XY).RESULTS: X chromosome absence was associated with increased attention problems, hyperactivity, and deficits in inhibitory control, compared with female children with XX (all p<0.003). Conversely, X chromosome excess was associated with weakness in working memory (p=0.018) and approached significance for attention problems (p=0.071) but not with hyperactivity, or weakness in inhibitory control relative to male children with XY. Using non-parametric effect size to quantify the clinical effect revealed that X chromosome absence affected attention, hyperactivity, executive function, and processing speed (all r>0.4), while X excess affected in-laboratory as well as parent-reported working memory (all r>0.4).INTERPRETATION: Our observations provide compelling evidence that the absence or excess of an X chromosome distinctly affects cognition and behaviors associated with ADHD.

  View details for DOI 10.1111/dmcn.15020

  View details for PubMedID 34431088

• Empathy and Anxiety in Young Girls with Fragile X Syndrome. Journal of autism and developmental disorders Miller, J. G., Bartholomay, K. L., Lee, C. H., Bruno, J. L., Lightbody, A. A., Reiss, A. L. 2021

  Abstract

  We tested whether empathy is impaired and associated with anxiety in girls with fragile X syndrome (FXS). We measured parent-reported empathy and self-reported anxiety in young girls with FXS and in a developmentally-matched comparison group. Girls with FXS received higher parent-reported scores on cognitive and affective empathy but also self-reported more severe anxiety symptoms, particularly separation anxiety and phobia symptoms, than girls in the comparison group. Girls with FXS who received higher cognitive empathy scores, however, appeared buffered against risk for separation anxiety and phobia symptoms. Girls with FXS experience elevated empathy and anxiety relative to their developmentally-matched peers. Higher cognitive empathy in girls with FXS may indicate resilience against specific forms of anxiety that are commonly observed in FXS.

  View details for DOI 10.1007/s10803-021-05105-6

  View details for PubMedID 34081299

• Quantitative Measurement of Macromolecular Tissue Properties in White and Gray Matter in Healthy Aging and Amnestic MCI. NeuroImage Gozdas, E., Fingerhut, H., Wu, H., Bruno, J. L., Dacorro, L., Jo, B., O'Hara, R., Reiss, A. L., Hosseini, S. M. 2021: 118161

  Abstract

  Healthy and pathological aging influence brain microstructure via complex processes. Discerning these processes require measurements that are sensitive to specific biological properties of brain tissue. We integrated a novel quantitative R1 measure with multi-shell diffusion weighted imaging to map age-associated changes in macromolecular tissue volume (MTV) along major white matter tracts in healthy older adults and patients with amnestic Mild Cognitive Impairment (aMCI). Reduced MTV in association tracts was associated with older age in healthy aging, was correlated with memory performance, and distinguished aMCI from controls. We also mapped changes in gray matter tissue properties using quantitative R1 measurements. We documented a widespread decrease in R1 with advancing age across cortex and decreased R1 in aMCI compared with controls in regions implicated in episodic memory. Our data are the first to characterize MTV loss along major white matter tracts in aMCI and suggest that qMRI is a sensitive measure for detecting subtle degeneration of white and gray matter tissue that cannot be detected by conventional MRI and diffusion measures.

  View details for DOI 10.1016/j.neuroimage.2021.118161

  View details for PubMedID 34000394

• Cortical gray matter structure in boys with Klinefelter syndrome. Psychiatry research. Neuroimaging Foland-Ross, L. C., Gil, M., Shrestha, S. B., Chromik, L. C., Hong, D., Reiss, A. L. 2021; 313: 111299

  Abstract

  Klinefelter syndrome (KS, 47,XXY) is a common sex chromosome aneuploidy in males that is associated with a wide range of cognitive, social and emotional characteristics. The neural bases of these symptoms, however, are unclear. Brain structure in 19 pre- or early-pubertal boys with KS (11.5±1.8 years) and 22 typically developing (control) boys (8.1±2.3 years) was examined using surface-based analyses of cortical gray matter volume, thickness and surface area. Boys in the KS group were treatment-naive with respect to testosterone replacement therapy. Reduced volume in the insula and dorsomedial prefrontal cortex was observed in the KS relative to the TD group, as well as increased volume in the parietal, occipital and motor regions. Further inspection of surface-based metrics indicated that whereas KS-associated increases in volume were driven by differences in thickness, KS-associated reductions in volume were associated with decreases in surface area. Exploratory analyses additionally indicated several correlations between brain structure and behavior, providing initial support for a neural basis of cognitive and emotional symptoms of this condition. Taken together, these data add support for a neuroanatomical phenotype of KS and extend previous studies through clarifying the precise neuroanatomical structural characteristics of that give rise to volumetric alterations.

  View details for DOI 10.1016/j.pscychresns.2021.111299

  View details for PubMedID 34038819

• Novel Effects of Ras-MAPK Activating Mutations on Brain Development and Neuropsychiatry Rai, B., Naylor, P., Jo, B., Reiss, A., Green, T. ELSEVIER SCIENCE INC. 2021: S371

  View details for Web of Science ID 000645683800891

• Changes in Brain Volume Associated with Trauma-Focused Cognitive Behavioral Therapy Among Youth with Posttraumatic Stress Disorder. Journal of traumatic stress Garrett, A. S., Abazid, L., Cohen, J. A., van der Kooij, A., Carrion, V., Zhang, W., Jo, B., Franklin, C., Blader, J., Zack, S., Reiss, A. L., Agras, W. S. 2021

  Abstract

  This study investigated group differences and longitudinal changes in brain volume before and after trauma-focused cognitive behavioral therapy (TF-CBT) in 20 unmedicated youth with maltreatment-related posttraumatic stress disorder (PTSD) and 20 non-trauma-exposed healthy control (HC) participants. We collected MRI scans of brain anatomy before and after 5 months of TF-CBT or the same time interval for the HC group. FreeSurfer software was used to segment brain images into 95 cortical and subcortical volumes, which were submitted to optimal scaling regression with lasso variable selection. The resulting model of group differences at baseline included larger right medial orbital frontal and left posterior cingulate corticies and smaller right midcingulate and right precuneus corticies in the PTSD relative to the HC group, R2 = .67. The model of group differences in pre- to posttreatment change included greater longitudinal changes in right rostral middle frontal, left pars triangularis, right entorhinal, and left cuneus corticies in the PTSD relative to the HC group, R2 = .69. Within the PTSD group, pre- to posttreatment symptom improvement was modeled by longitudinal decreases in the left posterior cingulate cortex, R2 = .45, and predicted by baseline measures of a smaller right isthmus (retrosplenial) cingulate and larger left caudate, R2 = .77. In sum, treatment was associated with longitudinal changes in brain regions that support executive functioning but not those that discriminated PTSD from HC participants at baseline. Additionally, results confirm a role for the posterior/retrosplenial cingulate as a correlate of PTSD symptom improvement and predictor of treatment outcome.

  View details for DOI 10.1002/jts.22678

  View details for PubMedID 33881197

• Effects of X Chromosome Monosomy and Genomic Imprinting on Observational Markers of Social Anxiety in Prepubertal Girls with Turner Syndrome. Journal of autism and developmental disorders Hall, S. S., Riley, M. J., Weston, R. N., Lepage, J., Hong, D. S., Jo, B., Hallmayer, J., Reiss, A. L. 2021

  Abstract

  Previous studies have suggested that girls with Turner syndrome (TS) exhibit symptoms of social anxiety during interactions with others. However, few studies have quantified these behaviors during naturalistic face-to-face social encounters. In this study, we coded observational markers of social anxiety in prepubertal girls with TS and age-matched controls during a 10-min social encounter with an unfamiliar examiner. Results showed that girls with TS exhibited significantly higher levels of gaze avoidance compared to controls. Impairments in social gaze were particularly increased in girls with a maternally retained X chromosome (Xm), suggesting a genomic imprinting effect. These data indicate that social gaze avoidance may be a critical behavioral marker for identifying early social dysfunction in young girls with TS.

  View details for DOI 10.1007/s10803-021-04896-y

  View details for PubMedID 33751331

• Evaluation of smartphone interactions on drivers' brain function and vehicle control in an immersive simulated environment. Scientific reports Baker, J. M., Bruno, J. L., Piccirilli, A., Gundran, A., Harbott, L. K., Sirkin, D. M., Marzelli, M., Hosseini, S. M., Reiss, A. L. 2021; 11 (1): 1998

  Abstract

  Smartphones and other modern technologies have introduced multiple new forms of distraction that color the modern driving experience. While many smartphone functions aim to improve driving by providing the driver with real-time navigation and traffic updates, others, such as texting, are not compatible with driving and are often the cause of accidents. Because both functions elicit driver attention, an outstanding question is the degree to which drivers' naturalistic interactions with navigation and texting applications differ in regard to brain and behavioral indices of distracted driving. Here, we employed functional near-infrared spectroscopy to examine the cortical activity that occurs under parametrically increasing levels of smartphone distraction during naturalistic driving. Our results highlight a significant increase in bilateral prefrontal and parietal cortical activity that occurs in response to increasingly greater levels of smartphone distraction that, in turn, predicts changes in common indices of vehicle control.

  View details for DOI 10.1038/s41598-021-81208-5

  View details for PubMedID 33479322

  View details for PubMedCentralID PMC7820246

• Evaluation of smartphone interactions on drivers’ brain function and vehicle control in an immersive simulated environment Scientific Reports Baker, J. M., Bruno, J. K., Piccirilli, A., Gundran, A., Harbott, L. K., Sirkin, D. M., Marzelli, M., Hosseini, S., Reiss, A. L. 2021; 11

  View details for DOI 10.1038/s41598-021-81208-5

• Dyadic Sex Composition and Task Classification Using fNIRS Hyperscanning Data Kruse, L. A., Reiss, A. L., Kochenderfer, M. J., Balters, S., Wani, M. A., Sethi, Shi, W., Qu, G., Raicu, D. S., Jin, R. IEEE. 2021: 582-588

  View details for DOI 10.1109/ICMLA52953.2021.00097

  View details for Web of Science ID 000779208200090

• Covid-19 pandemic: Mental health in girls with and without fragile X syndrome Journal of Pediatric Psychology Jordan, T. L., Bartholomay, K. L., Lee, C. H., Miller, J. M., Lightbody, A. A., Reiss, A. L. 2021

  Abstract

  Children and adolescents, who have less developed coping skills, are affected by natural disasters and other traumatic events differently than adults. Emotional and behavioral effects are particularly pronounced during a pandemic-related disaster, when support networks that typically promote healthy coping, such as friends, teachers, and family members, may be less available. Children and adolescents with fragile X syndrome (FXS), who are at increased risk for developing anxiety and depression, may be particularly vulnerable to behavioral or emotional difficulties during a pandemic. This study examined the mental health outcomes of school-aged girls with FXS during the COVID-19 pandemic and associated stay-at-home orders.Participants included 47 school-aged girls with FXS and 33 age- and developmentally matched comparison girls. Associations between COVID-19 behavioral and emotional outcomes and prior academic, adaptive, behavioral, and emotional functioning as well as prior maternal mental health and characteristics of the mother-child relationship were examined. Qualitative data from the parental report of emotional and behavioral responses to the pandemic were also obtained.Results indicate that school-aged girls with FXS demonstrate a distinct profile of COVID-19 related associations compared to the comparison group, such that pandemic-related worries and emotional impact of pandemic restrictions were predicted by prior mental health factors for the comparison group but by prior social, behavioral, and relational factors for the FXS group.Findings provide insight into factors that may confer risk or resilience for youth with special needs, suggesting potential therapeutic targets and informing public health initiatives in response to the pandemic.

  View details for DOI 10.1093/jpepsy/jsab106

• COVID-19 Pandemic: Mental Health in Girls With and Without Fragile X Syndrome. Journal of pediatric psychology Jordan, T. L., Bartholomay, K. L., Lee, C. H., Miller, J. G., Lightbody, A. A., Reiss, A. L. 2021

  Abstract

  Children and adolescents, who have less developed coping skills, are affected by natural disasters and other traumatic events differently than adults. Emotional and behavioral effects are particularly pronounced during a pandemic-related disaster, when support networks that typically promote healthy coping, such as friends, teachers, and family members, may be less available. Children and adolescents with fragile X syndrome (FXS), who are at increased risk for developing anxiety and depression, may be particularly vulnerable to behavioral or emotional difficulties during a pandemic. This study examined the mental health outcomes of school-aged girls with FXS during the COVID-19 pandemic and associated stay-at-home orders.Participants included 47 school-aged girls with FXS and 33 age- and developmentally matched comparison girls. Associations between COVID-19 behavioral and emotional outcomes and prior academic, adaptive, behavioral, and emotional functioning as well as prior maternal mental health and characteristics of the mother-child relationship were examined. Qualitative data from the parental report of emotional and behavioral responses to the pandemic were also obtained.Results indicate that school-aged girls with FXS demonstrate a distinct profile of COVID-19 related associations compared to the comparison group, such that pandemic-related worries and emotional impact of pandemic restrictions were predicted by prior mental health factors for the comparison group but by prior social, behavioral, and relational factors for the FXS group.Findings provide insight into factors that may confer risk or resilience for youth with special needs, suggesting potential therapeutic targets and informing public health initiatives in response to the pandemic.

  View details for DOI 10.1093/jpepsy/jsab106

  View details for PubMedID 34718672

• The neurodevelopmental basis of humor appreciation: A fNIRS study of young children. PloS one Mayseless, N., Reiss, A. L. 2021; 16 (12): e0259422

  Abstract

  Humor is crucial for social development. Despite this, very few studies have examined the neurodevelopment of humor in very young children, and none to date have used functional near-infrared spectroscopy (fNIRS) to study this important cognitive construct. The main aim of the current study was to characterize the neural basis of humor processing in young children between the ages of 6-8 years. Thirty-five healthy children (6-8 years old) watched funny and neutral video clips while undergoing fNIRS imaging. We observed activation increases in left temporo-occipito-parietal junction (TOPJ), inferior-parietal lobe (IPL), dorsolateral-prefrontal cortex (DLPFC) and right inferior frontal gyrus (IFG) and superior parietal lobe (SPL) regions. Activation in left TOPJ was positively correlated with age. In addition, we found that coherence increased in humor viewing compared to neutral content, mainly between remote regions. This effect was different for boys and girls, as boys showed a more pronounced increase in coherence for funny compared to neutral videos, more so in frontoparietal networks. These results expand our understanding of the neurodevelopment of humor by highlighting the effect of age on the neural basis of humor appreciation as well as emphasizing different developmental trajectories of boys and girls.

  View details for DOI 10.1371/journal.pone.0259422

  View details for PubMedID 34879055

• A Methodological Review of fNIRS in Driving Research: Relevance to the Future of Autonomous Vehicles. Frontiers in human neuroscience Balters, S., Baker, J. M., Geeseman, J. W., Reiss, A. L. 2021; 15: 637589

  Abstract

  As automobile manufacturers have begun to design, engineer, and test autonomous driving systems of the future, brain imaging with functional near-infrared spectroscopy (fNIRS) can provide unique insights about cognitive processes associated with evolving levels of autonomy implemented in the automobile. Modern fNIRS devices provide a portable, relatively affordable, and robust form of functional neuroimaging that allows researchers to investigate brain function in real-world environments. The trend toward "naturalistic neuroscience" is evident in the growing number of studies that leverage the methodological flexibility of fNIRS, and in doing so, significantly expand the scope of cognitive function that is accessible to observation via functional brain imaging (i.e., from the simulator to on-road scenarios). While more than a decade's worth of study in this field of fNIRS driving research has led to many interesting findings, the number of studies applying fNIRS during autonomous modes of operation is limited. To support future research that directly addresses this lack in autonomous driving research with fNIRS, we argue that a cogent distillation of the methods used to date will help facilitate and streamline this research of tomorrow. To that end, here we provide a methodological review of the existing fNIRS driving research, with the overarching goal of highlighting the current diversity in methodological approaches. We argue that standardization of these approaches will facilitate greater overlap of methods by researchers from all disciplines, which will, in-turn, allow for meta-analysis of future results. We conclude by providing recommendations for advancing the use of such fNIRS technology in furthering understanding the adoption of safe autonomous vehicle technology.

  View details for DOI 10.3389/fnhum.2021.637589

  View details for PubMedID 33967721

• Activation Mutation in the Ras/MAPK Pathway Alters the Functional Resting-State Architecture Underlining Executive Function and Attention Bruno, J., Shrestha, S., Reiss, A., Saggar, M., Green, T. SPRINGERNATURE. 2020: 177–78

  View details for Web of Science ID 000596371000337

• Capturing Human Interaction in the Virtual Age: A Perspective on the Future of fNIRS Hyperscanning FRONTIERS IN HUMAN NEUROSCIENCE Balters, S., Baker, J. M., Hawthorne, G., Reiss, A. L. 2020; 14: 588494

  Abstract

  Advances in video conferencing capabilities combined with dramatic socio-dynamic shifts brought about by COVID-19, have redefined the ways in which humans interact in modern society. From business meetings to medical exams, or from classroom instruction to yoga class, virtual interfacing has permeated nearly every aspect of our daily lives. A seemingly endless stream of technological advances combined with our newfound reliance on virtual interfacing makes it likely that humans will continue to use this modern form of social interaction into the future. However, emergent evidence suggests that virtual interfacing may not be equivalent to face-to-face interactions. Ultimately, too little is currently understood about the mechanisms that underlie human interactions over the virtual divide, including how these mechanisms differ from traditional face-to-face interaction. Here, we propose functional near-infrared spectroscopy (fNIRS) hyperscanning-simultaneous measurement of two or more brains-as an optimal approach to quantify potential neurocognitive differences between virtual and in-person interactions. We argue that increased focus on this understudied domain will help elucidate the reasons why virtual conferencing doesn't always stack up to in-person meetings and will also serve to spur new technologies designed to improve the virtual interaction experience. On the basis of existing fNIRS hyperscanning literature, we highlight the current gaps in research regarding virtual interactions. Furthermore, we provide insight into current hurdles regarding fNIRS hyperscanning hardware and methodology that should be addressed in order to shed light on this newly critical element of everyday life.

  View details for DOI 10.3389/fnhum.2020.588494

  View details for Web of Science ID 000589689700001

  View details for PubMedID 33240067

  View details for PubMedCentralID PMC7669622

• PTPN11 Mutations in the Ras-MAPK Signaling Pathway Affect Human White Matter Microstructure. Cerebral cortex (New York, N.Y. : 1991) Fattah, M., Raman, M. M., Reiss, A. L., Green, T. 2020

  Abstract

  We examined whether PTPN11 mutations affect the white matter connectivity of the developing human brain. Germline activating mutations to the PTPN11 gene cause overactivation of the Ras-Mitogen-Activated Protein Kinase pathway. Activating mutations cause Noonan syndrome (NS), a developmental disorder associated with hyperactivity and cognitive weakness in attention, executive function, and memory. In mouse models of NS, PTPN11 mutations cause reduced axon myelination and white matter formation, while the effects of PTPN11 mutations on human white matter are largely unknown. For the first time, we assessed 17 children with NS (9 females, mean age, 8.68±2.39) and 17 age- and sex-matched controls (9 female, mean age, 8.71±2.40) using diffusion brain imaging for white matter connectivity and structural magnetic resonance imaging to characterize brain morphology. Children with NS showed widespread reductions in fractional anisotropy (FA; 82613 voxels, t=1.49, P<0.05) and increases in radial diffusivity (RD; 94044 voxels, t=1.22, P<0.05), denoting decreased white matter connectivity. In NS, the FA of the posterior thalamic radiation correlated positively with inhibition performance, whereas connectivity in the genu of the corpus callosum was inversely associated with auditory attention performance. Additionally, we observed negative and positive correlations, respectively, between memory and the cingulum hippocampus, and memory and the cingulum cingulate gyrus. These findings elucidate the neural mechanism underpinning the NS cognitive phenotype, and may serve as a brain-based biomarker.

  View details for DOI 10.1093/cercor/bhaa299

  View details for PubMedID 33119062

• Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder MOLECULAR PSYCHIATRY Hegarty, J. P., Pegoraro, L. L., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Monterrey, J. C., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2020; 25 (10): 2556–66

  View details for DOI 10.1038/s41380-018-0330-z

  View details for Web of Science ID 000572540100029

• PATHWAYS LEADING TO MENTAL HEALTH PHENOTYPES AND THEIR TREATMENTS: INSIGHTS FROM NEUROGENETIC SYNDROMES Gothelf, D., Green, T., Reiss, A. L. ELSEVIER SCIENCE INC. 2020: S266–S267

  View details for DOI 10.1016/j.jaac.2020.07.547

  View details for Web of Science ID 000579844101279

• Finding the neural correlates of collaboration using a three-person fMRI hyperscanning paradigm. Proceedings of the National Academy of Sciences of the United States of America Xie, H., Karipidis, I. I., Howell, A., Schreier, M., Sheau, K. E., Manchanda, M. K., Ayub, R., Glover, G. H., Jung, M., Reiss, A. L., Saggar, M. 2020

  Abstract

  Humans have an extraordinary ability to interact and cooperate with others. Despite the social and evolutionary significance of collaboration, research on finding its neural correlates has been limited partly due to restrictions on the simultaneous neuroimaging of more than one participant (also known as hyperscanning). Several studies have used dyadic fMRI hyperscanning to examine the interaction between two participants. However, to our knowledge, no study to date has aimed at revealing the neural correlates of social interactions using a three-person (or triadic) fMRI hyperscanning paradigm. Here, we simultaneously measured the blood-oxygenation level-dependent signal from 12 triads (n = 36 participants), while they engaged in a collaborative drawing task based on the social game of Pictionary General linear model analysis revealed increased activation in the brain regions previously linked with the theory of mind during the collaborative phase compared to the independent phase of the task. Furthermore, using intersubject correlation analysis, we revealed increased synchronization of the right temporo-parietal junction (R TPJ) during the collaborative phase. The increased synchrony in the R TPJ was observed to be positively associated with the overall team performance on the task. In sum, our paradigm revealed a vital role of the R TPJ among other theory-of-mind regions during a triadic collaborative drawing task.

  View details for DOI 10.1073/pnas.1917407117

  View details for PubMedID 32843342

• Integrated functional genomic analyses of Klinefelter and Turner syndromes reveal global network effects of altered X chromosome dosage. Proceedings of the National Academy of Sciences of the United States of America Zhang, X., Hong, D., Ma, S., Ward, T., Ho, M., Pattni, R., Duren, Z., Stankov, A., Bade Shrestha, S., Hallmayer, J., Wong, W. H., Reiss, A. L., Urban, A. E. 2020

  Abstract

  In both Turner syndrome (TS) and Klinefelter syndrome (KS) copy number aberrations of the X chromosome lead to various developmental symptoms. We report a comparative analysis of TS vs. KS regarding differences at the genomic network level measured in primary samples by analyzing gene expression, DNA methylation, and chromatin conformation. X-chromosome inactivation (XCI) silences transcription from one X chromosome in female mammals, on which most genes are inactive, and some genes escape from XCI. In TS, almost all differentially expressed escape genes are down-regulated but most differentially expressed inactive genes are up-regulated. In KS, differentially expressed escape genes are up-regulated while the majority of inactive genes appear unchanged. Interestingly, 94 differentially expressed genes (DEGs) overlapped between TS and female and KS and male comparisons; and these almost uniformly display expression changes into opposite directions. DEGs on the X chromosome and the autosomes are coexpressed in both syndromes, indicating that there are molecular ripple effects of the changes in X chromosome dosage. Six potential candidate genes (RPS4X, SEPT6, NKRF, CX0rf57, NAA10, and FLNA) for KS are identified on Xq, as well as candidate central genes on Xp for TS. Only promoters of inactive genes are differentially methylated in both syndromes while escape gene promoters remain unchanged. The intrachromosomal contact map of the X chromosome in TS exhibits the structure of an active X chromosome. The discovery of shared DEGs indicates the existence of common molecular mechanisms for gene regulation in TS and KS that transmit the gene dosage changes to the transcriptome.

  View details for DOI 10.1073/pnas.1910003117

  View details for PubMedID 32071206

• Brain Function Differences in Children With Type 1 Diabetes: An fMRI Study of Working Memory. Diabetes Foland-Ross, L. C., Tong, G. n., Mauras, N. n., Cato, A. n., Aye, T. n., Tansey, M. n., White, N. H., Weinzimer, S. A., Englert, K. n., Shen, H. n., Mazaika, P. K., Reiss, A. L. 2020

  Abstract

  Glucose is a primary fuel source to the brain, yet the influence of dysglycemia on neurodevelopment in children with type 1 diabetes remains unclear. We examined brain activation using functional MRI in 80 children with type 1 diabetes (mean age ± SD, 11.5±1.8 years; 46% female) and 47 children without diabetes ("control", mean age 11.8±1.5 years; 51% female) as they performed a visuospatial working memory (N-back) task. Results indicated that in both groups, activation scaled positively with increasing working memory load across many areas, including the frontoparietal cortex, caudate and cerebellum. Between groups, children with diabetes exhibited reduced performance on the N-back task relative to control children, as well as greater modulation of activation (i.e., showed greater a increase in activation with higher working memory load). Post-hoc analyses indicated that greater modulation was associated in the diabetes group with better working memory function and with an earlier age of diagnosis. These findings suggest that increased modulation may occur as a compensatory mechanism, helping in part to preserve working memory ability, and further, that children with an earlier onset require additional compensation. Future studies that test whether these patterns change as a function of improved glycemic control are warranted.

  View details for DOI 10.2337/db20-0123

  View details for PubMedID 32471809

• Neural bases of social feedback processing and self-other distinction in late childhood: The role of attachment and age. Cognitive, affective & behavioral neuroscience Miller, J. G., Shrestha, S. n., Reiss, A. L., Vrtička, P. n. 2020

  Abstract

  Attachment plays a key role in how children process information about the self and others. Here, we examined the neural bases of interindividual differences in attachment in late childhood and tested whether social cognition-related neural activity varies as function of age. In a small sample of 8-year-old to 12-year-old children (n = 21/19), we used functional magnetic resonance imaging to measure neural responses during social feedback processing and self-other distinction. Attachment was assessed using child self-report. The social feedback processing task presented smiling and angry faces either confirming or disconfirming written information about participant performance on a perceptual game. In addition to observing main effects of facial emotion and performance, an increase in age was related to a shift from negative (i.e., angry faces/bad performance) to positive (i.e., smiling faces/good performance) information processing in the left amygdala/hippocampus, bilateral fusiform face area, bilateral anterior temporal pole (ATP), and left anterior insula. There were no effects of attachment on social feedback processing. The self-other distinction task presented digital morphs between children's own faces and faces of their mother or stranger females. We observed differential activation in face processing and mentalizing regions in response to self and mother faces versus morphed faces. Furthermore, left ATP activity was associated with attachment anxiety such that greater attachment anxiety was related to a shift from heightened processing of self and mother faces to morphed faces. There were no effects of age on self-other distinction. We discuss our preliminary findings in the context of attachment theory and previous work on social evaluation and self-other processing.

  View details for DOI 10.3758/s13415-020-00781-w

  View details for PubMedID 32141028

• Focal white matter disruptions along the cingulum tract explain cognitive decline in amnestic mild cognitive impairment (aMCI). Scientific reports Gozdas, E. n., Fingerhut, H. n., Chromik, L. C., O'Hara, R. n., Reiss, A. L., Hosseini, S. M. 2020; 10 (1): 10213

  Abstract

  White matter abnormalities of the human brain are implicated in typical aging and neurodegenerative diseases. However, our understanding of how fine-grained changes in microstructural properties along white matter tracts are associated with memory and cognitive decline in normal aging and mild cognitive impairment remains elusive. We quantified tract profiles with a newer method that can reliably measure fine-grained changes in white matter properties along the tracts using advanced multi-shell diffusion magnetic resonance imaging in 25 patients with amnestic mild cognitive impairment (aMCI) and 23 matched healthy controls (HC). While the changes in tract profiles were parallel across aMCI and HC, we found a significant focal shift in the profile at specific locations along major tracts sub-serving memory in aMCI. Particularly, our findings depict white matter alterations at specific locations on the right cingulum cingulate, the right cingulum hippocampus and anterior corpus callosum (CC) in aMCI compared to HC. Notably, focal changes in white matter tract properties along the cingulum tract predicted memory and cognitive functioning in aMCI. The results suggest that white matter disruptions at specific locations of the cingulum bundle may be a hallmark for the early prediction of Alzheimer's disease and a predictor of cognitive decline in aMCI.

  View details for DOI 10.1038/s41598-020-66796-y

  View details for PubMedID 32576866

• Glucocorticoid regulation and neuroanatomy in fragile x syndrome Journal of Psychiatric Research Bruno, J. L., Hong, D. S., Lightbody, A. A., Hosseini, S., Hallmayer, J., Reiss, A. L. 2020

  View details for DOI 10.1016/j.jpsychires.2020.12.015

• Functional Near-Infrared Spectroscopy (fNIRS) detects increased activation of the brain frontal-parietal network in youth with type 1 diabetes. Pediatric diabetes Mazaika, P. K., Marzelli, M. n., Tong, G. n., Foland-Ross, L. C., Buckingham, B. A., Aye, T. n., Reiss, A. L. 2020

  Abstract

  When considered as a group, children with type 1 diabetes have subtle cognitive deficits relative to neurotypical controls. However, the neural correlates of these differences remain poorly understood. Using functional near-infrared spectroscopy (fNIRS), we investigated the brain functional activations of young adolescents (19 individuals with type 1 diabetes, 18 healthy controls, ages 8-16 years) during a Go/No-Go response inhibition task. Both cohorts had the same performance on the task, but the individuals with type 1 diabetes subjects had higher activations in a frontal-parietal network including the bilateral supramarginal gyri and bilateral rostrolateral prefrontal cortices. The activations in these regions were positively correlated with fewer parent-reported conduct problems (i.e. lower Conduct Problem scores) on the BASC-2 behavioral assessment. Lower Conduct Problem scores are characteristic of less rule-breaking behavior suggesting a link between this brain network and better self-control. These findings are consistent with a large functional magnetic resonance imaging (fMRI) study of children with type 1 diabetes using completely different participants. Perhaps surprisingly, the between-group activation results from fNIRS were statistically stronger than the results using fMRI. This pilot study is the first fNIRS investigation of executive function for individuals with type 1 diabetes. The results suggest that fNIRS is a promising functional neuroimaging resource for detecting the brain correlates of behavior in the pediatric clinic. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/pedi.12992

  View details for PubMedID 32003523

• Executive task-based brain function in children with type 1 diabetes: An observational study. PLoS medicine Foland-Ross, L. C., Buckingam, B., Mauras, N., Arbelaez, A. M., Tamborlane, W. V., Tsalikian, E., Cato, A., Tong, G., Englert, K., Mazaika, P. K., Reiss, A. L., Diabetes Research in Children Network (DirecNet) 2019; 16 (12): e1002979

  Abstract

  BACKGROUND: Optimal glycemic control is particularly difficult to achieve in children and adolescents with type 1 diabetes (T1D), yet the influence of dysglycemia on the developing brain remains poorly understood.METHODS AND FINDINGS: Using a large multi-site study framework, we investigated activation patterns using functional magnetic resonance imaging (fMRI) in 93 children with T1D (mean age 11.5 ± 1.8 years; 45.2% female) and 57 non-diabetic (control) children (mean age 11.8 ± 1.5 years; 50.9% female) as they performed an executive function paradigm, the go/no-go task. Children underwent scanning and cognitive and clinical assessment at 1 of 5 different sites. Group differences in activation occurring during the contrast of "no-go > go" were examined while controlling for age, sex, and scan site. Results indicated that, despite equivalent task performance between the 2 groups, children with T1D exhibited increased activation in executive control regions (e.g., dorsolateral prefrontal and supramarginal gyri; p = 0.010) and reduced suppression of activation in the posterior node of the default mode network (DMN; p = 0.006). Secondary analyses indicated associations between activation patterns and behavior and clinical disease course. Greater hyperactivation in executive control regions in the T1D group was correlated with improved task performance (as indexed by shorter response times to correct "go" trials; r = -0.36, 95% CI -0.53 to -0.16, p < 0.001) and with better parent-reported measures of executive functioning (r values < -0.29, 95% CIs -0.47 to -0.08, p-values < 0.007). Increased deficits in deactivation of the posterior DMN in the T1D group were correlated with an earlier age of T1D onset (r = -0.22, 95% CI -0.41 to -0.02, p = 0.033). Finally, exploratory analyses indicated that among children with T1D (but not control children), more severe impairments in deactivation of the DMN were associated with greater increases in hyperactivation of executive control regions (T1D: r = 0.284, 95% CI 0.08 to 0.46, p = 0.006; control: r = 0.108, 95% CI -0.16 to 0.36, p = 0.423). A limitation to this study involves glycemic effects on brain function; because blood glucose was not clamped prior to or during scanning, future studies are needed to assess the influence of acute versus chronic dysglycemia on our reported findings. In addition, the mechanisms underlying T1D-associated alterations in activation are unknown.CONCLUSIONS: These data indicate that increased recruitment of executive control areas in pediatric T1D may act to offset diabetes-related impairments in the DMN, ultimately facilitating cognitive and behavioral performance levels that are equivalent to that of non-diabetic controls. Future studies that examine whether these patterns change as a function of improved glycemic control are warranted.

  View details for DOI 10.1371/journal.pmed.1002979

  View details for PubMedID 31815939

• On the relationship between mathematics and visuospatial processing in Turner syndrome. Journal of psychiatric research Baker, J. M., Klabunde, M., Jo, B., Green, T., Reiss, A. L. 2019; 121: 135–42

  Abstract

  A common neurocognitive phenotype of Turner syndrome (TS) includes coincident deficits in math and visuospatial reasoning while overall IQ remains intact. However, research has highlighted disparities in the relationship between these properties in women with TS, suggesting that not all visuospatial domains are equally related to mathematics in this group. Here, we present findings from a longitudinal investigation of visuospatial processing and its relationship to math performance in adolescent girls with TS and age-matched healthy controls. Participants completed a standardized battery of math and visuospatial tests once a year for 4 years. Linear mixed effects modeling was used to examine the relationship between mathematics and each visuospatial domain over time. Our results indicate that math performance was related to visual tracking, visual-motor coordination, and figure-ground processing. Such visuospatial domains appear to be uniquely affected by TS and could contribute to their deficits in math performance. Furthermore, differences in math and visuospatial test performance between girls with TS and healthy controls remain stable over time. Our results have important implications for the role of visuospatial processing in early math performance and may inform the development of effective interventions aimed at improving math education in children with TS.

  View details for DOI 10.1016/j.jpsychires.2019.11.004

  View details for PubMedID 31812933

• Functional neuroanatomy of interoceptive processing in children and adolescents: a pilot study. Scientific reports Klabunde, M., Juszczak, H., Jordan, T., Baker, J. M., Bruno, J., Carrion, V., Reiss, A. L. 2019; 9 (1): 16184

  Abstract

  In adults, interoception - the sense of the physiological condition of the body - appears to influence emotion processing, cognition, behavior and various somatic and mental health disorders. Adults demonstrate frontal-insula-parietal-anterior cingulate cortex activation during the heartbeat detection task, a common interoceptive measure. Little, however, is known about the functional neuroanatomy underlying interoception in children. The current pilot study examined interoceptive processing in children and adolescents with fMRI while using the heartbeat detection task. Our main findings demonstrate that children as young as the age of six activate the left insula, cuneus, inferior parietal lobule and prefrontal regions. These findings are similar to those in adults when comparing heartbeat and tone detection conditions. Age was associated with increased activation within the dACC, orbital frontal cortex and the mid-inferior frontal gyri. Thus, our pilot study may provide important information about the neurodevelopment of interoceptive processing abilities in children and a task for future interoception neuroimaging studies in children.

  View details for DOI 10.1038/s41598-019-52776-4

  View details for PubMedID 31700095

• Genetic and environmental influences on corticostriatal circuits in twins with autism Journal of psychiatry & neuroscience : JPN Hegarty II, J. P., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019; 44 (6): 190030

  Abstract

  Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs.We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6–15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity.Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated.We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors.Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD.

  View details for DOI 10.1503/jpn.190030

  View details for PubMedID 31603639

• Prenatal exposure to organophosphate pesticides and functional neuroimaging in adolescents living in proximity to pesticide application. Proceedings of the National Academy of Sciences of the United States of America Sagiv, S. K., Bruno, J. L., Baker, J. M., Palzes, V., Kogut, K., Rauch, S., Gunier, R., Mora, A. M., Reiss, A. L., Eskenazi, B. 2019

  Abstract

  We have reported consistent associations of prenatal organophosphate pesticide (OP) exposure with poorer cognitive function and behavior problems in our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a birth cohort of Mexican American youth in California's agricultural Salinas Valley. However, there is little evidence on how OPs affect neural dynamics underlying associations. We used functional near-infrared spectroscopy (fNIRS) to measure cortical activation during tasks of executive function, attention, social cognition, and language comprehension in 95 adolescent CHAMACOS participants. We estimated associations of residential proximity to OP use during pregnancy with cortical activation in frontal, temporal, and parietal regions using multiple regression models, adjusting for sociodemographic characteristics. OP exposure was associated with altered brain activation during tasks of executive function. For example, with a 10-fold increase in total OP pesticide use within 1 km of maternal residence during pregnancy, there was a bilateral decrease in brain activation in the prefrontal cortex during a cognitive flexibility task (beta = -4.74; 95% CI: -8.18, -1.31 and beta = -4.40; 95% CI: -7.96, -0.84 for the left and right hemispheres, respectively). We also found that prenatal OP exposure was associated with sex differences in brain activation during a language comprehension task. This first functional neuroimaging study of prenatal OP exposure suggests that pesticides may impact cortical brain activation, which could underlie previously reported OP-related associations with cognitive and behavioral function. Use of fNIRS in environmental epidemiology offers a practical alternative to neuroimaging technologies and enhances our efforts to assess the impact of chemical exposures on neurodevelopment.

  View details for DOI 10.1073/pnas.1903940116

  View details for PubMedID 31451641

• Creativity slumps and bumps: Examining the neurobehavioral basis of creativity development during middle childhood NEUROIMAGE Saggar, M., Xie, H., Beaty, R. E., Stankov, A. D., Schreier, M., Reiss, A. L. 2019; 196: 94–101

  View details for DOI 10.1016/j.neuroimage.2019.03.080

  View details for Web of Science ID 000470833800009

• Longitudinal changes in brain function associated with symptom improvement in youth with PTSD JOURNAL OF PSYCHIATRIC RESEARCH Garrett, A., Cohen, J. A., Zack, S., Carrion, V., Jo, B., Blader, J., Rodriguez, A., Vanasse, T. J., Reiss, A. L., Agras, W. 2019; 114: 161–69

  View details for DOI 10.1016/j.jpsychires.2019.04.021

  View details for Web of Science ID 000472127300024

• PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention CEREBRAL CORTEX Johnson, E. M., Ishak, A. D., Naylor, P. E., Stevenson, D. A., Reiss, A. L., Green, T. 2019; 29 (7): 2915–23

  View details for DOI 10.1093/cercor/bhy158

  View details for Web of Science ID 000477708300011

• Manganese exposure and working memory-related brain activity in smallholder farmworkers in Costa Rica: Results from a pilot study ENVIRONMENTAL RESEARCH Palzes, V. A., Sagiv, S. K., Baker, J. M., Rojas-Valverde, D., Gutierrez-Vargas, R., Winkler, M. S., Fuhrimann, S., Staudacher, P., Menezes-Filho, J. A., Reiss, A. L., Eskenazi, B., Mora, A. M. 2019; 173: 539–48

  View details for DOI 10.1016/j.envres.2019.04.006

  View details for Web of Science ID 000469162200056

• The Utility of Functional Near-infrared Spectroscopy for Measuring Cortical Activity during Cycling Exercise MEDICINE AND SCIENCE IN SPORTS AND EXERCISE Tempest, G. D., Reiss, A. L. 2019; 51 (5): 979–87

  View details for DOI 10.1249/MSS.0000000000001875

  View details for Web of Science ID 000465009400017

• The Utility of Functional Near-infrared Spectroscopy for Measuring Cortical Activity during Cycling Exercise. Medicine and science in sports and exercise Tempest, G. D., Reiss, A. L. 2019; 51 (5): 979-987

  Abstract

  Real-time measurement of dynamic brain activity during exercise can help advance our understanding of the role of exercise upon brain health and function. In exercise science, functional near infrared spectroscopy (fNIRS) has primarily been used to measure the effects of exercise intensity on hemodynamic responses in the cerebral cortex. However, the utility of fNIRS to measure discreet hemodynamic responses underlying brain activation associated with motor and cognitive function during exercise has not been systematically examined. Here, we compared brain activation associated with a motor and cognitive task at rest and during cycling exercise at different intensities.In separate sessions, 13 participants performed cycling exercise on an indoor trainer at a low, moderate and high intensity. We measured changes in oxygenated (HbO) and deoxygenated (HbR) hemoglobin from prefrontal, parietal, and motor regions of the cerebral cortex during a handgrip and working-memory task.Our findings show significant brain activation (a concurrent increase in HbO and decrease in HbR) in contralateral motor cortex during the handgrip task and left prefrontal cortex during the working-memory task at rest and during exercise at low, moderate and high (motor task HbO only) intensities (P < 0.05). Moreover, brain activation during the handgrip and working-memory tasks was not significantly different at rest and during exercise (P > 0.05).This study shows that fNIRS can robustly measure motor and cognitive task-evoked changes in brain activation during cycling exercise comparable to rest. An implication of these new findings is that fNIRS can be used to determine real-time changes in brain function during exercise in healthy and clinical populations.

  View details for DOI 10.1249/MSS.0000000000001875

  View details for PubMedID 30985584

• Longitudinal changes in brain function associated with symptom improvement in youth with PTSD. Journal of psychiatric research Garrett, A., Cohen, J. A., Zack, S., Carrion, V., Jo, B., Blader, J., Rodriguez, A., Vanasse, T. J., Reiss, A. L., Agras, W. S. 2019; 114: 161–69

  Abstract

  BACKGROUND: Previous studies indicate that youth with posttraumatic stress disorder (PTSD) have abnormal activation in brain regions important for emotion processing. It is unknown whether symptom improvement is accompanied by normative changes in these regions. This study identified neural changes associated with symptom improvement with the long-term goal of identifying malleable targets for interventions.METHODS: A total of 80 functional magnetic resonance imaging (fMRI) scans were collected, including 20 adolescents with PTSD (ages 9-17) and 20 age- and sex-matched healthy control subjects, each scanned before and after a 5-month period. Trauma-focused cognitive behavioral therapy was provided to the PTSD group to ensure improvement in symptoms. Whole brain voxel-wise activation and region of interest analyses of facial expression task data were conducted to identify abnormalities in the PTSD group versus HC at baseline (BL), and neural changes correlated with symptom improvement from BL to EOS of study (EOS).RESULTS: At BL, the PTSD group had abnormally elevated activation in the cingulate cortex, hippocampus, amygdala, and medial frontal cortex compared to HC. From BL to EOS, PTSD symptoms improved an average of 39%. Longitudinal improvement in symptoms of PTSD was associated with decreasing activation in posterior cingulate, mid-cingulate, and hippocampus, while improvement in dissociative symptoms was correlated with decreasing activation in the amygdala.CONCLUSIONS: Abnormalities in emotion-processing brain networks in youth with PTSD normalize when symptoms improve, demonstrating neural plasticity of these regions in young patients and the importance of early intervention.

  View details for PubMedID 31082658

• Creativity slumps and bumps: Examining neurobehavioral basis of creativity development during middle childhood. NeuroImage Saggar, M., Xie, H., Beaty, R. E., Stankov, A. D., Schreier, M., Reiss, A. L. 2019

  Abstract

  Developmental research has found that children's creative thinking ability tends to decline during middle childhood. However, this decline has not been consistently demonstrated, and the underlying neural and behavioral factors that affect fluctuations in children's creative thinking ability remain uncharacterized. Using a longitudinal cohort-sequential experimental design, we investigated the neurobehavioral basis of creative thinking ability during middle childhood in a sample of 48 children (n = 21 starting 3rd grade, n = 27 starting 4th grade) assessed longitudinally at three time-points across one year. For the first time, we used data-driven methods to reveal distinct trajectories in creative thinking ability during middle childhood. We found that although some children show a classic decline in creative ability, others exhibit a significant increase in creativity over time. These trajectories were not associated with differences in intelligence, age, or sex, but rather other developmentally-relevant constructs, including heightened externalizing behavior (i.e., rule-breaking and aggression). Using functional near-infrared spectroscopy (fNIRS) in a smaller cohort (n = 26), we examined longitudinal changes in bilateral frontal neural connectivity and found that increased right lateral frontal segregation or functional specialization tracked developmental improvements in creative thinking ability. Taken together, the findings reveal distinct profiles of change in creative thinking ability during middle childhood and identify behavioral and neural mechanisms potentially underlying changes in children's ability to think creatively.

  View details for PubMedID 30959195

• Androgen treatment effects on hippocampus structure in boys with Klinefelter syndrome PSYCHONEUROENDOCRINOLOGY Foland-Ross, L. C., Ross, J. L., Reiss, A. L. 2019; 100: 223–28

  View details for DOI 10.1016/j.psyneuen.2018.09.039

  View details for Web of Science ID 000457820600030

• Inter-brain synchrony in mother-child dyads during cooperation: An fNIRS hyperscanning study NEUROPSYCHOLOGIA Miller, J. G., Vrticka, P., Cui, X., Shrestha, S., Hosseini, S., Baker, J. M., Reiss, A. L. 2019; 124: 117–24

  View details for DOI 10.1016/j.evolhumbehav.2018.12.021

  View details for Web of Science ID 000461003000012

• Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder. Molecular psychiatry Hegarty, J. P., Pegoraro, L. F., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. F., Monterrey, J. C., Cleveland, S. C., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019

  Abstract

  Atypical growth patterns of the brain have been previously reported in autism spectrum disorder (ASD) but these alterations are heterogeneous across individuals, which may be associated with the variable effects of genetic and environmental influences on brain development. Monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD (aged 6-15 years) were recruited to participate in this study. T1-weighted MRIs (n=164) were processed with FreeSurfer to evaluate structural brain measures. Intra-class correlations were examined within twin pairs and compared across diagnostic groups. ACE modeling was also completed. Structural brain measures, including cerebral and cerebellar gray matter (GM) and white matter (WM) volume, surface area, and cortical thickness, were primarily influenced by genetic factors in TD twins; however, mean curvature appeared to be primarily influenced by environmental factors. Similarly, genetic factors accounted for the majority of variation in brain size in twins with ASD, potentially to a larger extent regarding curvature and subcortical GM; however, there were also more environmental contributions in twins with ASD on some structural brain measures, such that cortical thickness and cerebellar WM volume were primarily influenced by environmental factors. These findings indicate potential neurobiological outcomes of the genetic and environmental risk factors that have been previously associated with ASD and, although preliminary, may help account for some of the previously outlined neurobiological heterogeneity across affected individuals. This is especially relevant regarding the role of genetic and environmental factors in the development of ASD, in which certain brain structures may be more sensitive to specific influences.

  View details for PubMedID 30659287

• Closing the Gender Gap in Fragile X Syndrome: Review on Females with FXS and Preliminary Research Findings. Brain sciences Bartholomay, K. L., Lee, C. H., Bruno, J. L., Lightbody, A. A., Reiss, A. L. 2019; 9 (1)

  Abstract

  Fragile X syndrome (FXS) is a genetic condition known to increase the risk of cognitive impairment and socio-emotional challenges in affected males and females. To date, the vast majority of research on FXS has predominantly targeted males, who usually exhibit greater cognitive impairment compared to females. Due to their typically milder phenotype, females may have more potential to attain a higher level of independence and quality of life than their male counterparts. However, the constellation of cognitive, behavioral, and, particularly, socio-emotional challenges present in many females with FXS often preclude them from achieving their full potential. It is, therefore, critical that more research specifically focuses on females with FXS to elucidate the role of genetic, environmental, and socio-emotional factors on outcome in this often-overlooked population.

  View details for PubMedID 30642066

• Neural correlates of liraglutide effects in persons at risk for Alzheimer's disease BEHAVIOURAL BRAIN RESEARCH Watson, K. T., Wroolie, T. E., Tong, G., Foland-Ross, L. C., Frangou, S., Singh, M., McIntyre, R. S., Roat-Shumway, S., Myoraku, A., Reiss, A. L., Rasgon, N. L. 2019; 356: 271–78

  View details for DOI 10.1016/j.bbr.2018.08.006

  View details for Web of Science ID 000449894800031

• Brain circuitry, behavior, and cognition: A randomized placebo-controlled trial of donepezil in fragile X syndrome JOURNAL OF PSYCHOPHARMACOLOGY Bruno, J. L., Hosseini, S., Lightbody, A. A., Manchanda, M. K., Reiss, A. L. 2019; 33 (8): 975-85

  View details for DOI 10.1177/0269881119858304

• Genetic and Environmental Influences on Lobar Brain Structures in Twins With Autism. Cerebral cortex (New York, N.Y. : 1991) Hegarty, J. P., Lazzeroni, L. C., Raman, M. M., Pegoraro, L. F., Monterrey, J. C., Cleveland, S. C., Hallmayer, J. F., Wolke, O. N., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019

  Abstract

  This investigation examined whether the variation of cerebral structure is associated with genetic or environmental factors in children with autism spectrum disorder (ASD) compared with typically developing (TD) controls. T1-weighted magnetic resonance imaging scans were obtained from twin pairs (aged 6-15 years) in which at least one twin was diagnosed with ASD or both were TD. Good quality data were available from 30 ASD, 18 discordant, and 34 TD pairs (n = 164). Structural measures (volume, cortical thickness, and surface area) were generated with FreeSurfer, and ACE modeling was completed. Lobar structures were primarily genetically mediated in TD twins (a2 = 0.60-0.89), except thickness of the temporal (a2 = 0.33 [0.04, 0.63]) and occipital lobes (c2 = 0.61 [0.45, 0.77]). Lobar structures were also predominantly genetically mediated in twins with ASD (a2 = 0.70-1.00); however, thickness of the frontal (c2 = 0.81 [0.71, 0.92]), temporal (c2 = 0.77 [0.60, 0.93]), and parietal lobes (c2 = 0.87 [0.77, 0.97]), and frontal gray matter (GM) volume (c2 = 0.79 [0.63, 0.95]), were associated with environmental factors. Conversely, occipital thickness (a2 = 0.93 [0.75, 1.11]) did not exhibit the environmental contributions that were found in controls. Differences in GM volume were associated with social communication impairments for the frontal (r = 0.52 [0.18, 0.75]), temporal (r = 0.61 [0.30, 0.80]), and parietal lobes (r = 0.53 [0.19, 0.76]). To our knowledge, this is the first investigation to suggest that environmental factors influence GM to a larger extent in children with ASD, especially in the frontal lobe.

  View details for DOI 10.1093/cercor/bhz215

  View details for PubMedID 31711118

• The Influence of Hyperactivity, Impulsivity, and Attention Problems on Social Functioning in Adolescents and Young Adults With Fragile X Syndrome JOURNAL OF ATTENTION DISORDERS Chromik, L. C., Quintin, E., Lepage, J., Hustyi, K. M., Lightbody, A. A., Reiss, A. L. 2019; 23 (2): 181–88

  View details for DOI 10.1177/1087054715571739

  View details for Web of Science ID 000453416600008

• Brain circuitry, behavior, and cognition: A randomized placebo-controlled trial of donepezil in fragile X syndrome. Journal of psychopharmacology (Oxford, England) Bruno, J. L., Hosseini, S. H., Lightbody, A. A., Manchanda, M. K., Reiss, A. L. 2019: 269881119858304

  Abstract

  Fragile X syndrome, the most common inherited cause for intellectual disability, is associated with alterations in cholinergic among other neurotransmitter systems. This study investigated the effects of donepezil hydrochloride, a cholinesterase inhibitor that has potential to correct aberrant cholinergic signaling.Forty-two individuals with fragile X syndrome (mean age=19.61 years) were randomized to receive 2.5-10.0 mg of donepezil (n=20, seven females) or placebo (n=22, eight females) per day. One individual in the active group withdrew at week 7. Outcomes included the contingency naming test, the aberrant behavior checklist, and behavior and brain activation patterns during a functional magnetic resonance imaging gaze discrimination task.There were no significant differences between active and placebo groups on cognitive (contingency naming task) or behavioral (total score or subscales of the aberrant behavior checklist) outcomes. At baseline, the active and placebo groups did not differ in functional magnetic resonance imaging activation patterns during the gaze task. After 12 weeks of treatment the active group displayed reduced activation in response to the averted vs direct gaze contrast, relative to the placebo group, in the left superior frontal gyrus.Reduced functional brain activation for the active group may represent less arousal in response to direct eye gaze, relative to the placebo group. Change in functional magnetic resonance imaging activation patterns may serve as a more sensitive metric and predictor of response to treatment when compared to cognitive and behavioral assessments. Our results suggest that donepezil may have an impact on brain functioning, but longer term follow-up and concomitant behavioral intervention may be required to demonstrate improvement in cognition and behavior.

  View details for DOI 10.1177/0269881119858304

  View details for PubMedID 31264943

• Genetic and environmental influences on cortico-striatal circuits in twins with autism. Genetic and environmental influences on cortico-striatal circuits in twins with autism. Hegarty, J. P., Lazzeroni, L. C., Raman, M. M., Hallmayer, J. C., Cleveland, S. C., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2019

  View details for DOI 10.1503/jpn.190030

• Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies NEUROPSYCHOPHARMACOLOGY Green, T., Flash, S., Reiss, A. L. 2019; 44 (1): 9–21

  View details for DOI 10.1038/s41386-018-0153-2

  View details for Web of Science ID 000450178000003

• Closing the Gender Gap in Fragile X Syndrome: Review of Females with Fragile X Syndrome and Preliminary Research Findings BRAIN SCIENCES Bartholomay, K. L., Lee, C. H., Bruno, J. L., Lightbody, A. A., Reiss, A. L. 2019; 9 (1)

  View details for DOI 10.3390/brainsci9010011

  View details for Web of Science ID 000457169900010

• Inter-Brain Synchrony in Mother-Child Dyads During Cooperation: An fNIRS Hyperscanning Study. Neuropsychologia Miller, J. G., Vrticka, P., Cui, X., Shrestha, S., Hosseini, S. M., Baker, J. M., Reiss, A. L. 2018

  Abstract

  Coordinated brain activity between individuals, or inter-brain synchrony, has been shown to increase during cooperation and correlate with cooperation success. However, few studies have examined parent-child inter-brain synchrony and whether it is associated with meaningful aspects of the parent-child relationship. Here, we measured inter-brain synchrony in the right prefrontal (PFC) and temporal cortices in mother-child dyads while they engaged in a cooperative and independent task. We tested whether inter-brain synchrony in mother-child dyads (1) increases during cooperation, (2) differs in mother-son versus mother-daughter dyads, and (3) is related to cooperation performance and the attachment relationship. Overall inter-brain synchrony in the right hemisphere, and the right dorsolateral and frontopolar PFC in particular, was higher during cooperation. Mother-son dyads showed less inter-brain synchrony during the independent task and a stronger increase in synchrony in response to cooperation than mother-daughter dyads. Lastly, we did not find strong evidence for links between inter-brain synchrony and child attachment. Mother-child cooperation may increase overall inter-brain synchrony, although differently for mother-son versus mother-daughter dyads. More research is needed to better understand the potential role of overall inter-brain synchrony in mother-child cooperation, and the potential link between inter-brain synchrony and attachment.

  View details for PubMedID 30594570

• The Utility of fNIRS for Measuring Cortical Activity during Cycling-Exercise. Medicine and science in sports and exercise Tempest, G. D., Reiss, A. L. 2018

  Abstract

  PURPOSE: Real-time measurement of dynamic brain activity during exercise can help advance our understanding of the role of exercise upon brain health and function. In exercise science, functional near infrared spectroscopy (fNIRS) has primarily been used to measure the effects of exercise intensity upon hemodynamic responses in the cerebral cortex. However, the utility of fNIRS to measure discreet hemodynamic responses underlying brain activation associated with motor and cognitive function during exercise has not been systematically examined. Here, we compared brain activation associated with a motor and cognitive task at rest and during cycling-exercise at different intensities.METHODS: In separate sessions, 13 participants performed cycling-exercise on an indoor trainer at a low, moderate and high intensity. We measured changes in oxygenated (HbO) and deoxygenated (HbR) hemoglobin from prefrontal, parietal and motor regions of the cerebral cortex during a handgrip and working-memory task.RESULTS: Our findings show significant brain activation (a concurrent increase in HbO and decrease in HbR) in contralateral motor cortex during the handgrip task and left prefrontal cortex during the working-memory task at rest and during exercise at low, moderate and high (motor task HbO only) intensities (P < .05). Moreover, brain activation during the handgrip and working-memory tasks was not significantly different at rest and during exercise (P > .05).CONCLUSIONS: This study shows that fNIRS can robustly measure motor and cognitive task-evoked changes in brain activation during cycling-exercise comparable to rest. An implication of these new findings is that fNIRS can be used to determine real-time changes in brain function during exercise in healthy and clinical populations.

  View details for PubMedID 30570587

• Neuroanatomical abnormalities in fragile X syndrome during the adolescent and young adult years JOURNAL OF PSYCHIATRIC RESEARCH Sandoval, G. M., Shim, S., Hong, D. S., Garrett, A. S., Quintin, E., Marzelli, M. J., Patnaik, S., Lightbody, A. A., Reiss, A. L. 2018; 107: 138–44

  View details for DOI 10.1016/j.jpsychires.2018.10.014

  View details for Web of Science ID 000451490800020

• Neuroanatomical abnormalities in fragile X syndrome during the adolescent and young adult years. Journal of psychiatric research Sandoval, G. M., Shim, S., Hong, D. S., Garrett, A. S., Quintin, E., Marzelli, M. J., Patnaik, S., Lightbody, A. A., Reiss, A. L. 2018; 107: 138–44

  Abstract

  Abnormal brain development and cognitive dysfunction have been reported both in children and in adults with fragile X syndrome (FXS). However, few studies have examined neuroanatomical abnormalities in FXS during adolescence. In this study we focus on adolescent subjects with FXS (N = 54) as compared to age- and sex-matched subjects with idiopathic intellectual disability (Comparison Group) (N = 32), to examine neuroanatomical differences during this developmental period. Brain structure was assessed with voxel-based morphometry and independent groups t-test in SPM8 software. Results showed that the FXS group, relative to the comparison group, had significantly larger gray matter volume (GMV) in only one region: the bilateral caudate nucleus, but have smaller GMV in several regions including bilateral medial frontal, pregenual cingulate, gyrus rectus, insula, and superior temporal gyrus. Group differences also were noted in white matter regions. Within the FXS group, lower FMRP levels were associated with less GMV in several regions including cerebellum and gyrus rectus, and less white matter volume (WMV) in pregenual cingulate, middle frontal gyrus, and other regions. Lower full scale IQ within the FXS group was associated with larger right caudate nucleus GMV. In conclusion, adolescents and young adults with FXS demonstrate neuroanatomical abnormalities consistent with those previously reported in children and adults with FXS. These brain variations likely result from reduced FMRP during early neurodevelopment and mediate downstream deleterious effects on cognitive function.

  View details for PubMedID 30408626

• Androgen treatment effects on hippocampus structure in boys with Klinefelter syndrome. Psychoneuroendocrinology Foland-Ross, L. C., Ross, J. L., Reiss, A. L. 2018; 100: 223–28

  Abstract

  Klinefelter syndrome (KS, 47,XXY) is the most common sex chromosome aneuploidy in males. A variety of complex clinical needs is associated with KS, including physical, cognitive and psychosocial impairments. Standard treatment for KS consists of androgen replacement therapy in adolescence to offset testosterone deficiency. Such treatment has a beneficial effect on the physical and behavioral manifestations of this syndrome. Whether androgen supplementation has a significant influence on the brain, however, is unknown. In the current study, we examined regional gray matter volume in boys with KS to assess whether treatment with oxandrolone, a synthetic hormone analog of testosterone, was associated with structural changes in the brain. Specifically, we focused our investigation on the hippocampus, given (1) its involvement in KS, and (2) the high concentration of androgen receptors found in this region. Structural magnetic resonance imaging data was acquired from a subsample of boys who completed a 2-year double-blind clinical trial in which patients were randomized to treatment with oxandrolone or to placebo, as well as from a sample of typically developing (TD) boys. Group differences in hippocampal volume were examined. A significant main effect of group was observed. Pairwise comparisons indicated smaller hippocampal volume in the placebo group relative to the oxandrolone group, as well as smaller volume in the placebo group relative to the TD control group. No difference in volume was observed between the treatment and TD groups. Moreover, across KS subgroups, a significant positive association was observed between hippocampus volume and performance on a spatial memory task, indicating treatment-based changes in brain structure may underlie cognitive change. These findings confirm prior reports implicating a role of the hippocampus in KS and are important in extending previous research by demonstrating a significant effect of androgens on brain structure.

  View details for PubMedID 30388596

• Mind over motor mapping: Driver response to changing vehicle dynamics HUMAN BRAIN MAPPING Bruno, J. L., Baker, J. M., Gundran, A., Harbott, L. K., Stuart, Z., Piccirilli, A. M., Hosseini, S., Gerdes, J., Reiss, A. L. 2018; 39 (10): 3915–27

  View details for DOI 10.1002/hbm.24220

  View details for Web of Science ID 000443941200008

• INTEGRATING CLINICAL GENETICS INTO CHILD PSYCHIATRY: LESSONS FROM NEUROGENETICS CLINICS Schneider, B., Reiss, A. L., Bernier, R. ELSEVIER SCIENCE INC. 2018: S15

  View details for DOI 10.1016/j.jaac.2018.07.063

  View details for Web of Science ID 000544087500048

• X-Chromosome Effects on Attention Networks: Insights from Imaging Resting-State Networks in Turner Syndrome CEREBRAL CORTEX Green, T., Saggar, M., Ishak, A., Hong, D. S., Reiss, A. L. 2018; 28 (9): 3176–83

  View details for DOI 10.1093/cercor/bhx188

  View details for Web of Science ID 000443545600008

• Longitudinal assessment of hippocampus structure in children with type 1 diabetes PEDIATRIC DIABETES Foland-Ross, L. C., Reiss, A. L., Mazaika, P. K., Mauras, N., Weinzimer, S. A., Aye, T., Tansey, M. J., White, N. H., Diabet Res Children Network DirecN 2018; 19 (6): 1116–23

  View details for DOI 10.1111/pedi.12683

  View details for Web of Science ID 000440556000011

• Neural correlates of liraglutide effects in persons at risk for Alzheimer's Disease. Behavioural brain research Watson, K. T., Wroolie, T. E., Tong, G., Foland-Ross, L. C., Frangou, S., Singh, M., McIntyre, R., Roat-Shumway, S., Myoraku, A., Reiss, A. L., Rasgon, N. L. 2018

  Abstract

  Insulin resistance (IR) is a metabolic state preceding development of type 2 diabetes (DM2), cardiovascular disease, and neurodegenerative disorders, including Alzheimer's Disease (AD). Liraglutide, a glucagon-like peptide-1 (GLP) agonist, is an insulin-sensitizing agent with neuroprotective properties, as shown in animal studies. The purpose of this double-blinded, placebo-controlled study was to examine the neural effects of administration of liraglutide in cognitively normal late middle-aged individuals with subjective cognitive complaints (half of subjects had family history of AD). Seed-based resting state connectivity using functional magnetic resonance imaging (fMRI) conducted before and after 12 weeks of liraglutide treatment or placebo. Neuropsychological testing was conducted before and after treatment to determine whether there were any potential behavioral correlates to neural changes.RESULTS: At baseline (time point 1), higher fasting plasma glucose (FPG) was associated with decreased connectivity between bilateral hippocampal and anterior medial frontal structures. At time point 2, we observed significant improvement in intrinsic connectivity within the default mode network (DMN) in the active group relative to placebo. There were no detectable cognitive differences between study groups after this duration of treatment. To our knowledge, this is the first placebo-controlled study to report neural effects of liraglutide in a middle-aged population with subjective cognitive complaints. Larger and longer duration studies are warranted to determine whether liraglutide has neuroprotective benefit for individuals at risk for AD.

  View details for PubMedID 30099030

• fNIRS measurement of cortical activation and functional connectivity during a visuospatial working memory task PLOS ONE Baker, J. M., Bruno, J. L., Gundran, A., Hosseini, S., Reiss, A. L. 2018; 13 (8)

  View details for DOI 10.1371/journal.pone.0201486

  View details for Web of Science ID 000440778600047

• PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention. Cerebral cortex (New York, N.Y. : 1991) Johnson, E. M., Ishak, A. D., Naylor, P. E., Stevenson, D. A., Reiss, A. L., Green, T. 2018

  Abstract

  The Ras-MAPK pathway has an established role in neural development and synaptic signaling. Mutations in this pathway are associated with a collection of neurodevelopmental syndromes, Rasopathies; among these, Noonan syndrome (NS) is the most common (1:2000). Prior research has focused on identifying genetic mutations and cellular mechanisms of the disorder, however, effects of NS on the human brain remain unknown. Here, imaging and cognitive data were collected from 12 children with PTPN11-related NS, ages 4.0-11.0 years (8.98 ± 2.33) and 12 age- and sex-matched typically developing controls (8.79 ± 2.17). We observe reduced gray matter volume in bilateral corpus striatum (Cohen's d = -1.0:-1.3), reduced surface area in temporal regions (d = -1.8:-2.2), increased cortical thickness in frontal regions (d = 1.2-1.3), and reduced cortical thickness in limbic regions (d = -1.6), including limbic structures integral to the circuitry of the hippocampus. Further, we find high levels of inattention, hyperactivity, and memory deficits in children with NS. Taken together, these results identify effects of NS on specific brain regions associated with ADHD and learning in children. While our research lays the groundwork for elucidating the neural and behavioral mechanisms of NS, it also adds an essential tier to understanding the Ras-MAPK pathway's role in human brain development.

  View details for PubMedID 30059958

• Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Green, T., Flash, S., Reiss, A. L. 2018

  Abstract

  The study of sexual dimorphism in psychiatric and neurodevelopmental disorders is challenging due to the complex interplay of diverse biological, psychological, and social factors. Males are more susceptible to neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and attention-deficit activity disorder. Conversely, after puberty, females are more prone to major depressive disorder and anxiety disorders compared to males. One major biological factor contributing to sex differences is the sex chromosomes. First, the X and Y chromosomes have unique and specific genetic effects as well as downstream gonadal effects. Second, males have one X chromosome and one Y chromosome, while females have two X chromosomes. Thus, sex chromosome constitution also differs between the sexes. Due to this complexity, determining genetic and downstream biological influences on sexual dimorphism in humans is challenging. Sex chromosome aneuploidies, such as Turner syndrome (X0) and Klinefelter syndrome (XXY), are common genetic conditions in humans. The study of individuals with sex chromosome aneuploidies provides a promising framework for studying sexual dimorphism in neurodevelopmental and psychiatric disorders. Here we will review and contrast four syndromes caused by variation in the number of sex chromosomes: Turner syndrome, Klinefelter syndrome, XYY syndrome, and XXX syndrome. Overall we describe an increased rate of attention-deficit hyperactivity disorder and autism spectrum disorder, along with the increased rates of major depressive disorder and anxiety disorders in one or more of these conditions. In addition to contributing unique insights about sexual dimorphism in neuropsychiatric disorders, awareness of the increased risk of neurodevelopmental and psychiatric disorders in sex chromosome aneuploidies can inform appropriate management of these common genetic disorders.

  View details for PubMedID 30127341

• Persistence of abnormalities in white matter in children with type 1 diabetes DIABETOLOGIA Fox, L. A., Hershey, T., Mauras, N., Arbelaez, A., Tamborlane, W. V., Buckingham, B., Tsalikian, E., Englert, K., Raman, M., Jo, B., Shen, H., Reiss, A., Mazaika, P., Diabet Res Children Network Direct 2018; 61 (7): 1538–47

  Abstract

  Prior studies suggest white matter growth is reduced and white matter microstructure is altered in the brains of young children with type 1 diabetes when compared with brains of non-diabetic children, due in part to adverse effects of hyperglycaemia. This longitudinal observational study examines whether dysglycaemia alters the developmental trajectory of white matter microstructure over time in young children with type 1 diabetes.One hundred and eighteen children, aged 4 to <10 years old with type 1 diabetes and 58 age-matched, non-diabetic children were studied at baseline and 18 months, at five Diabetes Research in Children Network clinical centres. We analysed longitudinal trajectories of white matter using diffusion tensor imaging. Continuous glucose monitoring profiles and HbA1c levels were obtained every 3 months.Axial diffusivity was lower in children with diabetes at baseline (p = 0.022) and at 18 months (p = 0.015), indicating that differences in white matter microstructure persist over time in children with diabetes. Within the diabetes group, lower exposure to hyperglycaemia, averaged over the time since diagnosis, was associated with higher fractional anisotropy (p = 0.037). Fractional anisotropy was positively correlated with performance (p < 0.002) and full-scale IQ (p < 0.02).These results suggest that hyperglycaemia is associated with altered white matter development, which may contribute to the mild cognitive deficits in this population.

  View details for PubMedID 29654376

  View details for PubMedCentralID PMC5991628

• Large Changes in Brain Volume Observed in an Asymptomatic Young Child With Type 1 Diabetes DIABETES CARE Mazaika, P. K., Aye, T., Reiss, A. L., Buckingham, B. A. 2018; 41 (7): 1535–37

  View details for DOI 10.2337/dc17-2503

  View details for Web of Science ID 000435926000040

• Longitudinal assessment of hippocampus structure in children with type 1 diabetes. Pediatric diabetes Foland-Ross, L. C., Reiss, A. L., Mazaika, P. K., Mauras, N., Weinzimer, S. A., Aye, T., Tansey, M. J., White, N. H., Diabetes Research in Children Network (DirecNet) 2018

  Abstract

  The extant literature finds that children with type 1 diabetes mellitus (T1D) experience mild cognitive alterations compared to healthy age-matched controls. The neural basis of these cognitive differences is unclear but may relate in part to the effects of dysglycemia on the developing brain. We investigated longitudinal changes in hippocampus volume in young children with early-onset T1D. Structural magnetic resonance imaging data were acquired from 142 children with T1D and 65 age-matched control subjects (4-10years of age at study entry) at 2 time points, 18 months apart. The effects of diabetes and glycemic exposure on hippocampal volume and growth were examined. Results indicated that although longitudinal hippocampus growth did not differ between children with T1D and healthy control children, slower growth of the hippocampus was associated with both increased exposure to hyperglycemia (interval HbA1c) and greater glycemic variability (MAGE) in T1D. These observations indicate that the current practice of tolerating some hyperglycemia to minimize the risk of hypoglycemia in young children with T1D may not be optimal for the developing brain. Efforts that continue to assess the factors influencing neural and cognitive development in children with T1D will be critical in minimizing the deleterious effects of diabetes.

  View details for PubMedID 29675980

• Large Changes in Brain Volume Observed in an Asymptomatic Young Child With Type 1 Diabetes. Diabetes care Mazaika, P. K., Aye, T., Reiss, A. L., Buckingham, B. A. 2018; 41 (7): 1535–37

  View details for PubMedID 29934482

• Impact of Early Diabetic Ketoacidosis on the Developing Brain. Diabetes care Aye, T. n., Mazaika, P. K., Mauras, N. n., Marzelli, M. J., Shen, H. n., Hershey, T. n., Cato, A. n., Weinzimer, S. A., White, N. H., Tsalikian, E. n., Jo, B. n., Reiss, A. L. 2018

  Abstract

  This study examined whether a history of diabetic ketoacidosis (DKA) is associated with changes in longitudinal cognitive and brain development in young children with type 1 diabetes.Cognitive and brain imaging data were analyzed from 144 children with type 1 diabetes, ages 4 to <10 years, who participated in an observational study of the Diabetes Research in Children Network (DirecNet). Participants were grouped according to history of DKA severity (none/mild or moderate/severe). Each participant had unsedated MRI scans and cognitive testing at baseline and 18 months.In 48 of 51 subjects, the DKA event occurred at the time of onset, at an average of 2.9 years before study entry. The moderate/severe DKA group gained more total and regional white and gray matter volume over the observed 18 months compared with the none/mild group. When matched by age at time of enrollment and average HbA1c during the 18-month interval, participants who had a history of moderate/severe DKA compared with none/mild DKA were observed to have significantly lower Full Scale Intelligence Quotient scores, cognitive performance on the Detectability and Commission subtests of the Conners' Continuous Performance Test II, and the Dot Locations subtest of the Children's Memory Scale.A single episode of moderate/severe DKA in young children at diagnosis is associated with lower cognitive scores and altered brain growth. Further studies are needed to assess whether earlier diagnosis of type 1 diabetes and prevention of DKA may reduce the long-term effect of ketoacidosis on the developing brain.

  View details for DOI 10.2337/dc18-1405

  View details for PubMedID 30573652

• fNIRS measurement of cortical activation and functional connectivity during a visuospatial working memory task. PloS one Baker, J. M., Bruno, J. L., Gundran, A., Hosseini, S. M., Reiss, A. L. 2018; 13 (8): e0201486

  Abstract

  Demands on visuospatial working memory are a ubiquitous part of everyday life. As such, significant efforts have been made to understand how the brain responds to these demands in real-world environments. Multiple brain imaging studies have highlighted a fronto-parietal cortical network that underlies visuospatial working memory, is modulated by cognitive load, and that appears to respond uniquely to encoding versus retrieval components. Furthermore, multiple studies have identified functional connectivity in regions of the fronto-parietal network during working memory tasks. Together, these findings have helped outline important aspects of the neural architecture that underlies visuospatial working memory. Here, we provide results from the first fNIRS-based investigation of fronto-parietal signatures of cortical activation and functional connectivity during a computer-based visuospatial working memory task. Our results indicate that the local maxima of cortical activation and functional coherence do not necessarily overlap spatially, and that cortical activation is significantly more susceptible to task-specific demands compared to functional connectivity. These results highlight important and novel information regarding neurotypical signatures of cortical activation and functional connectivity during visuospatial working memory. Our findings also demonstrate the utility of fNIRS for interrogating these cognitive processes.

  View details for PubMedID 30071072

• Creativity in the Twenty-first Century: The Added Benefit of Training and Cooperation DESIGN THINKING RESEARCH: MAKING DISTINCTIONS: COLLABORATION VERSUS COOPERATION Mayseless, N., Saggar, M., Hawthorne, G., Reiss, A., Plattner, H., Meinel, C., Leifer, L. 2018: 239–49

  View details for DOI 10.1007/978-3-319-60967-6_12

  View details for Web of Science ID 000432741300013

• Mind over motor mapping: Driver response to changing vehicle dynamics. Human brain mapping Bruno, J. L., Baker, J. M., Gundran, A. n., Harbott, L. K., Stuart, Z. n., Piccirilli, A. M., Hosseini, S. M., Gerdes, J. C., Reiss, A. L. 2018

  Abstract

  Improvements in vehicle safety require understanding of the neural systems that support the complex, dynamic task of real-world driving. We used functional near infrared spectroscopy (fNIRS) and pupilometry to quantify cortical and physiological responses during a realistic, simulated driving task in which vehicle dynamics were manipulated. Our results elucidate compensatory changes in driver behavior in response to changes in vehicle handling. We also describe associated neural and physiological responses under different levels of mental workload. The increased cortical activation we observed during the late phase of the experiment may indicate motor learning in prefrontal-parietal networks. Finally, relationships among cortical activation, steering control, and individual personality traits suggest that individual brain states and traits may be useful in predicting a driver's response to changes in vehicle dynamics. Results such as these will be useful for informing the design of automated safety systems that facilitate safe and supportive driver-car communication.

  View details for PubMedID 29885097

• Anomalous prefrontal-limbic activation and connectivity in youth at high risk for bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Chang, K., Garrett, A., Kelley, R., Howe, M., Sanders, E., Acquaye, T., Bararpour, L., Li, S., Singh, M., Jo, B., Hallmayer, J., Reiss, A. 2017; 222: 7–13

  Abstract

  Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported in pediatric bipolar disorder (BD). However, it is less clear whether these abnormalities exist prior to onset of mania, thus representing a biomarker predicting development of BD.We examined brain activation in 50 youth at high risk for BD (HR-BD), compared with 29 age- and gender-matched healthy control (HC) subjects. HR-BD was defined as having a parent with BD, as well as current mood or attentiondeficit/ hyperactivity disorder (ADHD) symptoms, or a history of at least one depressive episode. FMRI data were collected during an implicit emotion perception task using facial expression stimuli. Activation to fearful faces versus calm faces was compared between HR-BD and HC groups, including analyses of functional connectivity, and comparison of allele subgroups of the serotonin transporter (5-HTTLPR) gene.While viewing fearful versus calm faces, HR-BD youth had significantly greater activation than HC youth in the right amygdala, ventrolateral prefrontal cortex (VLPFC), superior frontal cortex, cerebellum, and lingual gyrus. HR-BD youth, relative to HC youth, had greater functional connectivity between the right amygdala and the VLPFC as well as visual cortical regions Within the HR-BD group, youth with the s-allele had a trend for greater activation in the right amygdala and subgenual cingulate cortex CONCLUSIONS: Similar to youth with BD, youth at high risk for BD have greater activation than healthy controls in the amygdala and ventrolateral prefrontal cortex in response to fearful faces, as well greater functional connectivity between these regions. HR-BD youth with the s-allele of the 5-HTTLPR gene may be at greatest risk for developing BD.

  View details for PubMedID 28667891

• Portable Functional Neuroimaging as an Environmental Epidemiology Tool: A How-To Guide for the Use of fNIRS in Field Studies ENVIRONMENTAL HEALTH PERSPECTIVES Baker, J. M., Rojas-Valverde, D., Gutierrez, R., Winkler, M., Fuhrimann, S., Eskenazi, B., Reiss, A. L., Moral, A. M. 2017; 125 (9): 094502

  Abstract

  The widespread application of functional neuroimaging within the field of environmental epidemiology has the potential to greatly enhance our understanding of how environmental toxicants affect brain function. Because many epidemiological studies take place in remote and frequently changing environments, it is necessary that the primary neuroimaging approach adopted by the epidemiology community be robust to many environments, easy to use, and, preferably, mobile. Here, we outline our use of functional near-infrared spectroscopy (fNIRS) to collect functional brain imaging data from Costa Rican farm workers enrolled in an epidemiological study on the health effects of chronic pesticide exposure. While couched in this perspective, we focus on the methodological considerations that are necessary to conduct a mobile fNIRS study in a diverse range of environments. Thus, this guide is intended to be generalizable to all research scenarios and projects in which fNIRS may be used to collect functional brain imaging data in epidemiological field surveys. https://doi.org/10.1289/EHP2049.

  View details for PubMedID 28937962

  View details for PubMedCentralID PMC5915206

• Neural, physiological, and behavioral correlates of visuomotor cognitive load. Scientific reports Hosseini, S. M., Bruno, J. L., Baker, J. M., Gundran, A., Harbott, L. K., Gerdes, J. C., Reiss, A. L. 2017; 7 (1): 8866

  Abstract

  Visuomotor ability is quite crucial for everyday functioning, particularly in driving and sports. While there is accumulating evidence regarding neural correlates of visuomotor transformation, less is known about the brain regions that accommodate visuomotor mapping under different cognitive demands. We concurrently measured cortical activity and pupillary response, using functional near infrared spectroscopy (fNIRS) and eye-tracking glasses, to examine the neural systems linked to pupil dilation under varying cognitive demands. Twenty-three healthy adults performed two sessions of a navigation task, in which the cognitive load was manipulated by either reversing the visuomotor mapping or increasing the speed of the moving object. We identified a region in the right superior parietal lobule that responded to both types of visuomotor load and its activity was associated with larger pupillary response and better performance in the task. Our multimodal analyses suggest that activity in this region arises from the need for increased attentional effort and alertness for visuomotor control and is an ideal candidate for objective measurement of visuomotor cognitive load. Our data extend previous findings connecting changes in pupil diameter to neural activity under varying cognitive demand and have important implications for examining brain-behavior associations in real-world tasks such as driving and sports.

  View details for DOI 10.1038/s41598-017-07897-z

  View details for PubMedID 28821719

  View details for PubMedCentralID PMC5562732

• Updated report on tools to measure outcomes of clinical trials in fragile X syndrome JOURNAL OF NEURODEVELOPMENTAL DISORDERS Budimirovic, D. B., Berry-Kravis, E., Erickson, C. A., Hall, S. S., Hessl, D., Reiss, A. L., King, M. K., Abbeduto, L., Kaufmann, W. E. 2017; 9: 14

  Abstract

  Fragile X syndrome (FXS) has been the neurodevelopmental disorder with the most active translation of preclinical breakthroughs into clinical trials. This process has led to a critical assessment of outcome measures, which resulted in a comprehensive review published in 2013. Nevertheless, the disappointing outcome of several recent phase III drug trials in FXS, and parallel efforts at evaluating behavioral endpoints for trials in autism spectrum disorder (ASD), has emphasized the need for re-assessing outcome measures and revising recommendations for FXS.After performing an extensive database search (PubMed, Food and Drug Administration (FDA)/National Institutes of Health (NIH)'s www.ClinicalTrials.gov, etc.) to determine progress since 2013, members of the Working Groups who published the 2013 Report evaluated the available outcome measures for FXS and related neurodevelopmental disorders using the COSMIN grading system of levels of evidence. The latter has also been applied to a British survey of endpoints for ASD. In addition, we also generated an informal classification of outcome measures for use in FXS intervention studies as instruments appropriate to detect shorter- or longer-term changes.To date, a total of 22 double-blind controlled clinical trials in FXS have been identified through www.ClinicalTrials.gov and an extensive literature search. The vast majority of these FDA/NIH-registered clinical trials has been completed between 2008 and 2015 and has targeted the core excitatory/inhibitory imbalance present in FXS and other neurodevelopmental disorders. Limited data exist on reliability and validity for most tools used to measure cognitive, behavioral, and other problems in FXS in these trials and other studies. Overall, evidence for most tools supports a moderate tool quality grading. Data on sensitivity to treatment, currently under evaluation, could improve ratings for some cognitive and behavioral tools. Some progress has also been made at identifying promising biomarkers, mainly on blood-based and neurophysiological measures.Despite the tangible progress in implementing clinical trials in FXS, the increasing data on measurement properties of endpoints, and the ongoing process of new tool development, the vast majority of outcome measures are at the moderate quality level with limited information on reliability, validity, and sensitivity to treatment. This situation is not unique to FXS, since reviews of endpoints for ASD have arrived at similar conclusions. These findings, in conjunction with the predominance of parent-based measures particularly in the behavioral domain, indicate that endpoint development in FXS needs to continue with an emphasis on more objective measures (observational, direct testing, biomarkers) that reflect meaningful improvements in quality of life. A major continuous challenge is the development of measurement tools concurrently with testing drug safety and efficacy in clinical trials.

  View details for PubMedID 28616097

  View details for PubMedCentralID PMC5467057

• Multivariate Investigation of Brain and Behavioral Outcomes in Individuals with FMR1 Full Mutation Bruno, J., Hosseini, H., Reiss, A. ELSEVIER SCIENCE INC. 2017: S299–S300

  View details for DOI 10.1016/j.biopsych.2017.02.806

  View details for Web of Science ID 000400348700736

• A Novel fNIRS-Based Neurocognitive Intervention for Targeted Enhancement of Executive Function Network in ADHD Hosseini, H., Tam, G., Gosse, L., Reiss, A. ELSEVIER SCIENCE INC. 2017: S258–S259

  View details for DOI 10.1016/j.biopsych.2017.02.508

  View details for Web of Science ID 000400348700635

• Inhibited Temperament and Hippocampal Volume in Offspring of Parents with Bipolar Disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Kim, E., Garrett, A., Boucher, S., Park, M., Howe, M., Sanders, E., Kelley, R. G., Reiss, A. L., Chang, K. D., Singh, M. K. 2017; 27 (3): 258-265

  Abstract

  Prior studies have suggested that inhibited temperament may be associated with an increased risk for developing anxiety or mood disorder, including bipolar disorder. However, the neurobiological basis for this increased risk is unknown. The aim of this study was to examine temperament in symptomatic and asymptomatic child offspring of parents with bipolar disorder (OBD) and to investigate whether inhibited temperament is associated with aberrant hippocampal volumes compared with healthy control (HC) youth.The OBD group consisted of 45 youth, 24 of whom had current psychiatric symptoms (OBD(+)s) and 21 without any psychiatric symptoms (OBD(-)s), and were compared with 24 HC youth. Temperament characteristics were measured by using the Revised Dimensions of Temperament Survey. Magnetic resonance imaging was used to measure hippocampal volumes. The association between temperament and hippocampal volumes was tested by using multiple regression analysis.Compared with the OBD(-)s group, the OBD(+)s group had significantly more inhibited temperament traits, less flexibility, more negative mood, and less regular rhythm in their daily routines. In contrast, the OBD(-)s group was more likely to approach novel situations compared with OBD(+)s or HC groups. Within the OBD(+)s group, a more inhibited temperament was associated with smaller right hippocampal volumes.In this study, symptomatic OBD were characterized by an inhibited temperament that was inversely correlated with hippocampal volume. Additional longitudinal studies are needed to determine whether inverse correlations between hippocampal volume and inhibited temperament represent early markers of risk for later developing bipolar disorder.

  View details for DOI 10.1089/cap.2016.0086

  View details for Web of Science ID 000399535900007

• Androgen Treatment Effects on Motor Function, Cognition, and Behavior in Boys with Klinefelter Syndrome. journal of pediatrics Ross, J. L., Kushner, H., Kowal, K., Bardsley, M., Davis, S., Reiss, A. L., Tartaglia, N., Roeltgen, D. 2017

  Abstract

  To examine the effects of early low-dose androgen on motor, cognitive, and behavioral function in prepubertal boys with Klinefelter syndrome (47,XXY).Double-blind trial of 84 boys, ages 4-12 years, randomized to oxandrolone (Ox; 0.06 mg/kg daily; n = 43) or placebo (Pl; n = 41) for 24 months. Standardized assessments were performed at baseline and every 12 months for 24 months evaluating motor, cognitive, and behavioral function.The 24-month outcomes were better in the Ox vs. Pl group on 1 of 5 primary endpoints (motor function/strength): Bruininks Visual-Motor scale (P = .005), without significant differences between the 2 groups for the other 4 components. Secondary analyses suggested improvement in the Ox vs. Pl group in the anxiety/depression (P = .03) and social problems (P = .01) scales on the Child Behavior Checklist, anxiety (P = .04) on the Piers Harris Self Concept Scale, and interpersonal problems (P = .02) on the Children's Depression Inventory, without significant differences in hyperactive or aggressive behaviors.This double-blind, randomized trial demonstrates that 24 months of childhood low-dose androgen treatment in boys with Klinefelter syndrome benefited 1 of 5 primary endpoints (visual-motor function). Secondary analyses demonstrated positive effects of androgen on aspects of psychosocial function (anxiety, depression, social problems), without significant effects on cognitive function, or hyperactive or aggressive behaviors.ClinicalTrials.gov: NCT00348946.

  View details for DOI 10.1016/j.jpeds.2017.02.036

  View details for PubMedID 28285751

• Altered Brain Network Segregation in Fragile X Syndrome Revealed by Structural Connectomics CEREBRAL CORTEX Bruno, J. L., Hosseini, S. M., Saggar, M., Quintin, E., Raman, M. M., Reiss, A. L. 2017; 27 (3): 2249-2259

  Abstract

  Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder, is associated with significant behavioral, social, and neurocognitive deficits. Understanding structural brain network topology in FXS provides an important link between neurobiological and behavioral/cognitive symptoms of this disorder. We investigated the connectome via whole-brain structural networks created from group-level morphological correlations. Participants included 100 individuals: 50 with FXS and 50 with typical development, age 11-23 years. Results indicated alterations in topological properties of structural brain networks in individuals with FXS. Significantly reduced small-world index indicates a shift in the balance between network segregation and integration and significantly reduced clustering coefficient suggests that reduced local segregation shifted this balance. Caudate and amygdala were less interactive in the FXS network further highlighting the importance of subcortical region alterations in the neurobiological signature of FXS. Modularity analysis indicates that FXS and typically developing groups' networks decompose into different sets of interconnected sub networks, potentially indicative of aberrant local interconnectivity in individuals with FXS. These findings advance our understanding of the effects of fragile X mental retardation protein on large-scale brain networks and could be used to develop a connectome-level biological signature for FXS.

  View details for DOI 10.1093/cercor/bhw055

  View details for Web of Science ID 000397636600043

• Compensatory Hyperconnectivity in Developing Brains of Young Children With Type 1 Diabetes DIABETES Saggar, M., Tsalikian, E., Mauras, N., Mazaika, P., White, N. H., Weinzimer, S., Buckingham, B., Hershey, T., Reiss, A. L. 2017; 66 (3): 754-762

  Abstract

  Sustained dysregulation of blood glucose (hyper or hypoglycemia) associated with type 1 diabetes (T1D) has been linked to cognitive deficits and altered brain anatomy and connectivity. However, a significant gap remains with respect to how T1D affects spontaneous at-rest connectivity in young developing brains. Here, using a large multi-site study, resting state functional Magnetic Resonance Imaging (rsfMRI) data were examined in young children with T1D (N=57, mean age=7.88 years; 27F) as compared to age-matched non-diabetic controls (N=26, mean age=7.43 years; 14F). Using both model-driven seed-based analysis and model-free independent component analysis (ICA) and controlling for age, site and sex, converging results were obtained suggesting increased connectivity in young children with T1D as compared to non-diabetic controls. Further, increased connectivity in children with T1D was observed to be positively associated with cognitive functioning. The observed positive association of connectivity with cognitive functioning in T1D, without overall group differences in cognitive function, suggests a putative compensatory role of hyper-intrinsic connectivity in the brain in children with this condition. Altogether, our study attempts to fill a critical gap in knowledge regarding how dysglycemia in T1D might affect the brain's intrinsic connectivity at very young ages.

  View details for DOI 10.2337/db16-0414

  View details for Web of Science ID 000394634100020

• Optical-imaging-based neurofeedback to enhance therapeutic intervention in adolescents with autism: methodology and initial data. Neurophotonics Liu, N., Cliffer, S., Pradhan, A. H., Lightbody, A., Hall, S. S., Reiss, A. L. 2017; 4 (1): 011003-?

  Abstract

  Impaired facial processing may contribute to social dysfunction in certain individuals with autism spectrum disorder (ASD). Prior studies show that electroencephalogram-based and functional magnetic resonance imaging-based neurofeedback might help some individuals with ASD learn to modulate regional brain activity and thus reduce symptoms. Here, we report for the first time the feasibility of employing functional near-infrared spectroscopy (fNIRS)-based neurofeedback training in children with ASD. We developed a method to study physiological self-regulation of oxy-hemoglobin using real-time feedback. The paradigm is illustrated with initial data from four subjects who engaged in a facial-identity recognition training program during which an implicit reinforcement was given based on the participant's brain activity and behavioral performance. Two participants had a confirmed diagnosis of ASD, and the other two were typically developing (TD). One participant with ASD and one TD participant received real-feedback (real-FB) during the training, whereas the other two received sham-feedback (sham-FB). After five training sessions, the subjects who received real-FB showed more improvement in facial recognition performance compared with those receiving sham-FB, particularly in the participant with ASD. These results suggest fNIRS-based neurofeedback could enhance therapeutic intervention in children with ASD.

  View details for DOI 10.1117/1.NPh.4.1.011003

  View details for PubMedID 27570790

  View details for PubMedCentralID PMC4981748

• Neural, physiological, and behavioral correlates of visuomotor cognitive load Scientific Reports Hosseini, S., Bruno, J. L., Baker, J. M., Gundran, A., Harbott, L. K., Gerdes, J., Reiss, A. L. 2017: 8866

  Abstract

  Visuomotor ability is quite crucial for everyday functioning, particularly in driving and sports. While there is accumulating evidence regarding neural correlates of visuomotor transformation, less is known about the brain regions that accommodate visuomotor mapping under different cognitive demands. We concurrently measured cortical activity and pupillary response, using functional near infrared spectroscopy (fNIRS) and eye-tracking glasses, to examine the neural systems linked to pupil dilation under varying cognitive demands. Twenty-three healthy adults performed two sessions of a navigation task, in which the cognitive load was manipulated by either reversing the visuomotor mapping or increasing the speed of the moving object. We identified a region in the right superior parietal lobule that responded to both types of visuomotor load and its activity was associated with larger pupillary response and better performance in the task. Our multimodal analyses suggest that activity in this region arises from the need for increased attentional effort and alertness for visuomotor control and is an ideal candidate for objective measurement of visuomotor cognitive load. Our data extend previous findings connecting changes in pupil diameter to neural activity under varying cognitive demand and have important implications for examining brain-behavior associations in real-world tasks such as driving and sports.

  View details for DOI 10.1038/s41598-017-07897-z

  View details for PubMedCentralID PMC5562732

• X-Chromosome Effects on Attention Networks: Insights from Imaging Resting-State Networks in Turner Syndrome. Cerebral cortex (New York, N.Y. : 1991) Green, T. n., Saggar, M. n., Ishak, A. n., Hong, D. S., Reiss, A. L. 2017: 1–8

  Abstract

  Attention deficit hyperactivity disorder (ADHD) is strongly affected by sex, but sex chromosomes' effect on brain attention networks and cognition are difficult to examine in humans. This is due to significant etiologic heterogeneity among diagnosed individuals. In contrast, individuals with Turner syndrome (TS), who have substantially increased risk for ADHD symptoms, share a common genetic risk factor related to the absence of the X-chromosome, thus serving as a more homogeneous genetic model. Resting-state functional MRI was employed to examine differences in attention networks between girls with TS (n = 40) and age- sex- and Tanner-matched controls (n = 33). We compared groups on resting-state functional connectivity measures from data-driven independent components analysis (ICA) and hypothesis-based seed analysis. Using ICA, reduced connectivity was observed in both frontoparietal and dorsal attention networks. Similarly, using seeds in the bilateral intraparietal sulcus (IPS), reduced connectivity was observed between IPS and frontal and cerebellar regions. Finally, we observed a brain-behavior correlation between IPS-cerebellar connectivity and cognitive attention measures. These findings indicate that X-monosomy contributes affects to attention networks and cognitive dysfunction that might increase risk for ADHD. Our findings not only have clinical relevance for girls with TS, but might also serve as a biological marker in future research examining the effects of the intervention that targets attention skills.

  View details for PubMedID 28981595

• Multi-Table Differential Correlation Analysis of Neuroanatomical and Cognitive Interactions in Turner Syndrome. Neuroinformatics Seiler, C. n., Green, T. n., Hong, D. n., Chromik, L. n., Huffman, L. n., Holmes, S. n., Reiss, A. L. 2017

  Abstract

  Girls and women with Turner syndrome (TS) have a completely or partially missing X chromosome. Extensive studies on the impact of TS on neuroanatomy and cognition have been conducted. The integration of neuroanatomical and cognitive information into one consistent analysis through multi-table methods is difficult and most standard tests are underpowered. We propose a new two-sample testing procedure that compares associations between two tables in two groups. The procedure combines multi-table methods with permutation tests. In particular, we construct cluster size test statistics that incorporate spatial dependencies. We apply our new procedure to a newly collected dataset comprising of structural brain scans and cognitive test scores from girls with TS and healthy control participants (age and sex matched). We measure neuroanatomy with Tensor-Based Morphometry (TBM) and cognitive function with Wechsler IQ and NEuroPSYchological tests (NEPSY-II). We compare our multi-table testing procedure to a single-table analysis. Our new procedure reports differential correlations between two voxel clusters and a wide range of cognitive tests whereas the single-table analysis reports no differences. Our findings are consistent with the hypothesis that girls with TS have a different brain-cognition association structure than healthy controls.

  View details for PubMedID 29270892

• A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder. Progress in neuro-psychopharmacology & biological psychiatry Hegarty, J. P., Gu, M. n., Spielman, D. M., Cleveland, S. C., Hallmayer, J. F., Lazzeroni, L. C., Raman, M. M., Frazier, T. W., Phillips, J. M., Reiss, A. L., Hardan, A. Y. 2017

  Abstract

  Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same-sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with (1)H magnetic resonance spectroscopy (MRS) utilizing a multi-voxel PRESS sequence and were referenced to creatine+phosphocreatine (tCr). N-acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n=47) compared to typically-developing (TD) controls (n=33), and this finding was confirmed in a sub-sample of co-twins discordant for ASD (n=11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate+glutamine (Glx) was also reduced in affected versus unaffected co-twins. Additionally, NAA and Glx appeared to be primarily genetically-mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain-specific.

  View details for PubMedID 28941767

• Incidental brain MRI findings in an autism twin study. Autism research Monterrey, J. C., Philips, J., Cleveland, S., Tanaka, S., Barnes, P., Hallmayer, J. F., Reiss, A. L., Lazzeroni, L. C., Hardan, A. Y. 2017; 10 (1): 113-120

  Abstract

  Brain magnetic resonance imaging (MRI) studies suggest the prevalence of asymptomatic "incidental" findings (IF) in autism spectrum disorder (ASD) is similar to that of neurotypically developing (NT) controls. However, given the causes of IF may include both genetic and environmental factors, a twin study would facilitate comparing brain IF between ASD and NT subjects. MRI scans were examined to assess the prevalence of brain IF in twin "case pairs" (at least one twin with diagnosis of ASD) and twin "control pairs" (NT). Fifty case pairs and thirty-two control pairs were analyzed. IF were found in 68% of subjects with ASD, 71% of unaffected ASD siblings, and in 58% of control subjects (P = 0.4). IF requiring clinical follow-up occurred more frequently in subjects with ASD compared to NT controls (17% vs. 5%, respectively; P = 0.02). The concordance rate of IF in twins was 83%. A mixed effects model found younger age, male sex, and "family environment" to be significantly associated with IF. There was no difference in the prevalence rate of IF between ASD subjects and NT controls. More IF required clinical follow-up in ASD subjects compared to NT controls. The prevalence rate of IF observed in this twin study was higher than rates previously reported in singleton studies. Our results suggest the shared environment of twins - perhaps in utero - increases the risk of brain IF. Brain MRI in the initial work-up of ASD may be indicated in twins, especially in males. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

  View details for DOI 10.1002/aur.1720

  View details for PubMedID 27874265

• Genetics of the HPA-Axis Predict Limbic Connectivity Patterns Sudheimer, K., Keller, J., O'Hara, R., Hantke, N., Karna, R., Duvio, D., Beaudreau, S., Heinemeyer, E., Reiss, A., Murphy, G., Gomez, R., Garrett, A., Tennakoon, L., Schatzberg, A. NATURE PUBLISHING GROUP. 2016: S164

  View details for Web of Science ID 000440365600297

• The cognitive developmental profile associated with fragile X syndrome: A longitudinal investigation of cognitive strengths and weaknesses through childhood and adolescence. Development and psychopathology Quintin, E., Jo, B., Hall, S. S., Bruno, J. L., Chromik, L. C., Raman, M. M., Lightbody, A. A., Martin, A., Reiss, A. L. 2016; 28 (4): 1457-1469

  Abstract

  Few studies have investigated developmental strengths and weaknesses within the cognitive profile of children and adolescents with fragile X syndrome (FXS), a single-gene cause of inherited intellectual impairment. With a prospective longitudinal design and using normalized raw scores (Z scores) to circumvent floor effects, we measured cognitive functioning of 184 children and adolescents with FXS (ages 6 to 16) using the Wechsler Scale of Intelligence for Children on one to three occasions for each participant. Participants with FXS received lower raw scores relative to the Wechsler Scale of Intelligence for Children normative sample across the developmental period. Verbal comprehension, perceptual organization, and processing speed Z scores were marked by a widening gap from the normative sample, while freedom from distractibility Z scores showed a narrowing gap. Key findings include a relative strength for verbal skills in comparison with visuospatial-constructive skills arising in adolescence and a discrepancy between working memory (weakness) and processing speed (strength) in childhood that diminishes in adolescence. Results suggest that the cognitive profile associated with FXS develops dynamically from childhood to adolescence. Findings are discussed within the context of aberrant brain morphology in childhood and maturation in adolescence. We argue that assessing disorder-specific cognitive developmental profiles will benefit future disorder-specific treatment research.

  View details for PubMedID 26648140

• Altered Integration of Structural Covariance Networks in Young Children With Type 1 Diabetes. Human brain mapping Hosseini, S. M., Mazaika, P., Mauras, N., Buckingham, B., Weinzimer, S. A., Tsalikian, E., White, N. H., Reiss, A. L. 2016; 37 (11): 4034-4046

  Abstract

  Type 1 diabetes mellitus (T1D), one of the most frequent chronic diseases in children, is associated with glucose dysregulation that contributes to an increased risk for neurocognitive deficits. While there is a bulk of evidence regarding neurocognitive deficits in adults with T1D, little is known about how early-onset T1D affects neural networks in young children. Recent data demonstrated widespread alterations in regional gray matter and white matter associated with T1D in young children. These widespread neuroanatomical changes might impact the organization of large-scale brain networks. In the present study, we applied graph-theoretical analysis to test whether the organization of structural covariance networks in the brain for a cohort of young children with T1D (N = 141) is altered compared to healthy controls (HC; N = 69). While the networks in both groups followed a small world organization-an architecture that is simultaneously highly segregated and integrated-the T1D network showed significantly longer path length compared with HC, suggesting reduced global integration of brain networks in young children with T1D. In addition, network robustness analysis revealed that the T1D network model showed more vulnerability to neural insult compared with HC. These results suggest that early-onset T1D negatively impacts the global organization of structural covariance networks and influences the trajectory of brain development in childhood. This is the first study to examine structural covariance networks in young children with T1D. Improving glycemic control for young children with T1D might help prevent alterations in brain networks in this population. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/hbm.23293

  View details for PubMedID 27339089

• Compensatory Hyper-Connectivity in Developing Brains of Young Children with Type 1 Diabetes. Diabetes Saggar, M., Tsalikian, E., Mauras, N., Mazaika, P., White, N. H., Weinzimer, S., Buckingham, B., Hershey, T., Reiss, A. L. 2016

  Abstract

  Sustained dysregulation of blood glucose (hyper or hypoglycemia) associated with type 1 diabetes (T1D) has been linked to cognitive deficits and altered brain anatomy and connectivity. However, a significant gap remains with respect to how T1D affects spontaneous at-rest connectivity in young developing brains. Here, using a large multi-site study, resting state functional Magnetic Resonance Imaging (rsfMRI) data were examined in young children with T1D (N=57, mean age=7.88 years; 27F) as compared to age-matched non-diabetic controls (N=26, mean age=7.43 years; 14F). Using both model-driven seed-based analysis and model-free independent component analysis (ICA) and controlling for age, site and sex, converging results were obtained suggesting increased connectivity in young children with T1D as compared to non-diabetic controls. Further, increased connectivity in children with T1D was observed to be positively associated with cognitive functioning. The observed positive association of connectivity with cognitive functioning in T1D, without overall group differences in cognitive function, suggests a putative compensatory role of hyper-intrinsic connectivity in the brain in children with this condition. Altogether, our study attempts to fill a critical gap in knowledge regarding how dysglycemia in T1D might affect the brain's intrinsic connectivity at very young ages.

  View details for PubMedID 27702833

• THALAMIC METABOLITE LEVELS AND SENSORY PROCESSING IN TWINS WITH AUTISM SPECTRUM DISORDER Hegarty, J. P., Gu, M., Spielman, D., Cleveland, S., Hallmayer, J. J., Lazzeroni, L. C., Raman, M., Monterrey, J., Frazier, T., Phillips, J. M., Reiss, A. L., Hardan, A. ELSEVIER SCIENCE INC. 2016: S102

  View details for DOI 10.1016/j.jaac.2016.09.011

  View details for Web of Science ID 000541964300345

• The Role of Executive Function in Independent Living Skills in Female Adolescents and Young Adults With Fragile X Syndrome. American journal on intellectual and developmental disabilities Martin, A., Quintin, E., Hall, S. S., Reiss, A. L. 2016; 121 (5): 448-460

  Abstract

  Fragile X syndrome (FXS) is associated with executive function (EF) and independent living skills (ILS) deficits. We examined the role of childhood EF in ILS during adolescence/early adulthood in females with FXS and two comparison groups in the same age range (matched for IQ [IQ/Age group] and with another genetic condition, Turner syndrome [TS group]). EF and ILS were significantly higher for the FXS group than the IQ/Age group but did not differ from the TS group. For the FXS group, age and EF were significant predictors of ILS during adolescence/early adulthood, but there were no statistically significant longitudinal associations between EF and ILS. Our findings suggest that impairments in EF may have a significant effect on ILS in FXS.

  View details for DOI 10.1352/1944-7558-121.5.448

  View details for PubMedID 27611354

• Moving Toward Integrative, Multidimensional Research in Modern Psychiatry: Lessons Learned From Fragile X Syndrome BIOLOGICAL PSYCHIATRY Fung, L. K., Reiss, A. L. 2016; 80 (2): 100-111

  Abstract

  The field of psychiatry is approaching a major inflection point. The basic science behind cognition, emotion, behavior, and social processes has been advancing rapidly in the past 20 years. However, clinical research supporting the classification system in psychiatry has not kept up with these scientific advances. To begin organizing the basic science of psychiatry in a comprehensive manner, we begin by selecting fragile X syndrome, a neurogenetic disease with cognitive-behavioral manifestations, to illustrate key concepts in an integrative, multidimensional model. Specifically, we describe key genetic and molecular mechanisms (e.g., gamma-aminobutyric acidergic dysfunction and metabotropic glutamate receptor 5-associated long-term depression) relevant to the pathophysiology of fragile X syndrome as well as neural correlates of cognitive-behavioral symptoms. We then describe what we have learned from fragile X syndrome that may be applicable to other psychiatric disorders. We conclude this review by discussing current and future opportunities in diagnosing and treating psychiatric diseases.

  View details for DOI 10.1016/j.biopsych.2015.12.015

  View details for Web of Science ID 000378530200007

  View details for PubMedID 26868443

• Sex differences in neural and behavioral signatures of cooperation revealed by fNIRS hyperscanning SCIENTIFIC REPORTS Baker, J. M., Liu, N., Cui, X., Vrticka, P., Saggar, M., Hosseini, S. M., Reiss, A. L. 2016; 6

  Abstract

  Researchers from multiple fields have sought to understand how sex moderates human social behavior. While over 50 years of research has revealed differences in cooperation behavior of males and females, the underlying neural correlates of these sex differences have not been explained. A missing and fundamental element of this puzzle is an understanding of how the sex composition of an interacting dyad influences the brain and behavior during cooperation. Using fNIRS-based hyperscanning in 111 same- and mixed-sex dyads, we identified significant behavioral and neural sex-related differences in association with a computer-based cooperation task. Dyads containing at least one male demonstrated significantly higher behavioral performance than female/female dyads. Individual males and females showed significant activation in the right frontopolar and right inferior prefrontal cortices, although this activation was greater in females compared to males. Female/female dyad's exhibited significant inter-brain coherence within the right temporal cortex, while significant coherence in male/male dyads occurred in the right inferior prefrontal cortex. Significant coherence was not observed in mixed-sex dyads. Finally, for same-sex dyads only, task-related inter-brain coherence was positively correlated with cooperation task performance. Our results highlight multiple important and previously undetected influences of sex on concurrent neural and behavioral signatures of cooperation.

  View details for DOI 10.1038/srep26492

  View details for Web of Science ID 000377330900001

  View details for PubMedID 27270754

  View details for PubMedCentralID PMC4897646

• Sex Differences in Amygdala Shape: Insights from Turner Syndrome Green, T., Fierro, K. C., Raman, M., Foland-Ross, L., Hong, D. S., Reiss, A. L. ELSEVIER SCIENCE INC. 2016: 109S

  View details for Web of Science ID 000432440801107

• Surface-based morphometry reveals distinct cortical thickness and surface area profiles in Williams syndrome. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Green, T., Fierro, K. C., Raman, M. M., Saggar, M., Sheau, K. E., Reiss, A. L. 2016; 171B (3): 402-413

  Abstract

  Morphometric investigations of brain volumes in Williams syndrome (WS) consistently show significant reductions in gray matter volume compared to controls. Cortical thickness (CT) and surface area (SA) are two constituent parts of cortical gray matter volume that are considered genetically distinguishable features of brain morphology. Yet, little is known about the independent contribution of cortical CT and SA to these volumetric differences in WS. Thus, our objectives were: (i) to evaluate whether the microdeletion in chromosome 7 associated with WS has a distinct effect on CT and SA, and (ii) to evaluate age-related variations in CT and SA within WS. We compared CT and SA values in 44 individuals with WS to 49 age- and sex-matched typically developing controls. Between-group differences in CT and SA were evaluated across two age groups: young (age range 6.6-18.9 years), and adults (age range 20.2-51.5 years). Overall, we found contrasting effects of WS on cortical thickness (increases) and surface area (decreases). With respect to brain topography, the between-group pattern of CT differences showed a scattered pattern while the between-group surface area pattern was widely distributed throughout the brain. In the adult subgroup, we observed a cluster of increases in cortical thickness in WS across the brain that was not observed in the young subgroup. Our findings suggest that extensive early reductions in surface area are the driving force for the overall reduction in brain volume in WS. The age-related cortical thickness findings might reflect delayed or even arrested development of specific brain regions in WS. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32422

  View details for PubMedID 26852730

• Surface-based morphometry reveals distinct cortical thickness and surface area profiles in Williams syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Green, T., Fierro, K. C., Raman, M. M., Saggar, M., Sheau, K. E., Reiss, A. L. 2016; 171 (3): 402-413

  Abstract

  Morphometric investigations of brain volumes in Williams syndrome (WS) consistently show significant reductions in gray matter volume compared to controls. Cortical thickness (CT) and surface area (SA) are two constituent parts of cortical gray matter volume that are considered genetically distinguishable features of brain morphology. Yet, little is known about the independent contribution of cortical CT and SA to these volumetric differences in WS. Thus, our objectives were: (i) to evaluate whether the microdeletion in chromosome 7 associated with WS has a distinct effect on CT and SA, and (ii) to evaluate age-related variations in CT and SA within WS. We compared CT and SA values in 44 individuals with WS to 49 age- and sex-matched typically developing controls. Between-group differences in CT and SA were evaluated across two age groups: young (age range 6.6-18.9 years), and adults (age range 20.2-51.5 years). Overall, we found contrasting effects of WS on cortical thickness (increases) and surface area (decreases). With respect to brain topography, the between-group pattern of CT differences showed a scattered pattern while the between-group surface area pattern was widely distributed throughout the brain. In the adult subgroup, we observed a cluster of increases in cortical thickness in WS across the brain that was not observed in the young subgroup. Our findings suggest that extensive early reductions in surface area are the driving force for the overall reduction in brain volume in WS. The age-related cortical thickness findings might reflect delayed or even arrested development of specific brain regions in WS. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32422

  View details for Web of Science ID 000373029100011

• Sex differences in amygdala shape: Insights from Turner syndrome. Human brain mapping Green, T., Fierro, K. C., Raman, M. M., Foland-Ross, L., Hong, D. S., Reiss, A. L. 2016; 37 (4): 1593-1601

  Abstract

  Sex differences in the manifestation of psychiatric disorders, including anxiety disorders, are among the most prominent findings in psychiatry. The study of Turner syndrome (TS), caused by X-monosomy, has the potential to reveal mechanisms that underline male/female differences in neuropsychiatric disorders. The amygdala has been implicated in numerous neuropsychiatric disorders. Previous studies suggest an effect of TS on amygdala volume as well as on amygdala-related behaviors such as anxiety. Our objective is to investigate the amygdala shape in TS. Specifically, we tested whether amygdala enlargements in TS are localized to specific nuclei implicated in anxiety, such as the basomedial nucleus.We use a surface-based analytical modeling approach to contrast 41 pre-estrogen treatment girls with TS (mean age 8.6 ± 2.4) with 34 age-and sex-matched typically developing (TD) controls (mean age 8.0 ± 2.8). Anxiety symptoms were assessed using the Revised Children's Manifest Anxiety Scale - 2 (RCMAS-2) in both groups.TS was associated with anomalous enlargement of the amygdala. Surface-based modeling revealed shape differences (increased radial-distances) in bilateral basal and basomedial nuclei within the basolateral complex. RCMAS-2 Total Anxiety t-score was significantly higher in participants with TS compared with TD controls (P = 0.012).Group differences in global amygdala volumes were driven by local morphological increases in areas that are critically involved in face emotion processing and anxiety. In the context of increased amygdala volumes in TS, our results also showed increased worry and social anxiety in young girls with TS compared with TD. Hum Brain Mapp 37:1593-1601, 2016. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/hbm.23122

  View details for PubMedID 26819071

• Cover Image, Volume 171B, Number 3, April 2016. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Green, T., Fierro, K. C., Raman, M. M., Saggar, M., Sheau, K. E., Reiss, A. L. 2016; 171 (3): i-?

  Abstract

  The cover image, by Tamar Green et al., is based on the Research Article Surface-based morphometry reveals distinct cortical thickness and surface area profiles in Williams syndrome, DOI: 10.1002/ajmg.b.32422.

  View details for DOI 10.1002/ajmg.b.32447

  View details for PubMedID 27001917

• Altered Brain Network Segregation in Fragile X Syndrome Revealed by Structural Connectomics. Cerebral cortex Bruno, J. L., Hosseini, S. M., Saggar, M., Quintin, E., Raman, M. M., Reiss, A. L. 2016

  Abstract

  Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder, is associated with significant behavioral, social, and neurocognitive deficits. Understanding structural brain network topology in FXS provides an important link between neurobiological and behavioral/cognitive symptoms of this disorder. We investigated the connectome via whole-brain structural networks created from group-level morphological correlations. Participants included 100 individuals: 50 with FXS and 50 with typical development, age 11-23 years. Results indicated alterations in topological properties of structural brain networks in individuals with FXS. Significantly reduced small-world index indicates a shift in the balance between network segregation and integration and significantly reduced clustering coefficient suggests that reduced local segregation shifted this balance. Caudate and amygdala were less interactive in the FXS network further highlighting the importance of subcortical region alterations in the neurobiological signature of FXS. Modularity analysis indicates that FXS and typically developing groups' networks decompose into different sets of interconnected sub networks, potentially indicative of aberrant local interconnectivity in individuals with FXS. These findings advance our understanding of the effects of fragile X mental retardation protein on large-scale brain networks and could be used to develop a connectome-level biological signature for FXS.

  View details for PubMedID 27009247

• NIRS-Based Hyperscanning Reveals Inter-brain Neural Synchronization during Cooperative Jenga Game with Face-to-Face Communication FRONTIERS IN HUMAN NEUROSCIENCE Liu, N., Mok, C., Witt, E. E., Pradhans, A. H., Chen, J. E., Reiss, A. L. 2016; 10

  Abstract

  Functional near-infrared spectroscopy (fNIRS) is an increasingly popular technology for studying social cognition. In particular, fNIRS permits simultaneous measurement of hemodynamic activity in two or more individuals interacting in a naturalistic setting. Here, we used fNIRS hyperscanning to study social cognition and communication in human dyads engaged in cooperative and obstructive interaction while they played the game of Jenga™. Novel methods were developed to identify synchronized channels for each dyad and a structural node-based spatial registration approach was utilized for inter-dyad analyses. Strong inter-brain neural synchrony (INS) was observed in the posterior region of the right middle and superior frontal gyrus, in particular Brodmann area 8 (BA8), during cooperative and obstructive interaction. This synchrony was not observed during the parallel game play condition and the dialog section, suggesting that BA8 was involved in goal-oriented social interaction such as complex interactive movements and social decision-making. INS was also observed in the dorsomedial prefrontal cortex (dmPFC), in particular Brodmann 9, during cooperative interaction only. These additional findings suggest that BA9 may be particularly engaged when theory-of-mind (ToM) is required for cooperative social interaction. The new methods described here have the potential to significantly extend fNIRS applications to social cognitive research.

  View details for DOI 10.3389/fnhum.2016.00082

  View details for Web of Science ID 000371457400001

  View details for PubMedCentralID PMC4782164

• NIRS-Based Hyperscanning Reveals Inter-brain Neural Synchronization during Cooperative Jenga Game with Face-to-Face Communication. Frontiers in human neuroscience Liu, N., Mok, C., Witt, E. E., Pradhan, A. H., Chen, J. E., Reiss, A. L. 2016; 10: 82

  Abstract

  Functional near-infrared spectroscopy (fNIRS) is an increasingly popular technology for studying social cognition. In particular, fNIRS permits simultaneous measurement of hemodynamic activity in two or more individuals interacting in a naturalistic setting. Here, we used fNIRS hyperscanning to study social cognition and communication in human dyads engaged in cooperative and obstructive interaction while they played the game of Jenga™. Novel methods were developed to identify synchronized channels for each dyad and a structural node-based spatial registration approach was utilized for inter-dyad analyses. Strong inter-brain neural synchrony (INS) was observed in the posterior region of the right middle and superior frontal gyrus, in particular Brodmann area 8 (BA8), during cooperative and obstructive interaction. This synchrony was not observed during the parallel game play condition and the dialog section, suggesting that BA8 was involved in goal-oriented social interaction such as complex interactive movements and social decision-making. INS was also observed in the dorsomedial prefrontal cortex (dmPFC), in particular Brodmann 9, during cooperative interaction only. These additional findings suggest that BA9 may be particularly engaged when theory-of-mind (ToM) is required for cooperative social interaction. The new methods described here have the potential to significantly extend fNIRS applications to social cognitive research.

  View details for DOI 10.3389/fnhum.2016.00082

  View details for PubMedID 27014019

  View details for PubMedCentralID PMC4782164

• Longitudinal Evaluation of Cognitive Functioning in Young Children with Type 1 Diabetes over 18 Months. Journal of the International Neuropsychological Society Cato, M. A., Mauras, N., Mazaika, P., Kollman, C., Cheng, P., Aye, T., Ambrosino, J., Beck, R. W., Ruedy, K. J., Reiss, A. L., Tansey, M., White, N. H., Hershey, T. 2016; 22 (3): 293-302

  Abstract

  Decrements in cognitive function may already be evident in young children with type 1 diabetes (T1D). Here we report prospectively acquired cognitive results over 18 months in a large cohort of young children with and without T1D.A total of 144 children with T1D (mean HbA1c: 7.9%) and 70 age-matched healthy controls (mean age both groups 8.5 years; median diabetes duration 3.9 years; mean age of onset 4.1 years) underwent neuropsychological testing at baseline and after 18-months of follow-up. We hypothesized that group differences observed at baseline would be more pronounced after 18 months, particularly in those T1D patients with greatest exposure to glycemic extremes.Cognitive domain scores did not differ between groups at the 18 month testing session and did not change differently between groups over the follow-up period. However, within the T1D group, a history of diabetic ketoacidosis (DKA) was correlated with lower Verbal IQ and greater hyperglycemia exposure (HbA1c area under the curve) was inversely correlated to executive functions test performance. In addition, those with a history of both types of exposure performed most poorly on measures of executive function.The subtle cognitive differences between T1D children and nondiabetic controls observed at baseline were not observed 18 months later. Within the T1D group, as at baseline, relationships between cognition (Verbal IQ and executive functions) and glycemic variables (chronic hyperglycemia and DKA history) were evident. Continued longitudinal study of this T1D cohort and their carefully matched healthy comparison group is planned.

  View details for DOI 10.1017/S1355617715001289

  View details for PubMedID 26786245

• Women in Academic Medicine: Measuring Stereotype Threat Among Junior Faculty JOURNAL OF WOMENS HEALTH Fassiotto, M., Hamel, E. O., Ku, M., Correll, S., Grewal, D., Lavori, P., Periyakoil, V. J., Reiss, A., Sandborg, C., Walton, G., Winkleby, M., Valantine, H. 2016; 25 (3): 292-298

  Abstract

  Gender stereotypes in science impede supportive environments for women. Research suggests that women's perceptions of these environments are influenced by stereotype threat (ST): anxiety faced in situations where one may be evaluated using negative stereotypes. This study developed and tested ST metrics for first time use with junior faculty in academic medicine.Under a 2012 National Institutes of Health Pathfinder Award, Stanford School of Medicine's Office of Diversity and Leadership, working with experienced clinicians, social scientists, and epidemiologists, developed and administered ST measures to a representative group of junior faculty.174 School of Medicine junior faculty were recruited (62% women, 38% men; 75% assistant professors, 25% instructors; 50% white, 40% Asian, 10% underrepresented minority). Women reported greater susceptibility to ST than did men across all items including ST vulnerability (p < 0.001); rejection sensitivity (p = 0.001); gender identification (p < 0.001); perceptions of relative potential (p = 0.048); and, sense of belonging (p = 0.049). Results of career-related consequences of ST were more nuanced. Compared with men, women reported lower beliefs in advancement (p = 0.021); however, they had similar career interest and identification, felt just as connected to colleagues, and were equally likely to pursue careers outside academia (all p > 0.42).Innovative ST metrics can provide a more complete picture of academic medical center environments. While junior women faculty are susceptible to ST, they may not yet experience all of its consequences in their early careers. As such, ST metrics offer a tool for evaluating institutional initiatives to increase supportive environments for women in academic medicine.

  View details for DOI 10.1089/jwh.2015.5380

  View details for Web of Science ID 000372173200014

• A meta-analysis of math performance in Turner syndrome. Developmental medicine and child neurology Baker, J. M., Reiss, A. L. 2016; 58 (2): 123-130

  Abstract

  Studies investigating the relationship between Turner syndrome and math learning disability have used a wide variation of tasks designed to test various aspects of mathematical competencies. Although these studies have revealed much about the math deficits common to Turner syndrome, their diversity makes comparisons between individual studies difficult. As a result, the consistency of outcomes among these diverse measures remains unknown. The overarching aim of this review is to provide a systematic meta-analysis of the differences in math and number performance between females with Turner syndrome and age-matched neurotypical peers.We provide a meta-analysis of behavioral performance in Turner syndrome relative to age-matched neurotypical populations on assessments of math and number aptitude. In total, 112 comparisons collected across 17 studies were included.Although 54% of all statistical comparisons in our analyses failed to reject the null hypothesis, our results indicate that meaningful group differences exist on all comparisons except those that do not require explicit calculation.Taken together, these results help elucidate our current understanding of math and number weaknesses in Turner syndrome, while highlighting specific topics that require further investigation.

  View details for DOI 10.1111/dmcn.12961

  View details for PubMedID 26566693

• Variations in Brain Volume and Growth in Young Children With Type 1 Diabetes. Diabetes Mazaika, P. K., Weinzimer, S. A., Mauras, N., Buckingham, B., White, N. H., Tsalikian, E., Hershey, T., Cato, A., Aye, T., Fox, L., Wilson, D. M., Tansey, M. J., Tamborlane, W., Peng, D., Raman, M., Marzelli, M., Reiss, A. L. 2016; 65 (2): 476-485

  Abstract

  Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural MRI was performed on 141 children with diabetes (4-10 years of age at study entry) and 69 age-matched control subjects at two time points spaced 18 months apart. For the children with diabetes, the mean (±SD) HbA1c level was 7.9 ± 0.9% (63 ± 9.8 mmol/mol) at both time points. Relative to control subjects, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area and significantly less growth of white matter volume throughout the cortex and cerebellum. For the population with diabetes, the change in the blood glucose level at the time of scan across longitudinal time points was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with the development of surface curvature. These results demonstrate that early-onset type 1 diabetes has widespread effects on the growth of gray and white matter in children whose blood glucose levels are well within the current treatment guidelines for the management of diabetes.

  View details for DOI 10.2337/db15-1242

  View details for PubMedID 26512024

• Female-Specific Intergenerational Transmission Patterns of the Human Corticolimbic Circuitry JOURNAL OF NEUROSCIENCE Yamagata, B., Murayama, K., Black, J. M., Hancock, R., Mimura, M., Yang, T. T., Reiss, A. L., Hoeft, F. 2016; 36 (4): 1254-1260

  Abstract

  Parents have large genetic and environmental influences on offspring's cognition, behavior, and brain. These intergenerational effects are observed in mood disorders, with particularly robust association in depression between mothers and daughters. No studies have thus far examined the neural bases of these intergenerational effects in humans. Corticolimbic circuitry is known to be highly relevant in a wide range of processes, including mood regulation and depression. These findings suggest that corticolimbic circuitry may also show matrilineal transmission patterns. Therefore, we examined human parent-offspring association in this neurocircuitry and investigated the degree of association in gray matter volume between parent and offspring. We used voxelwise correlation analysis in a total of 35 healthy families, consisting of parents and their biological offspring. We found positive associations of regional gray matter volume in the corticolimbic circuit, including the amygdala, hippocampus, anterior cingulate cortex, and ventromedial prefrontal cortex between biological mothers and daughters. This association was significantly greater than mother-son, father-daughter, and father-son associations. The current study suggests that the corticolimbic circuitry, which has been implicated in mood regulation, shows a matrilineal-specific transmission patterns. Our preliminary findings are consistent with what has been found behaviorally in depression and may have clinical implications for disorders known to have dysfunction in mood regulation such as depression. Studies such as ours will likely bridge animal work examining gene expression in the brains and clinical symptom-based observations and provide promising ways to investigate intergenerational transmission patterns in the human brain.Parents have large genetic and environmental influences on the offspring, known as intergenerational effects. Specifically, depression has been shown to exhibit strong matrilineal transmission patterns. Although intergenerational transmission patterns in the human brain are virtually unknown, this would suggest that the corticolimbic circuitry relevant to a wide range of processes including mood regulation may also show matrilineal transmission patterns. Therefore, we examined the degree of association in corticolimbic gray matter volume (GMV) between parent and offspring in 35 healthy families. We found that positive correlations in maternal corticolimbic GMV with daughters were significantly greater than other parent-offspring dyads. Our findings provide new insight into the potential neuroanatomical basis of circuit-based female-specific intergenerational transmission patterns in depression.

  View details for DOI 10.1523/JNEUROSCI.4974-14.2016

  View details for Web of Science ID 000369180000019

  View details for PubMedID 26818513

  View details for PubMedCentralID PMC4728726

• Understanding the influence of personality on dynamic social gesture processing: An fMRI study. Neuropsychologia Saggar, M., Vrticka, P., Reiss, A. L. 2016; 80: 71-78

  Abstract

  This fMRI study aimed at investigating how differences in personality traits affect the processing of dynamic and natural gestures containing social versus nonsocial intent. We predicted that while processing gestures with social intent extraversion would be associated with increased activity within the reticulothalamic-cortical arousal system (RTCS), while neuroticism would be associated with increased activity in emotion processing circuits. The obtained findings partly support our hypotheses. We found a positive correlation between bilateral thalamic activity and extraversion scores while participants viewed social (versus nonsocial) gestures. For neuroticism, the data revealed a more complex activation pattern. Activity in the bilateral frontal operculum and anterior insula, extending into bilateral putamen and right amygdala, was moderated as a function of actor-orientation (i.e., first versus third-person engagement) and face-visibility (actor faces visible versus blurred). Our findings point to the existence of factors other than emotional valence that can influence social gesture processing in particular, and social cognitive affective processing in general, as a function of personality.

  View details for DOI 10.1016/j.neuropsychologia.2015.10.039

  View details for PubMedID 26541443

  View details for PubMedCentralID PMC4698311

• Profiles of aberrant white matter microstructure in fragile X syndrome. NeuroImage. Clinical Hall, S. S., Dougherty, R. F., Reiss, A. L. 2016; 11: 133-138

  Abstract

  Previous studies attempting to quantify white matter (WM) microstructure in individuals with fragile X syndrome (FXS) have produced inconsistent findings, most likely due to the various control groups employed, differing analysis methods, and failure to examine for potential motion artifact. In addition, analyses have heretofore lacked sufficient specificity to provide regional information. In this study, we used Automated Fiber-tract Quantification (AFQ) to identify specific regions of aberrant WM microstructure along WM tracts in patients with FXS that differed from controls who were matched on age, IQ and degree of autistic symptoms. Participants were 20 patients with FXS, aged 10 to 23 years, and 20 matched controls. Using Automated Fiber-tract Quantification (AFQ), we created Tract Profiles of fractional anisotropy and mean diffusivity along 18 major WM fascicles. We found that fractional anisotropy was significantly increased in the left and right inferior longitudinal fasciculus (ILF), right uncinate fasciculus, and left cingulum hippocampus in individuals with FXS compared to controls. Conversely, mean diffusivity was significantly decreased in the right ILF in patients with FXS compared to controls. Age was significantly negatively associated with MD values across both groups in 11 tracts. Taken together, these findings indicate that FXS results in abnormal WM microstructure in specific regions of the ILF and uncinate fasciculus, most likely caused by inefficient synaptic pruning as a result of decreased or absent Fragile X Mental Retardation Protein (FMRP). Longitudinal studies are needed to confirm these findings.

  View details for DOI 10.1016/j.nicl.2016.01.013

  View details for PubMedID 26937381

  View details for PubMedCentralID PMC4753809

• Designing a Creativity Assessment Tool for the Twenty-First Century: Preliminary Results and Insights from Developing a Design-Thinking Based Assessment of Creative Capacity DESIGN THINKING RESEARCH: MAKING DESIGN THINKING FOUNDATIONAL Hawthorne, G., Saggar, M., Quintin, E., Bott, N., Keinitz, E., Liu, N., Chien, Y., Hong, D., Royalty, A., Reiss, A. L., Plattner, H., Meinel, C., Leifer, L. 2016: 111–23

  View details for DOI 10.1007/978-3-319-19641-1_8

  View details for Web of Science ID 000371623000009

• Developing Novel Neuroimaging Paradigm to Assess Neural Correlates of Improvisation and Creative Thinking Using fMRI DESIGN THINKING RESEARCH: TAKING BREAKTHROUGH INNOVATION HOME Saggar, M., Chromik, L. C., Royalty, A., Hawthorne, G., Reiss, A. L., Plattner, H., Meinel, C., Leifer, L. 2016: 309–17

  View details for DOI 10.1007/978-3-319-40382-3_17

  View details for Web of Science ID 000399244000018

• Corrigendum: Sex differences in neural and behavioral signatures of cooperation revealed by fNIRS hyperscanning. Scientific reports Baker, J. M., Liu, N., Cui, X., Vrticka, P., Saggar, M., Hosseini, S. M., Reiss, A. L. 2016; 6: 30512-?

  View details for DOI 10.1038/srep30512

  View details for PubMedID 27541621

• Post-traumatic stress and age variation in amygdala volumes among youth exposed to trauma. Social cognitive and affective neuroscience Weems, C. F., Klabunde, M., Russell, J. D., Reiss, A. L., Carrión, V. G. 2015; 10 (12): 1661-1667

  Abstract

  Theoretically, normal developmental variation in amygdala volumes may be altered under conditions of severe stress. The purpose of this article was to examine whether posttraumatic stress moderates the association between age and amygdala volumes in youth exposed to traumatic events who are experiencing symptoms of post-traumatic stress disorder (PTSD). Volumetric imaging was conducted on two groups of youth aged 9-17 years: 28 with exposure to trauma and PTSD symptoms (boys = 15, girls = 13) and 26 matched (age, IQ) comparison youth (Controls; boys = 12, girls = 14). There was a significant group by age interaction in predicting right amygdala volumes. A positive association between age and right amygdala volumes was observed, but only in PTSD youth. These associations with age remained when controlling for IQ, total brain volumes and sex. Moreover, older youth with PTSD symptoms had relatively larger right amygdala volumes than controls. Findings provide evidence that severe stress may influence age-related variation in amygdala volumes. Results further highlight the importance of utilizing age as an interactive variable in pediatric neuroimaging research, in so far as age may act as an important moderator of group differences.

  View details for DOI 10.1093/scan/nsv053

  View details for PubMedID 25964500

• Women in Academic Medicine: Measuring Stereotype Threat Among Junior Faculty. Journal of women's health (2002) Fassiotto, M., Hamel, E. O., Ku, M., Correll, S., Grewal, D., Lavori, P., Periyakoil, V. J., Reiss, A., Sandborg, C., Walton, G., Winkleby, M., Valantine, H. 2015

  Abstract

  Gender stereotypes in science impede supportive environments for women. Research suggests that women's perceptions of these environments are influenced by stereotype threat (ST): anxiety faced in situations where one may be evaluated using negative stereotypes. This study developed and tested ST metrics for first time use with junior faculty in academic medicine.Under a 2012 National Institutes of Health Pathfinder Award, Stanford School of Medicine's Office of Diversity and Leadership, working with experienced clinicians, social scientists, and epidemiologists, developed and administered ST measures to a representative group of junior faculty.174 School of Medicine junior faculty were recruited (62% women, 38% men; 75% assistant professors, 25% instructors; 50% white, 40% Asian, 10% underrepresented minority). Women reported greater susceptibility to ST than did men across all items including ST vulnerability (p < 0.001); rejection sensitivity (p = 0.001); gender identification (p < 0.001); perceptions of relative potential (p = 0.048); and, sense of belonging (p = 0.049). Results of career-related consequences of ST were more nuanced. Compared with men, women reported lower beliefs in advancement (p = 0.021); however, they had similar career interest and identification, felt just as connected to colleagues, and were equally likely to pursue careers outside academia (all p > 0.42).Innovative ST metrics can provide a more complete picture of academic medical center environments. While junior women faculty are susceptible to ST, they may not yet experience all of its consequences in their early careers. As such, ST metrics offer a tool for evaluating institutional initiatives to increase supportive environments for women in academic medicine.

  View details for DOI 10.1089/jwh.2015.5380

  View details for PubMedID 26555562

• Estimating individual contribution from group-based structural correlation networks. NeuroImage Saggar, M., Hosseini, S. M., Bruno, J. L., Quintin, E., Raman, M. M., Kesler, S. R., Reiss, A. L. 2015; 120: 274-284

  Abstract

  Coordinated variations in brain morphology (e.g., cortical thickness) across individuals have been widely used to infer large-scale population brain networks. These structural correlation networks (SCNs) have been shown to reflect synchronized maturational changes in connected brain regions. Further, evidence suggests that SCNs, to some extent, reflect both anatomical and functional connectivity and hence provide a complementary measure of brain connectivity in addition to diffusion weighted networks and resting-state functional networks. Although widely used to study between-group differences in network properties, SCNs are inferred only at the group-level using brain morphology data from a set of participants, thereby not providing any knowledge regarding how the observed differences in SCNs are associated with individual behavioral, cognitive and disorder states. In the present study, we introduce two novel distance-based approaches to extract information regarding individual differences from the group-level SCNs. We applied the proposed approaches to a moderately large dataset (n=100) consisting of individuals with fragile X syndrome (FXS; n=50) and age-matched typically developing individuals (TD; n=50). We tested the stability of proposed approaches using permutation analysis. Lastly, to test the efficacy of our method, individual contributions extracted from the group-level SCNs were examined for associations with intelligence scores and genetic data. The extracted individual contributions were stable and were significantly related to both genetic and intelligence estimates, in both typically developing individuals and participants with FXS. We anticipate that the approaches developed in this work could be used as a putative biomarker for altered connectivity in individuals with neurodevelopmental disorders.

  View details for DOI 10.1016/j.neuroimage.2015.07.006

  View details for PubMedID 26162553

• Neural Correlates of Self-Injurious Behavior in Prader-Willi Syndrome HUMAN BRAIN MAPPING Klabunde, M., Saggar, M., Hustyi, K. M., Hammond, J. L., Reiss, A. L., Hall, S. S. 2015; 36 (10): 4135-4143

  Abstract

  Individuals with Prader-Willi syndrome (PWS), a genetic disorder caused by mutations to the q11-13 region on chromosome 15, commonly show severe skin-picking behaviors that can cause open wounds and sores on the body. To our knowledge, however, no studies have examined the potential neural mechanisms underlying these behaviors. Seventeen individuals with PWS, aged 6-25 years, who showed severe skin-picking behaviors, were recruited and scanned on a 3T scanner. We used functional magnetic resonance imaging (fMRI) while episodes of skin picking were recorded on an MRI-safe video camera. Three participants displayed skin picking continuously throughout the scan, three participants did not display skin picking, and the data for one participant evidenced significant B0 inhomogeneity that could not be corrected. The data for the remaining 10 participants (six male, four female) who displayed a sufficient number of picking and nonpicking episodes were subjected to fMRI analysis. Results showed that regions involved in interoceptive, motor, attention, and somatosensory processing were activated during episodes of skin-picking behavior compared with nonpicking episodes. Scores obtained on the Self-Injury Trauma scale were significantly negatively correlated with mean activation within the right insula and left precentral gyrus. These data indicate that itch and pain processes appear to underlie skin-picking behaviors in PWS, suggesting that interoceptive disturbance may contribute to the severity and maintenance of abnormal skin-picking behaviors in PWS. Implications for treatments are discussed. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/hbm.22903

  View details for Web of Science ID 000364219100031

  View details for PubMedID 26173182

• Quantifying naturalistic social gaze in fragile X syndrome using a novel eye tracking paradigm. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Hall, S. S., Frank, M. C., Pusiol, G. T., Farzin, F., Lightbody, A. A., Reiss, A. L. 2015; 168 (7): 564-572

  Abstract

  A hallmark behavioral feature of fragile X syndrome (FXS) is the propensity for individuals with the syndrome to exhibit significant impairments in social gaze during interactions with others. However, previous studies employing eye tracking methodology to investigate this phenomenon have been limited to presenting static photographs or videos of social interactions rather than employing a real-life social partner. To improve upon previous studies, we used a customized eye tracking configuration to quantify the social gaze of 51 individuals with FXS and 19 controls, aged 14-28 years, while they engaged in a naturalistic face-to-face social interaction with a female experimenter. Importantly, our control group was matched to the FXS group on age, developmental functioning, and degree of autistic symptomatology. Results showed that participants with FXS spent significantly less time looking at the face and had shorter episodes (and longer inter-episodes) of social gaze than controls. Regression analyses indicated that communication ability predicted higher levels of social gaze in individuals with FXS, but not in controls. Conversely, degree of autistic symptoms predicted lower levels of social gaze in controls, but not in individuals with FXS. Taken together, these data indicate that naturalistic social gaze in FXS can be measured objectively using existing eye tracking technology during face-to-face social interactions. Given that impairments in social gaze were specific to FXS, this paradigm could be employed as an objective and ecologically valid outcome measure in ongoing Phase II/Phase III clinical trials of FXS-specific interventions. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32331

  View details for PubMedID 26079280

• Examining the neural correlates of emergent equivalence relations in fragile X syndrome. Psychiatry research Klabunde, M., Saggar, M., Hustyi, K. M., Kelley, R. G., Reiss, A. L., Hall, S. S. 2015; 233 (3): 373-379

  Abstract

  The neural mechanisms underlying the formation of stimulus equivalence relations are poorly understood, particularly in individuals with specific learning impairments. As part of a larger study, we used functional magnetic resonance imaging (fMRI) while participants with fragile X syndrome (FXS), and age- and IQ-matched controls with intellectual disability, were required to form new equivalence relations in the scanner. Following intensive training on matching fractions to pie charts (A=B relations) and pie charts to decimals (B=C relations) outside the scanner over a 2-day period, participants were tested on the trained (A=B, B=C) relations, as well as emergent symmetry (i.e., B=A and C=B) and transitivity/equivalence (i.e., A=C and C=A) relations inside the scanner. Eight participants with FXS (6 female, 2 male) and 10 controls, aged 10-23 years, were able to obtain at least 66.7% correct on the trained relations in the scanner and were included in the fMRI analyses. Across both groups, results showed that the emergence of symmetry relations was correlated with increased brain activation in the left inferior parietal lobule, left postcentral gyrus, and left insula, broadly supporting previous investigations of stimulus equivalence research in neurotypical populations. On the test of emergent transitivity/equivalence relations, activation was significantly greater in individuals with FXS compared with controls in the right middle temporal gyrus, left superior frontal gyrus and left precuneus. These data indicate that neural execution was significantly different in individuals with FXS than in age- and IQ-matched controls during stimulus equivalence formation. Further research concerning how gene-brain-behavior interactions may influence the emergence of stimulus equivalence in individuals with intellectual disabilities is needed.

  View details for DOI 10.1016/j.pscychresns.2015.06.009

  View details for PubMedID 26250852

• Examining the neural correlates of emergent equivalence relations in fragile X syndrome PSYCHIATRY RESEARCH-NEUROIMAGING Klabunde, M., Saggar, M., Hustyi, K. M., Kelley, R. G., Reiss, A. L., Hall, S. S. 2015; 233 (3): 373-379

  Abstract

  The neural mechanisms underlying the formation of stimulus equivalence relations are poorly understood, particularly in individuals with specific learning impairments. As part of a larger study, we used functional magnetic resonance imaging (fMRI) while participants with fragile X syndrome (FXS), and age- and IQ-matched controls with intellectual disability, were required to form new equivalence relations in the scanner. Following intensive training on matching fractions to pie charts (A=B relations) and pie charts to decimals (B=C relations) outside the scanner over a 2-day period, participants were tested on the trained (A=B, B=C) relations, as well as emergent symmetry (i.e., B=A and C=B) and transitivity/equivalence (i.e., A=C and C=A) relations inside the scanner. Eight participants with FXS (6 female, 2 male) and 10 controls, aged 10-23 years, were able to obtain at least 66.7% correct on the trained relations in the scanner and were included in the fMRI analyses. Across both groups, results showed that the emergence of symmetry relations was correlated with increased brain activation in the left inferior parietal lobule, left postcentral gyrus, and left insula, broadly supporting previous investigations of stimulus equivalence research in neurotypical populations. On the test of emergent transitivity/equivalence relations, activation was significantly greater in individuals with FXS compared with controls in the right middle temporal gyrus, left superior frontal gyrus and left precuneus. These data indicate that neural execution was significantly different in individuals with FXS than in age- and IQ-matched controls during stimulus equivalence formation. Further research concerning how gene-brain-behavior interactions may influence the emergence of stimulus equivalence in individuals with intellectual disabilities is needed.

  View details for DOI 10.1016/j.pscychresns.2015.06.009

  View details for Web of Science ID 000360563800010

• Impact of 5-HTTLPR on hippocampal subregional activation in older adults TRANSLATIONAL PSYCHIATRY Garrett, A., Gupta, S., Reiss, A. L., Waring, J., Sudheimer, K., Anker, L., Sosa, N., Hallmayer, J. F., O'Hara, R. 2015; 5

  Abstract

  Studies have shown that a functional polymorphism of the serotonin transporter gene (5-HTTLPR) impacts performance on memory-related tasks and the hippocampal structures that subserve these tasks. The short (s) allele of 5-HTTLPR has been linked to greater susceptibility for impaired memory and smaller hippocampal volume compared to the long allele (l). However, previous studies have not examined the associations between 5-HTTLPR allele and activation in subregions of the hippocampus. In this study, we used functional magnetic resonance imaging (fMRI) to measure activation in hippocampal and temporal lobe subregions in 36 elderly non-clinical participants performing a face-name encoding and recognition task. Although there were no significant differences in task performance between s allele carriers and l homozygotes, right CA1 and right parahippocampal activation during recognition errors was significantly greater in individuals bearing the s allele. In an exploratory analysis, we determined that these effects were more pronounced in s allele carriers with the apolipoprotein ɛ4 allele. Our results suggest that older individuals with the s allele inefficiently allocate neural resources while making errors in recognizing face-name associations, which could negatively impact memory performance during more challenging tasks.

  View details for DOI 10.1038/tp.2015.131

  View details for Web of Science ID 000367663000002

  View details for PubMedCentralID PMC5068801

• Impact of 5-HTTLPR on hippocampal subregional activation in older adults. Translational psychiatry Garrett, A., Gupta, S., Reiss, A. L., Waring, J., Sudheimer, K., Anker, L., Sosa, N., Hallmayer, J. F., O'Hara, R. 2015; 5: e639

  Abstract

  Studies have shown that a functional polymorphism of the serotonin transporter gene (5-HTTLPR) impacts performance on memory-related tasks and the hippocampal structures that subserve these tasks. The short (s) allele of 5-HTTLPR has been linked to greater susceptibility for impaired memory and smaller hippocampal volume compared to the long allele (l). However, previous studies have not examined the associations between 5-HTTLPR allele and activation in subregions of the hippocampus. In this study, we used functional magnetic resonance imaging (fMRI) to measure activation in hippocampal and temporal lobe subregions in 36 elderly non-clinical participants performing a face-name encoding and recognition task. Although there were no significant differences in task performance between s allele carriers and l homozygotes, right CA1 and right parahippocampal activation during recognition errors was significantly greater in individuals bearing the s allele. In an exploratory analysis, we determined that these effects were more pronounced in s allele carriers with the apolipoprotein ɛ4 allele. Our results suggest that older individuals with the s allele inefficiently allocate neural resources while making errors in recognizing face-name associations, which could negatively impact memory performance during more challenging tasks.

  View details for DOI 10.1038/tp.2015.131

  View details for PubMedID 26393485

  View details for PubMedCentralID PMC5068801

• Proceedings From the Turner Resource Network Symposium: The Crossroads of Health Care Research and Health Care Delivery AMERICAN JOURNAL OF MEDICAL GENETICS PART A Backeljauw, P. F., Bondy, C., Chernausek, S. D., Cernich, J. T., Cole, D. A., Fasciano, L. P., Foodim, J., Hawley, S., Hong, D. S., Knickmeyer, R. C., Kruszka, P., Lin, A. E., Lippe, B. M., Lorigan, G. A., Maslen, C. L., Mauras, N., Page, D. C., Pemberton, V. L., Prakash, S. K., Quigley, C. A., Ranallo, K. C., Reiss, A. L., Sandberg, D. E., Scurlock, C., Silberbach, M. 2015; 167 (9): 1962-1971

  Abstract

  Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural "Turner Resource Network (TRN) Symposium" brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.

  View details for DOI 10.1002/ajmg.a.37121

  View details for Web of Science ID 000360056700005

  View details for PubMedCentralID PMC4714605

• Elucidating X chromosome influences on Attention Deficit Hyperactivity Disorder and executive function. Journal of psychiatric research Green, T., Bade Shrestha, S., Chromik, L. C., Rutledge, K., Pennington, B. F., Hong, D. S., Reiss, A. L. 2015; 68: 217-225

  Abstract

  To identify distinct behavioral and cognitive profiles associated with ADHD in Turner syndrome (TS), relative to idiopathic ADHD and neurotypical controls, in order to elucidate X-linked influences contributing to ADHD.We used a multilevel-model approach to compare 49 girls with TS to 37 neurotypical females, aged 5-12, on established measures of behavior (BASC-2) and neurocognitive function (NEPSY). We further compared girls with TS to BASC-2 and NEPSY age-matched reference data obtained from children with idiopathic ADHD.Within the TS group, 51% scored at or above the "at-risk" range for ADHD-associated behaviors on the BASC-2 (TS/+ADHD). The BASC-2 behavioral profile in this TS/+ADHD-subgroup was comparable to a reference group of boys with ADHD with respect to attentional problems and hyperactivity. However, the TS/+ADHD-subgroup had significantly higher hyperactivity scores relative to a reference sample of girls with ADHD (p = 0.016). The behavioral profile in TS was associated with significantly lower attention and executive function scores on the NEPSY relative to neurotypical controls (p = 0.015); but was comparable to scores from a reference sample of children with idiopathic ADHD. Deficits in attention and executive function were not observed in girls with TS having low levels of ADHD-associated behavior (TS/-ADHD).ADHD-associated behavioral and cognitive problems in TS are prevalent and comparable in severity to those found in children with idiopathic ADHD. The ADHD phenotype in TS also appears relatively independent of cognitive features typically associated with TS, like visuospatial weaknesses. These findings suggest that X-linked haploinsufficiency and downstream biological effects contribute to increased risk for ADHD.

  View details for DOI 10.1016/j.jpsychires.2015.06.021

  View details for PubMedID 26228422

• Proceedings from the Turner Resource Network symposium: the crossroads of health care research and health care delivery. American journal of medical genetics. Part A Backeljauw, P. F., Bondy, C., Chernausek, S. D., Cernich, J. T., Cole, D. A., Fasciano, L. P., Foodim, J., Hawley, S., Hong, D. S., Knickmeyer, R. C., Kruszka, P., Lin, A. E., Lippe, B. M., Lorigan, G. A., Maslen, C. L., Mauras, N., Page, D. C., Pemberton, V. L., Prakash, S. K., Quigley, C. A., Ranallo, K. C., Reiss, A. L., Sandberg, D. E., Scurlock, C., Silberbach, M. 2015; 167A (9): 1962-1971

  Abstract

  Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural "Turner Resource Network (TRN) Symposium" brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.

  View details for DOI 10.1002/ajmg.a.37121

  View details for PubMedID 25920614

• Elucidating X chromosome influences on Attention Deficit Hyperactivity Disorder and executive function JOURNAL OF PSYCHIATRIC RESEARCH Green, T., Shrestha, S. B., Chromik, L. C., Rutledge, K., Pennington, B. F., Hong, D. S., Reiss, A. L. 2015; 68: 217-225

  Abstract

  To identify distinct behavioral and cognitive profiles associated with ADHD in Turner syndrome (TS), relative to idiopathic ADHD and neurotypical controls, in order to elucidate X-linked influences contributing to ADHD.We used a multilevel-model approach to compare 49 girls with TS to 37 neurotypical females, aged 5-12, on established measures of behavior (BASC-2) and neurocognitive function (NEPSY). We further compared girls with TS to BASC-2 and NEPSY age-matched reference data obtained from children with idiopathic ADHD.Within the TS group, 51% scored at or above the "at-risk" range for ADHD-associated behaviors on the BASC-2 (TS/+ADHD). The BASC-2 behavioral profile in this TS/+ADHD-subgroup was comparable to a reference group of boys with ADHD with respect to attentional problems and hyperactivity. However, the TS/+ADHD-subgroup had significantly higher hyperactivity scores relative to a reference sample of girls with ADHD (p = 0.016). The behavioral profile in TS was associated with significantly lower attention and executive function scores on the NEPSY relative to neurotypical controls (p = 0.015); but was comparable to scores from a reference sample of children with idiopathic ADHD. Deficits in attention and executive function were not observed in girls with TS having low levels of ADHD-associated behavior (TS/-ADHD).ADHD-associated behavioral and cognitive problems in TS are prevalent and comparable in severity to those found in children with idiopathic ADHD. The ADHD phenotype in TS also appears relatively independent of cognitive features typically associated with TS, like visuospatial weaknesses. These findings suggest that X-linked haploinsufficiency and downstream biological effects contribute to increased risk for ADHD.

  View details for DOI 10.1016/j.jpsychires.2015.06.021

  View details for Web of Science ID 000359956100031

• The Relationship Between Autistic Symptomatology and Independent Living Skills in Adolescents and Young Adults with Fragile X Syndrome JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hustyi, K. M., Hall, S. S., Quintin, E., Chromik, L. C., Lightbody, A. A., Reiss, A. L. 2015; 45 (6): 1836-1844

  Abstract

  Few studies have examined the relationship between autistic symptomatology and competence in independent living skills in adolescents and young adults with fragile X syndrome (FXS). In this study, 70 individuals with FXS, aged 15-25 years, and 35 matched controls were administered direct measures of independent living skills and autistic symptomatology. Results showed that higher levels of autistic symptomatology were associated with lower levels of competence in independent living skills in individuals with FXS, but not in controls. These data indicated that the relationship between autistic symptomatology and independent living skills was syndrome-specific. Early intervention strategies that address autistic symptomatology are sorely needed to improve functional outcomes in this population.

  View details for DOI 10.1007/s10803-014-2342-0

  View details for Web of Science ID 000354977700027

  View details for PubMedID 25518824

• Widespread white matter tract aberrations in youth with familial risk for bipolar disorder. Psychiatry research Roybal, D. J., Barnea-Goraly, N., Kelley, R., Bararpour, L., Howe, M. E., Reiss, A. L., Chang, K. D. 2015; 232 (2): 184-192

  Abstract

  Few studies have examined multiple measures of white matter (WM) differences in youth with familial risk for bipolar disorder (FR-BD). To investigate WM in the FR-BD group, we used three measures of WM structure and two methods of analysis. We used fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) to analyze diffusion tensor imaging (DTI) findings in 25 youth with familial risk for bipolar disorder, defined as having both a parent with BD and mood dysregulation, and 16 sex-, age-, and IQ-matched healthy controls. We conducted a whole brain voxelwise analysis using tract based spatial statistics (TBSS). Subsequently, we conducted a complementary atlas-based, region-of-interest analysis using Diffeomap to confirm results seen in TBSS. When TBSS was used, significant widespread between-group differences were found showing increased FA, increased AD, and decreased RD in the FR-BD group in the bilateral uncinate fasciculus, cingulum, cingulate, superior fronto-occipital fasciculus (SFOF), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus, and corpus callosum. Atlas-based analysis confirmed significant between-group differences, with increased FA and decreased RD in the FR-BD group in the SLF, cingulum, and SFOF. We found significant widespread WM tract aberrations in youth with familial risk for BD using two complementary methods of DTI analysis.

  View details for DOI 10.1016/j.pscychresns.2015.02.007

  View details for PubMedID 25779034

• Widespread white matter tract aberrations in youth with familial risk for bipolar disorder PSYCHIATRY RESEARCH-NEUROIMAGING Roybal, D. J., Barnea-Goraly, N., Kelley, R., Bararpour, L., Howe, M. E., Reiss, A. L., Chang, K. D. 2015; 232 (2): 184-192

  Abstract

  Few studies have examined multiple measures of white matter (WM) differences in youth with familial risk for bipolar disorder (FR-BD). To investigate WM in the FR-BD group, we used three measures of WM structure and two methods of analysis. We used fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) to analyze diffusion tensor imaging (DTI) findings in 25 youth with familial risk for bipolar disorder, defined as having both a parent with BD and mood dysregulation, and 16 sex-, age-, and IQ-matched healthy controls. We conducted a whole brain voxelwise analysis using tract based spatial statistics (TBSS). Subsequently, we conducted a complementary atlas-based, region-of-interest analysis using Diffeomap to confirm results seen in TBSS. When TBSS was used, significant widespread between-group differences were found showing increased FA, increased AD, and decreased RD in the FR-BD group in the bilateral uncinate fasciculus, cingulum, cingulate, superior fronto-occipital fasciculus (SFOF), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus, and corpus callosum. Atlas-based analysis confirmed significant between-group differences, with increased FA and decreased RD in the FR-BD group in the SLF, cingulum, and SFOF. We found significant widespread WM tract aberrations in youth with familial risk for BD using two complementary methods of DTI analysis.

  View details for DOI 10.1016/j.pscychresns.2015.02.007

  View details for Web of Science ID 000353625700007

  View details for PubMedID 25779034

• Pictionary-based fMRI paradigm to study the neural correlates of spontaneous improvisation and figural creativity SCIENTIFIC REPORTS Saggar, M., Quintin, E., Kienitz, E., Bott, N. T., Sun, Z., Hong, W., Chien, Y., Liu, N., Dougherty, R. F., Royalty, A., Hawthorne, G., Reiss, A. L. 2015; 5

  Abstract

  A novel game-like and creativity-conducive fMRI paradigm is developed to assess the neural correlates of spontaneous improvisation and figural creativity in healthy adults. Participants were engaged in the word-guessing game of Pictionary(TM), using an MR-safe drawing tablet and no explicit instructions to be "creative". Using the primary contrast of drawing a given word versus drawing a control word (zigzag), we observed increased engagement of cerebellum, thalamus, left parietal cortex, right superior frontal, left prefrontal and paracingulate/cingulate regions, such that activation in the cingulate and left prefrontal cortices negatively influenced task performance. Further, using parametric fMRI analysis, increasing subjective difficulty ratings for drawing the word engaged higher activations in the left pre-frontal cortices, whereas higher expert-rated creative content in the drawings was associated with increased engagement of bilateral cerebellum. Altogether, our data suggest that cerebral-cerebellar interaction underlying implicit processing of mental representations has a facilitative effect on spontaneous improvisation and figural creativity.

  View details for DOI 10.1038/srep10894

  View details for Web of Science ID 000355548100001

  View details for PubMedID 26018874

  View details for PubMedCentralID PMC4446895

• Sensitivity of fNIRS measurement to head motion: An applied use of smartphones in the lab. Journal of neuroscience methods Cui, X., Baker, J. M., Liu, N., Reiss, A. L. 2015; 245: 37-43

  Abstract

  Powerful computing capabilities in small, easy to use hand-held devices have made smart technologies such as smartphones and tablets ubiquitous in today's society. The capabilities of these devices provide scientists with many tools that can be used to improve the scientific method.Here, we demonstrate how smartphones may be used to quantify the sensitivity of functional near-infrared spectroscopy (fNIRS) signal to head motion. By attaching a smartphone to participants' heads during the fNIRS scan, we were able to capture data describing the degree of head motion.Our results demonstrate that data recorded from an off-the-shelf smartphone accelerometer may be used to identify correlations between head-movement and fNIRS signal change. Furthermore, our results identify correlations between the magnitudes of head-movement and signal artifact, as well as a relationship between the direction of head movement and the location of the resulting signal noise.These data provide a valuable proof-of-concept for the use of off-the-shelf smart technologies in neuroimaging applications.

  View details for DOI 10.1016/j.jneumeth.2015.02.006

  View details for PubMedID 25687634

  View details for PubMedCentralID PMC4398057

• The Influence of Hyperactivity, Impulsivity, and Attention Problems on Social Functioning in Adolescents and Young Adults With Fragile X Syndrome. Journal of attention disorders Chromik, L. C., Quintin, E., Lepage, J., Hustyi, K. M., Lightbody, A. A., Reiss, A. L. 2015

  Abstract

  Individuals with fragile X syndrome (FXS) present primarily with cognitive and social deficits in addition to symptoms of ADHD. The relationship between symptoms of ADHD, cognitive functioning, and social skills has never been explicitly studied.Here, we analyzed both longitudinal (n = 70; Time 1: ages 6-18; Time 2: ages 15-26) and cross-sectional (n = 73; Time 2 only) data using hierarchical linear regression to assess how global intellectual functioning (IQ) and symptoms of ADHD influence social functioning in individuals with FXS.We found that ADHD symptoms at Times 1 and 2 consistently predict social functioning in both males and females with FXS at Time 2.Our results suggest that addressing ADHD symptoms in childhood may have positive, long-term effects on the social functioning of adolescents and young adults with FXS.

  View details for PubMedID 25731183

• Decreased hypothalamic functional connectivity with subgenual cortex in psychotic major depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Sudheimer, K., Keller, J., Gomez, R., Tennakoon, L., Reiss, A., Garrett, A., Kenna, H., O'Hara, R., Schatzberg, A. F. 2015; 40 (4): 849-860

  Abstract

  Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the hypothalamic pituitary adrenal (HPA) axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting-state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized that this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation. Resting-state functional magnetic resonance imaging (fMRI) scans were collected to observe low-frequency resting-state functional connectivity patterns of the hypothalamus in 39 healthy participants, 39 patients with major depression, and 22 patients with major depression with psychotic symptoms. Hourly overnight measures of cortisol secretion and multiple measures of psychiatric symptom severity were also collected on all. Strong hypothalamic functional connectivity with the subgenual cortex was observed in healthy participants. This connectivity was significantly reduced in patients with psychotic major depression. Increased cortisol secretion during the circadian nadir and reduced connectivity were both associated with symptom severity. Reduced connectivity and high cortisol secretion during the circadian nadir are both useful for explaining a significant amount of variance in symptom severity that occurs between healthy participants and depressed patients. However, only cortisol secretion was useful for explaining the severity of symptoms within the depressed groups. This study suggests that the communication between the hypothalamus and the subgenual cortex is disrupted in patients with major depression with psychotic features. It also suggests that these disruptions are associated with increased symptom severity and may be a cause or a consequence of cortisol dysregulation.

  View details for DOI 10.1038/npp.2014.259

  View details for PubMedID 25292261

  View details for PubMedCentralID PMC4330499

• Right arcuate fasciculus abnormality in chronic fatigue syndrome. Radiology Zeineh, M. M., Kang, J., Atlas, S. W., Raman, M. M., Reiss, A. L., Norris, J. L., Valencia, I., Montoya, J. G. 2015; 274 (2): 517-526

  Abstract

  Purpose To identify whether patients with chronic fatigue syndrome ( CFS chronic fatigue syndrome ) have differences in gross brain structure, microscopic structure, or brain perfusion that may explain their symptoms. Materials and Methods Fifteen patients with CFS chronic fatigue syndrome were identified by means of retrospective review with an institutional review board-approved waiver of consent and waiver of authorization. Fourteen age- and sex-matched control subjects provided informed consent in accordance with the institutional review board and HIPAA. All subjects underwent 3.0-T volumetric T1-weighted magnetic resonance (MR) imaging, with two diffusion-tensor imaging ( DTI diffusion-tensor imaging ) acquisitions and arterial spin labeling ( ASL arterial spin labeling ). Open source software was used to segment supratentorial gray and white matter and cerebrospinal fluid to compare gray and white matter volumes and cortical thickness. DTI diffusion-tensor imaging data were processed with automated fiber quantification, which was used to compare piecewise fractional anisotropy ( FA fractional anisotropy ) along 20 tracks. For the volumetric analysis, a regression was performed to account for differences in age, handedness, and total intracranial volume, and for the DTI diffusion-tensor imaging , FA fractional anisotropy was compared piecewise along tracks by using an unpaired t test. The open source software segmentation was used to compare cerebral blood flow as measured with ASL arterial spin labeling . Results In the CFS chronic fatigue syndrome population, FA fractional anisotropy was increased in the right arcuate fasciculus (P = .0015), and in right-handers, FA fractional anisotropy was also increased in the right inferior longitudinal fasciculus ( ILF inferior longitudinal fasciculus ) (P = .0008). In patients with CFS chronic fatigue syndrome , right anterior arcuate FA fractional anisotropy increased with disease severity (r = 0.649, P = .026). Bilateral white matter volumes were reduced in CFS chronic fatigue syndrome (mean ± standard deviation, 467 581 mm(3) ± 47 610 for patients vs 504 864 mm(3) ± 68 126 for control subjects, P = .0026), and cortical thickness increased in both right arcuate end points, the middle temporal (T = 4.25) and precentral (T = 6.47) gyri, and one right ILF inferior longitudinal fasciculus end point, the occipital lobe (T = 5.36). ASL arterial spin labeling showed no significant differences. Conclusion Bilateral white matter atrophy is present in CFS chronic fatigue syndrome . No differences in perfusion were noted. Right hemispheric increased FA fractional anisotropy may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA fractional anisotropy may serve as a biomarker for CFS chronic fatigue syndrome . © RSNA, 2014 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.14141079

  View details for PubMedID 25353054

• Changes in brain activation following psychotherapy for youth with mood dysregulation at familial risk for bipolar disorder PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Garrett, A. S., Miklowitz, D. J., Howe, M. E., Singh, M. K., Acquaye, T. K., Hawkey, C. G., Glover, G. H., Reiss, A. L., Chang, K. D. 2015; 56: 215-220

  Abstract

  Psychotherapy for youth with mood dysregulation can help stabilize mood and improve functioning, but the neural mechanisms of this improvement are not known. In this study we investigated the changes in brain activation underlying improvement in mood symptoms.Twenty-four subjects (ages 13-17) participated: 12 patients with clinically significant symptoms of depression and/or mania, and 12 healthy comparison subjects (HC) matched for age and sex. All subjects completed functional magnetic resonance imaging while viewing facial expressions. The patients then received up to 4 months of psychotherapy and were rescanned at end of treatment. Whole brain differences between patient and control groups were assessed with a voxel-wise analysis. Changes in activation from pre- to post-treatment within the patient group were tested for correlation with changes in mood symptoms.At baseline the patient group had hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and hyperactivation in the posterior cingulate cortex compared to the HC group. Between pre- and post-treatment activation increased in the DLPFC and decreased in the amygdala. Increases in DLPFC activation were significantly correlated with improvement in mania symptoms.Enhancement of frontal executive control brain regions may underlie improvement in mood dysregulation in pediatric patients at familial risk for bipolar disorder.

  View details for DOI 10.1016/j.pnpbp.2014.09.007

  View details for Web of Science ID 000345526400030

  View details for PubMedCentralID PMC4258439

• Changes in brain activation following psychotherapy for youth with mood dysregulation at familial risk for bipolar disorder. Progress in neuro-psychopharmacology & biological psychiatry Garrett, A. S., Miklowitz, D. J., Howe, M. E., Singh, M. K., Acquaye, T. K., Hawkey, C. G., Glover, G. H., Reiss, A. L., Chang, K. D. 2015; 56: 215-220

  Abstract

  Psychotherapy for youth with mood dysregulation can help stabilize mood and improve functioning, but the neural mechanisms of this improvement are not known. In this study we investigated the changes in brain activation underlying improvement in mood symptoms.Twenty-four subjects (ages 13-17) participated: 12 patients with clinically significant symptoms of depression and/or mania, and 12 healthy comparison subjects (HC) matched for age and sex. All subjects completed functional magnetic resonance imaging while viewing facial expressions. The patients then received up to 4 months of psychotherapy and were rescanned at end of treatment. Whole brain differences between patient and control groups were assessed with a voxel-wise analysis. Changes in activation from pre- to post-treatment within the patient group were tested for correlation with changes in mood symptoms.At baseline the patient group had hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and hyperactivation in the posterior cingulate cortex compared to the HC group. Between pre- and post-treatment activation increased in the DLPFC and decreased in the amygdala. Increases in DLPFC activation were significantly correlated with improvement in mania symptoms.Enhancement of frontal executive control brain regions may underlie improvement in mood dysregulation in pediatric patients at familial risk for bipolar disorder.

  View details for DOI 10.1016/j.pnpbp.2014.09.007

  View details for PubMedID 25283342

• Inferring deep-brain activity from cortical activity using functional near-infrared spectroscopy BIOMEDICAL OPTICS EXPRESS Liu, N., Cui, X., Bryant, D. M., Glover, G. H., Reiss, A. L. 2015; 6 (3): 1074-1089

  Abstract

  Functional near-infrared spectroscopy (fNIRS) is an increasingly popular technology for studying brain function because it is non-invasive, non-irradiating and relatively inexpensive. Further, fNIRS potentially allows measurement of hemodynamic activity with high temporal resolution (milliseconds) and in naturalistic settings. However, in comparison with other imaging modalities, namely fMRI, fNIRS has a significant drawback: limited sensitivity to hemodynamic changes in deep-brain regions. To overcome this limitation, we developed a computational method to infer deep-brain activity using fNIRS measurements of cortical activity. Using simultaneous fNIRS and fMRI, we measured brain activity in 17 participants as they completed three cognitive tasks. A support vector regression (SVR) learning algorithm was used to predict activity in twelve deep-brain regions using information from surface fNIRS measurements. We compared these predictions against actual fMRI-measured activity using Pearson's correlation to quantify prediction performance. To provide a benchmark for comparison, we also used fMRI measurements of cortical activity to infer deep-brain activity. When using fMRI-measured activity from the entire cortex, we were able to predict deep-brain activity in the fusiform cortex with an average correlation coefficient of 0.80 and in all deep-brain regions with an average correlation coefficient of 0.67. The top 15% of predictions using fNIRS signal achieved an accuracy of 0.7. To our knowledge, this study is the first to investigate the feasibility of using cortical activity to infer deep-brain activity. This new method has the potential to extend fNIRS applications in cognitive and clinical neuroscience research.

  View details for DOI 10.1364/BOE.6.001074

  View details for Web of Science ID 000350802000035

  View details for PubMedID 25798327

  View details for PubMedCentralID PMC4361422

• Developing Novel Methods to Assess Long-Term Sustainability of Creative Capacity Building and Applied Creativity DESIGN THINKING RESEARCH: BUILDING INNOVATORS Saggar, M., Hawthorne, G., Quintin, E., Kienitz, E., Bott, N. T., Hong, D., Chien, Y., Liu, N., Royalty, A., Reiss, A. L., Plattner, H., Meinel, C., Leifer, L. 2015: 29–39

  View details for DOI 10.1007/978-3-319-06823-7_3

  View details for Web of Science ID 000343288300004

• Longitudinal trajectories of aberrant behavior in fragile X syndrome. Research in developmental disabilities Hustyi, K. M., Hall, S. S., Jo, B., Lightbody, A. A., Reiss, A. L. 2014; 35 (11): 2691-2701

  Abstract

  The Aberrant Behavior Checklist-Community (ABC-C; Aman et al., 1995) has been increasingly adopted as a primary tool for measuring behavioral change in clinical trials for individuals with fragile X syndrome (FXS). To our knowledge, however, no study has documented the longitudinal trajectory of aberrant behaviors in individuals with FXS using the ABC-C. As part of a larger longitudinal study, we examined scores obtained on the ABC-C subscales for 124 children and adolescents (64 males, 60 females) with FXS who had two or more assessments (average interval between assessments was approximately 4 years). Concomitant changes in age-equivalent scores on the Vineland Adaptive Behavior Scales (VABS) were also examined. As expected for an X-linked genetic disorder, males with FXS obtained significantly higher scores on all subscales of the ABC-C and significantly lower age-equivalent scores on the VABS than females with FXS. In both males and females with FXS, scores on the Irritability/Agitation and Hyperactivity/Noncompliance subscales of the ABC-C decreased significantly with age, with little to no change occurring over time on the Lethargy/Social Withdrawal, Stereotypic Behavior, and Inappropriate Speech subscales. The decrease in scores on the Hyperactivity/Noncompliance domain was significantly greater for males than for females. In both males and females, age-equivalent scores on the VABS increased significantly over this developmental period. These results establish a basis upon which to evaluate long-term outcomes from intervention-based research. However, longitudinal direct observational studies are needed to establish whether the severity of problem behavior actually decreases over time in this population.

  View details for DOI 10.1016/j.ridd.2014.07.003

  View details for PubMedID 25129200

• Early signs of anomalous neural functional connectivity in healthy offspring of parents with bipolar disorder. Bipolar disorders Singh, M. K., Chang, K. D., Kelley, R. G., Saggar, M., Reiss, A. L., Gotlib, I. H. 2014; 16 (7): 678-689

  Abstract

  Bipolar disorder (BD) has been associated with dysfunctional brain connectivity and with family chaos. It is not known whether aberrant connectivity occurs before illness onset, representing vulnerability for developing BD amidst family chaos. We used resting-state functional magnetic resonance imaging (fMRI) to examine neural network dysfunction in healthy offspring living with parents with BD and healthy comparison youth.Using two complementary methodologies [data-driven independent component analysis (ICA) and hypothesis-driven region-of-interest (ROI)-based intrinsic connectivity], we examined resting-state fMRI data in 8-17-year-old healthy offspring of a parent with BD (n = 24; high risk) and age-matched healthy youth without any personal or family psychopathology (n = 25; low risk).ICA revealed that, relative to low-risk youth, high-risk youth showed increased connectivity in the ventrolateral prefrontal cortex (VLPFC) subregion of the left executive control network (ECN), which includes frontoparietal regions important for emotion regulation. ROI-based analyses revealed that high-risk versus low-risk youth had decreased connectivities between the left amygdala and pregenual cingulate, between the subgenual cingulate and supplementary motor cortex, and between the left VLPFC and left caudate. High-risk youth showed stronger connections in the VLPFC with age and higher functioning, which may be neuroprotective, and weaker connections between the left VLPFC and caudate with more family chaos, suggesting an environmental influence on frontostriatal connectivity.Healthy offspring of parents with BD show atypical patterns of prefrontal and subcortical intrinsic connectivity that may be early markers of resilience to or vulnerability for developing BD. Longitudinal studies are needed to determine whether these patterns predict outcomes.

  View details for DOI 10.1111/bdi.12221

  View details for PubMedID 24938878

• Early signs of anomalous neural functional connectivity in healthy offspring of parents with bipolar disorder BIPOLAR DISORDERS Singh, M. K., Chang, K. D., Kelley, R. G., Saggar, M., Reiss, A. L., Gotlib, I. H. 2014; 16 (7): 678-689

  Abstract

  Bipolar disorder (BD) has been associated with dysfunctional brain connectivity and with family chaos. It is not known whether aberrant connectivity occurs before illness onset, representing vulnerability for developing BD amidst family chaos. We used resting-state functional magnetic resonance imaging (fMRI) to examine neural network dysfunction in healthy offspring living with parents with BD and healthy comparison youth.Using two complementary methodologies [data-driven independent component analysis (ICA) and hypothesis-driven region-of-interest (ROI)-based intrinsic connectivity], we examined resting-state fMRI data in 8-17-year-old healthy offspring of a parent with BD (n = 24; high risk) and age-matched healthy youth without any personal or family psychopathology (n = 25; low risk).ICA revealed that, relative to low-risk youth, high-risk youth showed increased connectivity in the ventrolateral prefrontal cortex (VLPFC) subregion of the left executive control network (ECN), which includes frontoparietal regions important for emotion regulation. ROI-based analyses revealed that high-risk versus low-risk youth had decreased connectivities between the left amygdala and pregenual cingulate, between the subgenual cingulate and supplementary motor cortex, and between the left VLPFC and left caudate. High-risk youth showed stronger connections in the VLPFC with age and higher functioning, which may be neuroprotective, and weaker connections between the left VLPFC and caudate with more family chaos, suggesting an environmental influence on frontostriatal connectivity.Healthy offspring of parents with BD show atypical patterns of prefrontal and subcortical intrinsic connectivity that may be early markers of resilience to or vulnerability for developing BD. Longitudinal studies are needed to determine whether these patterns predict outcomes.

  View details for DOI 10.1111/bdi.12221

  View details for Web of Science ID 000344373100002

• Altered microstructure within social-cognitive brain networks during childhood in williams syndrome. Cerebral cortex Haas, B. W., Barnea-Goraly, N., Sheau, K. E., Yamagata, B., Ullas, S., Reiss, A. L. 2014; 24 (10): 2796-2806

  Abstract

  Williams syndrome (WS) is a neurodevelopmental condition caused by a hemizygous deletion of ∼26-28 genes on chromosome 7q11.23. WS is associated with a distinctive pattern of social cognition. Accordingly, neuroimaging studies show that WS is associated with structural alterations of key brain regions involved in social cognition during adulthood. However, very little is currently known regarding the neuroanatomical structure of social cognitive brain networks during childhood in WS. This study used diffusion tensor imaging to investigate the structural integrity of a specific set of white matter pathways (inferior fronto-occipital fasciculus [IFOF] and uncinate fasciculus [UF]) and associated brain regions [fusiform gyrus (FG), amygdala, hippocampus, medial orbitofrontal gyrus (MOG)] known to be involved in social cognition in children with WS and a typically developing (TD) control group. Children with WS exhibited higher fractional anisotropy (FA) and axial diffusivity values and lower radial diffusivity and apparent diffusion coefficient (ADC) values within the IFOF and UF, higher FA values within the FG, amygdala, and hippocampus and lower ADC values within the FG and MOG compared to controls. These findings provide evidence that the WS genetic deletion affects the development of key white matter pathways and brain regions important for social cognition.

  View details for DOI 10.1093/cercor/bht135

  View details for PubMedID 23709644

• Reward processing in healthy offspring of parents with bipolar disorder. JAMA psychiatry Singh, M. K., Kelley, R. G., Howe, M. E., Reiss, A. L., Gotlib, I. H., Chang, K. D. 2014; 71 (10): 1148-1156

  Abstract

  Bipolar disorder (BD) is highly familial and characterized by deficits in reward processing. It is not known, however, whether these deficits precede illness onset or are a consequence of the disorder.To determine whether anomalous neural processing of reward characterizes children at familial risk for BD in the absence of a personal history of a psychopathologic disorder.This study compared neural activity and behaviors of children at high and low risk for mania while they anticipate and respond to reward and loss. The study was performed from September 15, 2009, through February 17, 2012, in a university functional magnetic resonance imaging facility and included 8- to 15-year-old children without disorders born to a parent with BD (n = 20 high-risk children) and demographically matched healthy comparison children (n = 25 low-risk children).Neural activity, as measured with functional magnetic resonance imaging, during anticipation and receipt of reward and loss during a monetary incentive delay task.While anticipating losses, high-risk children had less activation in the pregenual cingulate than did their low-risk counterparts (t19 = -2.44, P = .02). When receiving rewards, high-risk children had greater activation in the left lateral orbitofrontal cortex than did low-risk children (t43 = -3.04, P = .004). High-risk children also had weaker functional connectivity between the pregenual cingulate and the right ventrolateral prefrontal cortex while anticipating rewards than did low-risk children (t19 = -4.38, P < .001) but had a stronger connectivity between these regions while anticipating losses (t24 = 2.76, P = .01). Finally, in high- but not low-risk children, novelty seeking was associated with increased striatal and amygdalar activation in the anticipation of losses, and impulsivity was associated with increased striatal and insula activation in the receipt of rewards.Aberrant prefrontal activations and connectivities during reward processing suggest mechanisms that underlie early vulnerabilities for developing dysfunctional regulation of goal pursuit and motivation in children at high risk for mania. Longitudinal studies are needed to examine whether these patterns of neural activation predict the onset of mania and other mood disorders in high-risk children.

  View details for DOI 10.1001/jamapsychiatry.2014.1031

  View details for PubMedID 25142103

• Aberrant face and gaze habituation in fragile x syndrome. American journal of psychiatry Bruno, J. L., Garrett, A. S., Quintin, E., Mazaika, P. K., Reiss, A. L. 2014; 171 (10): 1099-1106

  Abstract

  The authors sought to investigate neural system habituation to face and eye gaze in fragile X syndrome, a disorder characterized by eye-gaze aversion, among other social and cognitive deficits.Participants (ages 15-25 years) were 30 individuals with fragile X syndrome (females, N=14) and a comparison group of 25 individuals without fragile X syndrome (females, N=12) matched for general cognitive ability and autism symptoms. Functional MRI (fMRI) was used to assess brain activation during a gaze habituation task. Participants viewed repeated presentations of four unique faces with either direct or averted eye gaze and judged the direction of eye gaze.Four participants (males, N=4/4; fragile X syndrome, N=3) were excluded because of excessive head motion during fMRI scanning. Behavioral performance did not differ between the groups. Less neural habituation (and significant sensitization) in the fragile X syndrome group was found in the cingulate gyrus, fusiform gyrus, and frontal cortex in response to all faces (direct and averted gaze). Left fusiform habituation in female participants was directly correlated with higher, more typical levels of the fragile X mental retardation protein and inversely correlated with autism symptoms. There was no evidence for differential habituation to direct gaze compared with averted gaze within or between groups.Impaired habituation and accentuated sensitization in response to face/eye gaze was distributed across multiple levels of neural processing. These results could help inform interventions, such as desensitization therapy, which may help patients with fragile X syndrome modulate anxiety and arousal associated with eye gaze, thereby improving social functioning.

  View details for DOI 10.1176/appi.ajp.2014.13111464

  View details for PubMedID 24969119

• Aberrant Face and Gaze Habituation in Fragile X Syndrome AMERICAN JOURNAL OF PSYCHIATRY Bruno, J. L., Garrett, A. S., Quintin, E., Mazaika, P. K., Reiss, A. L. 2014; 171 (10): 1099-1106

  Abstract

  The authors sought to investigate neural system habituation to face and eye gaze in fragile X syndrome, a disorder characterized by eye-gaze aversion, among other social and cognitive deficits.Participants (ages 15-25 years) were 30 individuals with fragile X syndrome (females, N=14) and a comparison group of 25 individuals without fragile X syndrome (females, N=12) matched for general cognitive ability and autism symptoms. Functional MRI (fMRI) was used to assess brain activation during a gaze habituation task. Participants viewed repeated presentations of four unique faces with either direct or averted eye gaze and judged the direction of eye gaze.Four participants (males, N=4/4; fragile X syndrome, N=3) were excluded because of excessive head motion during fMRI scanning. Behavioral performance did not differ between the groups. Less neural habituation (and significant sensitization) in the fragile X syndrome group was found in the cingulate gyrus, fusiform gyrus, and frontal cortex in response to all faces (direct and averted gaze). Left fusiform habituation in female participants was directly correlated with higher, more typical levels of the fragile X mental retardation protein and inversely correlated with autism symptoms. There was no evidence for differential habituation to direct gaze compared with averted gaze within or between groups.Impaired habituation and accentuated sensitization in response to face/eye gaze was distributed across multiple levels of neural processing. These results could help inform interventions, such as desensitization therapy, which may help patients with fragile X syndrome modulate anxiety and arousal associated with eye gaze, thereby improving social functioning.

  View details for DOI 10.1176/appi.ajp.2014.13111464

  View details for Web of Science ID 000342713800015

• Reward Processing in Healthy Offspring of Parents With Bipolar Disorder JAMA PSYCHIATRY Singh, M. K., Kelley, R. G., Howe, M. E., Reiss, A. L., Gotlib, I. H., Chang, K. D. 2014; 71 (10): 1148-1156

  Abstract

  Bipolar disorder (BD) is highly familial and characterized by deficits in reward processing. It is not known, however, whether these deficits precede illness onset or are a consequence of the disorder.To determine whether anomalous neural processing of reward characterizes children at familial risk for BD in the absence of a personal history of a psychopathologic disorder.This study compared neural activity and behaviors of children at high and low risk for mania while they anticipate and respond to reward and loss. The study was performed from September 15, 2009, through February 17, 2012, in a university functional magnetic resonance imaging facility and included 8- to 15-year-old children without disorders born to a parent with BD (n = 20 high-risk children) and demographically matched healthy comparison children (n = 25 low-risk children).Neural activity, as measured with functional magnetic resonance imaging, during anticipation and receipt of reward and loss during a monetary incentive delay task.While anticipating losses, high-risk children had less activation in the pregenual cingulate than did their low-risk counterparts (t19 = -2.44, P = .02). When receiving rewards, high-risk children had greater activation in the left lateral orbitofrontal cortex than did low-risk children (t43 = -3.04, P = .004). High-risk children also had weaker functional connectivity between the pregenual cingulate and the right ventrolateral prefrontal cortex while anticipating rewards than did low-risk children (t19 = -4.38, P < .001) but had a stronger connectivity between these regions while anticipating losses (t24 = 2.76, P = .01). Finally, in high- but not low-risk children, novelty seeking was associated with increased striatal and amygdalar activation in the anticipation of losses, and impulsivity was associated with increased striatal and insula activation in the receipt of rewards.Aberrant prefrontal activations and connectivities during reward processing suggest mechanisms that underlie early vulnerabilities for developing dysfunctional regulation of goal pursuit and motivation in children at high risk for mania. Longitudinal studies are needed to examine whether these patterns of neural activation predict the onset of mania and other mood disorders in high-risk children.

  View details for DOI 10.1001/jamapsychiatry.2014.1031

  View details for Web of Science ID 000342900200009

• Predicting clinical outcome using brain activation associated with set-shifting and central coherence skills in Anorexia Nervosa. Journal of psychiatric research Garrett, A. S., Lock, J., Datta, N., Beenhaker, J., Kesler, S. R., Reiss, A. L. 2014; 57: 26-33

  Abstract

  Patients with Anorexia Nervosa (AN) have neuropsychological deficits in Set-Shifting (SS) and central coherence (CC) consistent with an inflexible thinking style and overly detailed processing style, respectively. This study investigates brain activation during SS and CC tasks in patients with AN and tests whether this activation is a biomarker that predicts response to treatment.FMRI data were collected from 21 females with AN while performing an SS task (the Wisconsin Card Sort) and a CC task (embedded figures), and used to predict outcome following 16 weeks of treatment (either 16 weeks of cognitive behavioral therapy or 8 weeks cognitive remediation therapy followed by 8 weeks of cognitive behavioral therapy).Significant activation during the SS task included bilateral dorsolateral and ventrolateral prefrontal cortex and left anterior middle frontal gyrus. Higher scores on the neuropsychological test of SS (measured outside the scanner at baseline) were correlated with greater DLPFC and VLPFC/insula activation. Improvements in SS following treatment were significantly predicted by a combination of low VLPFC/insula and high anterior middle frontal activation (R squared = .68, p = .001). For the CC task, visual and parietal cortical areas were activated, but were not significantly correlated with neuropsychological measures of CC and did not predict outcome.Cognitive flexibility requires the support of several prefrontal cortex resources. As previous studies suggest that the VLPFC is important for selecting context-appropriate responses, patients who have difficulties with this skill may benefit the most from cognitive therapy with or without cognitive remediation therapy. The ability to sustain inhibition of an unwanted response, subserved by the anterior middle frontal gyrus, is a cognitive feature that predicts favorable outcome to cognitive treatment. CC deficits may not be an effective predictor of clinical outcome.

  View details for DOI 10.1016/j.jpsychires.2014.06.013

  View details for PubMedID 25027478

  View details for PubMedCentralID PMC4127363

• Aberrant parietal cortex developmental trajectories in girls with Turner syndrome and related visual-spatial cognitive development: a preliminary study. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Green, T., Chromik, L. C., Mazaika, P. K., Fierro, K., Raman, M. M., Lazzeroni, L. C., Hong, D. S., Reiss, A. L. 2014; 165B (6): 531-540

  Abstract

  Turner syndrome (TS) arises from partial or complete absence of the X-chromosome in females. Girls with TS show deficits in visual-spatial skills as well as reduced brain volume and surface area in the parietal cortex which supports these cognitive functions. Thus, measuring the developmental trajectory of the parietal cortex and the associated visual-spatial cognition in TS may provide novel insights into critical brain-behavior associations. In this longitudinal study, we acquired structural MRI data and assessed visual-spatial skills in 16 (age: 8.23 ± 2.5) girls with TS and 13 age-matched controls over two time-points. Gray and white matter volume, surface area and cortical thickness were calculated from surfaced based segmentation of bilateral parietal cortices, and the NEPSY Arrows subtest was used to assess visual-spatial ability. Volumetric and cognitive scalars were modeled to obtain estimates of age-related change. The results show aberrant growth of white matter volume (P = 0.011, corrected) and surface area (P = 0.036, corrected) of the left superior parietal regions during childhood in girls with TS. Other parietal sub-regions were significantly smaller in girls with TS at both time-points but did not show different growth trajectories relative to controls. Furthermore, we found that visual-spatial skills showed a widening deficit for girls with TS relative to controls (P = 0.003). Young girls with TS demonstrate an aberrant trajectory of parietal cortical and cognitive development during childhood. Elucidating aberrant neurodevelopmental trajectories in this population is critical for determining specific stages of brain maturation that are particularly dependent on TS-related genetic and hormonal factors. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32256

  View details for PubMedID 25044604

• Aberrant parietal cortex developmental trajectories in girls with turner syndrome and related visual-spatial cognitive development: A preliminary study. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Green, T., Chromik, L. C., Mazaika, P. K., Fierro, K., Raman, M. M., Lazzeroni, L. C., Hong, D. S., Reiss, A. L. 2014; 165 (6): 531-540

  Abstract

  Turner syndrome (TS) arises from partial or complete absence of the X-chromosome in females. Girls with TS show deficits in visual-spatial skills as well as reduced brain volume and surface area in the parietal cortex which supports these cognitive functions. Thus, measuring the developmental trajectory of the parietal cortex and the associated visual-spatial cognition in TS may provide novel insights into critical brain-behavior associations. In this longitudinal study, we acquired structural MRI data and assessed visual-spatial skills in 16 (age: 8.23 ± 2.5) girls with TS and 13 age-matched controls over two time-points. Gray and white matter volume, surface area and cortical thickness were calculated from surfaced based segmentation of bilateral parietal cortices, and the NEPSY Arrows subtest was used to assess visual-spatial ability. Volumetric and cognitive scalars were modeled to obtain estimates of age-related change. The results show aberrant growth of white matter volume (P = 0.011, corrected) and surface area (P = 0.036, corrected) of the left superior parietal regions during childhood in girls with TS. Other parietal sub-regions were significantly smaller in girls with TS at both time-points but did not show different growth trajectories relative to controls. Furthermore, we found that visual-spatial skills showed a widening deficit for girls with TS relative to controls (P = 0.003). Young girls with TS demonstrate an aberrant trajectory of parietal cortical and cognitive development during childhood. Elucidating aberrant neurodevelopmental trajectories in this population is critical for determining specific stages of brain maturation that are particularly dependent on TS-related genetic and hormonal factors. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32256

  View details for PubMedID 25044604

• Topological methods reveal high and low functioning neuro-phenotypes within fragile X syndrome. Human brain mapping Romano, D., Nicolau, M., Quintin, E., Mazaika, P. K., Lightbody, A. A., Cody Hazlett, H., Piven, J., Carlsson, G., Reiss, A. L. 2014; 35 (9): 4904-4915

  Abstract

  Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability as well as the most common single-gene risk factor for autism. Our goal was to examine variation in brain structure in FXS with topological data analysis (TDA), and to assess how such variation is associated with measures of IQ and autism-related behaviors. To this end, we analyzed imaging and behavioral data from young boys (n = 52; aged 1.57-4.15 years) diagnosed with FXS. Application of topological methods to structural MRI data revealed two large subgroups within the study population. Comparison of these subgroups showed significant between-subgroup neuroanatomical differences similar to those previously reported to distinguish children with FXS from typically developing controls (e.g., enlarged caudate). In addition to neuroanatomy, the groups showed significant differences in IQ and autism severity scores. These results suggest that despite arising from a single gene mutation, FXS may encompass two biologically, and clinically separable phenotypes. In addition, these findings underscore the potential of TDA as a powerful tool in the search for biological phenotypes of neuropsychiatric disorders. Hum Brain Mapp 35:4904-4915, 2014. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/hbm.22521

  View details for PubMedID 24737721

  View details for PubMedCentralID PMC4113391

• Mapping Genetically Controlled Neural Circuits of Social Behavior and Visuo-Motor Integration by a Preliminary Examination of Atypical Deletions with Williams Syndrome PLOS ONE Hoeft, F., Dai, L., Haas, B. W., Sheau, K., Mimura, M., Mills, D., Galaburda, A., Bellugi, U., Korenberg, J. R., Reiss, A. L. 2014; 9 (8)

  Abstract

  In this study of eight rare atypical deletion cases with Williams-Beuren syndrome (WS; also known as 7q11.23 deletion syndrome) consisting of three different patterns of deletions, compared to typical WS and typically developing (TD) individuals, we show preliminary evidence of dissociable genetic contributions to brain structure and human cognition. Univariate and multivariate pattern classification results of morphometric brain patterns complemented by behavior implicate a possible role for the chromosomal region that includes: 1) GTF2I/GTF2IRD1 in visuo-spatial/motor integration, intraparietal as well as overall gray matter structures, 2) the region spanning ABHD11 through RFC2 including LIMK1, in social cognition, in particular approachability, as well as orbitofrontal, amygdala and fusiform anatomy, and 3) the regions including STX1A, and/or CYLN2 in overall white matter structure. This knowledge contributes to our understanding of the role of genetics on human brain structure, cognition and pathophysiology of altered cognition in WS. The current study builds on ongoing research designed to characterize the impact of multiple genes, gene-gene interactions and changes in gene expression on the human brain.

  View details for DOI 10.1371/journal.pone.0104088

  View details for Web of Science ID 000343231900037

  View details for PubMedID 25105779

  View details for PubMedCentralID PMC4126723

• Longitudinal profiles of adaptive behavior in fragile x syndrome. Pediatrics Klaiman, C., Quintin, E., Jo, B., Lightbody, A. A., Hazlett, H. C., Piven, J., Hall, S. S., Reiss, A. L. 2014; 134 (2): 315-324

  Abstract

  To examine longitudinally the adaptive behavior patterns in fragile X syndrome.Caregivers of 275 children and adolescents with fragile X syndrome and 225 typically developing children and adolescents (2-18 years) were interviewed with the Vineland Adaptive Behavior Scales every 2 to 4 years as part of a prospective longitudinal study.Standard scores of adaptive behavior in people with fragile X syndrome are marked by a significant decline over time in all domains for males and in communication for females. Socialization skills are a relative strength as compared with the other domains for males with fragile X syndrome. Females with fragile X syndrome did not show a discernible pattern of developmental strengths and weaknesses.This is the first large-scale longitudinal study to show that the acquisition of adaptive behavior slows as individuals with fragile X syndrome age. It is imperative to ensure that assessments of adaptive behavior skills are part of intervention programs focusing on childhood and adolescence in this condition.

  View details for DOI 10.1542/peds.2013-3990

  View details for PubMedID 25070318

• Using discrete trial training to identify specific learning impairments in boys with fragile x syndrome. Journal of autism and developmental disorders Hall, S. S., Hustyi, K. M., Hammond, J. L., Hirt, M., Reiss, A. L. 2014; 44 (7): 1659-1670

  Abstract

  We examined whether discrete trial training (DTT) could be used to identify learning impairments in mathematical reasoning in boys with fragile X syndrome (FXS). Boys with FXS, aged 10-23 years, and age and IQ-matched controls, were trained to match fractions to pie-charts and pie-charts to decimals either on a computer or with a trained behavior analyst using DTT. Participants with FXS obtained significantly lower learning rates on the fractions to pie-charts task, and were more likely to perseverate on previously reinforced responses during learning compared to controls. These data suggest that DTT can be used to identify specific learning impairments in boys with FXS, as well as other low-functioning individuals with developmental disabilities.

  View details for DOI 10.1007/s10803-014-2037-6

  View details for PubMedID 24452992

• Cognitive and Behavioral Correlates of Caudate Subregion Shape Variation in Fragile X Syndrome HUMAN BRAIN MAPPING Peng, D. X., Kelley, R. G., Quintin, E., Raman, M., Thompson, P. M., Reiss, A. L. 2014; 35 (6): 2861-2868

  Abstract

  Individuals with fragile X syndrome (FXS) exhibit frontal lobe-associated cognitive and behavioral deficits, including impaired general cognitive abilities, perseverative behaviors, and social difficulties. Neural signals related to these functions are communicated through frontostriatal circuits, which connect with distinct regions of the caudate nucleus (CN). Enlargement of the CN is the most robust and reproduced neuroanatomical abnormality in FXS, but very little is known on how this affects behavioral/cognitive outcomes in this condition. Here, we investigated topography within focal regions of the CN associated with prefrontal circuitry and its link with aberrant behavior and intellect in FXS. Imaging data were acquired from 48 individuals with FXS, 28 IQ-matched controls without FXS (IQ-CTL), and 36 typically developing controls (TD-CTL). Of the total participant count, cognitive and behavioral assessment data were obtained from 44 individuals with FXS and 27 participants in the IQ-CTL group. CN volume and topography were compared between groups. Correlations were performed between CN topography and cognitive as well as behavioral measures within FXS and IQ-CTL groups. As expected, the FXS group had larger CN compared with both IQ-CTL and TD-CTL groups. Correlations between focal CN topography and frontal lobe-associated cognitive and behavioral deficits in the FXS group supported the hypothesis that CN enlargement is related to abnormal orbitofrontal-caudate and dorsolateral-caudate circuitry in FXS. These findings deepen our understanding of neuroanatomical mechanisms underlying cognitive-behavioral problems in FXS and hold promise for informing future behavioral and psychopharmacological interventions targeting specific neural pathways.

  View details for DOI 10.1002/hbm.22376

  View details for Web of Science ID 000334555100028

  View details for PubMedID 24038999

• Aberrant Parietal Cortex Developmental Trajectories in Girls with Turner Syndrome and Related Visual-Spatial Cognitive Development: A Preliminary Study 69th Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry Green, T., Chromik, L. C., Mazaika, P. K., Fierro, K., Raman, M. M., Lazzeroni, L., Hong, D. S., Reiss, A. L. ELSEVIER SCIENCE INC. 2014: 346S–346S

  View details for Web of Science ID 000334101802222

• How Fragile X Syndrome Influences White Matter Structure? Investigating Differences in White Matter Between Individuals with Fragile X Syndrome and IQ-matched Controls Green, T., Barnea-Goraly, N., Raman, M. M., Quintin, E., Reiss, A. L. ELSEVIER SCIENCE INC. 2014: 99S

  View details for Web of Science ID 000334101800308

• Insula Measures and Emotional Cognitive Interplay in Youth with Post-Traumatic Stress Symptoms: Does Gender Matter? Carrion, V. G., Klabunde, M., Weems, C. F., Ramen, M., Reiss, A. L. ELSEVIER SCIENCE INC. 2014: 285S–286S

  View details for Web of Science ID 000334101802034

• Testing for association of the monoamine oxidase A promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome JOURNAL OF NEURODEVELOPMENTAL DISORDERS Wassink, T. H., Hazlett, H. C., Davis, L. K., Reiss, A. L., Piven, J. 2014; 6

  Abstract

  Autism and the fragile X syndrome (FXS) are related to each other genetically and symptomatically. A cardinal biological feature of both disorders is abnormalities of cerebral cortical brain volumes. We have previously shown that the monoamine oxidase A (MAOA) promoter polymorphism is associated with cerebral cortical volumes in children with autism, and we now sought to determine whether the association was also present in children with FXS.Participants included 47 2-year-old Caucasian boys with FXS, some of whom also had autism, as well as 34 2-year-old boys with idiopathic autism analyzed in a previous study. The MAOA promoter polymorphism was genotyped and tested for relationships with gray and white matter volumes of the cerebral cortical lobes and cerebro-spinal fluid volume of the lateral ventricles.MAOA genotype effects in FXS children were the same as those previously observed in idiopathic autism: the low activity MAOA promoter polymorphism allele was associated with increased gray and white matter volumes in all cerebral lobes. The effect was most pronounced in frontal lobe gray matter and all three white matter regions: frontal gray, F = 4.39, P = 0.04; frontal white, F = 5.71, P = 0.02; temporal white, F = 4.73, P = 0.04; parieto-occipital white, F = 5.00, P = 0.03. Analysis of combined FXS and idiopathic autism samples produced P values for these regions <0.01 and effect sizes of approximately 0.10.The MAOA promoter polymorphism is similarly associated with brain structure volumes in both idiopathic autism and FXS. These data illuminate a number of important aspects of autism and FXS heritability: a genetic effect on a core biological trait of illness, the specificity/generalizability of the genetic effect, and the utility of examining individual genetic effects on the background of a single gene disorder such as FXS.

  View details for DOI 10.1186/1866-1955-6-6

  View details for Web of Science ID 000334876800001

  View details for PubMedID 24669826

  View details for PubMedCentralID PMC3987046

• Influence of the x-chromosome on neuroanatomy: evidence from turner and klinefelter syndromes. journal of neuroscience Hong, D. S., Hoeft, F., Marzelli, M. J., Lepage, J., Roeltgen, D., Ross, J., Reiss, A. L. 2014; 34 (10): 3509-3516

  Abstract

  Studies of sex effects on neurodevelopment have traditionally focused on animal models investigating hormonal influences on brain anatomy. However, more recent evidence suggests that sex chromosomes may also have direct upstream effects that act independently of hormones. Sex chromosome aneuploidies provide ideal models to examine this framework in humans, including Turner syndrome (TS), where females are missing one X-chromosome (45X), and Klinefelter syndrome (KS), where males have an additional X-chromosome (47XXY). As these disorders essentially represent copy number variants of the sex chromosomes, investigation of brain structure across these disorders allows us to determine whether sex chromosome gene dosage effects exist. We used voxel-based morphometry to investigate this hypothesis in a large sample of children in early puberty, to compare regional gray matter volumes among individuals with one (45X), two (typically developing 46XX females and 46XY males), and three (47XXY) sex chromosomes. Between-group contrasts of TS and KS groups relative to respective sex-matched controls demonstrated highly convergent patterns of volumetric differences with the presence of an additional sex chromosome being associated with relatively decreased parieto-occipital gray matter volume and relatively increased temporo-insular gray matter volumes. Furthermore, z-score map comparisons between TS and KS cohorts also suggested that this effect occurs in a linear dose-dependent fashion. We infer that sex chromosome gene expression directly influences brain structure in children during early stages of puberty, extending our understanding of genotype-phenotype mechanisms underlying sex differences in the brain.

  View details for DOI 10.1523/JNEUROSCI.2790-13.2014

  View details for PubMedID 24599451

• Aberrant neurocognitive processing of fear in young girls with Turner syndrome SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE Hong, D. S., Bray, S., Haas, B. W., Hoeft, F., Reiss, A. L. 2014; 9 (3): 255-264

  Abstract

  Appraisal of fearful stimuli is an integral aspect of social cognition. Neural circuitry underlying this phenomenon has been well-described and encompasses a distributed network of affective and cognitive nodes. Interestingly, this ability to process fearful faces is impaired in Turner syndrome (TS), a genetic disorder of females in which all or part of an X chromosome is missing. However, neurofunctional correlates for this impairment have not been well-studied, particularly in young girls. Given that the core features of TS include X chromosome gene haploinsufficiency and secondary sex hormone deficiencies, investigation of fearful face processing may provide insights into the influence of X chromosome gene expression on this network. Therefore, we examined behavioral and neural responses during an explicit emotional face labeling task in 14 prepubertal girls with TS and 16 typically developing age-matched controls (6-13 years). We demonstrate that girls with TS have a specific impairment in the identification of fearful faces and show decreased activation in several cognitive control regions, including the anterior dorsal anterior cingulate cortex, dorsolateral prefrontal cortex and posterior cingulate gyrus. Our results indicate that aberrant functional activation in dorsal cognitive regions plays an integral role in appraisal of, and regulation of response to fear in TS.

  View details for DOI 10.1093/scan/nss133

  View details for Web of Science ID 000336488300001

  View details for PubMedID 23171616

  View details for PubMedCentralID PMC3980805

• Early signs of anomalous neural functional connectivity in healthy offspring of parents with bipolar disorder Singh, M., Chang, K. D., Kelley, R. G., Saggar, M., Reiss, A., Gotlib, I. H. WILEY-BLACKWELL. 2014: 47

  View details for Web of Science ID 000332169400083

• Early signs of anomalous neural functional connectivity in healthy offspring of parents with bipolar disorder Singh, M., Chang, K. D., Kelley, R. G., Saggar, M., Reiss, A., Gotlib, I. H. WILEY-BLACKWELL. 2014: 77

  View details for Web of Science ID 000332169400161

• Neuroanatomical correlates of inhibited temperament in offspring of parents with bipolar disorder Kim, E. J., Garrett, A., Boucher, S., Howe, M., Sanders, E., Reiss, A., Singh, M., Chang, K. D. WILEY-BLACKWELL. 2014: 89

  View details for Web of Science ID 000332169400200

• Regionally specific increased volume of the amygdala in Williams syndrome: Evidence from surface-based modeling HUMAN BRAIN MAPPING Haas, B. W., Sheau, K., Kelley, R. G., Thompson, P. M., Reiss, A. L. 2014; 35 (3): 866-874

  Abstract

  Williams syndrome (WS) is a condition caused by a contiguous deletion of approximately 26-28 genes from chromosome 7, and is characterized by abnormal social and emotional processing and abnormal structure and function of the amygdala. Prior studies show that the amygdala is relatively enlarged in WS, but very little is known regarding the regional specificity of increased amygdalar volume in this condition. Here we investigated the regional specificity of structural alterations of the amygdala in WS, compared to a typically developing (TD) control group. We acquired high resolution brain MRI data from 79 participants (39 WS, 40 TD) and used a surface-based analytical modeling approach. The WS group exhibited several areas of increased radial expansion of the amygdalar surface and no areas of decreased radial expansion of the amygdalar surface compared to TD controls. The areas found to exhibit particularly increased radial expansion in WS included the bilateral posterior cortical nucleus, lateral nucleus, and the central nucleus. This greater regional and anatomical specificity of altered amygdala structure in WS contributes to a model relating genetic risk in WS to the development of key brain regions for social and emotional functioning. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.

  View details for DOI 10.1002/hbm.22219

  View details for Web of Science ID 000334398500010

  View details for PubMedID 23152007

• Brain morphology in children with 47, XYY syndrome: a voxel- and surface-based morphometric study. Genes, brain, and behavior LePage, J., Hong, D. S., Raman, M., Marzelli, M., Roeltgen, D. P., Lai, S., Ross, J., Reiss, A. L. 2014; 13 (2): 127-134

  Abstract

  The neurocognitive and behavioral profile of individuals with 47,XYY is increasingly documented; however, very little is known about the effect of a supernumerary Y-chromosome on brain development. Establishing the neural phenotype associated with 47,XYY may prove valuable in clarifying the role of Y-chromosome gene dosage effects, a potential factor in several neuropsychiatric disorders that show a prevalence bias toward males, including autism spectrum disorders. Here, we investigated brain structure in 10 young boys with 47,XYY and 10 age-matched healthy controls by combining voxel-based morphometry (VBM) and surface-based morphometry (SBM). The VBM results show the existence of altered gray matter volume (GMV) in the insular and parietal regions of 47,XYY relative to controls, changes that were paralleled by extensive modifications in white matter (WM) bilaterally in the frontal and superior parietal lobes. The SBM analyses corroborated these findings and revealed the presence of abnormal surface area and cortical thinning in regions with abnormal GMV and WMV. Overall, these preliminary results demonstrate a significant impact of a supernumerary Y-chromosome on brain development, provide a neural basis for the motor, speech and behavior regulation difficulties associated with 47,XYY and may relate to sexual dimorphism in these areas.

  View details for DOI 10.1111/gbb.12107

  View details for PubMedID 24308542

  View details for PubMedCentralID PMC3918511

• Brain morphology in children with 47,XYY syndrome: a voxel- and surface-based morphometric study. Genes, brain, and behavior LePage, J., Hong, D. S., Raman, M., Marzelli, M., Roeltgen, D. P., Lai, S., Ross, J., Reiss, A. L. 2014; 13 (2): 127-134

  View details for DOI 10.1111/gbb.12107

  View details for PubMedID 24308542

• Cognitive functioning in young children with type 1 diabetes. Journal of the International Neuropsychological Society Cato, M. A., Mauras, N., Ambrosino, J., Bondurant, A., Conrad, A. L., Kollman, C., Cheng, P., Beck, R. W., Ruedy, K. J., Aye, T., Reiss, A. L., White, N. H., Hershey, T. 2014; 20 (2): 238-247

  Abstract

  The aim of this study was to assess cognitive functioning in children with type 1 diabetes (T1D) and examine whether glycemic history influences cognitive function. Neuropsychological evaluation of 216 children (healthy controls, n = 72; T1D, n = 144) ages 4-10 years across five DirecNet sites. Cognitive domains included IQ, Executive Functions, Learning and Memory, and Processing Speed. Behavioral, mood, parental IQ data, and T1D glycemic history since diagnosis were collected. The cohorts did not differ in age, gender or parent IQ. Median T1D duration was 2.5 years and average onset age was 4 years. After covarying age, gender, and parental IQ, the IQ and the Executive Functions domain scores trended lower (both p = .02, not statistically significant adjusting for multiple comparisons) with T1D relative to controls. Children with T1D were rated by parents as having more depressive and somatic symptoms (p < .001). Learning and memory (p = .46) and processing speed (p = .25) were similar. Trends in the data supported that the degree of hyperglycemia was associated with Executive Functions, and to a lesser extent, Child IQ and Learning and Memory. Differences in cognition are subtle in young children with T1D within 2 years of onset. Longitudinal evaluations will help determine whether these findings change or become more pronounced with time. (JINS, 2014, 20, 238-247).

  View details for DOI 10.1017/S1355617713001434

  View details for PubMedID 24512675

• High success rates of sedation-free brain MRI scanning in young children using simple subject preparation protocols with and without a commercial mock scanner-the Diabetes Research in Children Network (DirecNet) experience. Pediatric radiology Barnea-Goraly, N., Weinzimer, S. A., Ruedy, K. J., Mauras, N., Beck, R. W., Marzelli, M. J., Mazaika, P. K., Aye, T., White, N. H., Tsalikian, E., Fox, L., Kollman, C., Cheng, P., Reiss, A. L. 2014; 44 (2): 181-186

  Abstract

  The ability to lie still in an MRI scanner is essential for obtaining usable image data. To reduce motion, young children are often sedated, adding significant cost and risk.We assessed the feasibility of using a simple and affordable behavioral desensitization program to yield high-quality brain MRI scans in sedation-free children.222 children (4-9.9 years), 147 with type 1 diabetes and 75 age-matched non-diabetic controls, participated in a multi-site study focused on effects of type 1 diabetes on the developing brain. T1-weighted and diffusion-weighted imaging (DWI) MRI scans were performed. All children underwent behavioral training and practice MRI sessions using either a commercial MRI simulator or an inexpensive mock scanner consisting of a toy tunnel, vibrating mat, and video player to simulate the sounds and feel of the MRI scanner.205 children (92.3%), mean age 7 ± 1.7 years had high-quality T1-W scans and 174 (78.4%) had high-quality diffusion-weighted scans after the first scan session. With a second scan session, success rates were 100% and 92.5% for T1-and diffusion-weighted scans, respectively. Success rates did not differ between children with type 1 diabetes and children without diabetes, or between centers using a commercial MRI scan simulator and those using the inexpensive mock scanner.Behavioral training can lead to a high success rate for obtaining high-quality T1-and diffusion-weighted brain images from a young population without sedation.

  View details for DOI 10.1007/s00247-013-2798-7

  View details for PubMedID 24096802

  View details for PubMedCentralID PMC3946760

• Alterations in white matter structure in young children with type 1 diabetes. Diabetes care Barnea-Goraly, N., Raman, M., Mazaika, P., Marzelli, M., Hershey, T., Weinzimer, S. A., Aye, T., Buckingham, B., Mauras, N., White, N. H., Fox, L. A., Tansey, M., Beck, R. W., Ruedy, K. J., Kollman, C., Cheng, P., Reiss, A. L. 2014; 37 (2): 332-340

  Abstract

  To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children.Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects.These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

  View details for DOI 10.2337/dc13-1388

  View details for PubMedID 24319123

  View details for PubMedCentralID PMC3898758

• A preliminary longitudinal volumetric MRI study of amygdala and hippocampal volumes in autism PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Barnea-Goraly, N., Frazier, T. W., Piacenza, L., Minshew, N. J., Keshavan, M. S., Reiss, A. L., Hardan, A. Y. 2014; 48: 124-128

  Abstract

  Previous studies suggest that amygdala volume, when compared with healthy controls, is increased in young children with autism, is unchanged in cohorts of older youth, and is smaller in adults. Hippocampal volume, however, does not appear to have age-related changes, and it is unclear whether individuals with autism have volumetric differences in this structure. The goal of this pilot investigation is to characterize the developmental trajectories of the amygdala and hippocampus in children with autism between the ages of 8 and 14years and to examine clinical correlates of volume change.Twenty-three children with autism and 23 controls between the ages of 8 and 12 underwent a magnetic resonance imaging procedure of the brain (T1-weighted) at two time points. Nine children with autism and 14 controls had good quality scans from both time points; however, all usable scans from all subjects (15 children with autism and 22 controls) were included in a mixed effect analysis. Regression models were used to estimate group differences in amygdala and hippocampal volumes. Changes in amygdala and hippocampal volumes (Time 2-Time 1) were correlated with clinical severity measures.Amygdala volume changes with time were similar between the two groups. Within the autism group, right amygdala volume change was correlated with the ability to establish appropriate eye contact. Right hippocampal volume was significantly increased in the autism group when compared with controls. Differences in right hippocampal volume change with time between the two groups approached significance.This study provides preliminary evidence of normalization of amygdala volumes in late childhood and adolescence. It also suggests that hippocampal volumetric differences may exist in autism in late childhood and adolescence.

  View details for DOI 10.1016/j.pnpbp.2013.09.010

  View details for Web of Science ID 000328074200018

  View details for PubMedID 24075822

• Targeted intervention to increase creative capacity and performance: A randomized controlled pilot study THINKING SKILLS AND CREATIVITY Kienitz, E., Quintin, E., Saggar, M., Bott, N. T., Royalty, A., Hong, D. W., Liu, N., Chien, Y., Hawthorne, G., Reiss, A. L. 2014; 13: 57-66

  View details for DOI 10.1016/j.tsc.2014.03.002

  View details for Web of Science ID 000340692800006

• Alterations in white matter structure in young children with type 1 diabetes mellitus DIABETES CARE Barnea-Goraly, N., Raman, M., Mazaika, P., Marzelli, M., et al 2014: 332–40

  Abstract

  To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children.Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects.These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

  View details for DOI 10.2337/dc13-1388

  View details for PubMedCentralID PMC3898758

• Brain morphology in children with 47,XYY syndrome: a voxel-and surface-based morphometric study GENES, BRAIN AND BEHAVIOR Lepage, J., Hong, D. S., Raman, M., Marzelli, M., et al 2014: 127–34

  Abstract

  The neurocognitive and behavioral profile of individuals with 47,XYY is increasingly documented; however, very little is known about the effect of a supernumerary Y-chromosome on brain development. Establishing the neural phenotype associated with 47,XYY may prove valuable in clarifying the role of Y-chromosome gene dosage effects, a potential factor in several neuropsychiatric disorders that show a prevalence bias toward males, including autism spectrum disorders. Here, we investigated brain structure in 10 young boys with 47,XYY and 10 age-matched healthy controls by combining voxel-based morphometry (VBM) and surface-based morphometry (SBM). The VBM results show the existence of altered gray matter volume (GMV) in the insular and parietal regions of 47,XYY relative to controls, changes that were paralleled by extensive modifications in white matter (WM) bilaterally in the frontal and superior parietal lobes. The SBM analyses corroborated these findings and revealed the presence of abnormal surface area and cortical thinning in regions with abnormal GMV and WMV. Overall, these preliminary results demonstrate a significant impact of a supernumerary Y-chromosome on brain development, provide a neural basis for the motor, speech and behavior regulation difficulties associated with 47,XYY and may relate to sexual dimorphism in these areas.

  View details for DOI 10.1111/gbb.12107

  View details for PubMedCentralID PMC3918511

• Compact and Informative Representation of Functional Connectivity for Predictive Modeling 17th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) Rustamov, R. M., Romano, D., Reiss, A. L., Guibas, L. J. SPRINGER-VERLAG BERLIN. 2014: 153–60

  Abstract

  Resting state functional connectivity holds great potential for diagnostic prediction of neurological and psychiatric illness. This paper introduces a compact and information-rich representation of connectivity that is geared directly towards predictive modeling. Our representation does not require a priori identification of localized regions of interest, yet provides a mechanism for interpretation of classifier weights. Experiments confirm increased accuracy associated with our representation and yield interpretations consistent with known physiology.

  View details for Web of Science ID 000346250200020

• Revealing the neural networks associated with processing of natural social interaction and the related effects of actor-orientation and face-visibility NEUROIMAGE Saggar, M., Shelly, E. W., Lepage, J., Hoeft, F., Reiss, A. L. 2014; 84: 648-656

  Abstract

  Understanding the intentions and desires of those around us is vital for adapting to a dynamic social environment. In this paper, a novel event-related functional Magnetic Resonance Imaging (fMRI) paradigm with dynamic and natural stimuli (2s video clips) was developed to directly examine the neural networks associated with processing of gestures with social intent as compared to nonsocial intent. When comparing social to nonsocial gestures, increased activation in both the mentalizing (or theory of mind) and amygdala networks was found. As a secondary aim, a factor of actor-orientation was included in the paradigm to examine how the neural mechanisms differ with respect to personal engagement during a social interaction versus passively observing an interaction. Activity in the lateral occipital cortex and precentral gyrus was found sensitive to actor-orientation during social interactions. Lastly, by manipulating face-visibility we tested whether facial information alone is the primary driver of neural activation differences observed between social and nonsocial gestures. We discovered that activity in the posterior superior temporal sulcus (pSTS) and fusiform gyrus (FFG) was partially driven by observing facial expressions during social gestures. Altogether, using multiple factors associated with processing of natural social interaction, we conceptually advance our understanding of how social stimuli is processed in the brain and discuss the application of this paradigm to clinical populations where atypical social cognition is manifested as a key symptom.

  View details for DOI 10.1016/j.neuroimage.2013.09.046

  View details for Web of Science ID 000328868600059

  View details for PubMedID 24084068

  View details for PubMedCentralID PMC3903510

• Creativity training enhances goal-directed attention and information processing THINKING SKILLS AND CREATIVITY Bott, N., Quintin, E., Saggar, M., Kienitz, E., Royalty, A., Hong, D. W., Liu, N., Chien, Y., Hawthorne, G., Reiss, A. L. 2014; 13: 120-128

  View details for DOI 10.1016/j.tsc.2014.03.005

  View details for Web of Science ID 000340692800012

• Aberrant Functional Network Recruitment of Posterior Parietal Cortex in Turner Syndrome HUMAN BRAIN MAPPING Bray, S., Hoeft, F., Hong, D. S., Reiss, A. L. 2013; 34 (12): 3117-3128

  Abstract

  Turner syndrome is a genetic disorder caused by the complete or partial absence of an X chromosome in affected women. Individuals with TS show characteristic difficulties with executive functions, visual-spatial and mathematical cognition, with relatively intact verbal skills, and congruent abnormalities in structural development of the posterior parietal cortex (PPC). The functionally heterogeneous PPC has recently been investigated using connectivity-based clustering methods, which sub-divide a given region into clusters of voxels showing similar structural or functional connectivity to other brain regions. In the present study, we extended this method to compare connectivity-based clustering between groups and investigate whether functional networks differentially recruit the PPC in TS. To this end, we parcellated the PPC into sub-regions based on temporal correlations with other regions of the brain. fMRI data were collected from 15 girls with TS and 14 typically developing (TD) girls, aged 7-14, while they performed a visual-spatial task. Temporal correlations between voxels in the PPC and a set of seed regions were calculated, and the PPC divided into clusters of voxels showing similar connectivity. It was found that in general the PPC parcellates similarly in TS and TD girls, but that regions in bilateral inferior parietal lobules, and posterior right superior parietal lobule, were reliably recruited by different networks in TS relative to TD participants. These regions showed weaker correlation in TS with a set of regions involved in visual processing. These results suggest that abnormal development of visuospatial functional networks in TS may relate to the well documented cognitive difficulties in this disorder.

  View details for DOI 10.1002/hbm.22131

  View details for PubMedID 22711287

• Differential Effects of Estrogen Hormone Therapy on CA1 Hippocampal Subfield Volume Change over a 2-Year Observation Period in Postmenopausal Women at Risk for Alzheimer's Disease: Conjugated Equine Estrogen Versus Estradiol Kenna, H., Sheau, K., Wroolie, T., Kelley, R. G., Williams, K., Reiss, A., Rasgon, N. NATURE PUBLISHING GROUP. 2013: S137

  View details for Web of Science ID 000209477100255

• High Rates of Comorbid Depressive and Anxiety Disorders Among Women with Premutation of the FMR1 Gene AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Kenna, H. A., Tartter, M., Hall, S. S., Lightbody, A. A., Quynh Nguyen, Q., de los Angeles, C. P., Reiss, A. L., Rasgon, N. L. 2013; 162 (8): 872-878

  Abstract

  Phenotypic variations are emerging from investigations of carriers of the fragile X mental retardation 1 (FMR1) premutation gene (55 to 200 CGG repeats). Initial studies suggest elevated psychiatric and reproductive system dysfunction, but have largely used self-reports for assessment of psychiatric history. The present study used diagnostic psychiatric interviews and assessed reproductive and menstrual history in women with FMR1 premutation. History of psychiatric diagnoses and data on reproductive functioning were collected in 46 women with FMR1 premutation who were mothers of at least one child with the fragile X full mutation. Results showed a significantly earlier age of menopause (mean age = 45.6 years) relative to the national average age of menopause (mean age = 51 years) and a high rate (76%) of lifetime depressive or anxiety history, with 43% of the overall sample reporting a comorbid history of both diagnoses. Compared to those free of psychiatric history, significantly longer premutation length was observed among women with psychiatric history after adjusting for age, with comorbid women having the highest number of CGG repeats (mean = 95.8) compared to women free of psychiatric history (mean = 79.9). Psychiatric history did not appear significantly related to reproductive system dysfunction, though results may have been obscured by the high rates of psychiatric dysfunction in the sample. These data add to the growing evidence base that women with the FMR1 premutation have an increased risk of psychiatric illness and risk for early menopause. Future investigations may benefit from inclusion of biochemical reproductive markers and longitudinal assessment of psychiatric and reproductive functioning. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.b.32196

  View details for Web of Science ID 000326506700010

• Humor processing in children: Influence of temperament, age and IQ NEUROPSYCHOLOGIA Vrticka, P., Black, J. M., Neely, M., Shelly, E. W., Reiss, A. L. 2013; 51 (13): 2799-2811

  Abstract

  Emerging evidence from fMRI studies suggests that humor processing is a specific social cognitive-affective human function that comprises two stages. The first stage (cognitive humor component) involves the detection and resolution of incongruity, and is associated with activity in temporo-occipito-parietal brain areas. The second stage (emotional humor component) comprises positive feelings related to mirth/reward, and is linked with reward-related activity in mesocorticolimbic circuits. In healthy adults, humor processing was shown to be moderated by temperament traits like intro-/extraversion, neuroticism, or social anxiety, representing risk factors for psychopathology. However, comparable data from early developmental stages is crucially lacking. Here, we report for the first time data from 22 children (ages 6 to 13) revealing an influence of temperament on humor processing. Specifically, we assessed the effects of Emotionality, Shyness, and Sociability, which are analogous to neuroticism, behavioral inhibition/fear and extraversion in adults. We found Emotionality to be positively, but Shyness negatively associated with brain activity linked with both cognitive and emotional humor components. In addition, Shyness and Sociability were positively related to activity in the periaqueductal gray region during humor processing. These findings are of potential clinical relevance regarding the early detection of childhood psychopathology. Previous data on humor processing in both adults and children furthermore suggest that intelligence (IQ) supports incongruity detection and resolution, whereas mirth and associated brain activity diminishes with increasing age. Here, we found that increasing age and IQ were linked with stronger activity to humor in brain areas implicated in the cognitive component of humor. Such data suggest that humor processing undergoes developmental changes and is moderated by higher IQ scores, both factors likely improving incongruity detection and resolution.

  View details for DOI 10.1016/j.neuropsycho1ogia.2013.09.028

  View details for Web of Science ID 000328869400033

  View details for PubMedID 24060844

• Deformations of amygdala morphology in familial pediatric bipolar disorder BIPOLAR DISORDERS Kelley, R., Chang, K. D., Garrett, A., Alegria, D., Thompson, P., Howe, M., Reiss, A. L. 2013; 15 (7): 795-802

  Abstract

  Smaller amygdalar volumes have been consistently observed in pediatric bipolar disorder subjects compared to healthy control subjects. Whether smaller amygdalar volume is a consequence or antecedent of the first episode of mania is not known. Additionally, smaller volume has not been localized to specific amygdala subregions.We compared surface contour maps of the amygdala between 22 youths at high risk for bipolar disorder, 26 youths meeting full diagnostic criteria for pediatric familial bipolar disorder, and 24 healthy control subjects matched for age, gender, and intelligence quotient. Amygdalae were manually delineated on three-dimensional spoiled gradient echo images by a blinded rater using established tracing protocols. Statistical surface mesh modeling algorithms supported by permutation statistics were used to identify regional surface differences between the groups.When compared to high-risk subjects and controls, youth with bipolar disorder showed surface deformations in specific amygdalar subregions, suggesting smaller volume of the basolateral nuclei. The high-risk subjects did not differ from controls in any subregion.These findings support previous reports of smaller amygdala volume in pediatric bipolar disorder and map the location of abnormality to specific amygdala subregions. These subregions have been associated with fear conditioning and emotion-enhanced memory. The absence of amygdala size abnormalities in youth at high risk for bipolar disorder suggests that reductions might occur after the onset of mania.

  View details for DOI 10.1111/bdi.12114

  View details for Web of Science ID 000330039800008

• Identifying large-scale brain networks in fragile x syndrome. JAMA psychiatry Hall, S. S., Jiang, H., Reiss, A. L., Greicius, M. D. 2013; 70 (11): 1215-1223

  Abstract

  Fragile X syndrome (FXS) is an X-linked neurogenetic disorder characterized by a cognitive and behavioral phenotype resembling features of autism spectrum disorder. Until now, research has focused largely on identifying regional differences in brain structure and function between individuals with FXS and various control groups. Very little is known about the large-scale brain networks that may underlie the cognitive and behavioral symptoms of FXS.To identify large-scale, resting-state networks in FXS that differ from control individuals matched on age, IQ, and severity of behavioral and cognitive symptoms.Cross-sectional, in vivo neuroimaging study conducted in an academic medical center. Participants (aged 10-23 years) included 17 males and females with FXS and 16 males and females serving as controls.Univariate voxel-based morphometric analyses, fractional amplitude of low-frequency fluctuations (fALFF) analysis, and group-independent component analysis with dual regression.Patients with FXS showed decreased functional connectivity in the salience, precuneus, left executive control, language, and visuospatial networks compared with controls. Decreased fALFF in the bilateral insular, precuneus, and anterior cingulate cortices also was found in patients with FXS compared with control participants. Furthermore, fALFF in the left insular cortex was significantly positively correlated with IQ in patients with FXS. Decreased gray matter density, resting-state connectivity, and fALFF converged in the left insular cortex in patients with FXS.Fragile X syndrome results in widespread reductions in functional connectivity across multiple cognitive and affective brain networks. Converging structural and functional abnormalities in the left insular cortex, a region also implicated in individuals diagnosed with autism spectrum disorder, suggests that insula integrity and connectivity may be compromised in FXS. This method could prove useful in establishing an imaging biomarker for FXS.

  View details for DOI 10.1001/jamapsychiatry.2013.247

  View details for PubMedID 24068330

• Developmental Variation in Amygdala Volumes Among Children With Posttraumatic Stress DEVELOPMENTAL NEUROPSYCHOLOGY Weems, C. F., Scott, B. G., Russell, J. D., Reiss, A. L., Carrion, V. G. 2013; 38 (7): 481-495

  Abstract

  This article examined associations between indices of maturation (age and Tanner stage) and amygdala volumes in 24 youth (aged 7-14) with posttraumatic stress disorder symptoms and a matched control group. Fifteen of the youth with exposure to trauma were also re-evaluated one year later. A positive association between maturation and right amygdala volumes was observed in the trauma group but not in controls. Associations with maturation remained when controlling for a number of possible covariates and over time. Developmentally younger youth (Tanner stage 1 and 2) showed increases and older (Tanner stage 3 and 4) decreases in right amygdala volumes.

  View details for DOI 10.1080/87565641.2013.820307

  View details for Web of Science ID 000326069700004

  View details for PubMedID 24138217

• Cortical Brain Morphology in Young, Estrogen-Naive, and Adolescent, Estrogen-Treated Girls with Turner Syndrome CEREBRAL CORTEX Lepage, J., Mazaika, P. K., Hong, D. S., Raman, M., Reiss, A. L. 2013; 23 (9): 2159-2168

  Abstract

  Turner syndrome (TS) is a genetic condition that permits direct investigation of the complex interaction among genes, hormones, behavior, and brain development. Here, we used automated segmentation and surface-based morphometry to characterize the differences in brain morphology in children (n = 30) and adolescents (n = 16) with TS relative to age- and sex-matched control groups (n = 21 and 24, respectively). Our results show that individuals with TS, young and adolescent, present widespread reduction of gray matter volume, white matter volume and surface area (SA) over both parietal and occipital cortices bilaterally, as well as enlarged amygdala. In contrast to the young cohort, adolescents with TS showed significantly larger mean cortical thickness and significantly smaller total SA compared with healthy controls. Exploratory developmental analyses suggested aberrant regional brain maturation in the parahippocampal gyrus and orbitofrontal regions from childhood to adolescence in TS. These findings show the existence of abnormal brain morphology early in development in TS, but also suggest the presence of altered neurodevelopmental trajectories in some regions, which could potentially be the consequences of estrogen deficiency, both pre- and postnatally.

  View details for DOI 10.1093/cercor/bhs195

  View details for Web of Science ID 000322661100013

  View details for PubMedID 22806268

• Outcome Measures for Clinical Trials in Fragile X Syndrome JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Berry-Kravis, E., Hessl, D., Abbeduto, L., Reiss, A. L., Beckel-Mitchener, A., Urv, T. K. 2013; 34 (7): 508-522

  Abstract

  Progress in basic neuroscience has led to identification of molecular targets for treatment in fragile X syndrome (FXS) and other neurodevelopmental disorders; however, there is a gap in translation to targeted therapies in humans. One major obstacle to the demonstration of efficacy in human trials has been the lack of generally accepted endpoints to assess improvement in function in individuals with FXS. To address this problem, the National Institutes of Health convened a meeting of leading scientists and clinicians with the goal of identifying and standardizing outcome measures for use as potential endpoints in clinical trials in FXS.Participants in the meeting included FXS experts, experts in the design and implementation of clinical trials and measure development, and representatives from advocacy groups, industry, and federal agencies.The group generated recommendations for optimal outcome measures in cognitive, behavioral, and biomarker/medical domains, including additional testing and validation of existing measures and development of new measures in areas of need. Although no one endpoint or set of endpoints could be identified that met all criteria as an optimal measure, recommendations are presented in this report.The report is expected to guide the selection of measures in clinical trials and lead to the use of a more consistent battery of measures across trials. Furthermore, this will help to direct research toward gaps in the development of validated FXS-specific outcome measures and to assist with interpretation of clinical trial data by creating templates for measurement of treatment efficacy.

  View details for Web of Science ID 000330359000008

  View details for PubMedID 24042082

• Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study JOURNAL OF NEURODEVELOPMENTAL DISORDERS Bruno, J. L., Shelly, E. W., Quintin, E., Rostami, M., Patnaik, S., Spielman, D., Mayer, D., Gu, M., Lightbody, A. A., Reiss, A. L. 2013; 5

  Abstract

  The profile of cognitive and behavioral variation observed in individuals with fragile X syndrome (FXS), the most common known cause of inherited intellectual impairment, suggests aberrant functioning of specific brain systems. Research investigating animal models of FXS, characterized by limited or lack of fragile X mental retardation protein, (FMRP), has linked brain dysfunction to deficits in the cholinergic and glutamatergic systems. Thus, we sought to examine in vivo levels of neurometabolites related to cholinergic and glutamatergic functioning in males and females with FXS.The study participants included 18 adolescents and young adults with FXS, and a comparison group of 18 individuals without FXS matched for age, sex and general intellectual functioning. Proton magnetic resonance spectroscopy (MRS) was used to assess neurometabolite levels in the caudate nucleus, a region known to be greatly enlarged and involved in abnormal brain circuitry in individuals with FXS. A general linear model framework was used to compare group differences in metabolite concentration.We observed a decrease in choline (P = 0.027) and in glutamate + glutamine (P = 0.032) in the caudate nucleus of individuals with FXS, relative to individuals in the comparison group.This study provides evidence of metabolite differences in the caudate nucleus, a brain region of potential importance to our understanding of the neural deficits underlying FXS. These metabolic differences may be related to aberrant receptor signaling seen in animal models. Furthermore, identification of the specific neurometabolites involved in FXS dysfunction could provide critical biomarkers for the design and efficacy tracking of disease-specific pharmacological treatments.

  View details for DOI 10.1186/1866-1955-5-20

  View details for Web of Science ID 000324055000001

  View details for PubMedCentralID PMC3766683

• Sex differences during humor appreciation in child-sibling pairs. Social neuroscience Vrticka, P., Neely, M., Walter Shelly, E., Black, J. M., Reiss, A. L. 2013; 8 (4): 291-304

  Abstract

  The developmental origin of sex differences in adult brain function is poorly understood. Elucidating neural mechanisms underlying comparable cognitive functionality in both children and adults is required to address this gap. Humor appreciation represents a particularly relevant target for such developmental research because explanatory theories apply across the life span, and underlying neurocircuitry shows sex differences in adults. As a positive mood state, humor is also of interest due to sex differences in rates of depression, a disorder afflicting twice as many women as men. In this study, we employed functional magnetic resonance imaging (fMRI) to investigate brain responses to funny versus positive (and neutral) video clips in 22 children, ages 6-13 years, including eight sibling-pairs. Our data revealed increased activity to funny clips in bilateral temporo-occipital cortex, midbrain, and amygdala in girls. Conversely, we found heightened activation to positive clips in bilateral inferior parietal lobule, fusiform gyrus, inferior frontal gyrus, amygdala, and ventromedial prefrontal cortex in boys. Many of these effects persisted when looking at sibling-pairs only. We interpret such findings as reflecting the presence of early sex divergence in reward saliency or expectation and stimulus relevance attribution. These findings are discussed in the context of evolutionary and developmental theories of humor function.

  View details for DOI 10.1080/17470919.2013.794751

  View details for PubMedID 23672302

• Applying tensor-based morphometry to parametric surfaces can improve MRI-based disease diagnosis NEUROIMAGE Wang, Y., Yuan, L., Shi, J., Greve, A., Ye, J., Toga, A. W., Reiss, A. L., Thompson, P. M. 2013; 74: 209-230

  Abstract

  Many methods have been proposed for computer-assisted diagnostic classification. Full tensor information and machine learning with 3D maps derived from brain images may help detect subtle differences or classify subjects into different groups. Here we develop a new approach to apply tensor-based morphometry to parametric surface models for diagnostic classification. We use this approach to identify cortical surface features for use in diagnostic classifiers. First, with holomorphic 1-forms, we compute an efficient and accurate conformal mapping from a multiply connected mesh to the so-called slit domain. Next, the surface parameterization approach provides a natural way to register anatomical surfaces across subjects using a constrained harmonic map. To analyze anatomical differences, we then analyze the full Riemannian surface metric tensors, which retain multivariate information on local surface geometry. As the number of voxels in a 3D image is large, sparse learning is a promising method to select a subset of imaging features and to improve classification accuracy. Focusing on vertices with greatest effect sizes, we train a diagnostic classifier using the surface features selected by an L1-norm based sparse learning method. Stability selection is applied to validate the selected feature sets. We tested the algorithm on MRI-derived cortical surfaces from 42 subjects with genetically confirmed Williams syndrome and 40 age-matched controls, multivariate statistics on the local tensors gave greater effect sizes for detecting group differences relative to other TBM-based statistics including analysis of the Jacobian determinant and the largest eigenvalue of the surface metric. Our method also gave reasonable classification results relative to the Jacobian determinant, the pair of eigenvalues of the Jacobian matrix and volume features. This analysis pipeline may boost the power of morphometry studies, and may assist with image-based classification.

  View details for DOI 10.1016/j.neuroimage.2013.02.011

  View details for Web of Science ID 000317441300022

  View details for PubMedID 23435208

  View details for PubMedCentralID PMC3641904

• Genomic imprinting effects of the x chromosome on brain morphology. journal of neuroscience Lepage, J., Hong, D. S., Mazaika, P. K., Raman, M., Sheau, K., Marzelli, M. J., Hallmayer, J., Reiss, A. L. 2013; 33 (19): 8567-8574

  Abstract

  There is increasing evidence that genomic imprinting, a process by which certain genes are expressed in a parent-of-origin-specific manner, can influence neurogenetic and psychiatric manifestations. While some data suggest possible imprinting effects of the X chromosome on physical and cognitive characteristics in humans, there is no compelling evidence that X-linked imprinting affects brain morphology. To address this issue, we investigated regional cortical volume, thickness, and surface area in 27 healthy controls and 40 prepubescent girls with Turner syndrome (TS), a condition caused by the absence of one X chromosome. Of the young girls with TS, 23 inherited their X chromosome from their mother (X(m)) and 17 from their father (X(p)). Our results confirm the existence of significant differences in brain morphology between girls with TS and controls, and reveal the presence of a putative imprinting effect among the TS groups: girls with X(p) demonstrated thicker cortex than those with X(m) in the temporal regions bilaterally, while X(m) individuals showed bilateral enlargement of gray matter volume in the superior frontal regions compared with X(p). These data suggest the existence of imprinting effects of the X chromosome that influence both cortical thickness and volume during early brain development, and help to explain variability in cognitive and behavioral manifestations of TS with regard to the parental origin of the X chromosome.

  View details for DOI 10.1523/JNEUROSCI.5810-12.2013

  View details for PubMedID 23658194

• Structural MRI Investigations in Twins with Autism 68th Annual Scientific Meeting of the Society-of-Biological-Psychiatry Hardan, A. Y., Hallmayer, J., Lazzeroni, L., Berquist, S., Raman, M. R., Patnaik, S., Phillips, J., Reiss, A. L., Cleveland, S. ELSEVIER SCIENCE INC. 2013: 88S–88S

  View details for Web of Science ID 000318671800269

• Longitudinal Changes in Emotion-Related Brain Function in Adolescents with and At-Risk for Bipolar Disorder Garrett, A., Reiss, A., Boucher, S., Kelley, R., Howe, M., Chang, K. ELSEVIER SCIENCE INC. 2013: 188S–189S

  View details for Web of Science ID 000318671800582

• Developmental Trajectory of Amygdala Volume in Prepubertal Girls with Turner Syndrome 68th Annual Scientific Meeting of the Society-of-Biological-Psychiatry Green, T., Hong, D., Fierro, K., Quintin, E., Raman, M., Reiss, A. ELSEVIER SCIENCE INC. 2013: 84S–84S

  View details for Web of Science ID 000318671800258

• Insular cortex abnormalities in psychotic major depression: relationship to gender and psychotic symptoms. Neuroscience research Cohen, J. D., Nichols, T., Keller, J., Gomez, R. G., Schatzberg, A. F., Reiss, A. L. 2013; 75 (4): 331-339

  Abstract

  Recent data suggests that psychotic major depression (PMD) may be a discrete disorder distinguishable from nonpsychotic major depression (NPMD), and that patients with PMD may be more similar to individuals with schizophrenia than individuals with NPMD. The insula is a brain region in which morphometric changes have been associated with psychotic symptom severity in schizophrenia and affective psychosis. It was hypothesized that insular volumes would be reduced in PMD compared to NPMD and controls, and insular volumes would correlate with psychosis but not depression severity. Insular gray matter volumes were measured in PMD and NPMD patients and matched healthy controls using magnetic resonance images and manual morphometry. Clinical measures of illness severity were obtained to determine their relationship with insular volume. Posterior insular volumes were significantly reduced in PMD compared to HC. There were also significant group-by-gender interactions for total, anterior and posterior insular volumes. Using Pearson product-moment correlations, anterior insular volumes did not correlate with depression severity. Left anterior insular volume was significantly correlated with total and positive symptom psychosis severity in the PMD group. Atypical insular morphometry may be related to the inability to distinguish between internally and externally generated sensory inputs characteristic of psychosis.

  View details for DOI 10.1016/j.neures.2013.02.005

  View details for PubMedID 23471015

  View details for PubMedCentralID PMC3662543

• Impact of cognitive profile on social functioning in prepubescent females with Turner syndrome CHILD NEUROPSYCHOLOGY Lepage, J., Dunkin, B., Hong, D. S., Reiss, A. L. 2013; 19 (2): 161-172

  Abstract

  Social deficits are prevalent in Turner syndrome (TS); however, the extent to which these difficulties are secondary to characteristic cognitive impairments is not well known. Here, we sought to establish the relative contribution of executive functions, visuospatial abilities, and IQ to social difficulties in young girls with TS. Forty TS girls and 19 typically developing (TD) children were assessed with the Social Responsiveness Scale (SRS), the Motor-Free Visual Spatial Test (MVPT-3), the Behavior Rating Inventory of Executive Function (BRIEF), and an IQ test. Hierarchical multiple regression analyses were conducted with the SRS subscales as outcome variables. In a first step, the cognitive factors were entered (verbal IQ, BRIEF global score, MVPT-3, and age), followed by the group variable in a second step. In comparison to TD, TS participants were significantly impaired on all main measures. All six regression models with the SRS subscales were significant and revealed that global executive functions explained the largest portion of the variance on all subscales and the total score. Even after controlling for cognitive elements, the group factor still explained a significant portion of the variance of the Social Cognition, Social Awareness, and Autistic Mannerisms subscales. In contrast, the group factor was not a significant predictor of Social Motivation and Social Communication scores. These results suggest that executive dysfunctions play a role in social impairments encountered in TS, but also that some specific aspects of social behavior are altered beyond what can be attributed to cognitive difficulties in this population.

  View details for DOI 10.1080/09297049.2011.647900

  View details for PubMedID 22372383

• Fasting plasma insulin and the default mode network in women at risk for Alzheimer's disease NEUROBIOLOGY OF AGING Kenna, H., Hoeft, F., Kelley, R., Wroolie, T., Demuth, B., Reiss, A., Rasgon, N. 2013; 34 (3): 641-649

  Abstract

  Brain imaging studies in Alzheimer's disease research have demonstrated structural and functional perturbations in the hippocampus and default mode network (DMN). Additional evidence suggests risk for pathological brain aging in association with insulin resistance (IR). This study piloted investigation of associations of IR with DMN-hippocampal functional connectivity among postmenopausal women at risk for Alzheimer's disease. Twenty middle-aged women underwent resting state functional magnetic resonance imaging. Subjects were dichotomized relative to fasting plasma insulin levels (i.e., > 8 μIU/mL [n = 10] and < 8 μIU/mL [n = 10]), and functional connectivity analysis contrasted their respective blood oxygen level-dependent signal correlation between DMN and hippocampal regions. Higher-insulin women had significantly reduced positive associations between the medial prefrontal cortex and bilateral parahippocampal regions extending to the right hippocampus, and conversely, between the left and right hippocampus and medial prefrontal cortex. Neuropsychological data (all within normal ranges) also showed significant differences with respect to executive functioning and global intelligence. The results provide further evidence of deleterious effects of IR on the hippocampus and cognition. Further imaging studies of the IR-related perturbations in DMN-hippocampal functional connectivity are needed.

  View details for DOI 10.1016/j.neurobiolaging.2012.06.006

  View details for Web of Science ID 000313117900001

  View details for PubMedID 22770543

• Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression. Psychiatry research Kelley, R., Garrett, A., Cohen, J., Gomez, R., Lembke, A., Keller, J., Reiss, A. L., Schatzberg, A. 2013; 211 (2): 119-126

  Abstract

  Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either "man-made" or "not man-made." For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.

  View details for DOI 10.1016/j.pscychresns.2012.06.008

  View details for PubMedID 23149036

  View details for PubMedCentralID PMC3645926

• Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression PSYCHIATRY RESEARCH-NEUROIMAGING Kelley, R., Garrett, A., Cohen, J., Gomez, R., Lembke, A., Keller, J., Reiss, A. L., Schatzberg, A. 2013; 211 (2): 119-126

  Abstract

  Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either "man-made" or "not man-made." For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.

  View details for DOI 10.1016/j.pscychresns.2012.06.008

  View details for Web of Science ID 000316828400004

  View details for PubMedID 23149036

  View details for PubMedCentralID PMC3645926

• Reward Processing in Adolescents With Bipolar I Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Singh, M. K., Chang, K. D., Kelley, R. G., Cui, X., Sherdell, L., Howe, M. E., Gotlib, I. H., Reiss, A. L. 2013; 52 (1): 68-83

  Abstract

  Bipolar disorder (BD) is a debilitating psychiatric condition that commonly begins in adolescence, a developmental period that has been associated with increased reward seeking. Because youth with BD are especially vulnerable to negative risk-taking behaviors, understanding the neural mechanisms by which dysregulated affect interacts with the neurobehavioral processing of reward is clearly important. One way to clarify how manic symptoms evolve in BD is to "prime" the affect before presenting rewarding stimuli. The objective of this study was to investigate the neural effects of an affective priming task designed to positively induce mood before reward processing in adolescents with and without BD.Neural activity and behaviors during the anticipation of and response to monetary reward and loss after an affective prime were compared using functional magnetic resonance imaging in 13- to 18-year-old adolescents with a recent onset of BD-I (n = 24) and demographically matched healthy comparison youth (n = 24).Compared with the healthy control youth, youth with BD had speeded reaction times and showed decreased activation in the thalamus and inferior temporal gyrus while anticipating gains after priming but increased activations in the middle frontal gyrus and parietal cortices while anticipating losses after priming. Youth with BD also showed less activation in the inferior parietal lobule, thalamus, and superior frontal gyrus while receiving losses after priming.Aberrant prefrontal and subcortical activations during reward processing suggest mechanisms that may underlie disordered self-awareness during goal pursuit and motivation in BD. Longitudinal studies are needed to examine whether this pattern of neural activation predicts a poorer long-term outcome.

  View details for DOI 10.1016/j.jaac.2012.10.004

  View details for PubMedID 23265635

• Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study. Journal of neurodevelopmental disorders Bruno, J. L., Shelly, E. W., Quintin, E., Rostami, M., Patnaik, S., Spielman, D., Mayer, D., Gu, M., Lightbody, A. A., Reiss, A. L. 2013; 5 (1): 20-?

  Abstract

  The profile of cognitive and behavioral variation observed in individuals with fragile X syndrome (FXS), the most common known cause of inherited intellectual impairment, suggests aberrant functioning of specific brain systems. Research investigating animal models of FXS, characterized by limited or lack of fragile X mental retardation protein, (FMRP), has linked brain dysfunction to deficits in the cholinergic and glutamatergic systems. Thus, we sought to examine in vivo levels of neurometabolites related to cholinergic and glutamatergic functioning in males and females with FXS.The study participants included 18 adolescents and young adults with FXS, and a comparison group of 18 individuals without FXS matched for age, sex and general intellectual functioning. Proton magnetic resonance spectroscopy (MRS) was used to assess neurometabolite levels in the caudate nucleus, a region known to be greatly enlarged and involved in abnormal brain circuitry in individuals with FXS. A general linear model framework was used to compare group differences in metabolite concentration.We observed a decrease in choline (P = 0.027) and in glutamate + glutamine (P = 0.032) in the caudate nucleus of individuals with FXS, relative to individuals in the comparison group.This study provides evidence of metabolite differences in the caudate nucleus, a brain region of potential importance to our understanding of the neural deficits underlying FXS. These metabolic differences may be related to aberrant receptor signaling seen in animal models. Furthermore, identification of the specific neurometabolites involved in FXS dysfunction could provide critical biomarkers for the design and efficacy tracking of disease-specific pharmacological treatments.

  View details for DOI 10.1186/1866-1955-5-20

  View details for PubMedID 23981510

• CREATIVITY TRAINING ENHANCES SELF-DIRECTED ATTENTION AND INFORMATION PROCESSING 20th Annual Meeting of the Cognitive-Neuroscience-Society Bott, N., Kienitz, E., Quintin, E., Saggar, M., Hawthorne, G., Royalty, A., Reiss, A. MIT PRESS. 2013: 40–41

  View details for Web of Science ID 000317030500086

• ABERRANT GAZE HABITUATION IN FRAGILE X SYNDROME 20th Annual Meeting of the Cognitive-Neuroscience-Society Bruno, J., Garrett, A., Quintin, E., Reiss, A. MIT PRESS. 2013: 216–216

  View details for Web of Science ID 000317030501204

• CREATIVITY TRAINING ENHANCES CREATIVE PERSISTENCE AND INCREASED ABSTRACT CONNECTIONS 20th Annual Meeting of the Cognitive-Neuroscience-Society Kienitz, E., Bott, N., Quintin, E., Saggar, M., Hawthorne, G., Royalty, A., Reiss, A. MIT PRESS. 2013: 244–244

  View details for Web of Science ID 000317030501338

• SEX DIFFERENCES DURING HUMOR APPRECIATION IN CHILD SIBLING-PAIRS 20th Annual Meeting of the Cognitive-Neuroscience-Society Vrticka, P., Neely, M., Walter, E., Black, J. M., Reiss, A. L. MIT PRESS. 2013: 154–154

  View details for Web of Science ID 000317030500622

• COGNITIVE TRAJECTORY IN MALES AND FEMALES WITH FRAGILE X SYNDROME 20th Annual Meeting of the Cognitive-Neuroscience-Society Quintin, E., Hall, S., Jo, B., Bruno, J., Chromik, L., Raman, M., Linghtbody, A., Reiss, A. MIT PRESS. 2013: 251–251

  View details for Web of Science ID 000317030501371

• Repetitive and self-injurious behaviors: associations with caudate volume in autism and fragile X syndrome. Journal of neurodevelopmental disorders Wolff, J. J., Hazlett, H. C., Lightbody, A. A., Reiss, A. L., Piven, J. 2013; 5 (1): 12-?

  Abstract

  Following from previous work suggesting that neurobehavioral features distinguish fragile X and idiopathic variants of autism, we investigated the relationships between four forms of repetitive behavior (stereotypy, self-injury, compulsivity, ritual behavior) and caudate nuclei volume in two groups: boys with fragile X syndrome, a subset of whom met criteria for autism, and a comparison group of boys with idiopathic autism.Bilateral caudate nuclei volumes were measured in boys aged 3 to 6 years with fragile X syndrome (n = 41), the subset of boys with fragile X syndrome and autism (n = 16), and boys with idiopathic autism (n = 30). Repetitive behaviors were measured using the Repetitive Behavior Scales-Revised.For boys with idiopathic autism, left caudate volume was modestly associated with self-injury, while both compulsive and ritual behaviors showed significant positive correlations with bilateral caudate nuclei volumes, replicating previous results. For boys with fragile X syndrome, there was no such association between caudate volume and compulsive behaviors. However, we did identify significant positive correlations between self-injury total scores and number of self-injury topographies with bilateral caudate nuclei volumes.These findings suggest a specific role for the caudate nucleus in the early pathogenesis of self-injurious behavior associated with both idiopathic autism and fragile X syndrome. Results further indicate that the caudate may be differentially associated with compulsive behavior, highlighting the utility of isolating discrete brain-behavior associations within and between subtypes of autism spectrum disorder.

  View details for DOI 10.1186/1866-1955-5-12

  View details for PubMedID 23639144

  View details for PubMedCentralID PMC3651404

• White Matter Aberrations in Prepubertal Estrogen-Naive Girls with Monosomic Turner Syndrome CEREBRAL CORTEX Yamagata, B., Barnea-Goraly, N., Marzelli, M. J., Park, Y., Hong, D. S., Mimura, M., Reiss, A. L. 2012; 22 (12): 2761-2768

  Abstract

  Turner syndrome (TS) offers a unique opportunity to investigate associations among genes, the brain, and cognitive phenotypes. In this study, we used 3 complementary analyses of diffusion tensor imaging (DTI) data (whole brain, region of interest, and fiber tractography) and a whole brain volumetric imaging technique to investigate white matter (WM) structure in prepubertal, nonmosaic, estrogen-naive girls with TS compared with age and sex matched typically developing controls. The TS group demonstrated significant WM aberrations in brain regions implicated in visuospatial abilities, face processing, and sensorimotor and social abilities compared with controls. Extensive spatial overlap between regions of aberrant WM structure (from DTI) and regions of aberrant WM volume were observed in TS. Our findings indicate that complete absence of an X chromosome in young females (prior to receiving exogenous estrogen) is associated with WM aberrations in specific regions implicated in characteristic cognitive features of TS.

  View details for DOI 10.1093/cercor/bhr355

  View details for PubMedID 22172580

• Evidence of a Distinct Behavioral Phenotype in Young Boys With Fragile X Syndrome and Autism JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Wolff, J. J., Bodfish, J. W., Hazlett, H. C., Lightbody, A. A., Reiss, A. L., Piven, J. 2012; 51 (12): 1324-1332

  Abstract

  How does the behavioral expression of autism in fragile X syndrome (FXS + Aut) compare with idiopathic autism (iAut)? Although social impairments and restricted, repetitive behaviors are common to these variants of autism, closer examination of these symptom domains may reveal meaningful similarities and differences. To this end, the specific behaviors comprising the social and repetitive behavioral domains in young children with FXS + Aut and iAut were profiled.Twenty-three male subjects 3 to 5 years old with FXS + Aut were matched by age to a group of 38 boys with iAut. Repetitive behavior was assessed using the Repetitive Behavior Scales-Revised. Social behavior was evaluated using Autism Diagnostic Observation Schedule social item severity scores.Rates of stereotypy, self-injury, and sameness behaviors did not differ between groups, whereas compulsive and ritual behavior scores were significantly lower for subjects with FXS + Aut compared with those with iAut. Those with FXS + Aut scored significantly lower (less severe) than the iAut group on five Autism Diagnostic Observation Schedule measurements of social behavior: gaze integration, quality of social overtures, social smile, facial expressions, and response to joint attention.The behavioral phenotype of FXS + Aut and iAut are most similar with respect to lower-order (motoric) restricted, repetitive behaviors and social approach, but differ in more complex forms of restricted, repetitive behaviors and some social response behaviors. These findings highlight the phenotypic heterogeneity of autism overall and its unique presentation in an etiologically distinct condition.

  View details for DOI 10.1016/j.jaac.2012.09.001

  View details for Web of Science ID 000312046500012

  View details for PubMedID 23200289

  View details for PubMedCentralID PMC3513689

• Sex chromosomes and the brain: a study of neuroanatomy in XYY syndrome DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Bryant, D. M., Hoeft, F., Lai, S., Lackey, J., Roeltgen, D., Ross, J., Reiss, A. L. 2012; 54 (12): 1149-1156

  Abstract

  To assess global and regional brain matter variations associated with XYY syndrome by comparison with Klinefelter syndrome and typical development.We used two conceptually distinct voxel-based magnetic resonance imaging methods to examine brain structure in young males with XYY syndrome: (1) volumetric comparison to assess global grey and white matter volumes and (2) support vector machine-based multivariate pattern classification analysis to assess regional neuroanatomy. We assessed verbal, non-verbal, and spatial abilities with the Differential Ability Scales (DAS), and we measured autism diagnostic criteria in eight males with XYY syndrome using the Social Responsiveness Scale and the Autism Diagnostic Interview-Revised (ADI-R).A comparison of 36 typically developing males (mean age 11 y, SD 1 y 9 mo), 31 males with Klinefelter syndrome (mean age 9 y 8 mo, SD 1 y 8 mo), and eight males with XYY syndrome (mean age 11 y 6 mo, SD 1 y 11 mo) showed that total white and grey matter volumes were significantly, or nearly significantly, higher in males with XYY syndrome than in males belonging to the other two groups (grey matter: XYY males vs typically developing males, p<0.006; XYY vs males with Klinefelter syndrome, p<0.001; white matter: XYY males vs typically developing males, p=0.061; XYY males vs males with Klinefelter syndrome, p=0.004). Voxel-based multivariate pattern classification analysis indicates that, after controlling for global volumes, regional brain variations in XYY syndrome are more like those found in Klinefelter syndrome than those occurring in typical development. Further, visualization of classification parameters suggests that insular and frontotemporal grey matter and white matter, including known language areas, are reduced in males with XYY syndrome, similar to what is seen in Klinefelter syndrome. In males with XYY syndrome, DAS verbal and non-verbal scores were significantly lower than in typically developing participants (both p<0.001). DAS scores were not significantly different between XYY and Klinefelter syndrome groups. In five of eight males with XYY syndrome, the Social Responsiveness Scale score exceeded the cut-off for a likely diagnosis of autism spectrum disorder (ASD). In three of eight males with XYY syndrome, the ADI-R score met the cut-off for ASD diagnosis; in another two, ADI-R scores within the social and communication domains met the cut-off values for a diagnosis of ASD.The results suggest that genetic variations associated with XYY syndrome result in increased brain matter volumes, a finding putatively related to the increased frequency of ASDs in individuals with this condition. In addition, frontotemporal grey and white matter reductions in XYY syndrome provide a likely neuroanatomical correlate for observed language impairments.

  View details for DOI 10.1111/j.1469-8749.2012.04418.x

  View details for Web of Science ID 000311288900021

  View details for PubMedID 23057627

• White Matter Structural Differences in Young Children With Type 1 Diabetes: A Diffusion Tensor Imaging Study DIABETES CARE Aye, T., Barnea-Goraly, N., Ambler, C., Hoang, S., Schleifer, K., Park, Y., Drobny, J., Wilson, D. M., Reiss, A. L., Buckingham, B. A. 2012; 35 (11): 2167-2173

  Abstract

  To detect clinical correlates of cognitive abilities and white matter (WM) microstructural changes using diffusion tensor imaging (DTI) in young children with type 1 diabetes.Children, ages 3 to <10 years, with type 1 diabetes (n = 22) and age- and sex-matched healthy control subjects (n = 14) completed neurocognitive testing and DTI scans.Compared with healthy controls, children with type 1 diabetes had lower axial diffusivity (AD) values (P = 0.046) in the temporal and parietal lobe regions. There were no significant differences between groups in fractional anisotropy and radial diffusivity (RD). Within the diabetes group, there was a significant, positive correlation between time-weighted HbA(1c) and RD (P = 0.028). A higher, time-weighted HbA(1c) value was significantly correlated with lower overall intellectual functioning measured by the full-scale intelligence quotient (P = 0.03).Children with type 1 diabetes had significantly different WM structure (as measured by AD) when compared with controls. In addition, WM structural differences (as measured by RD) were significantly correlated with their HbA(1c) values. Additional studies are needed to determine if WM microstructural differences in young children with type 1 diabetes predict future neurocognitive outcome.

  View details for DOI 10.2337/dc12-0017

  View details for PubMedID 22966090

• A 'learning platform' approach to outcome measurement in fragile X syndrome: a preliminary psychometric study JOURNAL OF INTELLECTUAL DISABILITY RESEARCH Hall, S. S., Hammond, J. L., Hirt, M., Reiss, A. L. 2012; 56 (10): 947-960

  Abstract

  Clinical trials of medications to alleviate the cognitive and behavioural symptoms of individuals with fragile X syndrome (FXS) are now underway. However, there are few reliable, valid and/or sensitive outcome measures available that can be directly administered to individuals with FXS. The majority of assessments employed in clinical trials may be suboptimal for individuals with intellectual disability (ID) because they require face-to-face interaction with an examiner, taxing administration periods, and do not provide reinforcement and/or feedback during the test. We therefore examined the psychometric properties of a new computerised 'learning platform' approach to outcome measurement in FXS.A brief computerised test, incorporated into the Discrete Trial Trainer©- a commercially available software program designed for children with ID - was administered to 13 girls with FXS, 12 boys with FXS and 15 matched ID controls aged 10 to 23 years (mental age = 4 to 12 years). The software delivered automated contingent access to reinforcement, feedback, token delivery and prompting procedures (if necessary) on each trial to facilitate responding. The primary outcome measure was the participant's learning rate, derived from the participant's cumulative record of correct responses.All participants were able to complete the test and floor effects appeared to be minimal. Learning rates averaged approximately five correct responses per minute, ranging from one to eight correct responses per minute in each group. Test-retest reliability of the learning rates was 0.77 for girls with FXS, 0.90 for boys with FXS and 0.90 for matched ID controls. Concurrent validity with raw scores obtained on the Arithmetic subtest of the Wechsler Intelligence Scale for Children-III was 0.35 for girls with FXS, 0.80 for boys with FXS and 0.56 for matched ID controls. The learning rates were also highly sensitive to change, with effect sizes of 1.21, 0.89 and 1.47 in each group respectively following 15 to 20, 15-min sessions of intensive discrete trial training conducted over 1.5 days.These results suggest that a learning platform approach to outcome measurement could provide investigators with a reliable, valid and highly sensitive measure to evaluate treatment efficacy, not only for individuals with FXS but also for individuals with other ID.

  View details for DOI 10.1111/j.1365-2788.2012.01560.x

  View details for Web of Science ID 000308872200003

  View details for PubMedID 22533667

  View details for PubMedCentralID PMC3417081

• Volumetric reductions in the subgenual anterior cingulate cortex in adolescents with bipolar I disorder BIPOLAR DISORDERS Singh, M. K., Chang, K. D., Chen, M. C., Kelley, R. G., Garrett, A., Mitsunaga, M. M., Bararpour, L., Howe, M., Reiss, A. L., Gotlib, I. H. 2012; 14 (6): 585-596

  Abstract

  A range of prefrontal and subcortical volumetric abnormalities have been found in adults and adolescents with bipolar disorder. It is unclear, however, if these deficits are present early in the onset of mania or are a consequence of multiple mood episodes or prolonged exposure to medication. The goal of this study was to examine whether youth with bipolar I disorder who recently experienced their first episode of mania are characterized by brain volumetric abnormalities.Anatomical images from magnetic resonance imaging of 26 13- to 18-year-old adolescents with bipolar I disorder and 24 age-comparable healthy controls with no personal or family history of psychopathology were analyzed using whole-brain voxel-based morphometry (VBM).Compared with healthy controls, adolescents with bipolar I disorder had significantly less gray matter volume in the left subgenual cingulate cortex [p<0.05, family-wise error (FWE)-corrected].Adolescents with a recent single episode of mania have smaller subgenual cingulate cortex volume than do their healthy counterparts, suggesting that this anomaly occurs early in the onset of, or may predate the disorder. Longitudinal studies are needed to examine the impact of this volumetric reduction on the course and outcome of this disorder.

  View details for DOI 10.1111/j.1399-5618.2012.01043.x

  View details for PubMedID 22938166

• Trajectories of Early Brain Volume Development in Fragile X Syndrome and Autism JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hazlett, H. C., Poe, M. D., Lightbody, A. A., Styner, M., MacFall, J. R., Reiss, A. L., Piven, J. 2012; 51 (9): 921-933

  Abstract

  To examine patterns of early brain growth in young children with fragile X syndrome (FXS) compared with a comparison group (controls) and a group with idiopathic autism.The study included 53 boys 18 to 42 months of age with FXS, 68 boys with idiopathic autism (autism spectrum disorder), and a comparison group of 50 typically developing and developmentally delayed controls. Structural brain volumes were examined using magnetic resonance imaging across two time points, at 2 to 3 and again at 4 to 5 years of age, and total brain volumes and regional (lobar) tissue volumes were examined. In addition, a selected group of subcortical structures implicated in the behavioral features of FXS (e.g., basal ganglia, hippocampus, amygdala) was studied.Children with FXS had larger global brain volumes compared with controls but were not different than children with idiopathic autism, and the rate of brain growth from 2 to 5 years of age paralleled that seen in controls. In contrast to children with idiopathic autism who had generalized cortical lobe enlargement, children with FXS showed specific enlargement in the temporal lobe white matter, cerebellar gray matter, and caudate nucleus, but a significantly smaller amygdala.This structural longitudinal magnetic resonance imaging study of preschoolers with FXS observed generalized brain overgrowth in children with FXS compared with controls, evident at age 2 and maintained across ages 4 to 5. In addition, different patterns of brain growth that distinguished boys with FXS from boys with idiopathic autism were found.

  View details for DOI 10.1016/j.jaac.2012.07.003

  View details for Web of Science ID 000308054800010

  View details for PubMedID 22917205

  View details for PubMedCentralID PMC3428739

• Abnormal Amygdala and Prefrontal Cortex Activation to Facial Expressions in Pediatric Bipolar Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Garrett, A. S., Reiss, A. L., Howe, M. E., Kelley, R. G., Singh, M. K., Adleman, N. E., Karchemskiy, A., Chang, K. D. 2012; 51 (8): 821-831

  Abstract

  Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar disorder (BD) have reported greater amygdala and less dorsolateral prefrontal cortex (DLPFC) activation to facial expressions compared to healthy controls. The current study investigates whether these differences are associated with the early or late phase of activation, suggesting different temporal characteristics of brain responses.A total of 20 euthymic adolescents with familial BD (14 male) and 21 healthy control subjects (13 male) underwent fMRI scanning during presentation of happy, sad, and neutral facial expressions. Whole-brain voxelwise analyses were conducted in SPM5, using a three-way analysis of variance (ANOVA) with factors group (BD and healthy control [HC]), facial expression (happy, sad, and neutral versus scrambled), and phase (early and late, corresponding to the first and second half of each block of faces).There were no significant group differences in task performance, age, gender, or IQ. Significant activation from the main effect of group included greater DLPFC activation in the HC group, and greater amygdala/hippocampal activation in the BD group. The interaction of Group × Phase identified clusters in the superior temporal sulcus/insula and visual cortex, where activation increased from the early to late phase of the block for the BD but not the HC group.These findings are consistent with previous studies that suggest deficient prefrontal cortex regulation of heightened amygdala response to emotional stimuli in pediatric BD. Increasing activation over time in superior temporal and visual cortices suggests difficulty processing or disengaging attention from emotional faces in BD.

  View details for DOI 10.1016/j.jaac.2012.06.005

  View details for PubMedID 22840553

• Cortical Brain Morphology in Young, Estrogen-Naive, and Adolescent, Estrogen-Treated Girls with Turner Syndrome. Cerebral cortex (New York, N.Y. : 1991) Lepage, J. F., Mazaika, P. K., Hong, D. S., Raman, M., Reiss, A. L. 2012

  Abstract

  Turner syndrome (TS) is a genetic condition that permits direct investigation of the complex interaction among genes, hormones, behavior, and brain development. Here, we used automated segmentation and surface-based morphometry to characterize the differences in brain morphology in children (n = 30) and adolescents (n = 16) with TS relative to age- and sex-matched control groups (n = 21 and 24, respectively). Our results show that individuals with TS, young and adolescent, present widespread reduction of gray matter volume, white matter volume and surface area (SA) over both parietal and occipital cortices bilaterally, as well as enlarged amygdala. In contrast to the young cohort, adolescents with TS showed significantly larger mean cortical thickness and significantly smaller total SA compared with healthy controls. Exploratory developmental analyses suggested aberrant regional brain maturation in the parahippocampal gyrus and orbitofrontal regions from childhood to adolescence in TS. These findings show the existence of abnormal brain morphology early in development in TS, but also suggest the presence of altered neurodevelopmental trajectories in some regions, which could potentially be the consequences of estrogen deficiency, both pre- and postnatally.

  View details for DOI 10.1093/cercor/bhs195

  View details for PubMedID 22806268

• Psychometric Study of the Aberrant Behavior Checklist in Fragile X Syndrome and Implications for Targeted Treatment JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Sansone, S. M., Widaman, K. F., Hall, S. S., Reiss, A. L., Lightbody, A., Kaufmann, W. E., Berry-Kravis, E., Lachiewicz, A., Brown, E. C., Hessl, D. 2012; 42 (7): 1377-1392

  Abstract

  Animal studies elucidating the neurobiology of fragile X syndrome (FXS) have led to multiple controlled trials in humans, with the Aberrant Behavior Checklist-Community (ABC-C) commonly adopted as a primary outcome measure. A multi-site collaboration examined the psychometric properties of the ABC-C in 630 individuals (ages 3-25) with FXS using exploratory and confirmatory factor analysis. Results support a six-factor structure, with one factor unchanged (Inappropriate Speech), four modified (Irritability, Hyperactivity, Lethargy/Withdrawal, and Stereotypy), and a new Social Avoidance factor. A comparison with ABC-C data from individuals with general intellectual disability and a list of commonly endorsed items are also reported. Reformulated ABC-C scores based on this FXS-specific factor structure may provide added outcome measure specificity and sensitivity in FXS clinical trials.

  View details for DOI 10.1007/s10803-011-1370-2

  View details for Web of Science ID 000305231000009

  View details for PubMedID 21972117

  View details for PubMedCentralID PMC3290710

• Diffusion tensor imaging reveals white matter abnormalities in Attention-Deficit/Hyperactivity Disorder PSYCHIATRY RESEARCH-NEUROIMAGING Tamm, L., Barnea-Goraly, N., Reiss, A. L. 2012; 202 (2): 150-154

  Abstract

  The specific brain structures or neural mechanisms underlying dysfunction in individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) are not well established, particularly in regard to white matter (WM). Diffusion tensor imaging (DTI) was used to investigate WM in 12 adolescent males diagnosed with ADHD only and 12 typically developing controls (group matched; mean age=15.64 years, SD=1.15). In addition to fractional anisotropy (FA), we also examined axial and radial diffusivity (AD and RD) in an effort to help elucidate conflicting findings suggesting that both lower and higher FA values are characteristic of ADHD. Tract-based spatial statistics and voxel-wide analyses were conducted on the data utilizing a pre-frontal mask to enable focus on fronto-striatal and prefrontal pathways. Adolescents with ADHD had significantly higher FA and AD values in fronto-striatal pathways compared with controls. No differences were observed for RD. These results contribute to the growing literature implicating prefrontal WM variations in neuropsychiatric disorders, and are consistent with findings suggesting a role for fronto-striatal pathways in ADHD pathophysiology.

  View details for DOI 10.1016/j.pscychresns.2012.04.001

  View details for Web of Science ID 000307424600009

  View details for PubMedID 22703620

  View details for PubMedCentralID PMC3398227

• Cognition and behavior in Turner syndrome: a brief review. Pediatric endocrinology reviews : PER Hong, D. S., Reiss, A. L. 2012; 9: 710-712

  Abstract

  There is increasing evidence that Turner syndrome is associated with a distinct pattern of cognitive and neurophysiological characteristics. Typically this has been characterized by relative strengths in verbal skills, contrasting with relative weaknesses in arithmetic, visuospatial and executive function domains. Potential differences in social cognitive processing have also been identified. More recently, applications of neuroimaging techniques have further elucidated underlying differences in brain structure, function and connectivity in individuals with Turner syndrome. Ongoing research in this area is focused on establishing a unified mechanistic model incorporating genetic influences from the X chromosome, sex hormone contributions, neuroanatomical variation and differences in cognitive processes. This review broadly covers current understanding of how X-monosomy impacts neurocognitive phenotype both from the perspective of cognitive-behavioral and neuroimaging studies. Furthermore, relevant clinical aspects of identifying potential learning difficulties and providing anticipatory guidance for affected individuals with TS, are briefly discussed.

  View details for PubMedID 22946281

• BRAIN ACTIVATION TO FACIAL EXPRESSIONS IN YOUTH WITH PTSD SYMPTOMS DEPRESSION AND ANXIETY Garrett, A. S., Carrion, V., Kletter, H., Karchemskiy, A., Weems, C. F., Reiss, A. 2012; 29 (5): 449-459

  Abstract

  This study examined activation to facial expressions in youth with a history of interpersonal trauma and current posttraumatic stress symptoms (PTSS) compared to healthy controls (HC).Twenty-three medication-naive youth with PTSS and 23 age- and gender-matched HC underwent functional magnetic resonance imaging (fMRI) while viewing fearful, angry, sad, happy, and neutral faces. Data were analyzed for group differences in location of activation, as well as timing of activation during the early versus late phase of the block. Using SPM5, significant activation (P < .05 FWE [Family-Wise Error] corrected, extent = 10 voxels) associated with the main effect of group was identified. Activation from selected clusters was extracted to SPSS software for further analysis of specific facial expressions and temporal patterns of activation.The PTSS group showed significantly greater activation than controls in several regions, including the amygdala/hippocampus, medial prefrontal cortex, insula, and ventrolateral prefrontal cortex, and less activation than controls in the dorsolateral prefrontal cortex (DLPFC). These group differences in activation were greatest during angry, happy, and neutral faces, and predominantly during the early phase of the block. Post hoc analyses showed significant Group × Phase interactions in the right amygdala and left hippocampus.Traumatic stress may impact development of brain regions important for emotion processing. Timing of activation may be altered in youth with PTSS.

  View details for DOI 10.1002/da.21892

  View details for PubMedID 22553009

• Neuroanatomical Similarities and Differences in Twin Pairs with Autism 67th Annual Meeting of the Society-of-Biological-Psychiatry Harden, A. Y., Hallmayer, J., Frazier, T., Lazzeroni, L., Reiss, A. ELSEVIER SCIENCE INC. 2012: 188S–188S

  View details for Web of Science ID 000302466000589

• Evidence of Abnormal Cortical Gray Matter Development in Never-Depressed Daughters of Mothers with Recurrent Depression Foland-Ross, L. C., Gilbert, B. L., Raman, M., Burley, H., Reiss, A. L., Gotlib, I. H. ELSEVIER SCIENCE INC. 2012: 204S

  View details for Web of Science ID 000302466000635

• Resting State Functional Connectivity in Healthy Offspring of Parents with Bipolar Disorder Singh, M. K., Kelley, R. G., Shoemaker, V. R., Li, S., Boucher, S., Gotlib, I. H., Reiss, A. L., Chang, K. D. ELSEVIER SCIENCE INC. 2012: 204S–205S

  View details for Web of Science ID 000302466000636

• Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome CURRENT OPINION IN NEUROLOGY Fung, L. K., Quintin, E., Haas, B. W., Reiss, A. L. 2012; 25 (2): 112-124

  Abstract

  The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders.Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive-behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well - microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development.Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene-brain-behavior links occurring in neurodevelopmental disorders.

  View details for DOI 10.1097/WCO.0b013e328351823c

  View details for Web of Science ID 000301288000003

  View details for PubMedID 22395002

• Behavioral and Social Phenotypes in Boys With 47, XYY Syndrome or 47, XXY Klinefelter Syndrome PEDIATRICS Ross, J. L., Roeltgen, D. P., Kushner, H., Zinn, A. R., Reiss, A., Bardsley, M. Z., McCauley, E., Tartaglia, N. 2012; 129 (4): 769-778

  Abstract

  To contrast the behavioral and social phenotypes including a screen for autistic behaviors in boys with 47,XYY syndrome (XYY) or 47,XXY Klinefelter syndrome (KS) and controls and investigate the effect of prenatal diagnosis on the phenotype.Patients included 26 boys with 47,XYY, 82 boys with KS, and 50 control boys (ages 4-15 years). Participants and parents completed a physical examination, behavioral questionnaires, and intellectual assessments.Most boys with XYY or KS had Child Behavior Checklist parental ratings within the normal range. On the Child Behavior Checklist, mean problem behaviors t scores were higher in the XYY versus KS groups for the Problem Behavior, Externalizing, Withdrawn, Thought Problems, and Attention Problems subscales. On the Conners' Parent Rating Scale-Revised, the XYY versus KS group had increased frequency of hyperactive/impulsive symptoms (P < .006). In addition, 50% and 12% of the XYY and KS groups, respectively, had scores >15 for autism screening from the Social Communication Questionnaire. For the boys with KS, prenatal diagnosis was associated with fewer problem behaviors.A subset of the XYY and KS groups had behavioral difficulties that were more severe in the XYY group. These findings could guide clinical practice and inform patients and parents. Boys diagnosed with XYY or KS should receive a comprehensive psychoeducational evaluation and be screened for learning disabilities, attention-deficit/hyperactivity disorder, and autism spectrum disorders.

  View details for DOI 10.1542/peds.2011-0719

  View details for Web of Science ID 000302541700057

  View details for PubMedID 22412026

  View details for PubMedCentralID PMC3356148

• Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome PSYCHONEUROENDOCRINOLOGY Hall, S. S., Lightbody, A. A., McCarthy, B. E., Parker, K. J., Reiss, A. L. 2012; 37 (4): 509-518

  Abstract

  Fragile X syndrome (FXS) is a rare inherited genetic disorder causing severe intellectual disability and autistic-like symptoms. Individuals with FXS, males in particular, often exhibit extreme eye gaze avoidance and hyperarousal when they encounter stressful social situations. We investigated whether oxytocin (OT), a hormone with prosocial and anxiolytic effects, could alleviate symptoms of social anxiety in this population. A randomized double-blind placebo-controlled single-dose trial was performed with intranasal administration of placebo, 24 IU OT and 48 IU OT. Measures of eye gaze frequency, heart rate, respiratory sinus arrhythmia (RSA), heart rate variability (HRV) and salivary cortisol were obtained during a structured social challenge conducted 50 min following OT administration. Ten low-functioning males with FXS (aged 13-28 years) traveled to Stanford for the initial visit: 8 completed the study. Eye gaze frequency improved significantly in response to the 24 IU OT dose and salivary cortisol levels decreased significantly in response to the 48 IU OT dose. There was no effect of OT on heart rate, RSA or HRV although individual plots of the heart rate data suggested that OT increased heart rate in some participants and decreased heart rate in others. These findings suggest that intranasal administration of OT may ameliorate some symptoms of social anxiety in patients with FXS. Further double-blind placebo-controlled studies of OT, conducted in combination with behavioral treatment programs, may be warranted.

  View details for DOI 10.1016/j.psyneuen.2011.07.020

  View details for Web of Science ID 000302044800007

  View details for PubMedID 21862226

  View details for PubMedCentralID PMC3353652

• Genomic Imprinting Effects on Cognitive and Social Abilities in Prepubertal Girls with Turner Syndrome JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Lepage, J., Hong, D. S., Hallmayer, J., Reiss, A. L. 2012; 97 (3): E460-E464

  Abstract

  Recent evidence suggests that the cognitive and social manifestations associated with Turner syndrome (TS) might be influenced by epigenetic factors in the form of genomic imprinting. However, due to small and heterogeneous samples, inconsistent results have emerged from these studies.The objective of this prospective study was to establish the impact of genomic imprinting on neurocognitive abilities and social functioning in young girls with TS.An extensive battery of neuropsychological assessments was administered to 65 children with TS who had never been exposed to estrogen treatment, 24 of whom had an X-chromosome from paternal origin (Xpat) and 41 from maternal origin (Xmat).The Wechsler scales of intelligence, the Motor-Free Visual Spatial test-3, the Wide Range Assessment of Visual Motor Ability, and the attention/executive domain of the NEPSY were used to assess cognitive abilities. Social functioning was assessed with the Social Responsiveness Scale and the Behavior Assessment System for Children-2.Results showed that although individuals with Xpat obtained lower scores than their counterparts with Xmat on most cognitive and social measures, only the Perceptual Reasoning Index of the intelligence scale yielded significant differences after correction for multiple comparisons.Overall, these results suggest that although some aspects of the neuropsychological profile of TS may be influenced by epigenetic factors, the sociocognitive phenotype associated with the disorder is not modulated by genomic imprinting.

  View details for DOI 10.1210/jc.2011-2916

  View details for PubMedID 22238395

• NIRS-based hyperscanning reveals increased interpersonal coherence in superior frontal cortex during cooperation NEUROIMAGE Cui, X., Bryant, D. M., Reiss, A. L. 2012; 59 (3): 2430-2437

  Abstract

  We used Near-Infrared Spectroscopy (NIRS) to simultaneously measure brain activity in two people while they played a computer-based cooperation game side by side. Inter-brain activity coherence was calculated between the two participants. We found that the coherence between signals generated by participants' right superior frontal cortices increased during cooperation, but not during competition. Increased coherence was also associated with better cooperation performance. To our knowledge, this work represents the first use of a single NIRS instrument for simultaneous measurements of brain activity in two people. This study demonstrates the use of NIRS-based hyperscanning in studies of social interaction in a naturalistic environment.

  View details for DOI 10.1016/j.neuroimage.2011.09.003

  View details for Web of Science ID 000299494000044

  View details for PubMedID 21933717

  View details for PubMedCentralID PMC3254802

• Preliminary evidence of abnormal white matter related to the fusiform gyrus in Williams syndrome: a diffusion tensor imaging tractography study GENES BRAIN AND BEHAVIOR Haas, B. W., Hoeft, F., Barnea-Goraly, N., Golarai, G., Bellugi, U., Reiss, A. L. 2012; 11 (1): 62-68

  Abstract

  Williams syndrome (WS) is a genetic condition caused by a hemizygous microdeletion on chromosome 7q11.23. WS is characterized by a distinctive social phenotype composed of increased drive toward social engagement and attention toward faces. In addition, individuals with WS exhibit abnormal structure and function of brain regions important for the processing of faces such as the fusiform gyrus. This study was designed to investigate if white matter tracts related to the fusiform gyrus in WS exhibit abnormal structural integrity as compared to typically developing (TD; age matched) and developmentally delayed (DD; intelligence quotient matched) controls. Using diffusion tensor imaging data collected from 40 (20 WS, 10 TD and 10 DD) participants, white matter fibers were reconstructed that project through the fusiform gyrus and two control regions (caudate and the genu of the corpus callosum). Macro-structural integrity was assessed by calculating the total volume of reconstructed fibers and micro-structural integrity was assessed by calculating fractional anisotropy (FA) and fiber density index (FDi) of reconstructed fibers. WS participants, as compared to controls, exhibited an increase in the volume of reconstructed fibers and an increase in FA and FDi for fibers projecting through the fusiform gyrus. No between-group differences were observed in the fibers that project through the control regions. Although preliminary, these results provide further evidence that the brain anatomy important for processing faces is abnormal in WS.

  View details for DOI 10.1111/j.1601-183X.2011.00733.x

  View details for Web of Science ID 000298989400006

  View details for PubMedID 21939500

• Neural Correlates of Humor Detection and Appreciation in Children JOURNAL OF NEUROSCIENCE Neely, M. N., Walter, E., Black, J. M., Reiss, A. L. 2012; 32 (5): 1784-1790

  Abstract

  Humor is a vital component of human well-being. Neuroimaging studies conducted with adults indicate that humor activates specific brain regions, including the temporo-occipito-parietal junction (TOPJ), involved in incongruity resolution, and mesolimbic regions, involved in reward processing. However, no study to date has used neuroimaging to examine humor in typically developing children. Here, we illuminate the neural network involved in the detection and appreciation of humor in childhood. Fifteen typically developing children (ages, 6-12 years) were invited to watch and respond to video clips while neural activity was imaged with a 3T GE Discovery MR750 scanner. Before presentation during functional imaging, the clips were evaluated by age-matched controls and were representative of three categories: Funny, Positive (enjoyable but not funny), and Neutral (not intended to evoke any emotional response). We found TOPJ and mesolimbic activation in children's response to humor, suggesting these regions may form a humor-essential neural network already present in childhood. Furthermore, in a novel comparison of Funny to Positive stimuli, we found that bilateral TOPJ activation may be specific to humor processing and not part of a general constellation of neural activity in response to reward. Finally, we observed greater activation in the inferior frontal gyrus and nucleus accumbens in younger participants, indicating humor activation intensity changes during development. By providing a crucial link in studying the neurodevelopment of humor processing across the lifespan, our findings contribute valuable information about the evolution of how children understand their world.

  View details for DOI 10.1523/JNEUROSCI.4172-11.2012

  View details for Web of Science ID 000299977200024

  View details for PubMedID 22302817

• Maternal history of reading difficulty is associated with reduced language-related gray matter in beginning readers NEUROIMAGE Black, J. M., Tanaka, H., Stanley, L., Nagamine, M., Zakerani, N., Thurston, A., Kesler, S., Hulme, C., Lyytinen, H., Glover, G. H., Serrone, C., Raman, M. M., Reiss, A. L., Hoeft, F. 2012; 59 (3): 3021-3032

  Abstract

  Family history and poor preliteracy skills (referred to here as familial and behavioral risk, respectively) are critical predictors of developmental dyslexia. This study systematically investigated the independent contribution of familial and behavioral risks on brain structures, which had not been explored in past studies. We also examined the differential effects of maternal versus paternal history on brain morphometry, and familial risk dimensionally versus categorically, which were also novel aspects of the study. We assessed 51 children (5 to 6 years of age) with varying degrees of familial and behavioral risks for developmental dyslexia and examined associations with brain morphometry. We found that greater maternal history of reading disability was associated with smaller bilateral prefrontal and parieto-temporal gray, but not white matter volumes. Regressing out behavioral risk, socioeconomic status, and maternal education and other confounds did not change the results. No such relationship was observed for paternal reading history and behavioral risk. Results of cortical surface area and thickness further showed that there was a significant negative relationship between cortical surface area (but not thickness) and greater severity of maternal history, in particular within the left inferior parietal lobule, suggesting prenatal influence of maternal history on children's brain morphometry. The results suggested greater maternal, possibly prenatal, influence on language-related brain structures. These results help to guide future neuroimaging research focusing on environmental and genetic influences and provide new information that may help predict which child will develop dyslexia in the future.

  View details for DOI 10.1016/j.neuroimage.2011.10.024

  View details for Web of Science ID 000299494000100

  View details for PubMedID 22023744

  View details for PubMedCentralID PMC3628690

• Social brain development in williams syndrome: the current status and directions for future research. Frontiers in psychology Haas, B. W., Reiss, A. L. 2012; 3: 186-?

  Abstract

  Williams syndrome (WS) is a neurodevelopmental condition that occurs as a result of a contiguous deletion of ∼26-28 genes on chromosome 7q11.23. WS is often associated with a distinctive social phenotype characterized by an increased affinity toward processing faces, reduced sensitivity to fear related social stimuli and a reduced ability to form concrete social relationships. Understanding the biological mechanisms that underlie the social phenotype in WS may elucidate genetic and neural factors influencing the typical development of the social brain. In this article, we review available studies investigating the social phenotype of WS throughout development and neuroimaging studies investigating brain structure and function as related to social and emotional functioning in this condition. This review makes an important contribution by highlighting several neuro-behavioral mechanisms that may be a cause or a consequence of atypical social development in WS. In particular, we discuss how distinctive social behaviors in WS may be associated with alterations or delays in the cortical representation of faces, connectivity within the ventral stream, structure and function of the amygdala and how long- and short-range connections develop within the brain. We integrate research on typical brain development and from existing behavioral and neuroimaging research on WS. We conclude with a discussion of how genetic and environmental factors might interact to influence social brain development in WS and how future neuroimaging and behavioral research can further elucidate social brain development in WS. Lastly, we describe how ongoing studies may translate to improved social developmental outcomes for individuals with WS.

  View details for DOI 10.3389/fpsyg.2012.00186

  View details for PubMedID 22701108

• Amygdalar, hippocampal, and thalamic volumes in youth at high risk for development of bipolar disorder PSYCHIATRY RESEARCH-NEUROIMAGING Karchemskiy, A., Garrett, A., Howe, M., Adleman, N., Simeonova, D. I., Alegria, D., Reiss, A., Chang, K. 2011; 194 (3): 319-325

  Abstract

  Children of parents with bipolar disorder (BD), especially those with attention deficit hyperactivity disorder (ADHD) and symptoms of depression or mania, are at significantly high risk for developing BD. As we have previously shown amygdalar reductions in pediatric BD, the current study examined amygdalar volumes in offspring of parents (BD offspring) who have not yet developed a full manic episode. Youth participating in the study included 22 BD offspring and 22 healthy controls of comparable age, gender, handedness, and IQ. Subjects had no history of a manic episode, but met criteria for ADHD and moderate mood symptoms. MRI was performed on a 3T GE scanner, using a 3D volumetric spoiled gradient echo series. Amygdalae were manually traced using BrainImage Java software on positionally normalized brain stacks. Bipolar offspring had similar amygdalar volumes compared to the control group. Exploratory analyses yielded no differences in hippocampal or thalamic volumes. Bipolar offspring do not show decreased amygdalar volume, possibly because these abnormalities occur after more prolonged illness rather than as a preexisting risk factor. Longitudinal studies are needed to determine whether amygdalar volumes change during and after the development of BD.

  View details for DOI 10.1016/j.pscychresns.2011.03.006

  View details for PubMedID 22041532

• Contribution of Executive Functions to Visuospatial Difficulties in Prepubertal Girls With Turner Syndrome DEVELOPMENTAL NEUROPSYCHOLOGY Lepage, J., Dunkin, B., Hong, D. S., Reiss, A. L. 2011; 36 (8): 988-1002

  Abstract

  Turner syndrome (TS) is a genetic disorder caused by the absence of one X-chromosome in females. Individuals with TS often demonstrate a cognitive profile characterized by poor visuospatial abilities, which may in part be due to executive function impairments. Here, we assessed the neuropsychological profile of 36 prepubertal girls with TS and 20 typically developing children to examine the relationship between executive function and visuospatial abilities. Multiple linear regression analyses revealed that executive functions were closely associated with visuospatial abilities in TS but not in controls. These results suggest that executive dysfunctions observed in TS contribute to their visuospatial impairments.

  View details for DOI 10.1080/87565641.2011.584356

  View details for PubMedID 22004020

• Insulin resistance and hippocampal volume in women at risk for Alzheimer's disease NEUROBIOLOGY OF AGING Rasgon, N. L., Kenna, H. A., Wroolie, T. E., Kelley, R., Silverman, D., Brooks, J., Williams, K. E., Powers, B. N., Hallmayer, J., Reiss, A. 2011; 32 (11): 1942-1948

  Abstract

  Insulin resistance (IR) is the main pathological condition underlying vascular disorders, such as diabetes and cardiovascular disease, which are well established risk factors for cognitive decline and Alzheimer disease (AD). Hippocampal atrophy has been associated with cognitive decline, but little is known about the influence of IR on hippocampus integrity in non-diabetic, cognitively intact individuals. Herein, 50 women ages 50-65, current users of hormone therapy, underwent magnetic resonance imaging, cognitive testing, and homeostatic assessment of insulin resistance (HOMA-IR), as part of a longitudinal study examining brain structure and function in postmenopausal women at risk for AD. Results demonstrated a significant negative relationship between HOMA-IR and right and total hippocampal volume, overall cognitive performance, and selective tests of verbal and non-verbal memory. The main effect of HOMA-IR on brain structure and cognition was not altered by the presence of APOE-ε4 allele or by reproductive history, such as duration of endogenous and exogenous estrogen exposure. These results suggest that IR in middle-aged individuals at risk for AD may be biomarker for dementia risk.

  View details for DOI 10.1016/j.neurobiolaging.2009.12.005

  View details for Web of Science ID 000295220700003

  View details for PubMedID 20031276

  View details for PubMedCentralID PMC2891925

• Aberrant Frontal Lobe Maturation in Adolescents with Fragile X Syndrome is Related to Delayed Cognitive Maturation BIOLOGICAL PSYCHIATRY Bray, S., Hirt, M., Jo, B., Hall, S. S., Lightbody, A. A., Walter, E., Chen, K., Patnaik, S., Reiss, A. L. 2011; 70 (9): 852-858

  Abstract

  Fragile X syndrome (FXS) is the most common known heritable cause of intellectual disability. Prior studies in FXS have observed a plateau in cognitive and adaptive behavioral development in early adolescence, suggesting that brain development in FXS may diverge from typical development during this period.In this study, we examined adolescent brain development using structural magnetic resonance imaging data acquired from 59 individuals with FXS and 83 typically developing control subjects aged 9 to 22, a subset of whom were followed up longitudinally (1-5 years; typically developing: 17, FXS: 19). Regional volumes were modeled to obtain estimates of age-related change.We found that while structures such as the caudate showed consistent volume differences from control subjects across adolescence, prefrontal cortex (PFC) gyri showed significantly aberrant maturation. Furthermore, we found that PFC-related measures of cognitive functioning followed a similarly aberrant developmental trajectory in FXS.Our findings suggest that aberrant maturation of the PFC during adolescence may contribute to persistent or increasing intellectual deficits in FXS.

  View details for DOI 10.1016/j.biopsych.2011.05.038

  View details for Web of Science ID 000296228000012

  View details for PubMedID 21802660

  View details for PubMedCentralID PMC3191299

• The Brain Basis of the Phonological Deficit in Dyslexia Is Independent of IQ PSYCHOLOGICAL SCIENCE Tanaka, H., Black, J. M., Hulme, C., Stanley, L. M., Kesler, S. R., Whitfield-Gabrieli, S., Reiss, A. L., Gabrieli, J. D., Hoeft, F. 2011; 22 (11): 1442-1451

  Abstract

  Although the role of IQ in developmental dyslexia remains ambiguous, the dominant clinical and research approaches rely on a definition of dyslexia that requires reading skill to be significantly below the level expected given an individual's IQ. In the study reported here, we used functional MRI (fMRI) to examine whether differences in brain activation during phonological processing that are characteristic of dyslexia were similar or dissimilar in children with poor reading ability who had high IQ scores (discrepant readers) and in children with poor reading ability who had low IQ scores (nondiscrepant readers). In two independent samples including a total of 131 children, using univariate and multivariate pattern analyses, we found that discrepant and nondiscrepant poor readers exhibited similar patterns of reduced activation in brain areas such as left parietotemporal and occipitotemporal regions. These results converge with behavioral evidence indicating that, regardless of IQ, poor readers have similar kinds of reading difficulties in relation to phonological processing.

  View details for DOI 10.1177/0956797611419521

  View details for Web of Science ID 000300826400015

  View details for PubMedID 22006060

• Reduced Functional Connectivity during Working Memory in Turner Syndrome CEREBRAL CORTEX Bray, S., Dunkin, B., Hong, D. S., Reiss, A. L. 2011; 21 (11): 2471-2481

  Abstract

  Turner syndrome (TS) is a genetic disorder affecting females, resulting from the complete or partial absence of an X chromosome. The cognitive profile of TS shows relative strengths in the verbal domain and weaknesses in the procedural domain, including working memory. Neuroimaging studies have identified differences in the morphology of the parietal lobes, and white matter pathways linking frontal and parietal regions, as well as abnormal activation in dorsal frontal and parietal regions. Taken together these findings suggest that abnormal functional connectivity between frontal and parietal regions may be related to working memory impairments in TS, a hypothesis we tested in the present study. We scanned TS and typically developing participants with functional magnetic resonance imaging while they performed visuospatial and phonological working memory tasks. We generated a seed region in parietal cortex based on structural differences in TS and found that functional connectivity with dorsal frontal regions was reduced during working memory in TS. Finally, we found that connectivity was correlated with task performance in TS. These findings suggest that structural brain abnormalities in TS affect not only regional activity but also the functional interactions between regions and that this has important consequences for behavior.

  View details for DOI 10.1093/cercor/bhr017

  View details for PubMedID 21441396

• Striatal volumes in pediatric bipolar patients with and without comorbid ADHD PSYCHIATRY RESEARCH-NEUROIMAGING Liu, I. Y., Howe, M., Garrett, A., Karchemskiy, A., Kelley, R., Alegria, D., Reiss, A., Chang, K. 2011; 194 (1): 14-20

  Abstract

  The most prevalent comorbid disorder in pediatric bipolar disorder (BD) is attention-deficit/hyperactivity disorder (ADHD). As caudate volume abnormalities have been demonstrated in both BD and ADHD, this study sought to determine whether these findings could be attributed to separable effects from either diagnosis. High resolution anatomical magnetic resonance (MRI) images were obtained from youth in 4 groups: BD with comorbid ADHD (n=17), BD without comorbid ADHD (n=12), youth with ADHD alone (n=11), and healthy control subjects (n=24). Caudate, putamen, and globus pallidus volumes were manually traced for each subject using BrainImageJava software by a reliable rater blinded to diagnosis. There was a significant effect of diagnosis on striatal volumes, with ADHD associated with decreased caudate and putamen volumes, and BD associated with increased caudate, putamen, and globus pallidus volumes. Thus, the presence or absence of comorbid ADHD in patients with BD was associated with distinct alterations in caudate volumes, suggesting that these groups have different, but related, mechanisms of neuropathology.

  View details for DOI 10.1016/j.pscychresns.2011.06.008

  View details for Web of Science ID 000296544300003

  View details for PubMedID 21875781

• Psychosocial Functioning and Social Cognitive Processing in Girls with Turner Syndrome JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Hong, D. S., Dunkin, B., Reiss, A. L. 2011; 32 (7): 512-520

  Abstract

  Turner syndrome (TS) is a common genetic disorder caused by partial or complete absence of the second X chromosome in females and is associated with a characteristic neurocognitive profile traditionally described by discrepancy between verbal and performance IQ. Difficulties in social functioning have also been increasingly identified in this population. The purpose of this study was to examine elements of social competence and cognition in a pre-estrogen population of girls with TS.The authors administered psychosocial and neurocognitive measures to examine metrics of social function and intelligence in a group of young girls with TS, pre-estrogen treatment (n = 42) and control peers (n = 32), aged between 3 and 12 years.Girls with TS demonstrated significantly decreased social competency on all dimensions of the Social Responsiveness Scale, with the exception of the Social Motivation subscale, where ratings were comparable with typically developing peers. Performance on social cognitive tasks was also impaired on NEPSY Memory for Faces and Theory of Mind tasks. Differences were further observed on Behavioral Assessment Scales for Children subscales of Hyperactivity, Atypicality, Attention, Social Skills, Activities of Daily Living, and Functional Communication. Group differences in social cognition or behavior remained significant after adjusting for verbal IQ.This study supports the hypothesis that young girls with TS who have not yet received estrogen treatment demonstrate significantly impaired social cognition. Improved understanding of differences in social competence and cognition can increase awareness and inform clinical approaches to identifying and treating social difficulties in individuals with TS.

  View details for DOI 10.1097/DBP.0b013e3182255301

  View details for PubMedID 21743350

• The Feasibility of Detecting Neuropsychologic and Neuroanatomic Effects of Type 1 Diabetes in Young Children DIABETES CARE Aye, T., Reiss, A. L., Kesler, S., Hoang, S., Drobny, J., Park, Y., Schleifer, K., Baumgartner, H., Wilson, D. M., Buckingham, B. A. 2011; 34 (7): 1458-1462

  Abstract

  To determine if frequent exposures to hypoglycemia and hyperglycemia during early childhood lead to neurocognitive deficits and changes in brain anatomy.In this feasibility, cross-sectional study, young children, aged 3 to 10 years, with type 1 diabetes and age- and sex-matched healthy control (HC) subjects completed neuropsychologic (NP) testing and magnetic resonance imaging (MRI) scans of the brain.NP testing and MRI scanning was successfully completed in 98% of the type 1 diabetic and 93% of the HC children. A significant negative relationship between HbA1c and Wechsler Intelligence Scale for Children (WISC) verbal comprehension was observed. WISC index scores were significantly reduced in type 1 diabetic subjects who had experienced seizures. White matter volume did not show the expected increase with age in children with type 1 diabetes compared with HC children (diagnosis by age interaction, P=0.005). A similar trend was detected for hippocampal volume. Children with type 1 diabetes who had experienced seizures showed significantly reduced gray matter and white matter volumes relative to children with type 1 diabetes who had not experienced seizures.It is feasible to perform MRI and NP testing in young children with type 1 diabetes. Further, early signs of neuroanatomic variation may be present in this population. Larger cross-sectional and longitudinal studies of neurocognitive function and neuroanatomy are needed to define the effect of type 1 diabetes on the developing brain.

  View details for DOI 10.2337/dc10-2164

  View details for PubMedID 21562318

• The Use of Diffusion Tensor Imaging (DTI) in Young Children with Type 1 Diabetes Aye, T., Barnea-Goraly, N., Park, Y., Wilson, D. M., Reiss, A. L., Buckingham, B. A. AMER DIABETES ASSOC. 2011: A44–A45

  View details for Web of Science ID 000461640000162

• Consequence of Preterm Birth in Early Adolescence: The Role of Language on Auditory Short-term Memory JOURNAL OF CHILD NEUROLOGY Fraello, D., Maller-Kesselman, J., Vohr, B., Katz, K. H., Kesler, S., Schneider, K., Reiss, A., Ment, L., Spann, M. N. 2011; 26 (6): 738-742

  Abstract

  This study tested the hypothesis that preterm early adolescents' short-term memory is compromised when presented with increasingly complex verbal information and that associated neuroanatomical volumes would differ between preterm and term groups. Forty-nine preterm and 20 term subjects were evaluated at age 12 years with neuropsychological measures and magnetic resonance imaging (MRI). There were no differences between groups in simple short-term and working memory. Preterm subjects performed lower on learning and short-term memory tests that included increased verbal complexity. They had reduced right parietal, left temporal, and right temporal white matter volumes and greater bilateral frontal gray and right frontal white matter volumes. There was a positive association between complex working memory and the left hippocampus and frontal white matter in term subjects. While not correlated, memory scores and volumes of cortical regions known to subserve language and memory were reduced in preterm subjects. This study provides evidence of possible mechanisms for learning problems in former preterm infants.

  View details for DOI 10.1177/0883073810391904

  View details for Web of Science ID 000290961000012

  View details for PubMedID 21471553

  View details for PubMedCentralID PMC3581362

• Insular volume reduction in fragile X syndrome INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE Cohen, J. D., Nichols, T., Brignone, L., Hall, S. S., Reiss, A. L. 2011; 29 (4): 489-494

  Abstract

  Fragile X syndrome (FraX) is the most common form of inherited mental deficit and is caused by mutations of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome. While males and females with the full FMR1 mutation are affected differently because the disorder is X-linked, both suffer from varying degrees of cognitive impairment, attention deficits and social anxiety. The insula is a sensory integrative region that has been increasingly suggested as a critical area involved in anxiety manifestation. The current study was designed to examine possible changes in insular volume in FraX compared to age- and gender-matched typically developing healthy controls (HC) as well as age-, gender-, and intelligence-matched developmentally delayed controls (DD). An established native-space, manual morphometry method was utilized to quantify total and regional insular volumes using structural magnetic resonance imaging. Total, anterior and posterior insular volumes were found to be reduced in FraX compared to both HC and DD. The current data add to a growing literature concerning brain abnormalities in FraX and suggests that significant volume reduction of the insula is a component of the FraX neuroanatomical phenotype. This finding also provides an intriguing potential neural correlate for hyperarousal and gaze aversion, which are prominent behavioral symptoms of FraX.

  View details for DOI 10.1016/j.ijdevneu.2011.01.003

  View details for Web of Science ID 000291506000016

  View details for PubMedID 21291994

  View details for PubMedCentralID PMC3095676

• Neuroanatomical Phenotype of Klinefelter Syndrome in Childhood: A Voxel-Based Morphometry Study JOURNAL OF NEUROSCIENCE Bryant, D. M., Hoeft, F., Lai, S., Lackey, J., Roeltgen, D., Ross, J., Reiss, A. L. 2011; 31 (18): 6654-6660

  Abstract

  Klinefelter syndrome (KS) is a genetic disorder characterized by a supernumerary X chromosome. As such, KS offers a naturally occurring human model for the study of both X-chromosome gene expression and androgen on brain development. Previous neuroimaging studies have revealed neuroanatomical variations associated with KS, but have differed widely with respect to subject inclusion criteria, including mosaicism, pubertal status, and history of testosterone replacement therapy (TRT), all factors likely to influence neurodevelopment. We conducted a voxel-based morphometry study of regional gray and white matter (GM and WM, respectively) volumes in 31 KS males (mean age, 9.69 ± 1.70 years) and 36 typically developing (TD) male controls (10.99 ± 1.72 years). None of the participants with KS had received TRT, and all were prepubertal and had nonmosaic 47,XXY karyotypes. After controlling for age, males with KS showed trends (0.05 < p < 0.10) for significantly reduced total gray matter volume (TGMV) and total white matter volume (TWMV), relative to TD males. After controlling for TGMV and age, the KS group had significantly increased sensorimotor and parietal-occipital GM and significantly reduced amygdalar, hippocampal, insular, temporal, and inferior frontal GM relative to TD controls. After controlling for TWMV and age, the KS group had significantly increased left parietal WM as well as significantly reduced frontal and temporal WM. These findings are indicative of a characteristic prepubertal neuroanatomical phenotype that may be associated with cognitive-behavioral features of KS. This work offers new insight into the relationships among X-chromosome gene expression, neuroanatomy, and cognitive-behavioral functions impaired in KS, including language and attention.

  View details for DOI 10.1523/JNEUROSCI.5899-10.2011

  View details for Web of Science ID 000290212100006

  View details for PubMedID 21543594

  View details for PubMedCentralID PMC3148194

• Changes in Brain Activation Following Family-Focused Treatment in Youth At-Risk for Bipolar Disorder 66th Annual Meeting of the Society-of-Biological-Psychiatry Garrett, A. S., Reiss, A. L., Miklowitz, D. J., Acquaye, T. K., Cosgrove, V. E., Singh, M. K., Howe, M. E., Kelley, R. G., Taylor, D., George, E., Chang, K. ELSEVIER SCIENCE INC. 2011: 163S–163S

  View details for Web of Science ID 000290641800519

• Resting State Functional Connectivity in Adolescents with Bipolar I Disorder Singh, M. K., Kelley, R., Sanders, E. M., Li, S., Howe, M., Reiss, A. L., Chang, K. ELSEVIER SCIENCE INC. 2011: 175S

  View details for Web of Science ID 000290641800557

• White Matter Aberrations in Non-Mosaic and Estrogen-Naive Girls with Turner Syndrome Yamagata, B., Barnea-Goraly, N., Park, Y., Hong, D. S., Reiss, A. L. ELSEVIER SCIENCE INC. 2011: 84S

  View details for Web of Science ID 000290641800267

• Neurofunctional Correlates of Response to Quetiapine in Youth with Bipolar Depression Chang, K., DelBello, M., Kelley, R., Garrett, A., Howe, M., Bryan, H., Adler, C., Elliason, J., Mills, N., Strakowski, S., Reiss, A. ELSEVIER SCIENCE INC. 2011: 161S

  View details for Web of Science ID 000290641800514

• Deformations of Amygdala Morphology in Familial Pediatric Bipolar Disorder Kelley, R., Garrett, A., Alegria, D., Thompson, P., Howe, M., Reiss, A., Chang, K. ELSEVIER SCIENCE INC. 2011: 166S

  View details for Web of Science ID 000290641800530

• White Matter Tract Alterations in Youth at Risk for Bipolar Disorder 66th Annual Meeting of the Society-of-Biological-Psychiatry Roybal, D. J., Barnea-Goraly, N., Acquaye, T., Kelley, R., Barapour, L., Howe, M., Reiss, A. L., Chang, K. D. ELSEVIER SCIENCE INC. 2011: 174S–174S

  View details for Web of Science ID 000290641800554

• Increased Subgenual Cingulate Cortex Volume in Pediatric Bipolar Disorder Associated with Mood Stabilizer Exposure JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Mitsunaga, M. M., Garrett, A., Howe, M., Karchemskiy, A., Reiss, A., Chang, K. 2011; 21 (2): 149-155

  Abstract

  The subgenual cingulate (SGC) cortex has been implicated in the pathophysiology of mood disorders. We sought to study morphometric characteristics of the SGC in pediatric subjects with familial bipolar disorder (BD) compared with healthy controls.Twenty children and adolescents with BD (mean age = 14.6 years, 4 females) and 20 healthy age-, gender-, and intelligence quotient-matched controls underwent high-resolution anatomical magnetic resonance imaging. Patients were primarily euthymic and most were taking medications. SGC cortex volumes were determined by manual tracings from a reliable rater, blinded to diagnosis. Analyses of covariance were performed with total cerebral gray matter and age as covariates.No differences were found in SGC volumes between BD subjects and healthy controls. Further analysis revealed that BD subjects with past mood stabilizer exposure had significantly increased SGC volumes compared with BD subjects without mood stabilizer exposure, and compared with controls. The increase was driven by larger bilateral posterior SGC volumes.Youth with familial BD do not appear to have abnormalities in SGC volume. Mood stabilizer exposure, however, may be correlated with increases in SGC volume.

  View details for DOI 10.1089/cap.2010.0094

  View details for PubMedID 21486168

• Neuroanatomical spatial patterns in Turner syndrome NEUROIMAGE Marzelli, M. J., Hoeft, F., Hong, D. S., Reiss, A. L. 2011; 55 (2): 439-447

  Abstract

  Turner syndrome (TS) is a highly prevalent genetic condition caused by partial or complete absence of one X-chromosome in a female and is associated with a lack of endogenous estrogen during development secondary to gonadal dysgenesis. Prominent cognitive weaknesses in executive and visuospatial functions in the context of normal overall IQ also occur in affected individuals. Previous neuroimaging studies of TS point to a profile of neuroanatomical variation relative to age and sex matched controls. However, there are no neuroimaging studies focusing on young girls with TS before they receive exogenous estrogen treatment to induce puberty. Information obtained from young girls with TS may help to establish an early neural correlate of the cognitive phenotype associated with the disorder. Further, univariate analysis has predominantly been the method of choice in prior neuroimaging studies of TS. Univariate approaches examine between-group differences on the basis of individual image elements (i.e., a single voxel's intensity or the volume of an a priori defined brain region). This is in contrast to multivariate methods that can elucidate complex neuroanatomical profiles in a clinical population by determining the pattern of between-group differences from many image elements evaluated simultaneously. In this case, individual image elements might not be significantly different between groups but can still contribute to a significantly different overall spatial pattern. In this study, voxel-based morphometry (VBM) of high-resolution magnetic resonance images was used to investigate differences in brain morphology between 13 pediatric, pre-estrogen girls with monosomic TS and 13 age-matched typically developing controls (3.0 T imaging: mean age 9.1±2.1). A similar analysis was performed with an older cohort of 13 girls with monosomic TS and 13 age-matched typically developing controls (1.5 T imaging: mean age 15.8±4.5). A multivariate, linear support vector machine analysis using leave-one-out cross-validation was then employed to discriminate girls with TS from typically developing controls based on differences in neuroanatomical spatial patterns and to assess how accurately such patterns translate across heterogeneous cohorts. VBM indicated that both TS cohorts had significantly reduced gray matter volume in the precentral, postcentral, and supramarginal gyri and enlargement of the left middle and superior temporal gyri. Support vector machine (SVM) classifiers achieved high accuracy for discriminating brain morphology patterns in TS from typically developing controls and also displayed spatial patterns consistent with the VBM results. Furthermore, the SVM classifiers identified additional neuroanatomical variations in individuals with TS, localized in the hippocampus, orbitofrontal cortex, insula, caudate, and cuneus. Our results demonstrate robust spatial patterns of altered brain morphology in developmentally dynamic populations with TS, providing further insight into the neuroanatomical correlates of cognitive-behavioral features in this condition.

  View details for DOI 10.1016/j.neuroimage.2010.12.054

  View details for PubMedID 21195197

• Developmental changes in multivariate neuroanatomical patterns that predict risk for psychosis in 22q11.2 deletion syndrome JOURNAL OF PSYCHIATRIC RESEARCH Gothelf, D., Hoeft, F., Ueno, T., Sugiura, L., Lee, A. D., Thompson, P., Reiss, A. L. 2011; 45 (3): 322-331

  Abstract

  The primary objective of the current prospective study was to examine developmental patterns of voxel-by-voxel gray and white matter volumes (GMV, WMV, respectively) that would predict psychosis in adolescents with 22q11.2 deletion syndrome (22q11.2DS), the most common known genetic risk factor for schizophrenia. We performed a longitudinal voxel-based morphometry analysis using structural T1 MRI scans from 19 individuals with 22q11.2DS and 18 typically developing individuals. In 22q11.2DS, univariate analysis showed that greater reduction in left dorsal prefrontal cortical (dPFC) GMV over time predicted greater psychotic symptoms at Time2. This dPFC region also showed significantly reduced volumes in 22q11.2DS compared to typically developing individuals at Time1 and 2, greater reduction over time in 22q11.2DS COMT(Met) compared to COMT(Val), and greater reduction in those with greater decline in verbal IQ over time. Leave-one-out Multivariate pattern analysis results (MVPA) on the other hand, showed that patterns of GM and WM morphometric changes over time in regions including but not limited to the dPFC predicted risk for psychotic symptoms (94.7-100% accuracy) significantly better than using univariate analysis (63.1%). Additional predictive brain regions included medial PFC and dorsal cingulum. This longitudinal prospective study shows novel evidence of morphometric spatial patterns predicting the development of psychotic symptoms in 22q11.2DS, and further elucidates the abnormal maturational processes in 22q11.2DS. The use of neuroimaging using MVPA may hold promise to predict outcome in a variety of neuropsychiatric disorders.

  View details for DOI 10.1016/j.jpsychires.2010.07.008

  View details for Web of Science ID 000288723800005

  View details for PubMedID 20817203

  View details for PubMedCentralID PMC3000448

• Neuroanatomical Differences in Toddler Boys With Fragile X Syndrome and Idiopathic Autism ARCHIVES OF GENERAL PSYCHIATRY Hoeft, F., Walter, E., Lightbody, A. A., Hazlett, H. C., Chang, C., Piven, J., Reiss, A. L. 2011; 68 (3): 295-305

  Abstract

  Autism is an etiologically heterogeneous neurodevelopmental disorder for which there is no known unifying etiology or pathogenesis. Many conditions of atypical development can lead to autism, including fragile X syndrome (FXS), which is presently the most common known single-gene cause of autism.To examine whole-brain morphometric patterns that discriminate young boys with FXS from those with idiopathic autism (iAUT) as well as control participants.Cross-sectional, in vivo neuroimaging study.Academic medical centers.Young boys (n = 165; aged 1.57-4.15 years) diagnosed as having FXS or iAUT as well as typically developing and idiopathic developmentally delayed controls.Univariate voxel-based morphometric analyses, voxel-based morphometric multivariate pattern classification (linear support vector machine), and clustering analyses (self-organizing map).We found that frontal and temporal gray and white matter regions often implicated in social cognition, including the medial prefrontal cortex, orbitofrontal cortex, superior temporal region, temporal pole, amygdala, insula, and dorsal cingulum, were aberrant in FXS and iAUT as compared with controls. However, these differences were in opposite directions for FXS and iAUT relative to controls; in general, greater volume was seen in iAUT compared with controls, who in turn had greater volume than FXS. Multivariate analysis showed that the overall pattern of brain structure in iAUT generally resembled that of the controls more than FXS, both with and without AUT.Our findings demonstrate that FXS and iAUT are associated with distinct neuroanatomical patterns, further underscoring the neurobiological heterogeneity of iAUT.

  View details for Web of Science ID 000288086900009

  View details for PubMedID 21041609

• Neurochemical deficits in the cerebellar vermis in child offspring of parents with bipolar disorder BIPOLAR DISORDERS Singh, M. K., Spielman, D., Libby, A., Adams, E., Acquaye, T., Howe, M., Kelley, R., Reiss, A., Chang, K. D. 2011; 13 (2): 189-197

  Abstract

  We aimed to compare concentrations of N-acetyl aspartate, myo-inositol, and other neurometabolites in the cerebellar vermis of offspring at risk for bipolar disorder (BD) and healthy controls to examine whether changes in these neuronal metabolite concentrations occur in at-risk offspring prior to the onset of mania.A total of 22 children and adolescents aged 9-17 years with a familial risk for bipolar I or II disorder [at-risk offspring with non-bipolar I disorder mood symptoms (AR)], and 25 healthy controls (HC) were examined using proton magnetic resonance spectroscopy at 3T to study metabolite concentrations in an 8-cc voxel in the cerebellar vermis.Decreased myo-inositol and choline concentrations in the vermis were seen in the AR group compared to HC (p<0.01).Decreased cellular metabolism and interference with second messenger pathways may be present in the cerebellar vermis in youth at risk for BD as evident by decreased myo-inositol and choline concentrations in this region. These results may be limited by a cross-sectional design, co-occurring diagnoses, and medication exposure. Longitudinal studies are necessary to determine whether early neurochemical changes can predict the development of mania. Improved methods for identifying children with certain neurochemical vulnerabilities may inform preventive and early intervention strategies prior to the onset of mania.

  View details for DOI 10.1111/j.1399-5618.2011.00902.x

  View details for PubMedID 21443573

• A quantitative comparison of NIRS and fMRI across multiple cognitive tasks NEUROIMAGE Cui, X., Bray, S., Bryant, D. M., Glover, G. H., Reiss, A. L. 2011; 54 (4): 2808-2821

  Abstract

  Near infrared spectroscopy (NIRS) is an increasingly popular technology for studying brain function. NIRS presents several advantages relative to functional magnetic resonance imaging (fMRI), such as measurement of concentration changes in both oxygenated and deoxygenated hemoglobin, finer temporal resolution, and ease of administration, as well as disadvantages, most prominently inferior spatial resolution and decreased signal-to-noise ratio (SNR). While fMRI has become the gold standard for in vivo imaging of the human brain, in practice NIRS is a more convenient and less expensive technology than fMRI. It is therefore of interest to many researchers how NIRS compares to fMRI in studies of brain function. In the present study we scanned participants with simultaneous NIRS and fMRI on a battery of cognitive tasks, placing NIRS probes over both frontal and parietal brain regions. We performed detailed comparisons of the signals in both temporal and spatial domains. We found that NIRS signals have significantly weaker SNR, but are nonetheless often highly correlated with fMRI measurements. Both SNR and the distance between the scalp and the brain contributed to variability in the NIRS/fMRI correlations. In the spatial domain, we found that a photon path forming an ellipse between the NIRS emitter and detector correlated most strongly with the BOLD response. Taken together these findings suggest that, while NIRS can be an appropriate substitute for fMRI for studying brain activity related to cognitive tasks, care should be taken when designing studies with NIRS to ensure that: 1) the spatial resolution is adequate for answering the question of interest and 2) the design accounts for weaker SNR, especially in brain regions more distal from the scalp.

  View details for DOI 10.1016/j.neuroimage.2010.10.069

  View details for Web of Science ID 000286495800025

  View details for PubMedID 21047559

  View details for PubMedCentralID PMC3021967

• Preterm birth results in alterations in neural connectivity at age 16 years NEUROIMAGE Mullen, K. M., Vohr, B. R., Katz, K. H., Schneider, K. C., Lacadie, C., Hampson, M., Makuch, R. W., Reiss, A. L., Constable, R. T., Ment, L. R. 2011; 54 (4): 2563-2570

  Abstract

  Very low birth weight preterm (PT) children are at high risk for brain injury. Employing diffusion tensor imaging (DTI), we tested the hypothesis that PT adolescents would demonstrate microstructural white matter disorganization relative to term controls at 16 years of age. Forty-four PT subjects (600-1250 g birth weight) without neonatal brain injury and 41 term controls were evaluated at age 16 years with DTI, the Wechsler Intelligence Scale for Children-III (WISC), the Peabody Picture Vocabulary Test-Revised (PPVT), and the Comprehensive Test of Phonological Processing (CTOPP). PT subjects scored lower than term subjects on WISC full scale (p=0.003), verbal (p=0.043), and performance IQ tests (p=0.001), as well as CTOPP phonological awareness (p=0.004), but scored comparably to term subjects on PPVT and CTOPP Rapid Naming tests. PT subjects had lower fractional anisotropy (FA) values in multiple regions including bilateral uncinate fasciculi (left: p=0.01; right: p=0.004), bilateral external capsules (left: p<0.001; right: p<0.001), the splenium of the corpus callosum (p=0.008), and white matter serving the inferior frontal gyrus bilaterally (left: p<0.001; right: p=0.011). FA values in both the left and right uncinate fasciculi correlated with PPVT scores (a semantic language task) in the PT subjects (left: r=0.314, p=0.038; right: r=0.336, p=0.026). FA values in the left and right arcuate fasciculi correlated with CTOPP Rapid Naming scores (a phonologic task) in the PT subjects (left: r=0.424, p=0.004; right: r=0.301, p=0.047). These data support for the first time that dual pathways underlying language function are present in PT adolescents. The striking bilateral dorsal correlations for the PT group suggest that prematurely born subjects rely more heavily on the right hemisphere than typically developing adults for performance of phonological language tasks. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain.

  View details for DOI 10.1016/j.neuroimage.2010.11.019

  View details for Web of Science ID 000286495800002

  View details for PubMedID 21073965

  View details for PubMedCentralID PMC3020252

• Aberrant Brain Activation During a Working Memory Task in Psychotic Major Depression AMERICAN JOURNAL OF PSYCHIATRY Garrett, A., Kelly, R., Gomez, R., Keller, J., Schatzberg, A. F., Reiss, A. L. 2011; 168 (2): 173-182

  Abstract

  The authors sought to better understand the neural circuitry associated with working memory deficits in psychotic major depression by examining brain function during an N-back task.Study subjects were 16 patients with psychotic major depression, 15 patients with nonpsychotic major depression, and 19 healthy comparison subjects. Functional MRI data were collected while participants responded to letter stimuli that were repeated from the previous trial (1-back) or the one before that (2-back).Relative to the healthy comparison group, both the psychotic and nonpsychotic major depression groups had significantly greater activation in the right parahippocampal gyrus during the 2-back task, and the psychotic major depression group showed this overactivation during the 1-back task as well. The nonpsychotic major depression group showed significantly lower activation than other groups in the right dorsolateral prefrontal cortex and greater activation than the healthy comparison group in the superior occipital cortex. The psychotic major depression group was unique in showing greater activation than both other groups in the right temporoparietal junction, a cluster that also demonstrated connectivity with activation in the left prefrontal cortex.The psychotic major depression group showed aberrant parahippocampal activation at a lower demand level than observed in nonpsychotic major depression. While the nonpsychotic major depression group showed abnormalities in frontal executive regions, the psychotic major depression group showed abnormalities in temporoparietal regions associated with orienting to unexpected stimuli. Considering the functional connectivity of this cluster with left dorsolateral prefrontal cortex regions, these findings may reflect neural compensation for sensory gating deficits in psychotic major depression.

  View details for DOI 10.1176/appi.ajp.2010.09121718

  View details for Web of Science ID 000286972800011

  View details for PubMedID 21078708

• EXECUTIVE FUNCTIONING IN PEDIATRIC STEM CELL TRANSPLANTATION UTILIZING FMRI Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation(BMT) Tandem Williams, S. E., Hill, R., Craveiro, L., Agarwal-Hashmi, R., Weinberg, K., Reiss, A. L. ELSEVIER SCIENCE INC. 2011: S243–S243

  View details for Web of Science ID 000287350500242

• Neural systems predicting long-term outcome in dyslexia PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Hoeft, F., McCandliss, B. D., Black, J. M., Gantman, A., Zakerani, N., Hulme, C., Lyytinen, H., Whitfield-Gabrieli, S., Glover, G. H., Reiss, A. L., Gabrieli, J. D. 2011; 108 (1): 361-366

  Abstract

  Individuals with developmental dyslexia vary in their ability to improve reading skills, but the brain basis for improvement remains largely unknown. We performed a prospective, longitudinal study over 2.5 y in children with dyslexia (n = 25) or without dyslexia (n = 20) to discover whether initial behavioral or brain measures, including functional MRI (fMRI) and diffusion tensor imaging (DTI), can predict future long-term reading gains in dyslexia. No behavioral measure, including widely used and standardized reading and language tests, reliably predicted future reading gains in dyslexia. Greater right prefrontal activation during a reading task that demanded phonological awareness and right superior longitudinal fasciculus (including arcuate fasciculus) white-matter organization significantly predicted future reading gains in dyslexia. Multivariate pattern analysis (MVPA) of these two brain measures, using linear support vector machine (SVM) and cross-validation, predicted significantly above chance (72% accuracy) which particular child would or would not improve reading skills (behavioral measures were at chance). MVPA of whole-brain activation pattern during phonological processing predicted which children with dyslexia would improve reading skills 2.5 y later with >90% accuracy. These findings identify right prefrontal brain mechanisms that may be critical for reading improvement in dyslexia and that may differ from typical reading development. Brain measures that predict future behavioral outcomes (neuroprognosis) may be more accurate, in some cases, than available behavioral measures.

  View details for DOI 10.1073/pnas.1008950108

  View details for Web of Science ID 000285915000067

  View details for PubMedID 21173250

  View details for PubMedCentralID PMC3017159

• Changes in frontal-parietal activation and math skills performance following adaptive number sense training: Preliminary results from a pilot study NEUROPSYCHOLOGICAL REHABILITATION Kesler, S. R., Sheau, K., Koovakkattu, D., Reiss, A. L. 2011; 21 (4): 433-454

  Abstract

  Number sense is believed to be critical for math development. It is putatively an implicitly learned skill and may therefore have limitations in terms of being explicitly trained, particularly in individuals with altered neurodevelopment. A case series study was conducted using an adaptive, computerised programme that focused on number sense and general problem-solving skills. The study was designed to investigate training effects on performance as well as brain function in a group of children with Turner syndrome who are at risk for math difficulties and altered development of math-related brain networks. Standardised measurements of math and math-related cognitive skills as well as functional magnetic resonance imaging (fMRI) were used to assess behavioural and neurobiological outcomes following training. Participants demonstrated significantly increased basic math skills, including number sense, and calculation as well as processing speed, cognitive flexibility and visual-spatial processing skills. With the exception of calculation, increased scores also were clinically significant (i.e., recovered) based on reliable change analysis. Participants additionally demonstrated significantly increased bilateral parietal lobe activation and decreased frontal-striatal and mesial temporal activation following the training programme. These findings show proof of concept for an accessible training approach that may be potentially associated with improved number sense, math and related skills, as well as functional changes in math-related neural systems, even among individuals at risk for altered brain development.

  View details for DOI 10.1080/09602011.2011.578446

  View details for Web of Science ID 000299788700001

  View details for PubMedID 21714745

  View details for PubMedCentralID PMC3152634

• Aberrant Brain Activation During a Response Inhibition Task in Adolescent Eating Disorder Subtypes AMERICAN JOURNAL OF PSYCHIATRY Lock, J., Garrett, A., Beenhakker, J., Reiss, A. L. 2011; 168 (1): 55-64

  Abstract

  Behavioral and personality characteristics associated with excessive inhibition and disinhibition are observed in patients with eating disorders, but neural correlates of inhibitory control have not been examined in adolescents with these disorders.Thirteen female adolescents with binge eating and purging behaviors (i.e., bulimia nervosa or anorexia nervosa, binge eating/purging type);14 with anorexia nervosa, restricting type; and 13 healthy comparison subjects performed a rapid, jittered event-related go/no-go task. Functional magnetic resonance images were collected using a 3 Tesla GE scanner and a spiral pulse sequence. A whole-brain three-group analysis of variance in SPM5 was used to identify significant activation associated with the main effect of group for the comparison of correct no-go versus go trials. The mean activation in these clusters was extracted for further comparisons in SPSS.The binge eating/purging group showed significantly greater activation than the healthy comparison group in the bilateral precentral gyri, anterior cingulate cortex, and middle and superior temporal gyri as well as greater activation relative to both comparison and restricting type anorexia subjects in the hypothalamus and right dorsolateral prefrontal cortex. Within-group analysis found that only the restricting type anorexia group showed a positive correlation between the percent correct on no-go trials and activation in posterior visual and inferior parietal cortex regions.The present study provides preliminary evidence that during adolescence, eating disorder subtypes may be distinguishable in terms of neural correlates of inhibitory control. This distinction is consistent with differences in behavioral impulsivity in these patient groups.

  View details for DOI 10.1176/appi.ajp.2010.10010056

  View details for Web of Science ID 000285868100010

  View details for PubMedID 21123315

  View details for PubMedCentralID PMC3016457

• Speeded Near Infrared Spectroscopy (NIRS) Response Detection PLOS ONE Cui, X., Bray, S., Reiss, A. L. 2010; 5 (11)

  Abstract

  The hemodynamic response measured by Near Infrared Spectroscopy (NIRS) is temporally delayed from the onset of the underlying neural activity. As a consequence, NIRS based brain-computer-interfaces (BCIs) and neurofeedback learning systems, may have a latency of several seconds in responding to a change in participants' behavioral or mental states, severely limiting the practical use of such systems. To explore the possibility of reducing this delay, we used a multivariate pattern classification technique (linear support vector machine, SVM) to decode the true behavioral state from the measured neural signal and systematically evaluated the performance of different feature spaces (signal history, history gradient, oxygenated or deoxygenated hemoglobin signal and spatial pattern). We found that the latency to decode a change in behavioral state can be reduced by 50% (from 4.8 s to 2.4 s), which will enhance the feasibility of NIRS for real-time applications.

  View details for DOI 10.1371/journal.pone.0015474

  View details for Web of Science ID 000284087800027

  View details for PubMedID 21085607

  View details for PubMedCentralID PMC2978722

• Similar White Matter Aberrations in Children With Autism and Their Unaffected Siblings A Diffusion Tensor Imaging Study Using Tract-Based Spatial Statistics ARCHIVES OF GENERAL PSYCHIATRY Barnea-Goraly, N., Lotspeich, L. J., Reiss, A. L. 2010; 67 (10): 1052-1060

  Abstract

  Autism is a neurobiological condition with a strong genetic component. Recent diffusion tensor imaging (DTI) studies have indicated that white matter structure is aberrant in autism. To date, white matter structure has not been assessed in family members of children with autism.To determine whether white matter structure is aberrant in children with autism and their unaffected siblings compared with controls, and to test the hypothesis that white matter structure in autism is correlated with autism spectrum symptomatology.Cross-sectional, case-control, voxel-based, whole-brain DTI analysis using Tract-Based Spatial Statistics.University research center. Patients  A sample of 37 children: 13 subjects with autism, 13 of their unaffected siblings, and 11 controls. Controls were age- and intelligence quotient-matched to the unaffected siblings; all groups were age matched. Main Outcome Measure  Fractional anisotropy (FA) and axial and radial diffusivities. In addition, behavioral correlation analyses were conducted using the Autism Diagnostic Interview and Autism Diagnostic Observation Schedule subscales and FA values, as well as axial diffusivity values in the autism group.Compared with the control group, both the autism and sibling groups had widespread, significantly reduced white matter FA values (P ≤ .05, corrected) in the frontal parietal and temporal lobes and included, but were not restricted to, regions known to be important for social cognition. Within regions of reduced FA, significant reductions in axial diffusivity, but not radial diffusivity, were observed. There were no significant differences in white matter structure between the autism and sibling groups. There were no significant correlations between autism symptomatology and white matter FA or axial diffusivity.Our findings suggest that white matter structure may represent a marker of genetic risk for autism or vulnerability to development of this disorder.

  View details for Web of Science ID 000282917400009

  View details for PubMedID 20921121

• Decreased Prefrontal Cortical Volume Associated with Increased Bedtime Cortisol in Traumatized Youth BIOLOGICAL PSYCHIATRY Carrion, V. G., Weems, C. F., Richert, K., Hoffman, B. C., Reiss, A. L. 2010; 68 (5): 491-493

  Abstract

  The purpose of this study was to investigate prefrontal cortex (PFC) volumes in youth with posttraumatic stress symptoms (PTSS) and explore the relationship between cortisol secretion and PFC volumes.Total brain tissue volumes, segmented areas of the PFC, and diurnal cortisol secretion were examined in a sample of 33 youth aged 10 to 16 years. Cerebral volumes were available for 45 subjects (30 PTSS and 15 control subjects).Youth with PTSS had significantly decreased total brain tissue and total cerebral gray volumes in comparison with healthy control subjects. While controlling for total cerebral gray volume, the PTSS group demonstrated decreased left ventral and left inferior prefrontal gray volumes. A significant negative association was found between prebedtime cortisol levels and left ventral PFC gray volumes for the full sample.Findings suggest associations between posttraumatic stress and PFC neurodevelopment. Findings also suggest a link between PFC development and cortisol secretion.

  View details for DOI 10.1016/j.biopsych.2010.05.010

  View details for PubMedID 20579974

• Autism in Fragile X Syndrome: A Category Mistake? JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hall, S. S., Lightbody, A. A., Hirt, M., Rezvani, A., Reiss, A. L. 2010; 49 (9): 921-933

  Abstract

  Many investigators now routinely classify children with fragile X syndrome (FXS) according to whether or not they also meet diagnostic criteria for autism. To determine whether this classification is appropriate, we examined the profiles of autistic behaviors shown by boys and girls with FXS.Individuals with FXS, aged 5 to 25 years, were assessed on two established measures of autism, the Social Communication Questionnaire (SCQ) and the Autism Diagnostic Observation Schedule (ADOS).We found that 35.1% of boys and 4.3% of girls with FXS scored in the "autism" category on both instruments. Analysis of the symptom profile indicated that both boys and girls with FXS showed lower rates of impairment on communication and reciprocal social interaction items than the reference autism samples on the measures. Furthermore, a regression model showed that IQ was significantly negatively associated with the SCQ total score in both boys and girls with FXS, when controlling for age, medication use, and FMRP levels.These data suggest that there are significant differences in the profile of social and communicative symptomatology in FXS compared with individuals diagnosed with idiopathic autism. Given these differences, the implementation of standard autism interventions for individuals with FXS may not be optimal. Maintaining the conceptual distinction between FXS (an established biological disease) and idiopathic autism (a phenomenologically defined behavioral disorder) may also facilitate the development of more targeted and thus effective interventions for individuals with FXS in the future.

  View details for DOI 10.1016/j.jaac.2010.07.001

  View details for Web of Science ID 000281331400006

  View details for PubMedID 20732628

  View details for PubMedCentralID PMC2943372

• [Investigating the "social brain" through Williams syndrome]. Brain and nerve = Shinkei kenkyu no shinpo Nagamine, M., Mimura, M., Reiss, A. L., Hoeft, F. 2010; 62 (8): 877-884

  Abstract

  Recent advances in social cognitive neuroscience have led to the concept of the "social brain". The social brain includes neural processes specialized for processing social information necessary for the recognition of self and others, and interpersonal relationships. Because of its unique behavioral phenotypic features which includes 'hypersociability', Williams syndrome has gained popularity among social cognitive neuroscientists. Individuals with Williams syndrome share the same genetic risk factor for cognitive-behavioral dysfunction utilizing brain imaging to elucidate endophenotype provides us with an unprecendented opportunity to study gene, brain and behavior relationships especially those related to social cognition. In this review, we provide an overview of neuroimaging studies on social cognition in Williams syndrome and discuss the neural basis of the social brain.

  View details for PubMedID 20714036

• Reduced Hippocampal Activity in Youth with Posttraumatic Stress Symptoms: An fMRI Study JOURNAL OF PEDIATRIC PSYCHOLOGY Carrion, V. G., Haas, B. W., Garrett, A., Song, S., Reiss, A. L. 2010; 35 (5): 559-569

  Abstract

  Youth who experience interpersonal trauma and have posttraumatic stress symptoms (PTSS) develop cognitive deficits that impact their development. Our goal is to investigate the function of the hippocampus in adolescents with PTSS during a memory processing task.Twenty-seven adolescents between the ages of 10-17 years (16 with PTSS and 11 healthy controls) encoded and retrieved visually presented nouns (Verbal Declarative Memory Task) while undergoing fMRI scanning.The PTSS group demonstrated reduced activation of the right hippocampus during the retrieval component of the task. Further, severity of symptoms of avoidance and numbing correlated with reduced left hippocampal activation during retrieval.Decreased activity of the hippocampus during a verbal memory task may be a neurofunctional marker of PTSS in youth with history of interpersonal trauma. The results of this study may facilitate the development of focused treatments and may be of utility when assessing treatment outcome for PTSS.

  View details for DOI 10.1093/jpepsy/jsp112

  View details for PubMedID 19995868

• Affiliative behavior in Williams syndrome: Social perception and real-life social behavior NEUROPSYCHOLOGIA Jaervinen-Pasley, A., Adolphs, R., Yam, A., Hill, K. J., Grichanik, M., Reilly, J., Mills, D., Reiss, A. L., Korenberg, J. R., Bellugi, U. 2010; 48 (7): 2110-2119

  Abstract

  A frequently noted but largely anecdotal behavioral observation in Williams syndrome (WS) is an increased tendency to approach strangers, yet the basis for this behavior remains unknown. We examined the relationship between affect identification ability and affiliative behavior in participants with WS relative to a neurotypical comparison group. We quantified social behavior from self-judgments of approachability for faces, and from parent/other evaluations of real life. Relative to typical individuals, participants with WS were perceived as more sociable by others, exhibited perceptual deficits in affect identification, and judged faces of strangers as more approachable. In WS, high self-rated willingness to approach strangers was correlated with poor affect identification ability, suggesting that these two findings may be causally related. We suggest that the real-life hypersociability in WS may arise at least in part from abnormal perceptual processing of other people's faces, rather than from an overall bias at the level of behavior. While this did not achieve statistical significance, it provides preliminary evidence to suggest that impaired social-perceptual ability may play a role in increased approachability in WS.

  View details for DOI 10.1016/j.neuropsychologia.2010.03.032

  View details for Web of Science ID 000279023100025

  View details for PubMedCentralID PMC2881624

• Affiliative behavior in Williams syndrome: social perception and real-life social behavior. Neuropsychologia Järvinen-Pasley, A., Adolphs, R., Yam, A., Hill, K. J., Grichanik, M., Reilly, J., Mills, D., Reiss, A. L., Korenberg, J. R., Bellugi, U. 2010; 48 (7): 2110-2119

  Abstract

  A frequently noted but largely anecdotal behavioral observation in Williams syndrome (WS) is an increased tendency to approach strangers, yet the basis for this behavior remains unknown. We examined the relationship between affect identification ability and affiliative behavior in participants with WS relative to a neurotypical comparison group. We quantified social behavior from self-judgments of approachability for faces, and from parent/other evaluations of real life. Relative to typical individuals, participants with WS were perceived as more sociable by others, exhibited perceptual deficits in affect identification, and judged faces of strangers as more approachable. In WS, high self-rated willingness to approach strangers was correlated with poor affect identification ability, suggesting that these two findings may be causally related. We suggest that the real-life hypersociability in WS may arise at least in part from abnormal perceptual processing of other people's faces, rather than from an overall bias at the level of behavior. While this did not achieve statistical significance, it provides preliminary evidence to suggest that impaired social-perceptual ability may play a role in increased approachability in WS.

  View details for DOI 10.1016/j.neuropsychologia.2010.03.032

  View details for PubMedID 20385151

• A preliminary study of orbitofrontal activation and hypersociability in Williams Syndrome JOURNAL OF NEURODEVELOPMENTAL DISORDERS Mimura, M., Hoeft, F., Kato, M., Kobayashi, N., Sheau, K., Piggot, J., Mills, D., Galaburda, A., Korenberg, J. R., Bellugi, U., Reiss, A. L. 2010; 2 (2): 93-98

  Abstract

  Individuals with Williams syndrome (WS) demonstrate an abnormally positive social bias. However, the neural substrates of this hypersociability, i.e., positive attribution bias and increased drive toward social interaction, have not fully been elucidated. METHODS: We performed an event-related functional magnetic resonance imaging study while individuals with WS and typically developing controls (TD) matched positive and negative emotional faces. WS compared to TD showed reduced right amygdala activation during presentation of negative faces, as in the previous literature. In addition, WS showed a unique pattern of right orbitofrontal cortex activation. While TD showed medial orbitofrontal cortex activation in response to positive, and lateral orbitofrontal cortex activation to negative, WS showed the opposite pattern. In light of the general notion of a medial/lateral gradient of reward/punishment processing in the orbitofrontal cortex, these findings provide an additional biological explanation for, or correlate of positive attribution bias and hypersociability in WS.

  View details for DOI 10.1007/s11689-009-9041-8

  View details for Web of Science ID 000278580700004

  View details for PubMedCentralID PMC3034146

• Brain glutamatergic characteristics of pediatric offspring of parents with bipolar disorder PSYCHIATRY RESEARCH-NEUROIMAGING Singh, M., Spielman, D., Adleman, N., Alegria, D., Howe, M., Reiss, A., Chang, K. 2010; 182 (2): 165-171

  Abstract

  We wished to determine whether decreases in prefrontal glutamate concentrations occur in offspring of parents with bipolar disorder with and at high risk for mania. Sixty children and adolescents, 9-18 years old, of parents with bipolar I or II disorder (20 offspring with established history of mania, "BD", 20 offspring with symptoms subsyndromal to mania, "SS", and 20 healthy controls "HC") were examined using proton magnetic resonance spectroscopy at 3T to study glutamatergic metabolite concentrations in the anterior cingulate cortex (ACC). A signal for reductions in absolute glutamate concentrations in the ACC was seen in the BD compared with HC and SS groups. No other statistically significant differences among groups were found. Offspring of parents with BD with prior histories of mania may have disruptions in glutamatergic function compared with HC or children at risk for BD who have not yet developed mania. Longitudinal studies are necessary to confirm whether prefrontal glutamate decreases only after the onset of full mania.

  View details for DOI 10.1016/j.pscychresns.2010.01.003

  View details for PubMedID 20413280

• The Fusiform Face Area is Enlarged in Williams Syndrome JOURNAL OF NEUROSCIENCE Golarai, G., Hong, S., Haas, B. W., Galaburda, A. M., Mills, D. L., Bellugi, U., Grill-Spector, K., Reiss, A. L. 2010; 30 (19): 6700-6712

  Abstract

  Williams syndrome (WS) is a genetic condition characterized by atypical brain structure, cognitive deficits, and a life-long fascination with faces. Face recognition is relatively spared in WS, despite abnormalities in aspects of face processing and structural alterations in the fusiform gyrus, part of the ventral visual stream. Thus, face recognition in WS may be subserved by abnormal neural substrates in the ventral stream. To test this hypothesis, we used functional magnetic resonance imaging and examined the fusiform face area (FFA), which is implicated in face recognition in typically developed (TD) individuals, but its role in WS is not well understood. We found that the FFA was approximately two times larger among WS than TD participants (both absolutely and relative to the fusiform gyrus), despite apparently normal levels of face recognition performance on a Benton face recognition test. Thus, a larger FFA may play a role in face recognition proficiency among WS.

  View details for DOI 10.1523/JNEUROSCI.4268-09.2010

  View details for Web of Science ID 000277653600023

  View details for PubMedID 20463232

  View details for PubMedCentralID PMC3670816

• Prefrontal Grey Matter Volume Abnormalities in Adolescent First Episode Mania 65th Annual Convention of the Society-of-Biological-Psychiatry Singh, M. K., Chang, K. D., Reiss, A. L., Gotlib, I. H. ELSEVIER SCIENCE INC. 2010: 222S–223S

  View details for Web of Science ID 000277064200704

• Heightened Amygdala and Hippocampal Responsivity to Emotional Faces in Youth with Posttraumatic Stress Disorder Symptoms: An fMRI Study. Carrion, V. G., Garrett, A., Reiss, A. L. ELSEVIER SCIENCE INC. 2010: 119S

  View details for Web of Science ID 000277064200382

• Individual differences in social behavior predict amygdala response to fearful facial expressions in Williams syndrome NEUROPSYCHOLOGIA Haas, B. W., Hoeft, F., Searcy, Y. M., Mills, D., Bellugi, U., Reiss, A. 2010; 48 (5): 1283-1288

  Abstract

  Williams syndrome (WS) is a genetic condition often paired with abnormal social functioning and behavior. In particular, those with WS are characterized as being relatively hypersocial, overly emotional/empathic, and socially uninhibited or fearless. In addition, WS is associated with abnormal amygdala structure and function. Very little is known however about the relationship between specific social behaviors and altered amygdala function in WS. This study was designed to compare three models that relate abnormal social behavior with amygdala function in WS (indiscriminate sociability, emotional and empathic sociability and social fearlessness). We used a social behavior assessment procedure (Salk Institute Sociability Questionnaire), functional magnetic resonance imaging and an implicit emotion face processing task to test these models. Our findings provide support for a model of abnormal social fearlessness by showing that in WS, abnormal amygdala response to fear is paired with an increased tendency to approach strangers. Specifically, individuals with WS that exhibited less amygdala response to fearful facial expressions (compared to neutral) also exhibited an increased tendency to approach strangers. These findings contribute to our understanding of social and emotional functioning in neurodevelopmental conditions and provide evidence that in WS, amygdala response to fear modulates social behavior.

  View details for DOI 10.1016/j.neuropsychologia.2009.12.030

  View details for Web of Science ID 000276770800013

  View details for PubMedID 20036269

• Atypical hemispheric asymmetry in the perception of negative human vocalizations in individuals with Williams syndrome NEUROPSYCHOLOGIA Jaervinen-Pasley, A., Pollak, S. D., Yam, A., Hill, K. J., Grichanik, M., Mills, D., Reiss, A. L., Korenberg, J. R., Bellugi, U. 2010; 48 (4): 1047-1052

  Abstract

  Williams syndrome is a neurological condition associated with high levels of auditory reactivity and emotional expression combined with impaired perception of prosody. Yet, little is currently known about the neural organization of affective auditory processing in individuals with this disorder. The current study examines auditory emotion processing in individuals with Williams syndrome. Hemispheric organization for positive and negative human non-linguistic sound processing was compared in participants with and without the disorder using a dichotic listening paradigm. While controls exhibited an expected right cerebral hemisphere advantage for processing negative sounds, those with Williams syndrome showed the opposite pattern. No differences between the groups emerged for the positive stimuli. The results suggest aberrant processing of negative auditory information in Williams syndrome.

  View details for DOI 10.1016/j.neuropsychologia.2009.12.002

  View details for Web of Science ID 000275933500023

  View details for PubMedID 20005238

  View details for PubMedCentralID PMC2847456

• Cingulate gyrus morphology in children and adolescents with fetal alcohol spectrum disorders PSYCHIATRY RESEARCH-NEUROIMAGING Bjorkquist, O. A., Fryer, S. L., Reiss, A. L., Mattson, S. N., Riley, E. P. 2010; 181 (2): 101-107

  Abstract

  Alcohol consumption during pregnancy can lead to a variety of cognitive and other birth defects, collectively termed fetal alcohol spectrum disorders (FASD), and including the Fetal Alcohol Syndrome (FAS). This study examined the impact of gestational alcohol exposure on the morphology of the cingulate gyrus, given this region's role in cognitive control, attention, and emotional regulation, all of which are affected in children with FASD. Thirty-one youth (ages 8-16) with histories of heavy prenatal alcohol exposure (n=21) and demographically matched comparison subjects (n=10) underwent structural magnetic resonance imaging. The cingulate gyrus was manually delineated, and parcellated volumes of grey and white matter were compared across groups. Alcohol-exposed individuals had significantly smaller raw cingulate grey matter, white matter, and tissue volumes compared with controls. After adjustment for respective cranial tissue constituents, only white matter volumes remained significantly reduced, and this held regardless of whether or not the child qualified for a diagnosis of FAS. A correlation between posterior cingulate grey matter volume and the WISC-III Freedom from Distractibility Index was also observed in alcohol-exposed children. These data suggest that cingulate white matter is compromised beyond global white matter hypoplasia in alcohol-exposed individuals, regardless of FAS diagnosis. The observed volumetric reductions in the cingulate gyrus may contribute to the disruptive and emotionally dysregulated behavioral profile commonly observed in this population.

  View details for DOI 10.1016/j.pscychresns.2009.10.004

  View details for Web of Science ID 000275009200004

  View details for PubMedID 20080394

  View details for PubMedCentralID PMC2815126

• Functional near infrared spectroscopy (NIRS) signal improvement based on negative correlation between oxygenated and deoxygenated hemoglobin dynamics NEUROIMAGE Cui, X., Bray, S., Reiss, A. L. 2010; 49 (4): 3039-3046

  Abstract

  Near infrared spectroscopy (NIRS) is a promising technology for functional brain imaging which measures hemodynamic signals from the cortex, similar to functional magnetic resonance imaging (fMRI), but does not require the participant to lie motionless in a confined space. NIRS can therefore be used for more naturalistic experiments, including face to face communication, or natural body movements, and is well suited for real-time applications that may require lengthy training. However, improving signal quality and reducing noise, especially noise induced by head motion, is challenging, particularly for real time applications. Here we study the properties of head motion induced noise, and find that motion noise causes the measured oxygenated and deoxygenated hemoglobin signals, which are typically strongly negatively correlated, to become more positively correlated. Next, we develop a method to reduce noise based on the principle that the concentration changes of oxygenated and deoxygenated hemoglobin should be negatively correlated. We show that despite its simplicity, this method is effective in reducing noise and improving signal quality, for both online and offline noise reduction.

  View details for DOI 10.1016/j.neuroimage.2009.11.050

  View details for Web of Science ID 000274064500016

  View details for PubMedID 19945536

  View details for PubMedCentralID PMC2818571

• INSIGHTS INTO BRAIN DEVELOPMENT FROM NEUROGENETIC SYNDROMES: EVIDENCE FROM FRAGILE X SYNDROME, WILLIAMS SYNDROME, TURNER SYNDROME AND VELOCARDIOFACIAL SYNDROME (vol 164, pg 257, 2009) NEUROSCIENCE Walter, E., Mazaika, P. K., Reiss, A. L. 2010; 165 (3): 1011

  View details for DOI 10.1016/j.neuroscience.2009.11.014

  View details for Web of Science ID 000274002600035

• Neural Correlates of Response Inhibition in Pediatric Bipolar Disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Singh, M. K., Chang, K. D., Mazaika, P., Garrett, A., Adleman, N., Kelley, R., Howe, M., Reiss, A. 2010; 20 (1): 15-24

  Abstract

  Pediatric bipolar disorder is characterized by core deficits in mood and executive function and commonly co-occurs with attention-deficit/hyperactivity disorder (ADHD). We aimed to examine response inhibition in this population, as an element of executive function, which, if aberrant, may interfere with learning and information processing.Children (9-18 years) with bipolar I or II disorder (BD, n = 26) and age, gender, and intelligence quotient (IQ) comparable healthy children (HC, n = 22) without any psychopathology were given a standardized Go/NoGo computerized task measuring response inhibition. A whole-brain functional magnetic resonance imaging (MRI) group analysis was performed using statistical parametric mapping software (SPM2) for comparing NoGo to Go epochs.There were no statistically significant group differences between groups in age, gender, or ethnicity. The BD group had high rates of co-morbid disorders, including 81% with ADHD, 62% with oppositional defiant disorder (ODD), and 46% with anxiety disorders. This BD group had fewer correct responses on Go (84% vs. 96%, T[46] = 3.35, p = 0.002) and overall (85% vs. 94%, T[46] = 4.12, p = 0.0002) trials as compared to the HC group. However, there were no statistically significant group differences in response inhibition on NoGo trials (p = 0.11). In the NoGo-Go contrast, the BD group showed increased neural activation in the right dorsolateral prefrontal cortex (DLPFC) compared to HC (T[46] = 4.21, p < 0.001).During accurate NoGo but impaired Go trial performance, children with BD showed increased right DLPFC activation versus controls, suggesting increased recruitment of executive control regions for accurate response inhibition. Studies relating these results to mood regulation in pediatric BD are warranted.

  View details for DOI 10.1089/cap.2009.0004

  View details for PubMedID 20166792

• A preliminary study of orbitofrontal activation and hypersociability in Williams Syndrome. Journal of neurodevelopmental disorders Mimura, M., Hoeft, F., Kato, M., Kobayashi, N., Sheau, K., Piggot, J., Mills, D., Galaburda, A., Korenberg, J. R., Bellugi, U., Reiss, A. L. 2010; 2 (2): 93-98

  Abstract

  Individuals with Williams syndrome (WS) demonstrate an abnormally positive social bias. However, the neural substrates of this hypersociability, i.e., positive attribution bias and increased drive toward social interaction, have not fully been elucidated. METHODS: We performed an event-related functional magnetic resonance imaging study while individuals with WS and typically developing controls (TD) matched positive and negative emotional faces. WS compared to TD showed reduced right amygdala activation during presentation of negative faces, as in the previous literature. In addition, WS showed a unique pattern of right orbitofrontal cortex activation. While TD showed medial orbitofrontal cortex activation in response to positive, and lateral orbitofrontal cortex activation to negative, WS showed the opposite pattern. In light of the general notion of a medial/lateral gradient of reward/punishment processing in the orbitofrontal cortex, these findings provide an additional biological explanation for, or correlate of positive attribution bias and hypersociability in WS.

  View details for DOI 10.1007/s11689-009-9041-8

  View details for PubMedID 21304831

  View details for PubMedCentralID PMC3034146

• Morphometry of human insular cortex and insular volume reduction in Williams syndrome JOURNAL OF PSYCHIATRIC RESEARCH Cohen, J. D., Mock, J. R., Nichols, T., Zadina, J., Corey, D. M., Lemen, L., Bellugi, U., Galaburda, A., Reiss, A., Foundas, A. L. 2010; 44 (2): 81-89

  Abstract

  Functional imaging in humans and anatomical data in monkeys have implicated the insula as a multimodal sensory integrative brain region. The topography of insular connections is organized by its cytoarchitectonic regions. Previous attempts to measure the insula have utilized either indirect or automated methods. This study was designed to develop a reliable method for obtaining volumetric magnetic resonance imaging (MRI) measurements of the human insular cortex, and to validate that method by examining the anatomy of insular cortex in adults with Williams syndrome (WS) and healthy age-matched controls. Statistical reliability was obtained among three raters for this method, supporting its reproducibility not only across raters, but within different software packages. The procedure described here utilizes native-space morphometry as well as a method for dividing the insula into connectivity-based sub-regions estimated from cytoarchitectonics. Reliability was calculated in both ANALYZE (N=3) and BrainImageJava (N=10) where brain scans were measured once in each hemisphere by each rater. This highly reliable method revealed total, anterior, and posterior insular volume reduction bilaterally (all p's<.002) in WS, after accounting for reduced total brain volumes in these participants. Although speculative, the reduced insular volumes in WS may represent a neural risk for the development of hyperaffiliative social behavior with increased specific phobias, and implicate the insula as a critical limbic integrative region. Native-space quantification of the insula may be valuable in the study of neurodevelopmental or neuropsychiatric disorders related to anxiety and social behavior.

  View details for DOI 10.1016/j.jpsychires.2009.07.001

  View details for Web of Science ID 000275071600004

  View details for PubMedID 19660766

  View details for PubMedCentralID PMC2813413

• Cross-modal influences of affect across social and non-social domains in individuals with Williams syndrome NEUROPSYCHOLOGIA Jarvinen-Pasley, A., Vines, B. W., Hill, K. J., Yam, A., Grichanik, M., Mills, D., Reiss, A. L., Korenberg, J. R., Bellugi, U. 2010; 48 (2): 456-466

  Abstract

  The Williams syndrome (WS) cognitive profile is characterized by relative strengths in face processing, an attentional bias towards social stimuli, and an increased affinity and emotional reactivity to music. An audio-visual integration study examined the effects of auditory emotion on visual (social/non-social) affect identification in individuals with WS and typically developing (TD) and developmentally delayed (DD) controls. The social bias in WS was hypothesized to manifest as an increased ability to process social than non-social affect, and a reduced auditory influence in social contexts. The control groups were hypothesized to perform similarly across conditions. The results showed that while participants with WS exhibited indistinguishable performance to TD controls in identifying facial affect, DD controls performed significantly more poorly. The TD group outperformed the WS and DD groups in identifying non-social affect. The results suggest that emotionally evocative music facilitated the ability of participants with WS to process emotional facial expressions. These surprisingly strong facial-processing skills in individuals with WS may have been due to the effects of combining social and music stimuli and to a reduction in anxiety due to the music in particular. Several directions for future research are suggested.

  View details for DOI 10.1016/j.neuropsychologia.2009.10.003

  View details for Web of Science ID 000274371700012

  View details for PubMedID 19822162

• INSIGHTS INTO BRAIN DEVELOPMENT FROM NEUROGENETIC SYNDROMES: EVIDENCE FROM FRAGILE X SYNDROME, WILLIAMS SYNDROME, TURNER SYNDROME AND VELOCARDIOFACIAL SYNDROME NEUROSCIENCE Walter, E., MAZAIKA, P. K., Reiss, A. L. 2009; 164 (1): 257-271

  Abstract

  Over the past few decades, behavioral, neuroimaging and molecular studies of neurogenetic conditions, such as Williams, fragile X, Turner and velocardiofacial (22q11.2 deletion) syndromes, have led to important insights regarding brain development. These investigations allow researchers to examine "experiments of nature" in which the deletion or alteration of one gene or a contiguous set of genes can be linked to aberrant brain structure or function. Converging evidence across multiple imaging modalities has now begun to highlight the abnormal neural circuitry characterizing many individual neurogenetic syndromes. Furthermore, there has been renewed interest in combining analyses across neurogenetic conditions in order to search for common organizing principles in development. In this review, we highlight converging evidence across syndromes from multiple neuroimaging modalities, with a particular emphasis on functional imaging. In addition, we discuss the commonalities and differences pertaining to selective deficits in visuospatial processing that occur across four neurogenetic syndromes. We suggest avenues for future exploration, with the goal of achieving a deeper understanding of the neural abnormalities in these affected populations.

  View details for DOI 10.1016/j.neuroscience.2009.04.033

  View details for Web of Science ID 000271609000022

  View details for PubMedID 19376197

  View details for PubMedCentralID PMC2795482

• Hippocampal volume and declarative memory function in combat-related PTSD JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY Woodward, S. H., Kaloupek, D. G., Grande, L. J., Stegman, W. K., Kutter, C. J., Leskin, L., Prestel, R., Schaer, M., Reiss, A. L., Eliez, S. 2009; 15 (6): 830-839

  Abstract

  The proposition that declarative memory deficits are systematically related to smaller hippocampal volume was tested in a relatively large sample (n = 95) of U.S. military veterans with and without combat-related posttraumatic stress disorder. This correlative analysis was extended by including multiple measures of verbal and visual declarative memory and multiple memory-relevant regional brain volumes that had been shown to exhibit main effects of PTSD in prior work. Small-to-moderate effects were observed on verbal declarative memory in line with a recent meta-analysis; nevertheless, little or no evidence of systematic linear covariation between memory measures and brain volumes was observed.

  View details for DOI 10.1017/S1355617709990476

  View details for Web of Science ID 000272114500003

  View details for PubMedID 19703322

• The impact of spermine synthase (SMS) mutations on brain morphology NEUROGENETICS Kesler, S. R., Schwartz, C., Stevenson, R. E., Reiss, A. L. 2009; 10 (4): 299-305

  Abstract

  Snyder-Robinson syndrome (SRS) is a form of X-linked mental retardation resulting from mutations in spermine synthase (SMS), which impact neurodevelopment and cognitive outcome. We obtained cerebral, cerebellum, hippocampus, and red nucleus volumes from two males with SRS and 24 age- and gender-matched typically developing controls using volumetric neuroimaging analyses. Total brain volume was enlarged in males with SRS while cerebellum, hippocampus, and red nucleus volumes tended to be reduced compared to controls. Mutations of the X chromosome may modulate the risk for mental retardation through altered early neurodevelopment, disruption in receptor function, and ongoing neural organization and plasticity. Disruption of SMS function may negatively affect regional brain volumes that subserve cognitive and motor abilities. This research provides valuable insight into the effects of polyamine function on brain development.

  View details for DOI 10.1007/s10048-009-0184-2

  View details for Web of Science ID 000270386000003

  View details for PubMedID 19277733

  View details for PubMedCentralID PMC3061622

• Neuroanatomic Alterations and Social and Communication Deficits in Monozygotic Twins Discordant for Autism Disorder AMERICAN JOURNAL OF PSYCHIATRY Mitchell, S. R., Reiss, A. L., Tatusko, D. H., Ikuta, I., Kazmerski, D. B., Botti, J. C., Burnette, C. P., Kates, W. R. 2009; 166 (8): 917-925

  Abstract

  Investigating neuroanatomic differences in monozygotic twins who are discordant for autism can help unravel the relative contributions of genetics and environment to this pervasive developmental disorder. The authors used magnetic resonance imaging (MRI) to investigate several brain regions of interest in monozygotic twins who varied in degree of phenotypic discordance for narrowly defined autism.The subjects were 14 pairs of monozygotic twins between the ages of 5 and 14 years old and 14 singleton age- and gender-matched typically developing comparison subjects. The monozygotic twin group was a cohort of children with narrowly defined autistic deficits and their co-twins who presented with varying levels of autistic deficits. High-resolution MRIs were acquired and volumetric/area measurements obtained for the frontal lobe, amygdala, and hippocampus and subregions of the prefrontal cortex, corpus callosum, and cerebellar vermis.No neurovolumetric/area differences were found between twin pairs. Relative to typically developing comparison subjects, dorsolateral prefrontal cortex volumes and anterior areas of the corpus callosum were significantly altered in autistic twins, and volumes of the posterior vermis were altered in both autistic twins and co-twins. Intraclass correlation analysis of brain volumes between children with autism and their co-twins indicated that the degree of within-pair neuroanatomic concordance varied with brain region. In the group of subjects with narrowly defined autism only, dorsolateral prefrontal cortex, amygdala, and posterior vermis volumes were significantly associated with the severity of autism based on scores from the Autism Diagnostic Observation Schedule-Generic.These findings support previous research demonstrating alterations in the prefrontal cortex, corpus callosum, and posterior vermis in children with autism and further suggest that alterations are associated with the severity of the autism phenotype. Continued research involving twins who are concordant and discordant for autism is essential to disentangle the genetic and environmental contributions to autism.

  View details for DOI 10.1176/appi.ajp.2009.08101538

  View details for Web of Science ID 000268638900014

  View details for PubMedID 19605538

• Early white-matter abnormalities of the ventral frontostriatal pathway in fragile X syndrome DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Haas, B. W., Barnea-Goraly, N., Lightbody, A. A., Patnaik, S. S., Hoeft, F., Hazlett, H., Piven, J., Reiss, A. L. 2009; 51 (8): 593-599

  Abstract

  Fragile X syndrome is associated with cognitive deficits in inhibitory control and with abnormal neuronal morphology and development.In this study, we used a diffusion tensor imaging (DTI) tractography approach to reconstruct white-matter fibers in the ventral frontostriatal pathway in young males with fragile X syndrome (n=17; mean age 2y 9mo, SD 7mo, range 1y 7mo-3y 10mo), and two age-matched comparison groups: (1) typically developing (n=13; mean age 2y 3mo, SD 7mo, range 1y 7mo-3y 6mo) and (2) developmentally delayed (n=8; mean age 3y, SD 4mo, range 2y 9mo-3y 8mo).We observed that young males with fragile X syndrome exhibited increased density of DTI reconstructed fibers than those in the typically developing (p=0.001) and developmentally delayed (p=0.001) groups. Aberrant white-matter structure was localized in the left ventral frontostriatal pathway. Greater relative fiber density was found to be associated with lower IQ (Mullen composite scores) in the typically developing group (p=0.008).These data suggest that diminished or absent fragile X mental retardation 1 protein expression can selectively alter white-matter anatomy during early brain development and, in particular, neural pathways. The results also point to an early neurobiological marker for an important component of cognitive dysfunction associated with fragile X syndrome.

  View details for DOI 10.1111/j.1469-8749.2009.03295.x

  View details for Web of Science ID 000268029100006

  View details for PubMedID 19416325

  View details for PubMedCentralID PMC2715437

• Limbic and Corpus Callosum Aberrations in Adolescents with Bipolar Disorder: A Tract-Based Spatial Statistics Analysis BIOLOGICAL PSYCHIATRY Barnea-Goraly, N., Chang, K. D., Karchemskiy, A., Howe, M. E., Reiss, A. L. 2009; 66 (3): 238-244

  Abstract

  Bipolar disorder (BD) is a common and debilitating condition, often beginning in adolescence. Converging evidence from genetic and neuroimaging studies indicates that white matter abnormalities may be involved in BD. In this study, we investigated white matter structure in adolescents with familial bipolar disorder using diffusion tensor imaging (DTI) and a whole brain analysis.We analyzed DTI images using tract-based spatial statistics (TBSS), a whole-brain voxel-by-voxel analysis, to investigate white matter structure in 21 adolescents with BD, who also were offspring of at least one parent with BD, and 18 age- and IQ-matched control subjects. Fractional anisotropy (FA; a measure of diffusion anisotropy), trace values (average diffusivity), and apparent diffusion coefficient (ADC; a measure of overall diffusivity) were used as variables in this analysis. In a post hoc analysis, we correlated between FA values, behavioral measures, and medication exposure.Adolescents with BD had lower FA values than control subjects in the fornix, the left mid-posterior cingulate gyrus, throughout the corpus callosum, in fibers extending from the fornix to the thalamus, and in parietal and occipital corona radiata bilaterally. There were no significant between-group differences in trace or ADC values and no significant correlation between behavioral measures, medication exposure, and FA values.Significant white matter tract alterations in adolescents with BD were observed in regions involved in emotional, behavioral, and cognitive regulation. These results suggest that alterations in white matter are present early in the course of disease in familial BD.

  View details for DOI 10.1016/j.biopsych.2009.02.025

  View details for PubMedID 19389661

• Converging evidence for abnormalities of the prefrontal cortex and evaluation of midsagittal structures in pediatric posttraumatic stress disorder: An MRI study PSYCHIATRY RESEARCH-NEUROIMAGING Carrion, V. G., Weems, C. F., Watson, C., Eliez, S., Menon, V., Reiss, A. L. 2009; 172 (3): 226-234

  Abstract

  Volumetric imaging research has shown abnormal brain morphology in posttraumatic stress disorder (PTSD) when compared with control subjects. We present results on a study of brain morphology in the prefrontal cortex (PFC) and midline structures, via indices of gray matter volume and density, in pediatric PTSD. We hypothesized that both methods would demonstrate aberrant morphology in the PFC. Further, we hypothesized aberrant brainstem anatomy and reduced corpus callosum volume in children with PTSD. Twenty-four children (aged 7-14) with history of interpersonal trauma and 24 age- and gender-matched controls underwent structural magnetic resonance imaging (sMRI). Images of the PFC and midline brain structures were first analyzed using volumetric image analysis. The PFC data were then compared with whole brain voxel-based techniques using statistical parametric mapping (SPM). The PTSD group showed significantly increased gray matter volume in the right and left inferior and superior quadrants of the PFC and smaller gray matter volume in the pons and posterior vermis areas by volumetric image analysis. The voxel-by-voxel group comparisons demonstrated increased gray matter density mostly localized to ventral PFC as compared with the control group. Abnormal frontal lobe morphology, as revealed by separate-complementary image analysis methods, and reduced pons and posterior vermis areas are associated with pediatric PTSD. Voxel-based morphometry may help to corroborate and further localize data obtained by volume of interest methods in PTSD.

  View details for DOI 10.1016/j.pscychresns.2008.07.008

  View details for PubMedID 19349151

• Neurochemical substrates of risk in pediatric offspring of parents with bipolar disorder 8th International Conference on Bipolar Disorder Singh, M. K., Spielman, D., Kelley, R., ALEGRIA, D., Howe, M., Reiss, A., Chang, K. WILEY-BLACKWELL. 2009: 80–80

  View details for Web of Science ID 000268963500217

• William's syndrome: gene expression is related to parental origin and regional coordinate control JOURNAL OF HUMAN GENETICS Collette, J. C., Chen, X., Mills, D. L., Galaburda, A. M., Reiss, A. L., Bellugi, U., Korenberg, J. R. 2009; 54 (4): 193-198

  Abstract

  William's syndrome (WS) features a spectrum of neurocognitive and behavioral abnormalities due to a rare 1.5 MB deletion that includes about 24-28 genes on chromosome band 7q11.23. Study of the expression of these genes from the single normal copy provides an opportunity to elucidate the genetic and epigenetic controls on these genes as well as their roles in both WS and normal brain development and function. We used quantitative RT-PCR to determine the transcriptional level of 14 WS gene markers in a cohort of 77 persons with WS and 48 normal controls. Results reported here: (1) show that the expression of the genes deleted in WS is decreased in some but not all cases, (2) demonstrate that the parental origin of the deletion contributes to the level of expression of GTF2I independently of age and gender and (3) indicate that the correlation of expression between GTF2I and some other genes in the WS region differs in WS subjects and normal controls, which in turn points toward a regulatory role for this gene. Interspecies comparisons suggest GTF2I may play a key role in normal brain development.

  View details for DOI 10.1038/jhg.2009.5

  View details for Web of Science ID 000266218800001

  View details for PubMedID 19282872

  View details for PubMedCentralID PMC3556903

• USING PERCENTILE SCHEDULES TO INCREASE EYE CONTACT IN CHILDREN WITH FRAGILE X SYNDROME JOURNAL OF APPLIED BEHAVIOR ANALYSIS Hall, S. S., Maynes, N. P., Reiss, A. L. 2009; 42 (1): 171-176

  Abstract

  Aversion to eye contact is a common behavior of individuals diagnosed with Fragile X syndrome (FXS); however, no studies to date have attempted to increase eye-contact duration in these individuals. In this study, we employed a percentile reinforcement schedule with and without overcorrection to shape eye-contact duration of 6 boys with FXS. Results showed that although aversion to eye contact is often thought to be unamenable to change in FXS, it can be shaped in some individuals using percentile schedules either alone or in combination with overcorrection.

  View details for DOI 10.1901/jaba.2009.42-171

  View details for Web of Science ID 000263982700013

  View details for PubMedID 19721738

  View details for PubMedCentralID PMC2649838

• Physiological Correlates of Social Avoidance Behavior in Children and Adolescents With Fragile X Syndrome JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hall, S. S., Lightbody, A. A., Huffman, L. C., Lazzeroni, L. C., Reiss, A. L. 2009; 48 (3): 320-329

  Abstract

  To investigate whether eye-gaze avoidance, a striking phenotypic feature in fragile X syndrome (FXS), is associated with high levels of "hyperarousal" during social interactions with others. To date, almost all studies in this area have been confounded by inclusion of task demands in addition to social demands.We monitored the cardiovascular activity and eye-gaze avoidance of 50 boys and girls with FXS aged 5 to 20 years during a 25-minute intensive social interaction session with an unfamiliar experimenter. To control for possible family and genetic factors in cardiovascular activity, we compared each child with FXS with their same-sex typically developing biological sibling.Participants with FXS obtained significantly higher heart rates, lower vagal tone, and lower heart rate variability estimates both at baseline and during the social interaction session compared with their typically developing siblings. Although eye-gaze avoidance occurred at significantly higher levels in the children with FXS, this behavior decreased slightly over the course of the session (a "warm-up" effect) and did not seem to be associated with cardiovascular activity. In the girls with FXS, higher levels of the fragile X mental retardation protein were associated with higher (and more typical) heart rate variability.These data suggest that both sympathetic and parasympathetic nervous systems are dysregulated in FXS. However, given that prolonged exposure to social demands does not inevitably lead to increased anxiety or "hyperarousal," professionals should not be deterred from providing much needed social skills interventions for individuals with FXS.

  View details for DOI 10.1097/CHI.0b013e318195bd15

  View details for PubMedID 19182690

• The neural basis of auditory temporal discrimination in girls with fragile X syndrome JOURNAL OF NEURODEVELOPMENTAL DISORDERS Hall, S. S., Walter, E., Sherman, E., Hoeft, F., Reiss, A. L. 2009; 1 (1): 91-99

  Abstract

  Fragile X syndrome (FXS) is a common genetic disorder in which temporal processing may be impaired. To our knowledge however, no studies have examined the neural basis of temporal discrimination in individuals with FXS using functional magnetic resonance imaging (fMRI). Ten girls with fragile X syndrome and ten developmental age-matched typically developing controls performed an auditory temporal discrimination task in a 3T scanner. Girls with FXS showed significantly greater brain activation in a left-lateralized network, comprising left medial frontal gyrus, left superior and middle temporal gyrus, left cerebellum, and left brainstem (pons), when compared to a developmental age-matched typically developing group of subjects who had similar in-scanner task performance. There were no regions that showed significantly greater brain activation in the control group compared to individuals with FXS. These data indicate that networks of brain regions involved in auditory temporal processing may be dysfunctional in FXS. In particular, it is possible that girls with FXS employ left hemispheric resources to overcompensate for relative right hemispheric dysfunction.

  View details for DOI 10.1007/s11689-009-9007-x

  View details for Web of Science ID 000274727000008

  View details for PubMedID 19890439

  View details for PubMedCentralID PMC2772079

• Cholinergic Dysfunction in Fragile X Syndrome and Potential Intervention: A Preliminary H-1 MRS Study AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kesler, S. R., Lightbody, A. A., Reiss, A. L. 2009; 149A (3): 403-407

  Abstract

  Males with fragile X syndrome (FRAX) are at risk for significant cognitive and behavioral deficits, particularly those involving executive prefrontal systems. Disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency may contribute to the cognitive-behavioral impairments associated with fragile X. We measured choline in the dorsolateral prefrontal cortex of nine males with FRAX and 9 age-matched typically developing controls using (1)H magnetic resonance spectroscopy. Right choline/creatine was significantly reduced in the fragile X group compared to controls. In controls, both left and right choline was significantly positively correlated with intelligence and age was significantly negatively correlated with left choline. There were no correlations in the fragile X group. Subjects with FRAX participating in a pilot open-label trial of donepezil, an acetylcholinesterase inhibitor, demonstrated significantly improved cognitive-behavioral function. Studies utilizing biochemical neuroimaging techniques such as these have the potential to significantly impact the design of treatment strategies for FRAX and other genetic disorders by helping identify neurochemical targets for intervention as well as serving as metrics for treatment efficacy.

  View details for DOI 10.1002/ajmg.a.32697

  View details for Web of Science ID 000264142300018

  View details for PubMedID 19215057

  View details for PubMedCentralID PMC2728028

• Alterations in functional connectivity for language in prematurely born adolescents BRAIN Schafer, R. J., Lacadie, C., Vohr, B., Kesler, S. R., Katz, K. H., Schneider, K. C., Pugh, K. R., Makuch, R. W., Reiss, A. L., Constable, R. T., Ment, L. R. 2009; 132: 661-670

  Abstract

  Recent data suggest recovery of language systems but persistent structural abnormalities in the prematurely born. We tested the hypothesis that subjects who were born prematurely develop alternative networks for processing language. Subjects who were born prematurely (n = 22; 600-1250 g birth weight), without neonatal brain injury on neonatal cranial ultrasound, and 26 term control subjects were examined with a functional magnetic resonance imaging (fMRI) semantic association task, the Wechsler Intelligence Scale for Children-III (WISC-III) and the Clinical Evaluation of Language Fundamentals (CELF). In-magnet task accuracy and response times were calculated, and fMRI data were evaluated for the effect of group on blood oxygen level dependent (BOLD) activation, the correlation between task accuracy and activation and the functional connectivity between regions activating to task. Although there were differences in verbal IQ and CELF scores between the preterm (PT) and term control groups, there were no significant differences for either accuracy or response time for the in-magnet task. Both groups activated classic semantic processing areas including the left superior and middle temporal gyri and inferior frontal gyrus, and there was no significant difference in activation patterns between groups. Clear differences between the groups were observed in the correlation between task accuracy and activation to task at P < 0.01, corrected for multiple comparisons. Left inferior frontal gyrus correlated with accuracy only for term controls and left sensory motor areas correlated with accuracy only for PT subjects. Left middle temporal gyri correlated with task accuracy for both groups. Connectivity analyses at P < 0.001 revealed the importance of a circuit between left middle temporal gyri and inferior frontal gyrus for both groups. In addition, the PT subjects evidenced greater connectivity between traditional language areas and sensory motor areas but significantly fewer correlated areas within the frontal lobes when compared to term controls. We conclude that at 12 years of age, children born prematurely and children born at term had no difference in performance on a simple lexical semantic processing task and activated similar areas. Connectivity analyses, however, suggested that PT subjects rely upon different neural pathways for lexical semantic processing when compared to term controls. Plasticity in network connections may provide the substrate for improving language skills in the prematurely born.

  View details for DOI 10.1093/brain/awn353

  View details for Web of Science ID 000264889000011

  View details for PubMedID 19158105

  View details for PubMedCentralID PMC2664451

• Joint Sulcal Detection on Cortical Surfaces With Graphical Models and Boosted Priors IEEE TRANSACTIONS ON MEDICAL IMAGING Shi, Y., Tu, Z., Reiss, A. L., Dutton, R. A., Lee, A. D., Galaburda, A. M., Dinov, I., Thompson, P. M., Toga, A. W. 2009; 28 (3): 361-373

  Abstract

  In this paper, we propose an automated approach for the joint detection of major sulci on cortical surfaces. By representing sulci as nodes in a graphical model, we incorporate Markovian relations between sulci and formulate their detection as a maximum a posteriori (MAP) estimation problem over the joint space of major sulci. To make the inference tractable, a sample space with a finite number of candidate curves is automatically generated at each node based on the Hamilton-Jacobi skeleton of sulcal regions. Using the AdaBoost algorithm, we learn both individual and pairwise shape priors of sulcal curves from training data, which are then used to define potential functions in the graphical model based on the connection between AdaBoost and logistic regression. Finally belief propagation is used to perform the MAP inference and select the joint detection results from the sample spaces of candidate curves. In our experiments, we quantitatively validate our algorithm with manually traced curves and demonstrate the automatically detected curves can capture the main body of sulci very accurately. A comparison with independently detected results is also conducted to illustrate the advantage of the joint detection approach.

  View details for DOI 10.1109/TMI.2008.2004402

  View details for Web of Science ID 000263920500005

  View details for PubMedID 19244008

  View details for PubMedCentralID PMC2754577

• A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome JOURNAL OF NEURODEVELOPMENTAL DISORDERS Hessl, D., Nguyen, D. V., Green, C., Chavez, A., Tassone, F., Hagerman, R. J., Senturk, D., Schneider, A., Lightbody, A., Reiss, A. L., Hall, S. 2009; 1 (1): 33-45

  Abstract

  Intelligence testing in children with intellectual disabilities (ID) has significant limitations. The normative samples of widely used intelligence tests, such as the Wechsler Intelligence Scales, rarely include an adequate number of subjects with ID needed to provide sensitive measurement in the very low ability range, and they are highly subject to floor effects. The IQ measurement problems in these children prevent characterization of strengths and weaknesses, poorer estimates of cognitive abilities in research applications, and in clinical settings, limited utility for assessment, prognosis estimation, and planning intervention. Here, we examined the sensitivity of the Wechsler Intelligence Scale for Children (WISC-III) in a large sample of children with fragile X syndrome (FXS), the most common cause of inherited ID. The WISC-III was administered to 217 children with FXS (age 6-17 years, 83 girls and 134 boys). Using raw norms data obtained with permission from the Psychological Corporation, we calculated normalized scores representing each participant's actual deviation from the standardization sample using a z-score transformation. To validate this approach, we compared correlations between the new normalized scores versus the usual standard scores with a measure of adaptive behavior (Vineland Adaptive Behavior Scales) and with a genetic measure specific to FXS (FMR1 protein or FMRP). The distribution of WISC-III standard scores showed significant skewing with floor effects in a high proportion of participants, especially males (64.9%-94.0% across subtests). With the z-score normalization, the flooring problems were eliminated and scores were normally distributed. Furthermore, we found correlations between cognitive performance and adaptive behavior, and between cognition and FMRP that were very much improved when using these normalized scores in contrast to the usual standardized scores. The results of this study show that meaningful variation in intellectual ability in children with FXS, and probably other populations of children with neurodevelopmental disorders, is obscured by the usual translation of raw scores into standardized scores. A method of raw score transformation may improve the characterization of cognitive functioning in ID populations, especially for research applications.

  View details for DOI 10.1007/s11689-008-9001-8

  View details for Web of Science ID 000274727000004

  View details for PubMedID 19865612

  View details for PubMedCentralID PMC2768415

• Teasing apart the heterogeneity of autism: Same behavior, different brains in toddlers with fragile X syndrome and autism JOURNAL OF NEURODEVELOPMENTAL DISORDERS Hazlett, H. C., Poe, M. D., Lightbody, A. A., Gerig, G., MacFall, J. R., Ross, A. K., Provenzale, J., Martin, A., Reiss, A. L., Piven, J. 2009; 1 (1): 81-90

  Abstract

  To examine brain volumes in substructures associated with the behavioral features of children with FXS compared to children with idiopathic autism and controls. A cross-sectional study of brain substructures was conducted at the first time-point as part of an ongoing longitudinal MRI study of brain development in FXS. The study included 52 boys between 18-42 months of age with FXS and 118 comparison children (boys with autism-non FXS, developmental-delay, and typical development). Children with FXS and autistic disorder had substantially enlarged caudate volume and smaller amygdala volume; whereas those children with autistic disorder without FXS (i.e., idiopathic autism) had only modest enlargement in their caudate nucleus volumes but more robust enlargement of their amygdala volumes. Although we observed this double dissociation among selected brain volumes, no significant differences in severity of autistic behavior between these groups were observed. This study offers a unique examination of early brain development in two disorders, FXS and idiopathic autism, with overlapping behavioral features, but two distinct patterns of brain morphology. We observed that despite almost a third of our FXS sample meeting criteria for autism, the profile of brain volume differences for children with FXS and autism differed from those with idiopathic autism. These findings underscore the importance of addressing heterogeneity in studies of autistic behavior.

  View details for DOI 10.1007/s11689-009-9009-8

  View details for Web of Science ID 000274727000007

  View details for PubMedID 20700390

  View details for PubMedCentralID PMC2917990

• Longitudinal Brain Volume Changes in Preterm and Term Control Subjects During Late Childhood and Adolescence PEDIATRICS Ment, L. R., Kesler, S., Vohr, B., Katz, K. H., Baumgartner, H., Schneider, K. C., Delancy, S., Silbereis, J., Duncan, C. C., Constable, R. T., Makuch, R. W., Reiss, A. L. 2009; 123 (2): 503-511

  Abstract

  Although preterm very low birth weight infants have a high prevalence of neuroanatomical abnormalities when evaluated at term-equivalent age, patterns of brain growth in prematurely born infants during school age and adolescence remain largely unknown. Our goal was to test the hypothesis that preterm birth results in long-term dynamic changes in the developing brain.We performed serial volumetric MRI studies at ages 8 and 12 years in 55 preterm infants born weighing 600 to 1250 g and 20 term control children who participated in the follow-up component of a prospective, randomized, placebo-controlled intraventricular hemorrhage prevention study.Total brain volumes increased 2% to 3% between the ages of 8 and 12 years for both preterm and term children. These changes involved reductions in cerebral gray matter while white matter increased. Between 8 and 12 years of age, preterm subjects experienced a 2% decrease in left cerebral gray matter compared with a 10% reduction in left cerebral gray for term controls. For right cerebral gray matter, preterm children experienced a 3% decrease in volume between years 8 and 12, compared with 9% for term controls (group-by-time). In contrast, preterm subjects had a 10% increase in cerebral white matter volumes bilaterally between ages 8 and 12 years, compared with >26% increases for both hemispheres for term controls. Significant differences in regional volume changes between study groups were found in bilateral temporal gray and in parietal white matter.Preterm birth continues to perturb the trajectory of cerebral development during late childhood and early adolescence with preterm children, showing both lower gray matter reduction and less white matter gain over time compared with term control subjects.

  View details for DOI 10.1542/peds.2008-0025

  View details for Web of Science ID 000262678700012

  View details for PubMedID 19171615

  View details for PubMedCentralID PMC2679898

• Effect of Divalproex on Brain Morphometry, Chemistry, and Function in Youth at High-Risk for Bipolar Disorder: A Pilot Study 53rd Annual Meeting of the American-Academy-of-Child-and-Adolescent-Psychiatry Chang, K., Karchemskiy, A., Kelley, R., Howe, M., Garrett, A., Adleman, N., Reiss, A. MARY ANN LIEBERT INC. 2009: 51–59

  Abstract

  Divalproex has been found efficacious in treating adolescents with and at high risk for bipolar disorder (BD), but little is known about the effects of mood stabilizers on the brain itself. We sought to examine the effects of divalproex on the structure, chemistry, and function of specific brain regions in children at high-risk for BD.A total of 24 children with mood dysregulation but not full BD, all offspring of a parent with BD, were treated with divalproex monotherapy for 12 weeks. A subset of 11 subjects and 6 healthy controls were scanned with magnetic resonance imaging (MRI, magnetic resonance spectroscopy [MRS], and functional MRI [fMRI]) at baseline and after 12 weeks.There were no significant changes in amygdalar or cortical volume found over 12 weeks. Furthermore, no changes in neurometabolite ratios were found. However, we found the degree of decrease in prefrontal brain activation to correlate with degree of decrease in depressive symptom severity.Bipolar offspring at high risk for BD did not show gross morphometric, neurometabolite, or functional changes after 12 weeks of treatment with divalproex. Potential reasons include small sample size, short exposure to medications, or lack of significant neurobiological impact of divalproex in this particular population.

  View details for DOI 10.1089/cap.2008.060

  View details for PubMedID 19232023

• GENE, BRAIN, AND BEHAVIOR RELATIONSHIPS IN FRAGILE X SYNDROME: EVIDENCE FROM NEUROIMAGING STUDIES DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Lightbody, A. A., Reiss, A. L. 2009; 15 (4): 343-352

  Abstract

  Fragile X syndrome (FraX) remains the most common inherited cause of intellectual disability and provides a valuable model for studying gene-brain-behavior relationships. Over the past 15 years, structural and functional magnetic resonance imaging studies have emerged with the goal of better understanding the neural pathways contributing to the cognitive and behavioral outcomes seen in individuals with FraX. Specifically, structural MRI studies have established and begun to refine the specific topography of neuroanatomical variation associated with FraX. In addition, functional neuroimaging studies have begun to elucidate the neural underpinnings of many of the unique characteristics of FraX including difficulties with eye gaze, executive functioning, and behavioral inhibition. This review highlights studies with a focus on the relevant gene-brain-behavior connections observed in FraX. The relationship of brain regions and activation patterns to FMRP are discussed as well as the clinical cognitive and behavioral correlates of these neuroimaging findings.

  View details for DOI 10.1002/ddrr.77

  View details for Web of Science ID 000273207500010

  View details for PubMedID 20014368

• From genes to brain to behavior: the case of fragile X syndrome NEUROIMAGING IN DEVELOPMENTAL CLINICAL NEUROSCIENCE Rivera, S. M., Reiss, A. L., Rumsey, J. M., Ernst, M. 2009: 217–28

  View details for DOI 10.1017/CBO9780511757402.017

  View details for Web of Science ID 000313574600015

• The neural basis of auditory temporal discrimination in girls with fragile X syndrome. Journal of Neurodevelopmental Disorders Hall SS, Walter E, Sherman E, Hoeft F, Reiss AL 2009; 1 (1): 91-99
• Teasing apart the heterogeneity of autism: Same behavior, different brains in toddlers with fragile X syndrome and autism Journal of Neurodevelopmental Disorders Hazlett HC, Poe MD, Lightbody AA. Gerig G, MacFall JR, Ross AK, Provenzale J, Martin A, Reiss AL, Piven J 2009; 1 (1): 81-90
• STRUCTURAL AND FUNCTIONAL NEUROIMAGING IN KLINEFELTER (47,XXY) SYNDROME: A REVIEW OF THE LITERATURE AND PRELIMINARY RESULTS FROM A FUNCTIONAL MAGNETIC RESONANCE IMAGING STUDY OF LANGUAGE DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Steinman, K., Ross, J., Lai, S., Reiss, A., Hoeft, F. 2009; 15 (4): 295-308

  Abstract

  Klinefelter (47,XXY) syndrome (KS), the most common form of sex-chromosomal aneuploidy, is characterized by physical, endocrinologic, and reproductive abnormalities. Individuals with KS also exhibit a cognitive/behavioral phenotype characterized by language and language-based learning disabilities and executive and attentional dysfunction in the setting of normal general intelligence. The underlying neurobiologic mechanisms are just now beginning to be elucidated through structural and functional neuroimaging. Here, we review the literature of structural and functional neural findings in KS identified by neuroimaging and present preliminary results from a functional magnetic resonance imaging study examining brain activity during a verb generation task in KS.

  View details for DOI 10.1002/ddrr.84

  View details for Web of Science ID 000273207500005

  View details for PubMedID 20014370

  View details for PubMedCentralID PMC2876340

• Childhood developmental disorders: an academic and clinical convergence point for psychiatry, neurology, psychology and pediatrics JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Reiss, A. L. 2009; 50 (1-2): 87-98

  Abstract

  Significant advances in understanding brain development and behavior have not been accompanied by revisions of traditional academic structure. Disciplinary isolation and a lack of meaningful interdisciplinary opportunities are persistent barriers in academic medicine. To enhance clinical practice, research, and training for the next generation, academic centers will need to take bold steps that challenge traditional departmental boundaries. Such change is not only desirable but, in fact, necessary to bring about a truly innovative and more effective approach to treating disorders of the developing brain.I focus on developmental disorders as a convergence point for transcending traditional academic boundaries. First, the current taxonomy of developmental disorders is described with emphasis on how current diagnostic systems inadvertently hinder research progress. Second, I describe the clinical features of autism, a phenomenologically defined condition, and Rett and fragile X syndromes, neurogenetic diseases that are risk factors for autism. Finally, I describe how the fields of psychiatry, psychology, neurology, and pediatrics now have an unprecedented opportunity to promote an interdisciplinary approach to training, research, and clinical practice and, thus, advance a deeper understanding of developmental disorders.Research focused on autism is increasingly demonstrating the heterogeneity of individuals diagnosed by DSM criteria. This heterogeneity hinders the ability of investigators to replicate research results as well as progress towards more effective, etiology-specific interventions. In contrast, fragile X and Rett syndromes are 'real' diseases for which advances in research are rapidly accelerating towards more disease-specific human treatment trials.A major paradigm shift is required to improve our ability to diagnose and treat individuals with developmental disorders. This paradigm shift must take place at all levels - training, research and clinical activity. As clinicians and scientists who are currently constrained by disciplinary-specific history and training, we must move towards redefining ourselves as clinical neuroscientists with shared interests and expertise that permit a more cohesive and effective approach to improving the lives of patients.

  View details for DOI 10.1111/j.1469-7610.2008.02046.x

  View details for Web of Science ID 000262889700012

  View details for PubMedID 19220592

• Aberrant Neural Function During Emotion Attribution in Female Subjects With Fragile X Syndrome JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Hagan, C. C., Hoeft, F., Mackey, A., Mobbs, D., Reiss, A. L. 2008; 47 (12): 1443-1454

  Abstract

  Fragile X (FraX) syndrome is caused by mutations of the FraX mental retardation-1 gene-a gene responsible for producing FraX mental retardation protein. The neurocognitive phenotype associated with FraX in female subjects includes increased risk for emotional disorders including social anxiety, depression, and attention deficit. Here, the authors investigated the neurobiological systems underlying emotion attribution in female subjects with FraX syndrome.While undergoing functional magnetic resonance imaging, 10 high-functioning female subjects with FraX syndrome and 10 typically developing (TD) female subjects were presented with photographs of happy, sad, and neutral faces and instructed to determine the facial emotion.No significant group differences were found for the recognition of happy faces, although the FraX group showed a trend toward a significant difference for the recognition of sad faces and significantly poorer recognition of neutral faces. Controlling for between-group differences in IQ and performance accuracy, the TD group had greater activation than the FraX group in the anterior cingulate cortex (ACC) for neutral faces compared with scrambled faces and the caudate for sad faces compared with scrambled faces (but not for sad faces compared with neutral faces). In the FraX group, FraX mental retardation protein levels positively correlated with activation in the dorsal ACC for neutral, happy, and sad faces when independently compared with scrambled faces. Significantly greater negative correlation between IQ and insula activation for neutral faces relative to scrambled faces was observed in the FraX group compared with the TD group. Significantly greater positive correlation between IQ and ACC activation for neutral faces relative to scrambled faces was observed in the TD group compared with the FraX group.Although emotion recognition is generally spared in FraX syndrome, the emotion circuit (i.e., ACC, caudate, insula) that modulates emotional responses to facial stimuli may be disrupted.

  View details for DOI 10.1097/CHI.0b013e3181886e92

  View details for Web of Science ID 000261112200012

  View details for PubMedID 18981933

• Structural Brain Differences Between Autistic Children and Their Typically-Developing Siblings: a Voxel-Based Morphometry Analysis Steinman, K., Lotspeich, L., Patnaik, S., Hoefr, F., Reiss, A. WILEY-LISS. 2008: S155

  View details for Web of Science ID 000262112100051

• Neuroanatomical Abnormalities in Adolescents With Attention-Deficit/Hyperactivity Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Garrett, A., Penniman, L., Epstein, J. N., Casey, B. J., Hinshaw, S. P., Glover, G., Tonev, S., Vitolo, A., Davidson, M., Spicer, J., Greenhill, L. L., Reiss, A. L. 2008; 47 (11): 1321-1328

  Abstract

  Several neuroanatomic abnormalities have been reported in patients with attention-deficit/hyperactivity disorder (ADHD). However, findings are not always consistent, perhaps because of heterogeneous subject samples. Studying youths with documented familial ADHD provides an opportunity to examine a more homogeneous population.Twenty-four youths with a confirmed history of familial ADHD and 10 control youths underwent high-resolution structural magnetic resonance imaging examinations. Archived magnetic resonance imaging scan data from 12 control youths were included in the analysis to increase statistical power. Individually drawn region-of-interest methods were used to examine the frontal lobe gyri and caudate.Cerebral total tissue was similar between groups. The volumes of the right caudate and right inferior frontal lobe were larger in the ADHD youths compared with the control youths. Data from a subgroup of the ADHD youths suggest that increasing left caudate volume is associated with decreasing functional activation of this region.Because previous studies have focused primarily on younger subjects or used an extended age range, the present results may reflect neurodevelopmental changes specific to late adolescence in familial ADHD.

  View details for DOI 10.1097/CHI.0b013e318185d285

  View details for Web of Science ID 000260444800012

  View details for PubMedID 18827721

  View details for PubMedCentralID PMC2644065

• Aberrant Brain Activation During Gaze Processing in Boys With Fragile X Syndrome ARCHIVES OF GENERAL PSYCHIATRY Watson, C., Hoeft, F., Garrett, A. S., Hall, S. S., Reiss, A. L. 2008; 65 (11): 1315-1323

  Abstract

  Eye contact is a fundamental component of human social behavior. Individuals with fragile X syndrome (fraX), particularly male subjects, avoid eye contact and display other social deficits. To date (to our knowledge), this behavior in fraX has been studied only in female subjects, who show lesser degrees of gaze aversion.To determine the neural correlates of the perception of direct eye gaze in adolescent boys with fraX using functional magnetic resonance imaging.Cross-sectional study.Academic medical center.Thirteen adolescent boys with fraX, 10 boys with developmental delay, and 13 typically developing control subjects.Behavioral performance and brain activation during functional magnetic resonance imaging were evaluated during the presentation of faces with eye gaze directed to or averted away from subjects and during successive presentations of stimuli with eye gaze directed toward the subject. Whole-brain and region of interest analyses and regression analyses with task performance were performed.Significantly greater activation was observed in prefrontal cortices in controls compared with boys having fraX, who (in contrast) demonstrated elevated left insula activation to direct eye gaze stimuli. Furthermore, compared with controls, boys with fraX showed greater sensitization in the left amygdala with successive exposure to direct gaze.Compared with controls, boys with fraX display distinct patterns of brain activation in response to direct eye gaze. These results suggest that aberrant neural processing of direct eye gaze in subjects with fraX may be related to the associated avoidant response.

  View details for Web of Science ID 000260600300009

  View details for PubMedID 18981343

• Association Between Cerebral Shape and Social Use of Language in Williams Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Gothelf, D., Searcy, Y. M., Reilly, J., Lai, P. T., Lanre-Amos, T., Mills, D., Korenberg, J. R., Galaburda, A., Bellugi, U., Reiss, A. L. 2008; 146A (21): 2753-2761

  Abstract

  Williams syndrome (WS) is a neurogenetic disorder resulting from a hemizygous microdeletion at band 7q11.23. It is characterized by aberrant development of the brain and a unique profile of cognitive and behavioral features. We sought to identify the neuroanatomical abnormalities that are most strongly associated with WS employing signal detection methodology. Once identified with a Quality Receiver Operating Characteristic Curve (QROC), we hypothesized those brain regions distinguishing subjects with WS from controls would be linked to the social phenotype of individuals with this disorder. Thirty-nine adolescents and young adults with WS and 40 typically developing controls matched for age and gender were studied. The QROC identified a combination of an enlarged ventral anterior prefrontal cortex and large bending angle of the corpus callosum to distinguish between WS and controls with a sensitivity of 85.4% and specificity of 75.0%. Within the WS group, bending angle significantly correlated with ventral anterior prefrontal cortex size but not with other morphometric brain measures. Ventral anterior prefrontal size in subjects with WS was positively associated with the use of social engagement devices in a narrative task assessing the use of social and affective language. Our findings suggest that aberrant morphology of the ventral anterior prefrontal cortex is a pivotal contributing factor to the abnormal size and shape of the cerebral cortex and to the social-affective language use typical of individuals with WS.

  View details for DOI 10.1002/ajmg.a.32507

  View details for Web of Science ID 000260985400008

  View details for PubMedID 18924169

  View details for PubMedCentralID PMC2643356

• Neural phenotypes of common and rare genetic variants BIOLOGICAL PSYCHOLOGY Bearden, C. E., Glahn, D. C., Lee, A. D., Chiang, M., van Erp, T. G., Cannon, T. D., Reiss, A. L., Toga, A. W., Thompson, P. M. 2008; 79 (1): 43-57

  Abstract

  Neuroimaging methods offer a powerful way to bridge the gaps between genes, neurobiology and behavior. Such investigations may be further empowered by complementary strategies involving chromosomal abnormalities associated with particular neurobehavioral phenotypes, which can help to localize causative genes and better understand the genetics of complex traits in the general population. Here we review the evidence from studies using these convergent approaches to investigate genetic influences on brain structure: (1) studies of common genetic variations associated with particular neuroanatomic phenotypes, and (2) studies of possible 'genetic subtypes' of neuropsychiatric disorders with very high penetrance, with a focus on neuroimaging studies using novel computational brain mapping algorithms. Finally, we discuss the contribution of behavioral neurogenetics research to our understanding of the genetic basis of neuropsychiatric disorders in the broader population.

  View details for DOI 10.1016/j.biopsycho.2008.02.005

  View details for Web of Science ID 000258738800005

  View details for PubMedID 18395317

  View details for PubMedCentralID PMC2535822

• Morphometric spatial patterns differentiating boys with fragile X syndrome, typically developing boys, and developmentally delayed boys aged 1 to 3 years ARCHIVES OF GENERAL PSYCHIATRY Hoeft, F., Lightbody, A. A., Hazlett, H. C., Patnaik, S., Piven, J., Reiss, A. L. 2008; 65 (9): 1087-1097

  Abstract

  Brain maturation starts well before birth and occurs as a unified process with developmental interaction among different brain regions. Gene and environment play large roles in such a process. Studies of individuals with genetic disorders such as fragile X syndrome (FXS), which is a disorder caused by a single gene mutation resulting in abnormal dendritic and synaptic pruning, together with healthy individuals may provide valuable information.To examine morphometric spatial patterns that differentiate between FXS and controls in early childhood.A cross-sectional in vivo neuroimaging study.Academic medical centers.A total of 101 children aged 1 to 3 years, comprising 51 boys with FXS, 32 typically developing boys, and 18 boys with idiopathic developmental delay.Regional gray matter volume as measured by voxel-based morphometry and manual tracing, supplemented by permutation analyses; regression analyses between gray and white matter volumes, IQ, and fragile X mental retardation protein level; and linear support vector machine analyses to classify group membership.In addition to aberrant brain structures reported previously in older individuals with FXS, we found reduced gray matter volumes in regions such as the hypothalamus, insula, and medial and lateral prefrontal cortices. These findings are consistent with the cognitive and behavioral phenotypes of FXS. Further, multivariate pattern classification analyses discriminated FXS from typical development and developmental delay with more than 90% prediction accuracy. The spatial patterns that classified FXS from typical development and developmental delay included those that may have been difficult to identify previously using other methods. These included a medial to lateral gradient of increased and decreased regional brain volumes in the posterior vermis, amygdala, and hippocampus.These findings are critical in understanding interplay among genes, environment, brain, and behavior. They signify the importance of examining detailed spatial patterns of healthy and perturbed brain development.

  View details for Web of Science ID 000259089300014

  View details for PubMedID 18762595

• Longitudinal changes in intellectual development in children with Fragile X syndrome JOURNAL OF ABNORMAL CHILD PSYCHOLOGY Hall, S. S., Burns, D. D., Lightbody, A. A., Reiss, A. L. 2008; 36 (6): 927-939

  Abstract

  Structural equation modeling (SEM) was used to examine the development of intellectual functioning in 145 school-age pairs of siblings. Each pair included one child with Fragile X syndrome (FXS) and one unaffected sibling. All pairs of children were evaluated on the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) at time 1 and 80 pairs of children received a second evaluation at time 2 approximately 4 years later. Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points (r=0.55 and 0.64 respectively). However, when gender, age, and the time between assessments were included as covariates in the structural equation model, FMRP accounted for only 5% of the variance in intellectual ability scores at time 1 and 13% of the variance at time 2. The results of this study suggest that slower learning contributes to the low and declining standardized IQ scores observed in children with FXS.

  View details for DOI 10.1007/s10802-008-9223-y

  View details for Web of Science ID 000257726600010

  View details for PubMedID 18347972

• Persistent default-mode network connectivity during light sedation HUMAN BRAIN MAPPING Greicius, M. D., Kiviniemi, V., Tervonen, O., Vainionpaa, V., Alahuhta, S., Reiss, A. L., Menon, V. 2008; 29 (7): 839-847

  Abstract

  The default-mode network (DMN) is a set of specific brain regions whose activity, predominant in the resting-state, is attenuated during cognitively demanding, externally-cued tasks. The cognitive correlates of this network have proven difficult to interrogate, but one hypothesis is that regions in the network process episodic memories and semantic knowledge integral to internally-generated mental activity. Here, we compare default-mode functional connectivity in the same group of subjects during rest and conscious sedation with midazolam, a state characterized by anterograde amnesia and a reduced level of consciousness. Although the DMN showed functional connectivity during both rest and conscious sedation, a direct comparison found that there was significantly reduced functional connectivity in the posterior cingulate cortex during conscious sedation. These results confirm that low-frequency oscillations in the DMN persist and remain highly correlated even at reduced levels of consciousness. We hypothesize that focal reductions in DMN connectivity, as shown here in the posterior cingulate cortex, may represent a stable correlate of reduced consciousness.

  View details for DOI 10.1002/hbm.20537

  View details for Web of Science ID 000256674400012

  View details for PubMedID 18219620

  View details for PubMedCentralID PMC2580760

• Recent MRI studies in depression: Relationship to HPA axis activity Schatzberg, A. F., Keller, J., Lyons, D., Reiss, A. CAMBRIDGE UNIV PRESS. 2008: 17

  View details for Web of Science ID 000258855500072

• Hippocampal and amygdalar volumes in psychotic and nonpsychotic unipolar depression AMERICAN JOURNAL OF PSYCHIATRY Keller, J., Shen, L., Gomez, R. G., Garrett, A., Solvason, H. B., Reiss, A., Schatzberg, A. F. 2008; 165 (7): 872-880

  Abstract

  The limbic system is thought to underlie dysfunctional affective and cognitive processes in individuals with depression. Neuroanatomical studies of subjects with depression have often examined hippocampal and amygdalar structures, since they are two key structures of the limbic system. Research has often but not always found reduced hippocampal volume in patients with major depression. The purpose of the present study was to examine differences in hippocampal and amygdalar volumes in patients with depression subtypes relative to healthy comparison subjects.Participants were 1) patients with major depression with psychosis, 2) patients with major depression without psychosis, and 3) healthy comparison subjects. To examine hippocampal and amygdalar volumes, all participants underwent structural magnetic resonance imaging (MRI). The authors further examined the effects of clinical and chronicity data on these two brain structures.After age, gender, and total brain volume were controlled, depressed patients with psychosis had a significantly smaller mean amygdala volume relative to depressed patients without psychosis and healthy comparison subjects. There were no differences between depressed patients without psychosis and healthy comparison subjects. Correlational analyses suggested that age of depression onset was strongly associated with amygdala volume. No group differences in hippocampal volume were found.There were no differences between depressed patients and healthy comparison subjects in hippocampal volume. However, psychotic but not nonpsychotic depression was associated with reduced amygdala volume. Reduced amygdala volume was not associated with severity of depression or severity of psychosis but was associated with age at onset of depression. Smaller amygdala volume may be a risk factor for later development of psychotic depression. In addition, chronicity of depression and depression subtype might be two important factors associated with hippocampal and amygdalar volumes in depression.

  View details for DOI 10.1176/appi.ajp.2008.07081257

  View details for Web of Science ID 000257320100016

  View details for PubMedID 18450931

  View details for PubMedCentralID PMC3733673

• Anomalous Hypothalamic Responses to Humor in Cataplexy PLOS ONE Reiss, A. L., Hoeft, F., Tenforde, A. S., Chen, W., Mobbs, D., Mignot, E. J. 2008; 3 (5)

  Abstract

  Cataplexy is observed in a subset of patients with narcolepsy and affects approximately 1 in 2,000 persons. Cataplexy is most often triggered by strong emotions such as laughter, which can result in transient, yet debilitating, muscle atonia. The objective of this study was to examine the neural systems underlying humor processing in individuals with cataplexy.While undergoing functional Magnetic Resonance Imaging (fMRI), we showed ten narcolepsy-cataplexy patients and ten healthy controls humorous cartoons. In addition, we examined the brain activity of one subject while in a full-blown cataplectic attack. Behavioral results showed that participants with cataplexy rated significantly fewer humorous cartoons as funny compared to controls. Concurrent fMRI showed that patients, when compared to controls and in the absence of overt cataplexy symptoms, showed pronounced activity in the emotional network including the ventral striatum and hypothalamus while viewing humorous versus non-humorous cartoons. Increased activity was also observed in the right inferior frontal gyri--a core component of the inhibitory circuitry. In comparison, the one subject who experienced a cataplectic attack showed dramatic reductions in hypothalamic activity.These findings suggest an overdrive of the emotional circuitry and possible compensatory suppression by cortical inhibitory regions in cataplexy. Moreover, during cataplectic attacks, the hypothalamus is characterized by a marked decrease in activity similar to that observed during sleep. One possible explanation for these findings is an initial overdrive and compensatory shutdown of the hypothalamus resulting in full cataplectic symptoms.

  View details for DOI 10.1371/journal.pone.0002225

  View details for Web of Science ID 000262258700033

  View details for PubMedID 18493621

  View details for PubMedCentralID PMC2377337

• A preliminary functional magnetic resonance imaging study of prefrontal-amygdalar activation changes in adolescents with bipolar depression treated with lamotrigine 44th Annual Meeting of the American-College-Neuropsychopharmacology Chang, K. D., Wagner, C., Garrett, A., Howe, M., Reiss, A. WILEY-BLACKWELL PUBLISHING, INC. 2008: 426–31

  Abstract

  Hypotheses regarding mood dysregulation in bipolar disorder (BD) have centered on limbic overactivity with relative prefrontal underactivity during mood episodes. Therefore, we hypothesized that adolescents with bipolar depression successfully treated with lamotrigine would show decreases in amygdalar activation, and increases in prefrontal activation.Eight adolescents with BD underwent functional magnetic resonance imaging (fMRI) at baseline and after eight weeks of lamotrigine treatment. Blocks of negatively and neutrally valenced emotional pictures were presented during scanning, and subjects were asked to rate how each picture made them feel. Activation in bilateral amygdalae and dorsolateral prefrontal cortices (DLPFC) for negative minus neutral pictures was correlated with Children's Depression Rating Scale (CDRS) scores.Mean (SD) CDRS scores decreased significantly, from 53.0 (10.6) at baseline to 26.3 (5.3) at Week 8. This clinical improvement was correlated with decreased right amygdalar activation (r = 0.91, p = 0.002). At Week 8, but not baseline, CDRS score was positively correlated with bilateral amygdalar activation (r = 0.85, p = 0.007). DLPFC activation was not correlated with change in CDRS score.These preliminary results indicate that adolescents with BD treated with lamotrigine demonstrated less amygdalar activation when viewing negative stimuli as depressive symptoms improved. Larger controlled studies are needed to confirm these findings.

  View details for PubMedID 18402630

• Brain volume reductions within multiple cognitive systems in male preterm children at age twelve JOURNAL OF PEDIATRICS Kesler, S. R., Reiss, A. L., Vohr, B., Watson, C., Schneider, K. C., Katz, K. H., Maller-Kesselman, J., Silberes, J., Constable, R. T., Makuch, R. W., Ment, L. R. 2008; 152 (4): 513-520

  Abstract

  To more precisely examine regional and subregional microstructural brain changes associated with preterm birth.We obtained brain volumes from 29 preterm children, age 12 years, with no ultrasound scanning evidence of intraventricular hemorrhage or cystic periventricular leukomalacia in the newborn period, and 22 age- and sex-matched term control subjects.Preterm male subjects demonstrated significantly lower white matter volumes in bilateral cingulum, corpus callosum, corticospinal tract, prefrontal cortex, superior and inferior longitudinal fasciculi compared with term male subjects. Gray matter volumes in prefrontal cortex, basal ganglia, and temporal lobe also were significantly reduced in preterm male subjects. Brain volumes of preterm female subjects were not significantly different from those of term female control subjects. Voxel-based morphometry results were not correlated with perinatal variables or cognitive outcome. Higher maternal education was associated with higher cognitive performance in preterm male subjects.Preterm male children continue to demonstrate abnormal neurodevelopment at 12 years of age. However, brain morphology in preterm female children may no longer differ from that of term female children. The neurodevelopmental abnormalities we detected in preterm male subjects appear to be relatively diffuse, involving multiple neural systems. The relationship between aberrant neurodevelopment and perinatal variables may be mediated by genetic factors, environmental factors, or both reflected in maternal education level.

  View details for DOI 10.1016/j.jpeds.2007.08.009

  View details for Web of Science ID 000254543200024

  View details for PubMedID 18346506

  View details for PubMedCentralID PMC3270939

• Prematurely born children demonstrate white matter microstructural differences at 12 years of age, relative to term control subjects: An investigation of group and gender effects PEDIATRICS Constable, R. T., Ment, L. R., Vohr, B. R., Kesler, S. R., Fulbright, R. K., Lacadie, C., Delancy, S., Katz, K. H., Schneider, K. C., Schafer, R. J., Makuch, R. W., Reiss, A. R. 2008; 121 (2): 306-316

  Abstract

  The goal was to use diffusion tensor imaging to test the hypothesis that prematurely born children demonstrate long-term, white matter, microstructural differences, relative to term control subjects.Twenty-nine preterm subjects (birth weight: 600-1250 g) without neonatal brain injury and 22 matched, term, control subjects were evaluated at 12 years of age with MRI studies, including diffusion tensor imaging and volumetric imaging; voxel-based morphometric strategies were used to corroborate regional diffusion tensor imaging results. Subjects also underwent neurodevelopmental assessments.Neurodevelopmental assessments showed significant differences in full-scale, verbal, and performance IQ and Developmental Test of Visual Motor Integration scores between the preterm and term control subjects. Diffusion tensor imaging studies demonstrated widespread decreases in fractional anisotropy (a measure of fiber tract organization) in the preterm children, compared with the control subjects. Regions included both intrahemispheric association fibers subserving language skills, namely, the right inferior frontooccipital fasciculus and anterior portions of the uncinate fasciculi bilaterally, and the deep white matter regions to which they project, as well as the splenium of the corpus callosum. These changes in fractional anisotropy occurred in subjects with significant differences in frontal, temporal, parietal, and deep white matter volumes. Fractional anisotropy values in the left anterior uncinate correlated with verbal IQ, full-scale IQ, and Peabody Picture Vocabulary Test-Revised scores for preterm male subjects. In addition, preterm male subjects were found to have the lowest values for fractional anisotropy in the right anterior uncinate fasciculus, and fractional anisotropy values in that region correlated with both verbal IQ and Peabody Picture Vocabulary Test-Revised scores for the preterm groups; these findings were supported by changes identified with voxel-based morphometric analyses.Compared with term control subjects, prematurely born children with no neonatal ultrasound evidence of white matter injury manifest changes in neural connectivity at 12 years of age.

  View details for DOI 10.1542/peds.2007-0414

  View details for Web of Science ID 000252877600011

  View details for PubMedID 18245422

• Offering to share: How to put heads together in autism neuroimaging JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Belmonte, M. K., Mazziotta, J. C., Minshew, N. J., Evans, A. C., Courchesne, E., Dager, S. R., Bookheimer, S. Y., Aylward, E. H., Amaral, D. G., Cantor, R. M., Chugani, D. C., Dale, A. M., Davatzikos, C., Gerig, G., Herbert, M. R., Lainhart, J. E., Murphy, D. G., Piven, J., Reiss, A. L., Schultz, R. T., Zeffiro, T. A., Levi-Pearl, S., Lajonchere, C., Colamarino, S. A. 2008; 38 (1): 2-13

  Abstract

  Data sharing in autism neuroimaging presents scientific, technical, and social obstacles. We outline the desiderata for a data-sharing scheme that combines imaging with other measures of phenotype and with genetics, defines requirements for comparability of derived data and recommendations for raw data, outlines a core protocol including multispectral structural and diffusion-tensor imaging and optional extensions, provides for the collection of prospective, confound-free normative data, and extends sharing and collaborative development not only to data but to the analytical tools and methods applied to these data. A theme in these requirements is the need to preserve creative approaches and risk-taking within individual laboratories at the same time as common standards are provided for these laboratories to build on.

  View details for DOI 10.1007/s10803-006-0352-2

  View details for Web of Science ID 000252160700001

  View details for PubMedID 17347882

  View details for PubMedCentralID PMC3076291

• Compulsive, self-injurious, and autistic behavior in children and adolescents with fragile X syndrome AMERICAN JOURNAL ON MENTAL RETARDATION Hall, S. S., Lightbody, A. A., Reiss, A. L. 2008; 113 (1): 44-53

  Abstract

  Compulsive, self-injurious, and autistic behaviors were examined in 31 boys and 29 girls with fragile X syndrome aged 5 to 20 years. Self-injurious behavior occurred in 58% of boys and 17% of girls, whereas compulsive behavior occurred in 72% of boys and 55% of girls and did not appear to be associated with self-injurious behavior. Fifty percent of boys and 20% of girls met diagnostic criteria for autism on the ADOS-G. Girls who showed compulsive behavior had lower levels of FMRP than girls who did not show compulsive behavior, and boys with autistic symptoms had lowered levels of cortisol. Taken together, these data suggest that autistic and compulsive behaviors are highly prevalent in fragile X syndrome and that lowered levels of FMRP and cortisol may be biological markers for these behaviors.

  View details for Web of Science ID 000252702800004

  View details for PubMedID 18173299

• Anomolous hypothalamic responses to humor in cataplexy PLoS ONE Reiss AL, Hoeft F, Tenforde AS, Chen W, Mobbs D, Mignot EJ 2008; 3 (5): e22225
• Defining the social phenotype in Williams syndrome: A model for linking gene, the brain, and behavior DEVELOPMENT AND PSYCHOPATHOLOGY Jarvinen-Pasley, A., Bellugi, U., Reilly, J., Mills, D. L., Galaburda, A., Reiss, A. L., Korenberg, J. R. 2008; 20 (1): 1-35

  Abstract

  Research into phenotype-genotype correlations in neurodevelopmental disorders has greatly elucidated the contribution of genetic and neurobiological factors to variations in typical and atypical development. Etiologically relatively homogeneous disorders, such as Williams syndrome (WS), provide unique opportunities for elucidating gene-brain-behavior relationships. WS is a neurogenetic disorder caused by a hemizygous deletion of approximately 25 genes on chromosome 7q11.23. This results in a cascade of physical, cognitive-behavioral, affective, and neurobiological aberrations. WS is associated with a markedly uneven neurocognitive profile, and the mature state cognitive profile of WS is relatively well developed. Although anecdotally, individuals with WS have been frequently described as unusually friendly and sociable, personality remains a considerably less well studied area. This paper investigates genetic influences, cognitive-behavioral characteristics, aberrations in brain structure and function, and environmental and biological variables that influence the social outcomes of individuals with WS. We bring together a series of findings across multiple levels of scientific enquiry to examine the social phenotype in WS, reflecting the journey from gene to the brain to behavior. Understanding the complex multilevel scientific perspective in WS has implications for understanding typical social development by identifying important developmental events and markers, as well as helping to define the boundaries of psychopathology.

  View details for DOI 10.1017/S0954579408000011

  View details for Web of Science ID 000252689300001

  View details for PubMedID 18211726

  View details for PubMedCentralID PMC2892602

• Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP) ANNALS OF NEUROLOGY Gothelf, D., Furfaro, J. A., Hoeft, F., Eckert, M. A., Hall, S. S., O'Hara, R., Erba, H. W., Ringel, J., Hayashi, K. M., Patnaik, S., Golianu, B., Kraemer, H. C., Thompson, P. M., Piven, J., Reiss, A. L. 2008; 63 (1): 40-51

  Abstract

  To determine how neuroanatomic variation in children and adolescents with fragile X syndrome is linked to reduced levels of the fragile X mental retardation-1 protein and to aberrant cognition and behavior.This study included 84 children and adolescents with the fragile X full mutation and 72 typically developing control subjects matched for age and sex. Brain morphology was assessed with volumetric, voxel-based, and surface-based modeling approaches. Intelligence quotient was evaluated with standard cognitive testing, whereas abnormal behaviors were measured with the Autism Behavior Checklist and the Aberrant Behavior Checklist.Significantly increased size of the caudate nucleus and decreased size of the posterior cerebellar vermis, amygdala, and superior temporal gyrus were present in the fragile X group. Subjects with fragile X also demonstrated an abnormal profile of cortical lobe volumes. A receiver operating characteristic analysis identified the combination of a large caudate with small posterior cerebellar vermis, amygdala, and superior temporal gyrus as distinguishing children with fragile X from control subjects with a high level of sensitivity and specificity. Large caudate and small posterior cerebellar vermis were associated with lower fragile X mental retardation protein levels and more pronounced cognitive deficits and aberrant behaviors.Abnormal development of specific brain regions characterizes a neuroanatomic phenotype associated with fragile X syndrome and may mediate the effects of FMR1 gene mutations on the cognitive and behavioral features of the disorder. Fragile X syndrome provides a model for elucidating critical linkages among gene, brain, and cognition in children with serious neurodevelopmental disorders.

  View details for DOI 10.1002/ana.21243

  View details for Web of Science ID 000253008700007

  View details for PubMedID 17932962

  View details for PubMedCentralID PMC2773141

• Posttraumatic stress symptoms and brain function during a response-inhibition task: An fMRI study in youth DEPRESSION AND ANXIETY Carrion, V. G., Garrett, A., Menon, V., Weems, C. F., Reiss, A. L. 2008; 25 (6): 514-526

  Abstract

  Youth who experience interpersonal trauma and have posttraumatic stress symptoms (PTSS) can exhibit difficulties in executive function and physiological hyperarousal. Response inhibition has been identified as a core component of executive function. In this study, we investigate the functional neuroanatomical correlates of response inhibition in youth with PTSS. Thirty right-handed medication-naïve youth between the ages of 10 and 16 years underwent a 3-Tesla Functional Magnetic Resonance Imaging scan during a response-inhibition (Go/No-Go) task. Youth with PTSS (n = 16) were age and gender matched to a control group of healthy youth (n = 14). Between-groups analyses were conducted to identify brain regions of greater activation in the No/Go-Go contrasts. PTSS and control youth performed the task with similar accuracy and response times. Control subjects had greater middle frontal cortex activation when compared with PTSS subjects. PTSS subjects had greater medial frontal activation when compared with control subjects. A sub-group of youth with PTSS and a history of self-injurious behaviors demonstrated increased insula and orbitofrontal activation when compared with those PTSS youth with no self-injurious behaviors. Insula activation correlated positively with PTSS severity. Diminished middle frontal activity and enhanced medial frontal activity during response-inhibition tasks may represent underlying neurofunctional markers of PTSS.

  View details for DOI 10.1002/da.20346

  View details for PubMedID 17598145

• Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: A longitudinal study SCHIZOPHRENIA RESEARCH Gothelf, D., Penniman, L., Gu, E., Eliez, S., Reiss, A. L. 2007; 96 (1-3): 72-81

  Abstract

  The 22q11.2 deletion syndrome (22q11.2DS) is associated with very high rates of schizophrenia-like psychosis and cognitive deficits. Here we report the results of the first longitudinal study assessing brain development in individuals with 22q11.2DS. Twenty-nine children with 22q11.2DS and 29 age and gender matched controls were first assessed during childhood or early adolescence; Nineteen subjects with 22q11.2DS and 18 controls underwent follow-up during late adolescence-early adulthood. The 22q11.2DS subjects showed greater longitudinal increase in cranial and cerebellar white matter, superior temporal gyrus, and caudate nucleus volumes. They also had a more robust decrease in amygdala volume. Verbal IQ (VIQ) scores of the 22q11.2DS group that developed psychotic disorders declined significantly between assessments. Decline in VIQ in 22q11.2DS was associated with more robust reduction of left cortical grey matter volume. No volumetric differences were detected between psychotic and nonpsychotic subjects with 22q11.2DS. Brain maturation associated with verbal cognitive development in 22q11.2DS varies from that observed in healthy controls. Further longitudinal studies are likely to elucidate brain developmental trajectories in 22q11.2DS and their association to psychotic disorders and cognitive deficits in this population.

  View details for DOI 10.1016/j.schres.2007.07.021

  View details for Web of Science ID 000250690900007

  View details for PubMedID 17804201

  View details for PubMedCentralID PMC2642803

• Frontostriatal connectivity and its role in cognitive control in parent-child dyads with ADHD AMERICAN JOURNAL OF PSYCHIATRY Casey, B. J., Epstein, J. N., Buhle, J., Liston, C., Davidson, M. C., Tonev, S. T., Spicer, J., Niogi, S., Millner, A. J., Reiss, A., Garrett, A., Hinshaw, S. P., Greenhill, L. L., Shafritz, K. M., Vitolo, A., Kotler, L. A., Jarrett, M. A., Glover, G. 2007; 164 (11): 1729-1736

  Abstract

  Many studies have linked the structure and function of frontostriatal circuitry to cognitive control deficits in attention deficit hyperactivity disorder (ADHD). Few studies have examined the role of white matter tracts between these structures or the extent to which white matter tract myelination and regularity correlate in family members with the disorder.Functional imaging maps from a go/nogo task were used to identify portions of the ventral prefrontal cortex and striatum involved in suppressing an inappropriate action (i.e., cognitive control) in 30 parent-child dyads (N=60), including 20 dyads (N=40) with ADHD and 10 dyads (N=20) without ADHD. An automated fiber-tracking algorithm was used to delineate white matter fibers adjacent to these functionally defined regions based on diffusion tensor images. Fractional anisotropy, an index of white matter tract myelination and regularity derived from diffusion tensor images, was calculated to characterize the associations between white matter tracts and function.Fractional anisotropy in right prefrontal fiber tracts correlated with both functional activity in the inferior frontal gyrus and caudate nucleus and performance of a go/nogo task in parent-child dyads with ADHD, even after controlling for age. Prefrontal fiber tract measures were tightly associated between ADHD parents and their children.Collectively, these findings support previous studies suggesting heritability of frontostriatal structures among individuals with ADHD and suggest disruption in frontostriatal white matter tracts as one possible pathway to the disorder.

  View details for DOI 10.1176/appi.ajp.2007.06101754

  View details for Web of Science ID 000250811200020

  View details for PubMedID 17974939

• More is not always better: Increased fractional Anisotropy of superior longitudinal fasciculus associated with poor Visuospatial abilities in Williams syndrome JOURNAL OF NEUROSCIENCE Hoeft, F., Barnea-Goraly, N., Haas, B. W., Golarai, G., Ng, D., Mills, D., Korenberg, J., Bellugi, U., Galaburda, A., Reiss, A. L. 2007; 27 (44): 11960-11965

  Abstract

  We used diffusion tensor imaging to examine white matter integrity in the dorsal and ventral streams among individuals with Williams syndrome (WS) compared with two control groups (typically developing and developmentally delayed) and using three separate analysis methods (whole brain, region of interest, and fiber tractography). All analysis methods consistently showed that fractional anisotropy (FA; a measure of microstructural integrity) was higher in the right superior longitudinal fasciculus (SLF) in WS compared with both control groups. There was a significant association with deficits in visuospatial construction and higher FA in WS individuals. Comparable increases in FA across analytic methods were not observed in the left SLF or the bilateral inferior longitudinal fasciculus in WS subjects. Together, these findings suggest a specific role of right SLF abnormality in visuospatial construction deficits in WS.

  View details for DOI 10.1523/JNEUROSCI.3591-07.2007

  View details for Web of Science ID 000250577600025

  View details for PubMedID 17978036

• Brain, skull, and cerebrospinal fluid volumes in adult Posttraumatic stress disorder JOURNAL OF TRAUMATIC STRESS Woodward, S. H., Kaloupek, D. G., Streeter, C. C., Kimble, M. O., Reiss, A. L., Eliez, S., Wald, L. L., Renshaw, P. E., Frederick, B. B. 2007; 20 (5): 763-774

  Abstract

  Children and adolescents with maltreatment-related posttraumatic stress disorder (PTSD) exhibit smaller intracranial tissue volume than controls. Linear relationships have also been observed between intracranial tissue volume and the age of maltreatment onset. The authors explored associations among adult PTSD, early trauma, and cerebral volumes in 99 combat veterans. A bone-based estimate of cranial volume was developed to adjust for variation in body size. Posttraumatic stress disorder was not associated with smaller cerebral tissue volume, but rather with smaller cerebrospinal fluid (CSF) and cranial volumes. These findings co-occurred with expected effects of alcoholism and aging on cerebral tissue and CSF volumes. The results point to early developmental divergences between groups with and without PTSD following adult trauma.

  View details for DOI 10.1002/jts.20241

  View details for Web of Science ID 000250736400012

  View details for PubMedID 17955544

• Craniofacioskeletal syndrome: An X-linked dominant disorder with early lethality in males AMERICAN JOURNAL OF MEDICAL GENETICS PART A Stevenson, R. E., Brasington, C. K., Skinner, C., Simensen, R. J., Spence, J. E., Kesler, S., Reiss, A. L., Schwartz, C. E. 2007; 143A (19): 2321-2329

  Abstract

  A syndrome with multisystem manifestations has been observed in three generations of a Caucasian family. The findings in seven females provide a composite clinical picture of microcephaly, short stature, small retroverted ears, full tip of the nose overhanging the columella, short philtrum, thin upper lip, soft tissue excrescences at the angle of the mouth, small mandible, small hands and feet with brachydactyly, finger V clinodactyly, flat feet, an excessive number of fingerprint arches, and mild impairment of cognitive function. Two males were more severely affected and died in the initial months of life. They showed intrauterine growth retardation, broad cranium with wide sutures and fontanelles, cardiac defects, small hands and feet with abnormal digital creases and small nails, and genital abnormalities. The affected males had low serum calcium in the neonatal period. Serum calcium, phosphorous, and parathormone levels in the females were normal. Radiographs showed cortical thickening of the long bones, underdevelopment of the frontal sinuses, narrow pelvis and hypoplasia of the middle phalanx of finger five. MRI of the brain showed slightly reduced brain volumes and an extra gyrus of the superior temporal region. X-inactivation studies showed near complete skewing in two affected females, but were not informative in three others. X-linkage as the mode of inheritance is proposed on the basis of different severity in males/females, complete skewing of X-inactivation in informative females, and a lod score (1.5) suggestive of linkage to markers in Xq26-q27.

  View details for DOI 10.1002/ajmg.a.31928

  View details for Web of Science ID 000249829900013

  View details for PubMedID 17853486

  View details for PubMedCentralID PMC3061623

• ADHD- and medication-related brain activation effects in concordantly affected parent-child dyads with ADHD JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Epstein, J. N., Casey, B. J., Tonev, S. T., Davidson, M. C., Reiss, A. L., Garrett, A., Hinshaw, S. P., Greenhill, L. L., Glover, G., Shafritz, K. M., Vitolo, A., Kotler, L. A., Jarrett, M. A., Spicer, J. 2007; 48 (9): 899-913

  Abstract

  Several studies have documented fronto-striatal dysfunction in children and adolescents with attention deficit/hyperactivity disorder (ADHD) using response inhibition tasks. Our objective was to examine functional brain abnormalities among youths and adults with ADHD and to examine the relations between these neurobiological abnormalities and response to stimulant medication.A group of concordantly diagnosed ADHD parent-child dyads was compared to a matched sample of normal parent-child dyads. In addition, ADHD dyads were administered double-blind methylphenidate and placebo in a counterbalanced fashion over two consecutive days of testing. Frontostriatal function was measured using functional magnetic resonance imaging (fMRI) during performance of a go/no-go task.Youths and adults with ADHD showed attenuated activity in fronto-striatal regions. In addition, adults with ADHD appeared to activate non-fronto-striatal regions more than normals. A stimulant medication trial showed that among youths, stimulant medication increased activation in fronto-striatal and cerebellar regions. In adults with ADHD, increases in activation were observed in the striatum and cerebellum, but not in prefrontal regions.This study extends findings of fronto-striatal dysfunction to adults with ADHD and highlights the importance of frontostriatal and frontocerebellar circuitry in this disorder, providing evidence of an endophenotype for examining the genetics of ADHD.

  View details for DOI 10.1111/j.1469-7610.2007.01761.x

  View details for Web of Science ID 000249130800007

  View details for PubMedID 17714375

• Resting-state functional connectivity in major depression: Abnormally increased contributions from subgenual cingulate cortex and thalamus BIOLOGICAL PSYCHIATRY Greicius, M. D., Flores, B. H., Menon, V., Glover, G. H., Solvason, H. B., Kenna, H., Reiss, A. L., Schatzberg, A. F. 2007; 62 (5): 429-437

  Abstract

  Positron emission tomography (PET) studies of major depression have revealed resting-state abnormalities in the prefrontal and cingulate cortices. Recently, fMRI has been adapted to examine connectivity within a specific resting-state neural network--the default-mode network--that includes medial prefrontal and anterior cingulate cortices. The goal of this study was to examine resting-state, default-mode network functional connectivity in subjects with major depression and in healthy controls.Twenty-eight subjects with major depression and 20 healthy controls underwent 5-min fMRI scans while resting quietly. Independent component analysis was used to isolate the default-mode network in each subject. Group maps of the default-mode network were compared. A within-group analysis was performed in the depressed group to explore effects of depression refractoriness on functional connectivity.Resting-state subgenual cingulate and thalamic functional connectivity with the default-mode network were significantly greater in the depressed subjects. Within the depressed group, the length of the current depressive episode correlated positively with functional connectivity in the subgenual cingulate.This is the first study to explore default-mode functional connectivity in major depression. The findings provide cross-modality confirmation of PET studies demonstrating increased thalamic and subgenual cingulate activity in major depression. Further, the within-subject connectivity analysis employed here brings these previously isolated regions of hypermetabolism into the context of a disordered neural network. The correlation between refractoriness and subgenual cingulate functional connectivity within the network suggests that a quantitative, resting-state fMRI measure could be used to guide therapy in individual subjects.

  View details for DOI 10.1016/j.biopsych.2006.09.020

  View details for Web of Science ID 000249042800009

  View details for PubMedID 17210143

  View details for PubMedCentralID PMC2001244

• Frontostriatal dysfunction in Williams syndrome BIOLOGICAL PSYCHIATRY Mobbs, D., Eckert, M. A., Mills, D., Korenberg, J., Bellugi, U., Galaburda, A. M., Reiss, A. L. 2007; 62 (3): 256-261

  Abstract

  Williams syndrome (WS) has provided researchers with an exciting opportunity to understand the complex interplay among genes, neurobiological and cognitive functions. However, despite a well-characterized cognitive and behavioral phenotype, little attention has been paid to the marked deficits in social and behavioral inhibition. Here we explore the neural systems that mediate response inhibition in WS.We used functional MRI (fMRI) to obtain blood oxygenation level dependence (BOLD) signal maps during the performance of a Go/NoGo response inhibition task from 11 clinically and genetically diagnosed WS patients and 11 age- and gender-matched typically developing (TD) control subjects. Correlations between behavioral, neuropsychological measures, and BOLD signal were also conducted.Although TD control subjects showed significantly faster response times, no group differences in behavioral accuracy were observed. Compared with control subjects, WS participants demonstrated significantly reduced activity in the striatum, dorsolateral prefrontal, and dorsal anterior cingulate cortices. These findings support the hypothesis that persons with WS fail to activate critical cortical and subcortical structures involved in behavioral inhibition.Our results provide important evidence for reduced engagement of the frontostriatal circuits in WS and provide putative biological markers for the deficits in response inhibition and the unusual social phenotype.

  View details for DOI 10.1016/j.biopsych.2006.05.041

  View details for Web of Science ID 000248208100010

  View details for PubMedID 16996488

• 3D pattern of brain abnormalities in Williams syndrome visualized using tensor-based morphometry NEUROIMAGE Chiang, M., Reiss, A. L., Lee, A. D., Bellugi, U., Galaburda, A. M., Korenberg, J. R., Mills, D. L., Toga, A. W., Thompson, P. M. 2007; 36 (4): 1096-1109

  Abstract

  Williams syndrome (WS) is a neurodevelopmental disorder associated with deletion of approximately 20 contiguous genes in chromosome band 7q11.23. Individuals with WS exhibit mild to moderate mental retardation, but are relatively more proficient in specific language and musical abilities. We used tensor-based morphometry (TBM) to visualize the complex pattern of gray/white matter reductions in WS, based on fluid registration of structural brain images.3D T1-weighted brain MRIs of 41 WS subjects (age [mean+/-SD]: 29.2+/-9.2 years; 23F/18M) and 39 age-matched healthy controls (age: 27.5+/-7.4 years; 23F/16M) were fluidly registered to a minimum deformation target. Fine-scale volumetric differences were mapped between diagnostic groups. Local regions were identified where regional structure volumes were associated with diagnosis, and with intelligence quotient (IQ) scores. Brain asymmetry was also mapped and compared between diagnostic groups.WS subjects exhibited widely distributed brain volume reductions (approximately 10-15% reduction; P<0.0002, permutation test). After adjusting for total brain volume, the frontal lobes, anterior cingulate, superior temporal gyrus, amygdala, fusiform gyrus and cerebellum were found to be relatively preserved in WS, but parietal and occipital lobes, thalamus and basal ganglia, and midbrain were disproportionally decreased in volume (P<0.0002). These regional volumes also correlated positively with performance IQ in adult WS subjects (age > or = 30 years, P = 0.038).TBM facilitates 3D visualization of brain volume reductions in WS. Reduced parietal/occipital volumes may be associated with visuospatial deficits in WS. By contrast, frontal lobes, amygdala, and cingulate gyrus are relatively preserved or even enlarged, consistent with unusual affect regulation and language production in WS.

  View details for DOI 10.1016/j.neuroimage.2007.04.024

  View details for Web of Science ID 000248152400005

  View details for PubMedID 17512756

  View details for PubMedCentralID PMC2713103

• Fragile X syndrome: Assessment and treatment implications CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA Reiss, A. L., Hall, S. S. 2007; 16 (3): 663-?

  Abstract

  Fragile X syndrome (FraX) is the most common known cause of inherited mental impairment. FMR1 gene mutations, the cause of FraX, lead to reduced expression of FMR1 protein and an increased risk for a particular profile of cognitive, behavioral, and emotional dysfunction. The study of individuals with FraX provides a unique window of understanding into important disorders such as autism, social phobia, cognitive disability, and depression. This review highlights the typical phenotypic features of individuals with FraX, discussing the apparent strengths and weaknesses in intellectual functioning, as evidenced from longitudinal follow-up studies. It also discusses recent neuroanatomic findings that may pave the way for more focused disease-specific pharmacologic and behavioral interventions. This article describes the results of recent medication trials designed to target symptoms associated with FraX. It also describes some recent behavioral interventions that were conducted in our laboratory.

  View details for DOI 10.1016/j.chc.2007.03.001

  View details for Web of Science ID 000247944400010

  View details for PubMedID 17562585

• Stressing about posttraumatic stress disorder - In reply PEDIATRICS Carrion, V. G., Weems, C. F., Reiss, A. L. 2007; 120 (1): 234–35

  View details for DOI 10.1542/peds.2007-1024

  View details for Web of Science ID 000247719300030

• Prediction of children's reading skills using behavioral, functional, and structural neuroimaging measures BEHAVIORAL NEUROSCIENCE Hoeft, F., Ueno, T., Reiss, A. L., Meyler, A., Whitfield-Gabrieli, S., Glover, G. H., Keller, T. A., Kobayashi, N., Mazaika, P., Jo, B., Just, M. A., Gabrieli, J. D. 2007; 121 (3): 602-613

  Abstract

  The ability to decode letters into language sounds is essential for reading success, and accurate identification of children at high risk for decoding impairment is critical for reducing the frequency and severity of reading impairment. We examined the utility of behavioral (standardized tests), and functional and structural neuroimaging measures taken with children at the beginning of a school year for predicting their decoding ability at the end of that school year. Specific patterns of brain activation during phonological processing and morphology, as revealed by voxel-based morphometry (VBM) of gray and white matter densities, predicted later decoding ability. Further, a model combining behavioral and neuroimaging measures predicted decoding outcome significantly better than either behavioral or neuroimaging models alone. Results were validated using cross-validation methods. These findings suggest that neuroimaging methods may be useful in enhancing the early identification of children at risk for poor decoding and reading skills.

  View details for DOI 10.1037/0735-7044.121.3.602

  View details for Web of Science ID 000247359300017

  View details for PubMedID 17592952

• Reduced parietal and visual cortical activation during global processing in Williams syndrome DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Mobbs, D., Eckert, M. A., Menon, V., Mills, D., Korenberg, J., Galaburda, A. M., Rose, F. E., Bellugi, U., Reiss, A. L. 2007; 49 (6): 433-438

  Abstract

  Several lines of investigation suggest that individuals with Williams syndrome (WS), a neurodevelopmental disorder of well-characterized genetic etiology, have selective impairments in integrating local image elements into global configurations. We compared global processing abilities in 10 clinically and genetically diagnosed participants with WS (eight females, two males; mean age 31y 10mo [SD 9y 7mo], range 15y 5mo-48y 4mo) with a typically developed (TD) age- and sex-matched comparison group (seven females, one male; mean age 35y 2mo [SD 10y 10mo], range 24y-54y 7mo) using functional magnetic resonance imaging (fMRI). Behavioral data showed participants with WS to be significantly less accurate (p<0.042) together with a non-significant trend to be slower than the TD comparison group while performing the global processing task. fMRI data showed participants with WS to possess reduced activation in the visual and parietal cortices. Participants with WS also showed relatively normal activation in the ventral occipitotemporal cortex, but elevated activation in several posterior thalamic nuclei. These preliminary results largely confirm previous research findings and neural models implicating neurodevelopmental abnormalities in extended subcortical and cortical visual systems in WS, most notably dorsal-stream pathways.

  View details for Web of Science ID 000247346300010

  View details for PubMedID 17518929

• Fronto-striatal dysfunction and potential compensatory mechanisms in male adolescents with fragile X syndrome HUMAN BRAIN MAPPING Hoeft, F., Hernandez, A., Parthasarathy, S., Watson, C. L., Hall, S. S., Reiss, A. L. 2007; 28 (6): 543-554

  Abstract

  Response inhibition is an important facet of executive function. Fragile X syndrome (FraX), with a known genetic etiology (fragile X mental retardation-1 (FMR1) mutation) and deficits in response inhibition, may be an ideal condition for elucidating interactions among gene-brain-behavior relationships. Functional magnetic resonance imaging (fMRI) studies have shown evidence of aberrant neural activity when individuals with FraX perform executive function tasks, though the specific nature of this altered activity or possible compensatory processes has yet to be elucidated. To address this question, we examined brain activation patterns using fMRI during a go/nogo task in adolescent males with FraX and in controls. The critical comparison was made between FraX individuals and age, gender, and intelligent quotient (IQ)-matched developmentally delayed controls; in addition to a control group of age and gender-matched typically developing individuals. The FraX group showed reduced activation in the right ventrolateral prefrontal cortex (VLPFC) and right caudate head, and increased contralateral (left) VLPFC activation compared with both control groups. Individuals with FraX, but not controls, showed a significant positive correlation between task performance and activation in the left VLPFC. This potential compensatory activation was predicted by the interaction between FMR1 protein (FMRP) levels and right striatal dysfunction. These results suggest that right fronto-striatal dysfunction is likely an identifiable neuro-phenotypic feature of FraX and that activation of the left VLPFC during successful response inhibition may reflect compensatory processes. We further show that these putative compensatory processes can be predicted by a complex interaction between genetic risk and neural function.

  View details for DOI 10.1002/hbm.20406

  View details for Web of Science ID 000246628900009

  View details for PubMedID 17437282

• Abnormal cortical activation during response inhibition in 22q11.2 deletion syndrome HUMAN BRAIN MAPPING Gothelf, D., Hoeft, F., Hinard, C., Hallmayer, J. F., Stoecker, J. V., Antonarakis, S. E., Morris, M. A., Reiss, A. L. 2007; 28 (6): 533-542

  Abstract

  22q11.2 deletion syndrome (22q11.2DS) is a well-known genetic risk factor for schizophrenia. The catechol-O-methyltransferase (COMT) gene falls within the 22q11.2 minimal critical region of the deletion. Brain activity, as measured by functional magnetic resonance imaging (fMRI) during a Go/NoGo, response inhibition task was assessed in adolescents with 22q11.2DS (n = 13), typically developing (TD) controls (n = 14), and controls with developmental disability (DD, n = 9). Subjects with 22q11.2DS were also genotyped for the COMT Met/Val polymorphism. Groups did not differ on task performance. However, compared to both control groups, the 22q11.2DS group showed greater brain activation within left parietal regions. Comparison of brain activation between 22q11.2DS Met and Val subgroups revealed significantly increased activation (Met>Val) in the cingulate but not the dorsolateral prefrontal cortex. These preliminary findings suggest that adolescents with 22q11.2DS compensate for executive dysfunction via recruitment of parietal regions. Further, the COMT Met subgroup of 22q11.2DS may recruit additional cingulate activation for tasks requiring attention and inhibition. 22q11.2DS is a unique model for learning about the deleterious effects of decreased dosage of the COMT gene on brain function.

  View details for DOI 10.1002/hbm.20405

  View details for Web of Science ID 000246628900008

  View details for PubMedID 17427209

• Assessment and prevention of head motion during imaging of patients with attention deficit hyperactivity disorder PSYCHIATRY RESEARCH-NEUROIMAGING Epstein, J. N., Casey, B. J., Tonev, S. T., Davidson, M., Reiss, A. L., Garrett, A., Hinshaw, S. P., Greenhill, L. L., Vitolo, A., Kotler, L. A., Jarrett, M. A., Spicer, J. 2007; 155 (1): 75-82

  Abstract

  The present study serves to detail the specific procedures for a mock scanner protocol, report on its use in the context of a multi-site study, and make suggestions for improving such protocols based on data acquired during study scanning. Specifically, a mock scanner compliance training protocol was used in a functional imaging study with a group of adolescents and adults with Attention Deficit Hyperactivity Disorder (ADHD) and a matched sample of healthy children and adults. Head motion was measured during mock and actual scanning. Participants across groups exhibited excess motion (>2 mm) on 43% of runs during the mock scanner. During actual scanning, excessive motion was limited to 10% of runs. There was a clear task-correlated head motion during a go/no-go task that occurred even after the compliance training: participants had a tendency to respond with increased head motion immediately after committing an error. This study illustrates the need to (1) report data attrition due to head motion, (2) assess task-related motion, and (3) consider mock scanner training in functional imaging protocols.

  View details for DOI 10.1016/j.pscyhresns.2006.12.009

  View details for Web of Science ID 000246515400008

  View details for PubMedID 17395436

  View details for PubMedCentralID PMC1993908

• Automatic segmentation of the caudate nucleus from human brain MR images IEEE TRANSACTIONS ON MEDICAL IMAGING Xia, Y., Bettinger, K., Shen, L., Reiss, A. L. 2007; 26 (4): 509-517

  Abstract

  We describe a knowledge-driven algorithm to automatically delineate the caudate nucleus (CN) region of the human brain from a magnetic resonance (MR) image. Since the lateral ventricles (LVs) are good landmarks for positioning the CN, the algorithm first extracts the LVs, and automatically localizes the CN from this information guided by anatomic knowledge of the structure. The face validity of the algorithm was tested with 55 high-resolution T1-weighted magnetic resonance imaging (MRI) datasets, and segmentation results were overlaid onto the original image data for visual inspection. We further evaluated the algorithm by comparing automated segmentation results to a "gold standard" established by human experts for these 55 MR datasets. Quantitative comparison showed a high intraclass correlation between the algorithm and expert as well as high spatial overlap between the regions-of-interest (ROIs) generated from the two methods. The mean spatial overlap +/- standard deviation (defined by the intersection of the 2 ROIs divided by the union of the 2 ROIs) was equal to 0.873 +/- 0.0234. The algorithm has been incorporated into a public domain software program written in Java and, thus, has the potential to be of broad benefit to neuroimaging investigators interested in basal ganglia anatomy and function.

  View details for DOI 10.1109/TMI.2006.891481

  View details for Web of Science ID 000245599200009

  View details for PubMedID 17427738

• Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome AMERICAN JOURNAL OF PSYCHIATRY Gothelf, D., Feinstein, C., Thompson, T., Gu, E., Penniman, L., Van Stone, E., Kwon, H., Eliez, S., Reiss, A. L. 2007; 164 (4): 663-669

  Abstract

  The 22q11.2 deletion syndrome is the most common known genetic risk factor for the development of schizophrenia. The authors conducted a longitudinal evaluation of adolescents with 22q11.2 deletion syndrome to identify early risk factors for the development of psychotic disorders.Sixty children, 31 with 22q11.2 deletion syndrome and 29 comparison subjects with idiopathic developmental disability matched for age and IQ, underwent a baseline evaluation between 1998 and 2000; of these, 51 children (28 and 23 in the two groups, respectively) underwent follow-up evaluation between 2003 and 2005. A standardized comprehensive psychiatric, psychological, and adaptive functioning evaluation was conducted in both waves. Participants with 22q11.2 deletion syndrome were also genotyped for the catechol O-methyltransferase (COMT) Met/Val polymorphism and underwent magnetic resonance imaging scans.The two groups had similar baseline neuropsychiatric profiles. At follow-up, 32.1% of subjects with 22q11.2 deletion syndrome had developed psychotic disorders as compared with 4.3% of comparison subjects. In the 22q11.2 deletion syndrome group, baseline subthreshold psychotic symptoms interacted both with the COMT genotype and with baseline symptoms of anxiety or depression to predict 61% of the variance in severity of psychosis at follow-up evaluation. Lower baseline verbal IQ was also associated with more severe psychotic symptoms at follow-up evaluation.Genetic, cognitive, and psychiatric risk factors for the evolution of psychotic disorders in 22q11.2 deletion syndrome during adolescence were identified. Early intervention in the subgroup of children with subthreshold signs of psychosis and internalizing symptoms (especially anxiety symptoms) may reduce the risk of developing psychotic disorders during adolescence.

  View details for Web of Science ID 000245402600022

  View details for PubMedID 17403981

• Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin-Lowry syndrome NEUROGENETICS Kesler, S. R., Simensen, R. J., Voeller, K., Abidi, F., Stevenson, R. E., Schwartz, C. E., Reiss, A. L. 2007; 8 (2): 143-147

  Abstract

  Coffin-Lowry syndrome (CLS) is a rare form of X-linked mental retardation caused by mutations of the RSK2 gene, associated with cognitive impairment and skeletal malformations. We conducted the first morphometric study of CLS brain morphology by comparing brain volumes from two CLS families with healthy controls. Individuals with CLS consistently showed markedly reduced total brain volume. Cerebellum and hippocampus volumes were particularly impacted by CLS and may be associated with specific interfamilial RSK2 mutations. We provide preliminary evidence that the magnitude of hippocampus volume deviation from that of controls may predict general cognitive outcome in CLS.

  View details for DOI 10.1007/s10048-007-0080-6

  View details for Web of Science ID 000244692400009

  View details for PubMedID 17318637

  View details for PubMedCentralID PMC3055244

• Differential development of high-level visual cortex correlates with category-specific recognition memory NATURE NEUROSCIENCE Golarai, G., Ghahremani, D. G., Whitfield-Gabrieli, S., Reiss, A., Eberhardt, J. L., Gabrieli, J. D., Grill-Spector, K. 2007; 10 (4): 512-522

  Abstract

  High-level visual cortex in humans includes functionally defined regions that preferentially respond to objects, faces and places. It is unknown how these regions develop and whether their development relates to recognition memory. We used functional magnetic resonance imaging to examine the development of several functionally defined regions including object (lateral occipital complex, LOC)-, face ('fusiform face area', FFA; superior temporal sulcus, STS)- and place ('parahippocampal place area', PPA)-selective cortices in children (ages 7-11), adolescents (12-16) and adults. Right FFA and left PPA volumes were substantially larger in adults than in children. This development occurred by expansion of FFA and PPA into surrounding cortex and was correlated with improved recognition memory for faces and places, respectively. In contrast, LOC and STS volumes and object-recognition memory remained constant across ages. Thus, the ventral stream undergoes a prolonged maturation that varies temporally across functional regions, is determined by brain region rather than stimulus category, and is correlated with the development of category-specific recognition memory.

  View details for DOI 10.1038/nn1865

  View details for Web of Science ID 000245228600023

  View details for PubMedID 17351637

  View details for PubMedCentralID PMC3660101

• Affect, social behavior, and the brain in Williams syndrome CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE Bellugi, U., Jarvinen-Pasley, A., Doyle, T. F., Reilly, J., Reiss, A. L., Korenberg, J. R. 2007; 16 (2): 99-104

  View details for Web of Science ID 000245692500010

• Automated extraction of the cortical sulci based on a supervised learning approach IEEE TRANSACTIONS ON MEDICAL IMAGING Tu, Z., Zheng, S., Yuille, A. L., Reiss, A. L., Dutton, R. A., Lee, A. D., Galaburda, A. M., Dinov, I., Thompson, P. M., Toga, A. W. 2007; 26 (4): 541-552

  Abstract

  It is important to detect and extract the major cortical sulci from brain images, but manually annotating these sulci is a time-consuming task and requires the labeler to follow complex protocols. This paper proposes a learning-based algorithm for automated extraction of the major cortical sulci from magnetic resonance imaging (MRI) volumes and cortical surfaces. Unlike alternative methods for detecting the major cortical sulci, which use a small number of predefined rules based on properties of the cortical surface such as the mean curvature, our approach learns a discriminative model using the probabilistic boosting tree algorithm (PBT). PBT is a supervised learning approach which selects and combines hundreds of features at different scales, such as curvatures, gradients and shape index. Our method can be applied to either MRI volumes or cortical surfaces. It first outputs a probability map which indicates how likely each voxel lies on a major sulcal curve. Next, it applies dynamic programming to extract the best curve based on the probability map and a shape prior. The algorithm has almost no parameters to tune for extracting different major sulci. It is very fast (it runs in under 1 min per sulcus including the time to compute the discriminative models) due to efficient implementation of the features (e.g., using the integral volume to rapidly compute the responses of 3-D Haar filters). Because the algorithm can be applied to MRI volumes directly, there is no need to perform preprocessing such as tissue segmentation or mapping to a canonical space. The learning aspect of our approach makes the system very flexible and general. For illustration, we use volumes of the right hemisphere with several major cortical sulci manually labeled. The algorithm is tested on two groups of data, including some brains from patients with Williams Syndrome, and the results are very encouraging.

  View details for DOI 10.1109/TMI.2007.892506

  View details for Web of Science ID 000245599200012

  View details for PubMedID 17427741

• Functional and morphometric brain dissociation between dyslexia and reading ability PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Hoeft, F., Meyler, A., Hernandez, A., Juel, C., Taylor-Hill, H., Martindale, J. L., McMillon, G., Kolchugina, G., Black, J. M., Faizi, A., Deutsch, G. K., Siok, W. T., Reiss, A. L., Whitfield-Gabrieli, S., Gabrieli, J. D. 2007; 104 (10): 4234-4239

  Abstract

  In functional neuroimaging studies, individuals with dyslexia frequently exhibit both hypoactivation, often in the left parietotemporal cortex, and hyperactivation, often in the left inferior frontal cortex, but there has been no evidence to suggest how to interpret the differential relations of hypoactivation and hyperactivation to dyslexia. To address this question, we measured brain activation by functional MRI during visual word rhyme judgment compared with visual cross-hair fixation rest, and we measured gray matter morphology by voxel-based morphometry in dyslexic adolescents in comparison with (i) an age-matched group, and (ii) a reading-matched group younger than the dyslexic group but equal to the dyslexic group in reading performance. Relative to the age-matched group (n = 19; mean 14.4 years), the dyslexic group (n = 19; mean 14.4 years) exhibited hypoactivation in left parietal and bilateral fusiform cortices and hyperactivation in left inferior and middle frontal gyri, caudate, and thalamus. Relative to the reading-matched group (n = 12; mean 9.8 years), the dyslexic group (n = 12; mean 14.5 years) also exhibited hypoactivation in left parietal and fusiform regions but equal activation in all four areas that had exhibited hyperactivation relative to age-matched controls as well. In regions that exhibited atypical activation in the dyslexic group, only the left parietal region exhibited reduced gray matter volume relative to both control groups. Thus, areas of hyperactivation in dyslexia reflected processes related to the level of current reading ability independent of dyslexia. In contrast, areas of hypoactivation in dyslexia reflected functional atypicalities related to dyslexia itself, independent of current reading ability, and related to atypical brain morphology in dyslexia.

  View details for DOI 10.1073/pnas.0609399104

  View details for Web of Science ID 000244972400100

  View details for PubMedID 17360506

  View details for PubMedCentralID PMC1820738

• Stress predicts brain changes in children: A pilot longitudinal study on youth stress, posttraumatic stress disorder, and the hippocampus PEDIATRICS Carrion, V. G., Weems, C. F., Reiss, A. L. 2007; 119 (3): 509-516

  Abstract

  Does stress damage the brain? Studies of adults with posttraumatic stress disorder have demonstrated smaller hippocampal volumes when compared with the volumes of adults with no posttraumatic stress disorder. Studies of children with posttraumatic stress disorder have not replicated the smaller hippocampal findings in adults, which suggests that smaller hippocampal volume may be caused by neurodevelopmental experiences with stress. Animal research has demonstrated that the glucocorticoids secreted during stress can be neurotoxic to the hippocampus, but this has not been empirically demonstrated in human samples. We hypothesized that cortisol volumes would predict hippocampal volume reduction in patients with posttraumatic symptoms.We report data from a pilot longitudinal study of children (n = 15) with history of maltreatment who underwent clinical evaluation for posttraumatic stress disorder, cortisol, and neuroimaging.Posttraumatic stress disorder symptoms and cortisol at baseline predicted hippocampal reduction over an ensuing 12- to 18-month interval.Results from this pilot study suggest that stress is associated with hippocampal reduction in children with posttraumatic stress disorder symptoms and provide preliminary human evidence that stress may indeed damage the hippocampus. Additional studies seem to be warranted.

  View details for DOI 10.1542/peds.2006-2028

  View details for PubMedID 17332204

• Dissociable intrinsic connectivity networks for salience processing and executive control JOURNAL OF NEUROSCIENCE Seeley, W. W., Menon, V., Schatzberg, A. F., Keller, J., Glover, G. H., Kenna, H., Reiss, A. L., Greicius, M. D. 2007; 27 (9): 2349-2356

  Abstract

  Variations in neural circuitry, inherited or acquired, may underlie important individual differences in thought, feeling, and action patterns. Here, we used task-free connectivity analyses to isolate and characterize two distinct networks typically coactivated during functional MRI tasks. We identified a "salience network," anchored by dorsal anterior cingulate (dACC) and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an "executive-control network" that links dorsolateral frontal and parietal neocortices. These intrinsic connectivity networks showed dissociable correlations with functions measured outside the scanner. Prescan anxiety ratings correlated with intrinsic functional connectivity of the dACC node of the salience network, but with no region in the executive-control network, whereas executive task performance correlated with lateral parietal nodes of the executive-control network, but with no region in the salience network. Our findings suggest that task-free analysis of intrinsic connectivity networks may help elucidate the neural architectures that support fundamental aspects of human behavior.

  View details for DOI 10.1523/JNEUROSCI.5587-06.2007

  View details for Web of Science ID 000244758500023

  View details for PubMedID 17329432

  View details for PubMedCentralID PMC2680293

• 3D pattern of brain abnormalities in Fragile X syndrome visualized using tensor-based morphometry NEUROIMAGE Lee, A. D., Leow, A. D., Lu, A., Reiss, A. L., Hall, S., Chiang, M., Toga, A. W., Thompson, P. M. 2007; 34 (3): 924-938

  Abstract

  Fragile X syndrome (FraX), a genetic neurodevelopmental disorder, results in impaired cognition with particular deficits in executive function and visuo-spatial skills. Here we report the first detailed 3D maps of the effects of the Fragile X mutation on brain structure, using tensor-based morphometry. TBM visualizes structural brain deficits automatically, without time-consuming specification of regions-of-interest. We compared 36 subjects with FraX (age: 14.66+/-1.58 S.D., 18 females/18 males), and 33 age-matched healthy controls (age: 14.67+/-2.2 S.D., 17 females/16 males), using high-dimensional elastic image registration. All 69 subjects' 3D T1-weighted brain MRIs were spatially deformed to match a high-resolution single-subject average MRI scan in ICBM space, whose geometry was optimized to produce a minimal deformation target. Maps of the local Jacobian determinant (expansion factor) were computed from the deformation fields. Statistical maps showed increased caudate (10% higher; p = 0.001) and lateral ventricle volumes (19% higher; p = 0.003), and trend-level parietal and temporal white matter excesses (10% higher locally; p = 0.04). In affected females, volume abnormalities correlated with reduction in systemically measured levels of the Fragile X mental retardation protein (FMRP; Spearman's r < -0.5 locally). Decreased FMRP correlated with ventricular expansion (p = 0.042; permutation test), and anterior cingulate tissue reductions (p = 0.0026; permutation test) supporting theories that FMRP is required for normal dendritic pruning in fronto-striatal-limbic pathways. No sex differences were found; findings were confirmed using traditional volumetric measures in regions of interest. Deficit patterns were replicated by performing statistics after logarithmic transformation, which may be more appropriate for tensor-valued data. Investigation of how these anomalies emerge over time will accelerate our understanding of FraX and its treatment.

  View details for DOI 10.1016/j.neuroimage.2006.09.043

  View details for Web of Science ID 000243758700007

  View details for PubMedID 17161622

  View details for PubMedCentralID PMC1995408

• Modeling family dynamics in children with fragile X syndrome JOURNAL OF ABNORMAL CHILD PSYCHOLOGY Hall, S. S., Burns, D. D., Reiss, A. L. 2007; 35 (1): 29-42

  Abstract

  Few studies have examined the impact of children with genetic disorders and their unaffected siblings on family functioning. In this study, the reciprocal causal links between problem behaviors and maternal distress were investigated in 150 families containing a child with fragile X syndrome (FXS) and an unaffected sibling. Both children's behavior problems appeared to have strong, direct effects on maternal distress, but maternal distress did not appear to have any reciprocal causal effects on either child's behavior problems. Surprisingly, there were no significant differences in the effects of the two children's behavior problems on maternal distress. These data suggest that the problem behaviors of children with FXS, as well as their unaffected siblings, can have a substantial and additive impact on maternal depression and anxiety. Future research efforts should employ longitudinal research designs to confirm these findings.

  View details for DOI 10.1007/s10802-006-9081-4

  View details for Web of Science ID 000244835500003

  View details for PubMedID 17165142

• Hippocampal size positively correlates with verbal IQ in male children HIPPOCAMPUS Schumann, C. M., Hamstra, J., Goodlin-Jones, B. L., Kwon, H., Reiss, A. L., Amaral, D. G. 2007; 17 (6): 486-493

  Abstract

  Historically, there have been numerous proposals that the size of the brain correlates with its capacity to process information. Little is known, however, about which specific brain regions contribute to this correlation in children and adolescents. This study evaluated the relationship between intelligence and the size of various brain structures in typically developing male children 8-18 yrs of age. Magnetic resonance imaging (MRI) scans were used to measure the volume of the cerebrum, cerebral gray and white matter, cerebellum, amygdala, and hippocampus. Gray matter and hippocampal volume significantly correlated with full scale and verbal IQ. Since the hippocampus strongly correlated with verbal but not performance IQ, our findings reinforce the hypothesis that the hippocampus is involved in declarative and semantic learning, which contributes more notably to verbal IQ, than to performance IQ. Given the substantial evidence for environmentally induced changes in hippocampal structure, an unresolved issue is whether this relationship reflects genetically determined individual variation or learning induced plasticity.

  View details for DOI 10.1002/hipo.20282

  View details for Web of Science ID 000246971100009

  View details for PubMedID 17407128

• Joint sulci detection using graphical models and boosted priors 20th International Conference on Information Processing in Medical Imaging Shi, Y., Tu, Z., Reiss, A. L., Dutton, R. A., Lee, A. D., Galaburda, A. M., Dinov, I., Thompson, P. M., Toga, A. W. SPRINGER-VERLAG BERLIN. 2007: 98–109

  Abstract

  In this paper we propose an automated approach for joint sulci detection on cortical surfaces by using graphical models and boosting techniques to incorporate shape priors of major sulci and their Markovian relations. For each sulcus, we represent it as a node in the graphical model and associate it with a sample space of candidate curves, which is generated automatically using the Hamilton-Jacobi skeleton of sulcal regions. To take into account individual as well as joint priors about the shape of major sulci, we learn the potential functions of the graphical model using AdaBoost algorithm to select and fuse information from a large set of features. This discriminative approach is especially powerful in capturing the neighboring relations between sulcal lines, which are otherwise hard to be captured by generative models. Using belief propagation, efficient inferencing is then performed on the graphical model to estimate each sulcus as the maximizer of its final belief. On a data set of 40 cortical surfaces, we demonstrate the advantage of joint detection on four major sulci: central, precentral, postcentral and the sylvian fissure.

  View details for Web of Science ID 000247867400009

• Autonomous learning of stable quadruped locomotion ROBOCUP 2006: ROBOT SOCCER WORLD CUP X Saggar, M., D'Silva, T., Kohl, N., Stone, P. 2007; 4434: 98-109

  View details for Web of Science ID 000250044700009

• Hamilton-Jacobi skeletons on cortical surfaces with applications in characterizing the gyrification pattern in Williams syndrome 4th IEEE International Symposium on Biomedical Imaging Shi, Y., Reiss, A. L., Lee, A. D., Dutton, R. A., Bellugi, U., Galaburda, A. M., Korenberg, J. R., Mills, D. L., Dinov, I., Thompson, P. M., Toga, A. W. IEEE. 2007: 660–663

  View details for Web of Science ID 000252957300166

• Affect, social behavior, and the brain in Williams syndrome. Current Directions in Psychological Science Bellugi U, Jarvinen-Pasley A, Doyle TF, Reilly J, Reiss AL, Korenberg J 2007; 16 (2): 99-104
• Effects of divalproex on brain chemistry, morphometry, and function in adolescents at risk for bipolar disorder Chang, K., Wagner, C., Gallelli, K., Howe, M., Karchemskiy, A., Garrett, A., Reiss, A. NATURE PUBLISHING GROUP. 2006: S151–S152

  View details for Web of Science ID 000242215900410

• Screening for FMRI mutations among people with behavioral and psychiatric disorders: Recommendations of a focused advisory group Finucane, B., Gane, L., Coffey, S., Bourgeois, J., Braden, M., Chiu, S., Hall, S., Hessl, D., Reiss, A., Riley, K., Rogers, S., Shah, B., Hagerman, R. WILEY-BLACKWELL. 2006: 792–792

  View details for Web of Science ID 000240773500035

• Anomalous sylvian fissure morphology in Williams syndrome NEUROIMAGE Eckert, M. A., Galaburda, A. M., Karchemskiy, A., Liang, A., Thompson, P., Dutton, R. A., Lee, A. D., Bellugi, U., Korenberg, J. R., Mills, D., Rose, F. E., Reiss, A. L. 2006; 33 (1): 39-45

  Abstract

  The unusual sensitivity and attraction to auditory stimuli in people with Williams syndrome (WS) has been hypothesized to be the consequence of atypical development of brain regions surrounding the Sylvian fissure. Planum temporale surface area, which is determined in part by Sylvian fissure patterning, was examined in 42 WS and 40 control participants to determine if anomalous Sylvian fissure morphology is present in WS. WS participants had significantly reduced leftward asymmetry of the planum temporale compared to control participants, due to a significant expansion in the size of the right planum temporale. The increased right planum temporale size was largely due to WS participants (24%) who had a right hemisphere Sylvian fissure that coursed horizontally and failed to ascend into the parietal lobe. This sulcal pattern is unusual in the right hemisphere and is more commonly found in the left hemisphere of typically developing individuals. There were no control participants with this type of right hemisphere Sylvian fissure pattern. The right hemisphere Sylvian fissure sulcal patterns were also related to a measure of cortical complexity and the amount of right hemisphere occipital lobe volume, suggesting that intrinsic genetic influences leading to anomalous visual system development in WS have widespread influences on cortical morphology that are similar in manner to extrinsic embryonic visual system lesions.

  View details for DOI 10.1016/j.neuroimage.2006.05.062

  View details for Web of Science ID 000241209800006

  View details for PubMedID 16876437

• Increased local gyrification mapped in Williams syndrome NEUROIMAGE Gaser, C., Luders, E., Thompson, P. M., Lee, A. D., Dutton, R. A., Geaga, J. A., Hayashi, K. M., Bellugi, U., Galaburda, A. M., Korenberg, J. R., Mills, D. L., Toga, A. W., Reiss, A. L. 2006; 33 (1): 46-54

  Abstract

  Applying a recently developed method to analyze gyrification with excellent spatial resolution across thousands of points across the lateral and medial cortical surface, we mapped differences in cortical surface anatomy between subjects with Williams syndrome (WS; n=42) and an age-matched sample of healthy subjects (n=40). WS subjects showed increased gyrification bilaterally in occipital regions and over the cuneus. Differences were more pronounced in the left hemisphere than in the right, with additional regions of increased gyrification in WS in the left precuneus, posterior and anterior cingulate, paracentral and mesial frontal lobe. No cortical area was significantly more convoluted in healthy subjects relative to the WS subjects. On the lateral surfaces, the direction and pattern of gyrification asymmetries were similar in WS subjects and controls; posterior brain regions had greater gyrification in the left hemisphere, while anterior brain regions showed greater gyrification in the right hemisphere. On the medial surfaces, control subjects and WS individuals differed considerably with respect to the degree but also direction of gyrification asymmetry. Our findings confirm and extend previous studies measuring cortical complexity at the global whole-brain or hemispheric levels. The observed gyrification abnormalities in individuals with WS might be related to dysfunctions in neuronal circuits and consequently contribute to the distinct cognitive and behavioral profile accompanying the disorder.

  View details for DOI 10.1016/j.neuroimage.2006.06.018

  View details for Web of Science ID 000241209800007

  View details for PubMedID 16901723

• Autism and the development of face processing. Clinical neuroscience research Golarai, G., Grill-Spector, K., Reiss, A. L. 2006; 6 (3): 145-160

  Abstract

  Autism is a pervasive developmental condition, characterized by impairments in non-verbal communication, social relationships and stereotypical patterns of behavior. A large body of evidence suggests that several aspects of face processing are impaired in autism, including anomalies in gaze processing, memory for facial identity and recognition of facial expressions of emotion. In search of neural markers of anomalous face processing in autism, much interest has focused on a network of brain regions that are implicated in social cognition and face processing. In this review, we will focus on three such regions, namely the STS for its role in processing gaze and facial movements, the FFA in face detection and identification and the amygdala in processing facial expressions of emotion. Much evidence suggests that a better understanding of the normal development of these specialized regions is essential for discovering the neural bases of face processing anomalies in autism. Thus, we will also examine the available literature on the normal development of face processing. Key unknowns in this research area are the neuro-developmental processes, the role of experience and the interactions among components of the face processing system in shaping each of the specialized regions for processing faces during normal development and in autism.

  View details for PubMedID 18176635

• Autism and the development of face processing 85th Annual Conference of the Association-for-Reseach-in-Nervous-and-Mental-Disease Golarai, G., Grill-Spector, K., Reiss, A. L. ELSEVIER SCI LTD. 2006: 145–60

  Abstract

  Autism is a pervasive developmental condition, characterized by impairments in non-verbal communication, social relationships and stereotypical patterns of behavior. A large body of evidence suggests that several aspects of face processing are impaired in autism, including anomalies in gaze processing, memory for facial identity and recognition of facial expressions of emotion. In search of neural markers of anomalous face processing in autism, much interest has focused on a network of brain regions that are implicated in social cognition and face processing. In this review, we will focus on three such regions, namely the STS for its role in processing gaze and facial movements, the FFA in face detection and identification and the amygdala in processing facial expressions of emotion. Much evidence suggests that a better understanding of the normal development of these specialized regions is essential for discovering the neural bases of face processing anomalies in autism. Thus, we will also examine the available literature on the normal development of face processing. Key unknowns in this research area are the neuro-developmental processes, the role of experience and the interactions among components of the face processing system in shaping each of the specialized regions for processing faces during normal development and in autism.

  View details for DOI 10.1016/j.cnr.2006.08.001

  View details for Web of Science ID 000242486200006

  View details for PubMedCentralID PMC2174902

• Social escape behaviors in children with fragile X syndrome 30th Annual Meeting of the Association-for-Behavior-Analysis Hall, S., DeBernardis, M., Reiss, A. SPRINGER/PLENUM PUBLISHERS. 2006: 935–47

  Abstract

  Social escape behavior is a common behavioral feature of individuals with fragile X syndrome (fraX). In this observational study, we examined the effect of antecedent social and performance demands on problem behaviors in four conditions: face-to-face interview, silent reading, oral reading and a singing task. Results showed that problem behaviors were significantly more likely to occur during the interview and singing conditions. Higher levels of salivary cortisol were predictive of higher levels of fidgeting behavior and lower levels of eye contact in male participants. There were no associations between level of FMRP expression and social escape behaviors. These data suggest that specific antecedent biological and environmental factors evoke social escape behaviors in fragile X syndrome.

  View details for DOI 10.1007/s10803-006-0132-z

  View details for Web of Science ID 000241171600011

  View details for PubMedID 16897394

• The acquisition of stimulus equivalence in individuals with fragile X syndrome JOURNAL OF INTELLECTUAL DISABILITY RESEARCH Hall, S. S., DeBernardis, G. M., Reiss, A. L. 2006; 50: 643-651

  Abstract

  Few studies have employed stimulus equivalence procedures to teach individuals with intellectual disabilities (IDs) new skills. To date, no studies of stimulus equivalence have been conducted in individuals with fragile X syndrome (FXS), the most common known cause of inherited ID.Five adolescents with FXS were taught basic math and geography skills by using a computerized stimulus equivalence training programme administered over 2 days in 2-h sessions.Four of the five participants learned the math relations, with one participant demonstrating stimulus equivalence at post-test. Three of the five participants learned the geography relations, with all three of these participants demonstrating stimulus equivalence at post-test.These data indicate that computerized stimulus equivalence procedures, conducted in time-limited sessions, may help individuals with FXS learn new skills. Hypotheses concerning the failure of some participants to learn the training relations and to demonstrate stimulus equivalence at post-test are discussed.

  View details for DOI 10.1111/j.1365-2788.2006.00814.x

  View details for Web of Science ID 000239258100003

  View details for PubMedID 16901291

• To modulate or not to modulate: Differing results in uniquely shaped Williams syndrome brains NEUROIMAGE Eckert, M. A., Tenforde, A., Galaburda, A. M., Bellugi, U., Korenberg, J. R., Mills, D., Reiss, A. L. 2006; 32 (3): 1001-1007

  Abstract

  Voxel based morphometry (VBM) studies of Williams syndrome (WS) have demonstrated remarkably consistent findings of reduced posterior parietal gray matter compared to typical controls. Other WS VBM findings have been inconsistent, however. In particular, different findings have been reported for hypothalamus and orbitofrontal gray matter regions. We examined a sample of 8 WS and 9 control adults and show that the hypothalamus and orbitofrontal cortex results depend on whether the images undergo Jacobian modulation. Deformation based morphometry (DBM) analysis demonstrated that major brain shape differences between the groups accounted for the Jacobian modulated gray matter findings. These results indicate that cautious interpretations of modulated gray matter findings are warranted when there are gross shape and size differences between experimental groups. This study demonstrates the importance of methodological choices towards understanding a disorder like WS, but also highlights the consistency of parietal lobe, orbitofrontal, and midbrain findings for this disorder across methodologies, participants, and research groups.

  View details for DOI 10.1016/j.neuroimage.2006.05.014

  View details for Web of Science ID 000240470300003

  View details for PubMedID 16806978

• The neurobiology of Williams syndrome: Cascading influences of visual system impairment? CELLULAR AND MOLECULAR LIFE SCIENCES Eckert, M. A., Galaburda, A. M., Mills, D. L., Bellugi, U., Korenberg, J. R., Reiss, A. L. 2006; 63 (16): 1867-1875

  Abstract

  Williams syndrome (WS) is characterized by a unique pattern of cognitive, behavioral, and neurobiological findings that stem from a microdeletion of genes on chromosome 7. Visuospatial ability is particularly affected in WS and neurobiological studies of WS demonstrate atypical function and structure in posterior parietal, thalamic, and cerebellar regions that are important for performing space-based actions. This review summarizes the neurobiological findings in WS, and, based on these findings, we suggest that people with WS have a primary impairment in neural systems that support the performance of space-based actions. We also examine the question of whether impaired development of visual systems could affect the development of atypical social-emotional and language function in people with WS. Finally, we propose developmental explanations for the visual system impairments in WS. While hemizygosity for the transcription factor II-I gene family probably affects the development of visual systems, we also suggest that Lim-kinase 1 hemizygosity exacerbates the impairments in performing space-based actions.

  View details for DOI 10.1007/s00018-005-5553-x

  View details for Web of Science ID 000239928100006

  View details for PubMedID 16810457

• Chronological age, but not FMRP levels, predicts neuropsychological performance in girls with fragile X syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Lightbody, A. A., Hall, S. S., Reiss, A. L. 2006; 141B (5): 468-472

  Abstract

  The effect of FMRP levels and chronological age on executive functioning, visual-spatial abilities ,and verbal fluency tasks were examined in 46 school-age girls with fragile X syndrome (FXS). Results indicated that FMRP levels were not predictive of outcome on the neuropsychological tests but that performance on the executive functioning task tended to worsen with chronological age. This age effect was not observed on the tests of visual-spatial abilities or verbal fluency. These data indicate that relative deficits in executive functioning in girls with FXS become more pronounced with age. In contrast, the relative deficits in spatial and verbal abilities of these girls did not appear to increase with age, suggesting that these abilities may be spared.

  View details for DOI 10.1002/ajmg.b.30307

  View details for Web of Science ID 000238622300006

  View details for PubMedID 16741913

  View details for PubMedCentralID PMC2663575

• Selective alterations of white matter associated with visuospatial and sensorimotor dysfunction in Turner syndrome JOURNAL OF NEUROSCIENCE Holzapfel, M., Barnea-Goraly, N., Eckert, M. A., Kesler, S. R., Reiss, A. L. 2006; 26 (26): 7007-7013

  Abstract

  Turner syndrome (TS) is a neurogenetic disorder characterized by impaired spatial, numerical, and motor functioning but relatively spared verbal ability. Results from previous neuroimaging studies suggest that gray matter alterations in parietal and frontal regions may contribute to atypical visuospatial and executive functioning in TS. Recent findings in TS also indicate variations in the shape of parietal gyri and white matter microstructural anomalies of the temporal lobe. Diffusion tensor imaging and structural imaging methods were used to determine whether 10 females with TS and 10 age- and gender-matched control subjects exhibited differences in fractional anisotropy, white matter density, and local brain shape. Relative to controls, females with TS had lower fractional anisotropy (FA) values in the deep white matter of the left parietal-occipital region extending anteriorly along the superior longitudinal fasciculus into the deep white matter of the frontal lobe. In addition, decreased FA values were located bilaterally in the internal capsule extending into the globus pallidus and in the right prefrontal region. Voxel-based morphometry (VBM) analysis showed corresponding white matter density differences in the internal capsules and left centrum semiovale. Tensor-based morphometry analysis indicated that the FA and VBM results were not attributable to differences in the local shape of brain structures. Compared with controls, females with TS had increases in FA values and white matter density in language-related areas of the inferior parietal and temporal lobes. These complementary analyses provide evidence for alterations in white matter pathways that subserve affected and preserved cognitive functions in TS.

  View details for DOI 10.1523/JNEUROSCI.1764-06.2006

  View details for Web of Science ID 000238804400014

  View details for PubMedID 16807330

  View details for PubMedCentralID PMC3063771

• Social behavior and cortisol reactivity in children with fragile X syndrome JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Hessl, D., Glaser, B., Dyer-Friedman, J., Reiss, A. L. 2006; 47 (6): 602-610

  Abstract

  To examine the association between limbic-hypothalamic-pituitary-adrenal (L-HPA) axis reactivity and social behavior in children with fragile X syndrome (FXS).Salivary cortisol changes and concurrent anxiety-related behaviors consistent with the behavioral phenotype of FXS were measured in 90 children with the fragile X full mutation and their 90 unaffected siblings during a social challenge task in the home.Boys and girls with FXS demonstrated more gaze aversion, task avoidance, behavioral signs of distress, and poorer vocal quality than the unaffected siblings. Multiple regression analyses showed that after accounting for effects of IQ, gender, age, quality of the home environment, and basal cortisol level, cortisol reactivity to the task was significantly associated with social gaze in children with FXS. The most gaze-aversive children with FXS had cortisol reductions, whereas those with more eye contact demonstrated the most cortisol reactivity. Unaffected siblings demonstrated an opposite pattern in which less eye contact was associated with increased cortisol reactivity.Results of the study suggest a unique relation between abnormal gaze behavior and L-HPA mediated stress reactivity in FXS.

  View details for DOI 10.1111/j.1469-7610.2005.01556.x

  View details for Web of Science ID 000237636900009

  View details for PubMedID 16712637

• Parietal attentional system aberrations during target detection in adolescents with attention deficit hyperactivity disorder: Event-related fMRI evidence AMERICAN JOURNAL OF PSYCHIATRY Tamm, L., Menon, V., Reiss, A. L. 2006; 163 (6): 1033-1043

  Abstract

  Directed attention, the ability to allocate and direct attention toward a salient stimulus, is impaired in attention deficit hyperactivity disorder (ADHD). This construct is often assessed with target detection or oddball tasks, and individuals with ADHD perform poorly on such tasks. However, to date, the specific brain structures or neural mechanisms underlying target detection dysfunction in individuals with ADHD have not been identified. The authors' goal was to investigate neural correlates of target detection dysfunction in ADHD using event-related fMRI.Behavioral and brain activation data were collected while subjects performed a visual oddball task. Participants included 14 right-handed male adolescents with ADHD (combined type) and 12 typically developing age- and handedness-matched male comparison subjects.Individuals with ADHD made significantly more errors of commission than comparison subjects. Further, relative to comparison subjects, individuals with ADHD showed significantly less activation in the bilateral parietal lobes (including the superior parietal gyrus and supramarginal and angular gyri of the inferior parietal lobe), right precuneus, and thalamus.Adolescents with ADHD demonstrated significant impairments in their ability to direct and allocate attentional resources. These difficulties were associated with significant aberrations in the parietal attentional system, which is known to play a significant role in attention shifting and detecting specific or salient targets. Thus, dysfunction in the parietal attentional system may play a significant role in the behavioral phenotype of ADHD.

  View details for Web of Science ID 000237972300016

  View details for PubMedID 16741204

• Neurofunctional differences associated with arithmetic processing in turner syndrome CEREBRAL CORTEX Kesler, S. R., Menon, V., Reiss, A. L. 2006; 16 (6): 849-856

  Abstract

  Turner syndrome (TS) is a neurogenetic disorder characterized by the absence of one X chromosome in a phenotypic female. Individuals with TS are at risk for impairments in mathematics. We investigated the neural mechanisms underlying arithmetic processing in TS. Fifteen subjects with TS and 15 age-matched typically developing controls were scanned using functional MRI while they performed easy (two-operand) and difficult (three-operand) versions of an arithmetic processing task. Both groups activated fronto-parietal regions involved in arithmetic processing during the math tasks. Compared with controls, the TS group recruited additional neural resources in frontal and parietal regions during the easier, two-operand math task. During the more difficult three-operand task, individuals with TS demonstrated significantly less activation in frontal, parietal and subcortical regions than controls. However, the TS group's performance on both math tasks was comparable to controls. Individuals with TS demonstrate activation differences in fronto-parietal areas during arithmetic tasks compared with controls. They must recruit additional brain regions during a relatively easy task and demonstrate a potentially inefficient response to increased task difficulty compared with controls.

  View details for DOI 10.1093/cercor/bhj028

  View details for Web of Science ID 000237525900008

  View details for PubMedID 16135780

  View details for PubMedCentralID PMC3061626

• Symmetry of cortical folding abnormalities in Williams syndrome revealed by surface-based analyses JOURNAL OF NEUROSCIENCE Van Essen, D. C., Dierker, D., Snyder, A. Z., Raichle, M. E., Reiss, A. L., Korenberg, J. 2006; 26 (20): 5470-5483

  Abstract

  We analyzed folding abnormalities in the cerebral cortex of subjects with Williams syndrome (WS), a genetically based developmental disorder, using surface-based analyses applied to structural magnetic resonance imaging data. Surfaces generated from each individual hemisphere were registered to a common atlas target (the PALS-B12 atlas). Maps of sulcal depth (distance from the cerebral hull) were combined across individuals to generate maps of average sulcal depth for WS and control subjects, along with depth-difference maps and t-statistic maps that accounted for within-group variability. Significant structural abnormalities were identified in 33 locations, arranged as 16 bilaterally symmetric pairs plus a lateral temporal region in the right hemisphere. Discrete WS folding abnormalities extended across a broad swath from dorsoposterior to ventroanterior regions of each hemisphere, in cortical areas associated with multiple sensory modalities as well as regions implicated in cognitive and emotional behavior. Hemispheric asymmetry in the temporal cortex is reduced in WS compared with control subjects. These findings provide insights regarding possible developmental mechanisms that give rise to folding abnormalities and to the spectrum of behavioral characteristics associated with WS.

  View details for DOI 10.1523/JNEUROSCI.4154-05.2006

  View details for Web of Science ID 000237608400020

  View details for PubMedID 16707799

• Verbal declarative memory in pediatric PTSD: An fMRI study Carrion, V. G., Wagner, C., Garrett, A., Reiss, A. L. ELSEVIER SCIENCE INC. 2006: 248S

  View details for Web of Science ID 000236767301384

• Neurogenetic disorders as models for schizophrenia and anxiety disorders Reiss, A. L. ELSEVIER SCIENCE INC. 2006: 1S

  View details for Web of Science ID 000236767300005

• Effect of hemizygous COMT genotypes an cortical activation associated with response inhibition in 22q11.2 deletion syndrome Gothelf, D., Maeda, F., Hallmayer, J. F., Reiss, A. L. ELSEVIER SCIENCE INC. 2006: 188S

  View details for Web of Science ID 000236767301186

• Hippocampal volume, PTSD, and alcoholism in combat veterans AMERICAN JOURNAL OF PSYCHIATRY Woodward, S. H., Kaloupek, D. G., Streeter, C. C., Kimble, M. O., Reiss, A. L., Eliez, S., Wald, L. L., Renshaw, P. F., Frederick, B. B., Lane, B., Sheikh, J. I., Stegman, W. K., Kutter, C. J., Stewart, L. P., Prestel, R. S., Arsenault, N. J. 2006; 163 (4): 674-681

  Abstract

  Studies imposing rigorous control over lifetime alcohol intake have usually not found smaller hippocampal volumes in persons with posttraumatic stress disorder. Because the majority of negative studies have used adolescent samples, it has been suggested that chronicity is a necessary condition for such findings. To test the hypothesis that a smaller hippocampus in PTSD is unrelated to comorbid alcoholism or to chronicity, this study estimated hippocampal volume in a relatively large group (N=99) of combat veterans in which PTSD, lifetime alcohol abuse/dependence, and Vietnam versus Gulf War service were crossed. In subjects with histories of alcoholism, unadjusted hippocampal volume was 9% smaller in persons with PTSD than in those without PTSD. In nonalcoholic subjects, the PTSD-related difference in hippocampal volume was 3%. The failure to observe a strong association between PTSD and hippocampal volume in nonalcoholic subjects was not ascribable to younger age, reduced PTSD chronicity, or lower PTSD symptom severity. The possibility that smaller hippocampal volume is limited to groups in which PTSD is compounded by comorbid alcoholism is not necessarily incompatible with results suggesting a smaller hippocampus is predispositional to PTSD. Further examination of the role of alcoholism and other comorbid conditions in studies of brain structure and function in PTSD appears warranted.

  View details for Web of Science ID 000236541200020

  View details for PubMedID 16585443

• Mixed lateral preference in posttraumatic stress disorder JOURNAL OF NERVOUS AND MENTAL DISEASE Saltzman, K. M., Weems, C. F., Reiss, A. L., Carrion, V. G. 2006; 194 (2): 142-144

  Abstract

  Recent research indicates that adults with posttraumatic stress disorder (PTSD) have a higher incidence of mixed laterality with respect to handedness than the rest of the population. To test if this relationship also occurs early in life, we evaluated children with history of interpersonal trauma. Fifty-nine traumatized children were evaluated with the Clinician Administered PTSD Scale for Children and Adolescents and the Edinburgh Handedness Inventory. Forty matched healthy controls were used for comparison. Increased mixed laterality was found in all children exhibiting symptoms of PTSD when compared with healthy controls, and children who met DSM-IV diagnostic criteria for PTSD had more mixed laterality than the subthreshold traumatized group (F = 7.71; df = 2,96; p = 0.001). Within the entire traumatized group, there was a positive correlation between PTSD symptom severity and mixed laterality. Mixed laterality was positively associated with PTSD symptoms in traumatized children, suggesting that neurological abnormalities may be related to degree of PTSD symptom expression.

  View details for DOI 10.1097/01.nmd.0000198201.59824.37

  View details for PubMedID 16477196

• Use of 3-D cortical morphometry for mapping increased cortical gyrification and complexity in Williams syndrome IEEE International Symposium on Biomedical Imaging Tosun D, Reiss AL, Lee AD, Dutton RA, Geaga JA, Hayashi KM, Eckert MA, Bellugi U, Galaburda AM, Korenberg JR, Mills DL, Toga AW, Thompson PM 2006: 1172-1175
• A learning based algorithm for automatic extraction of the cortical sulci 9th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI 2006) Zheng, S., Tu, Z., Yuille, A. L., Reiss, A. L., Dutton, R. A., Lee, A. D., Galaburda, A. M., Thompson, P. M., Dinov, I., Toga, A. W. SPRINGER-VERLAG BERLIN. 2006: 695–703

  Abstract

  This paper presents a learning based method for automatic extraction of the major cortical sulci from MRI volumes or extracted surfaces. Instead of using a few pre-defined rules such as the mean curvature properties, to detect the major sulci, the algorithm learns a discriminative model by selecting and combining features from a large pool of candidates. We used the Probabilistic Boosting Tree algorithm to learn the model, which implicitly discovers and combines rules based on manually annotated sulci traced by neuroanatomists. The algorithm almost has no parameters to tune and is fast because of the adoption of integral volume and 3D Haar filters. For a given approximately registered MRI volume, the algorithm computes the probability of how likely it is that each voxel lies on a major sulcus curve. Dynamic programming is then applied to extract the curve based on the probability map and a shape prior. Because the algorithm can be applied to MRI volumes directly, there is no need to perform preprocessing such as tissue segmentation or mapping to a canonical space. The learning aspect makes the approach flexible and it also works on extracted cortical surfaces.

  View details for Web of Science ID 000241556300085

• Use of 3-D cortical morphometry for mapping increased cortical gyrification and complexity in Williams syndrome 3rd IEEE International Symposium on Biomedical Imaging Tosun, D., Reiss, A. L., Lee, A. D., Dutton, R. A., Hayashi, K. M., Bellugi, U., Galaburda, A. M., Korenberg, J. R., Mills, D. L., Toga, A. W., Thompson, P. M. IEEE. 2006: 1172–1175

  View details for Web of Science ID 000244446000296

• Regional differences of the prefrontal cortex in pediatric PTSD: an MRI study DEPRESSION AND ANXIETY Richert, K. A., Carrion, V. G., Karchemskiy, A., Reiss, A. L. 2006; 23 (1): 17-25

  Abstract

  Previous studies have revealed altered structural development of the frontal lobes and prefrontal cortex (PFC) in children with symptoms of posttraumatic stress disorder (PTSD). This study is the first to provide a detailed structural analysis of the PFC in children with and without PTSD symptoms. We compared gray and white matter volume in four subregions of the PFC between said groups, then explored whether volume was associated with PTSD symptom severity and functional impairment. PFC measurements were extracted from magnetic resonance imaging (MRI) data from a sample of 23 children (ages 7-14) with a history of trauma and symptoms of PTSD, who had undergone assessment for PTSD symptoms and functional impairment using the Child and Adolescent version of the Clinician-Administered PTSD Scale (CAPS-CA). These measurements were compared to data from an age-equivalent control group of 24 healthy children. Children with PTSD symptoms showed a significantly larger volume of gray matter in the delineated middle-inferior and ventral regions of the PFC than did control children. Decreased volume of gray matter in the dorsal PFC correlated with increased functional impairment scores. Results indicate that increased volume of the middle-inferior and ventral PFC may be associated with trauma and PTSD symptoms in children. Furthermore, the neuroanatomy of the dorsal PFC may influence the degree of functional impairment experienced by children with PTSD symptoms.

  View details for DOI 10.1002/da.20131

  View details for PubMedID 16247760

• A learning based algorithm for automatic extraction of the cortical sulci. Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention Zheng, S., Tu, Z., Yuille, A. L., Reiss, A. L., Dutton, R. A., Lee, A. D., Galaburda, A. M., Thompson, P. M., Dinov, I., Toga, A. W. 2006; 9: 695-703

  Abstract

  This paper presents a learning based method for automatic extraction of the major cortical sulci from MRI volumes or extracted surfaces. Instead of using a few pre-defined rules such as the mean curvature properties, to detect the major sulci, the algorithm learns a discriminative model by selecting and combining features from a large pool of candidates. We used the Probabilistic Boosting Tree algorithm to learn the model, which implicitly discovers and combines rules based on manually annotated sulci traced by neuroanatomists. The algorithm almost has no parameters to tune and is fast because of the adoption of integral volume and 3D Haar filters. For a given approximately registered MRI volume, the algorithm computes the probability of how likely it is that each voxel lies on a major sulcus curve. Dynamic programming is then applied to extract the curve based on the probability map and a shape prior. Because the algorithm can be applied to MRI volumes directly, there is no need to perform preprocessing such as tissue segmentation or mapping to a canonical space. The learning aspect makes the approach flexible and it also works on extracted cortical surfaces.

  View details for PubMedID 17354951

• Increased temporal lobe gyrification in preterm children NEUROPSYCHOLOGIA Kesler, S. R., Vohr, B., Schneider, K. C., Katz, K. H., Makuch, R. W., Reiss, A. L., Ment, L. R. 2006; 44 (3): 445-453

  Abstract

  Preterm birth often results in significant learning disability, and previous magnetic resonance imaging (MRI) studies of preterm children have demonstrated reduction in overall cortical tissue with particular vulnerability in the temporal lobe. We measured cortical gyrification in 73 preterm and 33 term control children at 8 years of age and correlated these findings with tests of language ability to determine the associations among preterm birth, neurodevelopment and functional outcome. Preterm children demonstrated significantly increased bilateral temporal lobe gyrification index compared to term controls. Left temporal gyrification index was significantly negatively correlated with left temporal lobe gray matter volume as well as reading recognition scores in the preterm group. Cortical development in the temporal lobe appears to be differentially vulnerable to preterm birth.

  View details for DOI 10.1016/j.neuropsychologia.2005.05.015

  View details for Web of Science ID 000235861600012

  View details for PubMedID 15985272

• White matter development during childhood and adolescence: A cross-sectional diffusion tensor imaging study CEREBRAL CORTEX Barnea-Goraly, N., Menon, V., Eckert, M., Tamm, L., Bammer, R., Karchemskiy, A., Dant, C. C., Reiss, A. L. 2005; 15 (12): 1848-1854

  Abstract

  Maturation of brain white matter pathways is an important factor in cognitive, behavioral, emotional and motor development during childhood and adolescence. In this study, we investigate white matter maturation as reflected by changes in anisotropy and white matter density with age. Thirty-four children and adolescents aged 6-19 years received diffusion-weighted magnetic resonance imaging scans. Among these, 30 children and adolescents also received high-resolution T1-weighed anatomical scans. A linear regression model was used to correlate fractional anisotropy (FA) values with age on a voxel-by-voxel basis. Within the regions that showed significant FA changes with age, a post hoc analysis was performed to investigate white matter density changes. With increasing age, FA values increased in prefrontal regions, in the internal capsule as well as in basal ganglia and thalamic pathways, the ventral visual pathways, and the corpus callosum. The posterior limb of the internal capsule, intrathalamic connections, and the corpus callosum showed the most significant overlaps between white matter density and FA changes with age. This study demonstrates that during childhood and adolescence, white matter anisotropy changes in brain regions that are important for attention, motor skills, cognitive ability, and memory. This typical developmental trajectory may be altered in individuals with disorders of development, cognition and behavior.

  View details for DOI 10.1093/cercor/bhi062

  View details for Web of Science ID 000233217300002

  View details for PubMedID 15758200

• Prefrontal-amygdalar abnormalities in pediatric bipolar disorder Chang, K. K., Garrett, A., Karchemskiy, A., Gallelli, K., Wagner, C., Howe, M., Reiss, A. NATURE PUBLISHING GROUP. 2005: S32–S33

  View details for Web of Science ID 000233442100093

• Prefrontal neurometabolite changes following lamotrigine treatment in adolescents with bipolar depression 44th Annual Meeting of the American-College-Neuropsychopharmacology Chang, K. K., Gallelli, K., Howe, M., Saxena, K., Wagner, C., Spielman, D., Reiss, A. NATURE PUBLISHING GROUP. 2005: S102–S103

  View details for Web of Science ID 000233442100277

• N-acetylaspartate levels in bipolar offspring with and at high-risk for bipolar disorder BIPOLAR DISORDERS Gallelli, K. A., Wagner, C. M., Karchemskiy, A., Howe, M., Spielman, D., Reiss, A., Chang, K. D. 2005; 7 (6): 589-597

  Abstract

  Studies have reported decreased N-acetylaspartate (NAA) in dorsolateral prefrontal cortex (DLPFC) of adults and children with bipolar disorder (BD), suggesting decreased neuronal density in this area. However, it is unclear if this finding represents neurodegeneration after or a trait marker present before BD onset. To address this question, we used proton magnetic resonance spectroscopy ((1)H-MRS) to compare DLPFC levels of NAA among bipolar offspring with early-onset BD, bipolar offspring with subsyndromal symptoms of BD and healthy children.Participants were 9-18 years old, and included 60 offspring of parents with bipolar I or II disorder (32 with BD and 28 with subsyndromal symptoms of BD), and 26 healthy controls. (1)H-MRS at 3 T was used to study 8-cm(3) voxels placed in left and right DLPFC.There were no significant group differences in mean right or left DLPFC NAA/Cr ratios. Exploratory analyses of additional metabolites (myoinositol, choline) also yielded no significant group differences. NAA/Cr ratios were not correlated with age, duration of illness, or exposure to lithium or valproate.Our findings suggest that DLPFC NAA/Cr ratios cannot be used as a trait marker for BD. Although we did not find decreased DLPFC NAA/Cr ratios in children and adolescents with BD, it is still possible that such levels begin to decrease after longer durations of illness into adulthood. Longitudinal neuroimaging studies of patients with BD accounting for developmental and treatment factors are needed to further clarify the neurodegenerative aspects of BD.

  View details for PubMedID 16403184

• Arithmetic ability and parietal alterations: A diffusion tensor imaging study in Velocardiofacial syndrome COGNITIVE BRAIN RESEARCH Barnea-Goraly, N., Eliez, S., Menon, V., Bammer, R., Reiss, A. L. 2005; 25 (3): 735-740

  Abstract

  Velocardiofacial syndrome (VCFS) is a congenital anomaly that causes somatic as well as cognitive and psychiatric impairments. Previous studies have found specific deficits in arithmetic abilities in subjects with VCFS. In this study, we investigated whether abnormalities in white matter pathways are correlated with reduced arithmetic ability. Nineteen individuals with VCFS aged 7-19 years received diffusion-weighted magnetic resonance imaging (MRI) scans. A linear regression model was used to correlate fractional anisotropy (FA) values with scores of the arithmetic subscale on the WISC/WAIS on a voxel-by-voxel basis, after covarying for any IQ- and age-related effects. There was a statistically significant positive correlation between the arithmetic score on the WISC/WAIS and FA values in white matter tracts adjacent to the left supramarginal and angular gyri, as well as along the left intraparietal sulcus. Inferior parietal lobe white matter structural aberrations may contribute to reduced arithmetic ability in VCFS.

  View details for DOI 10.1016/j.cogbrainres.2005.09.013

  View details for Web of Science ID 000234236500014

  View details for PubMedID 16260124

• Personality predicts activity in reward and emotional regions associated with humor PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Mobbs, D., Hagan, C. C., Azim, E., Menon, V., Reiss, A. L. 2005; 102 (45): 16502-16506

  Abstract

  Previous research and theory suggest that two stable personality dimensions, extroversion and neuroticism, differentially influence emotional reactivity to a variety of pleasurable phenomena. Here, we use event-related functional MRI to address the putative neural and behavioral associations between humor appreciation and the personality dimensions of introversion-extroversion and emotional stability-neuroticism. Our analysis showed extroversion to positively correlate with humor-driven blood oxygenation level-dependent signal in discrete regions of the right orbital frontal cortex, ventrolateral prefrontal cortex, and bilateral temporal cortices. Introversion correlated with increased activation in several regions, most prominently the bilateral amygdala. Although neuroticism did not positively correlate with any whole-brain activation, emotional stability (i.e., the inverse of neuroticism) correlated with increased activation in the mesocortical-mesolimbic reward circuitry encompassing the right orbital frontal cortex, caudate, and nucleus accumbens. Our findings tie together existing neurobiological studies of humor appreciation and are compatible with the notion that personality style plays a fundamental role in the neurobiological systems subserving humor appreciation.

  View details for DOI 10.1073/pnas.0408457102

  View details for Web of Science ID 000233283700067

  View details for PubMedID 16275930

  View details for PubMedCentralID PMC1277964

• Developmental changes in mental arithmetic: Evidence for increased functional specialization in the left inferior parietal cortex CEREBRAL CORTEX Rivera, S. M., Reiss, A. L., Eckert, M. A., Menon, V. 2005; 15 (11): 1779-1790

  Abstract

  Arithmetic reasoning is arguably one of the most important cognitive skills a child must master. Here we examine neurodevelopmental changes in mental arithmetic. Subjects (ages 8-19 years) viewed arithmetic equations and were asked to judge whether the results were correct or incorrect. During two-operand addition or subtraction trials, for which accuracy was comparable across age, older subjects showed greater activation in the left parietal cortex, along the supramarginal gyrus and adjoining anterior intra-parietal sulcus as well as the left lateral occipital temporal cortex. These age-related changes were not associated with alterations in gray matter density, and provide novel evidence for increased functional maturation with age. By contrast, younger subjects showed greater activation in the prefrontal cortex, including the dorsolateral and ventrolateral prefrontal cortex and the anterior cingulate cortex, suggesting that they require comparatively more working memory and attentional resources to achieve similar levels of mental arithmetic performance. Younger subjects also showed greater activation of the hippocampus and dorsal basal ganglia, reflecting the greater demands placed on both declarative and procedural memory systems. Our findings provide evidence for a process of increased functional specialization of the left inferior parietal cortex in mental arithmetic, a process that is accompanied by decreased dependence on memory and attentional resources with development.

  View details for DOI 10.1093/cercor/bhi055

  View details for Web of Science ID 000232595700014

  View details for PubMedID 15716474

• Maturation of medial temporal lobe response and connectivity during memory encoding COGNITIVE BRAIN RESEARCH Menon, V., Boyett-Anderson, J. M., Reiss, A. L. 2005; 25 (1): 379-385

  Abstract

  The medial temporal lobe (MTL) plays an important role in memory encoding. The development and maturation of MTL and other brain regions involved in memory encoding are, however, poorly understood. We used functional magnetic resonance imaging to examine activation and effective connectivity of the MTL in children and adolescents during encoding of outdoor visual scenes. Here, we show that MTL response decreases with age whereas its connectivity with the left dorsolateral prefrontal cortex (PFC) increases with age. Our findings provide evidence for dissociable maturation of local and distributed memory encoding processes involving the MTL and furthermore suggest that increased functional interactions between the MTL and the PFC may underlie the development of more effective memory encoding strategies.

  View details for DOI 10.1016/j.cogbrainres.2005.07.007

  View details for Web of Science ID 000232709600037

  View details for PubMedID 16122916

• Development of anxiety disorders in a traumatized pediatric population: A preliminary longitudinal evaluation CHILD ABUSE & NEGLECT Cortes, A. M., Saltzman, K. M., Weems, C. F., Regnault, H. P., Reiss, A. L., Carrion, V. G. 2005; 29 (8): 905-914

  Abstract

  The current study was conducted to determine if post-traumatic stress disorder (PTSD) symptomatology predicted later development of non-PTSD anxiety disorders in children and adolescents victimized by interpersonal trauma.Thirty-four children with a history of interpersonal trauma and no initial diagnosis of anxiety disorder participated in the study. Children were assessed at time one (T1) and then 12-18 months later at time two (T2). At T1, the Clinician Administered PTSD Scale for Children and Adolescents (CAPS-CA) and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL) were used to evaluate children's PTSD symptoms and comorbid non-PTSD anxiety disorder diagnosis. At T2, the CAPS-CA and the K-SADS-PL were repeated.The diagnosis of PTSD and PTSD symptoms in children exposed to interpersonal trauma at T1, particularly the symptoms associated with avoidance and constricted emotional expression (criteria C) as well as physiological hyperarousal (criteria D), predicted the development of other anxiety disorders at T2.Traumatized children with initial PTSD symptomatology may be at risk of later development of other anxiety disorders.

  View details for DOI 10.1016/j.chiabu.2004.12.010

  View details for Web of Science ID 000231777500005

  View details for PubMedID 16125233

• Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder 58th Annual Convention of the Society-of-Biological-Psychiatry Chang, K., Barnea-Goraly, N., Karchemskiy, A., Simeonova, D. I., Barnes, P., Ketter, T., Reiss, A. L. ELSEVIER SCIENCE INC. 2005: 197–203

  Abstract

  Morphometric magnetic resonance imaging (MRI) studies of pediatric bipolar disorder (BD) have not reported on gray matter volumes but have reported increased lateral ventricular size and presence of white matter hyperintensities (WMH). We studied gray matter volume, ventricular-to-brain ratios (VBR), and number of WMH in patients with familial, pediatric BD compared with control subjects.Twenty subjects with BD (aged 14.6 +/- 2.8 years; 4 female) according to the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia, each with a parent with BD, and 20 age-, gender-, and intelligence quotient-matched healthy control subjects (aged 14.1 +/- 2.8 years; 4 female) were scanned at 3 T. Most subjects were taking psychotropic medications. A high-resolution T1-weighted spoiled gradient echo three-dimensional MRI sequence was analyzed by BrainImage for volumetric measurements, and T2-weighted images were read by a neuroradiologist to determine presence of WMH.After covarying for age and total brain volume, there were no significant differences between subjects with BD and control subjects in volume of cerebral (p = .09) or prefrontal gray matter (p = .34). Subjects with BD did not have elevated numbers of WMH or greater VBR when compared with control subjects.Children and adolescents with familial BD do not seem to have decreased cerebral grey matter or increased numbers of WMH, dissimilar to findings in adults with BD. Gray matter decreases and development of WMH might be later sequelae of BD or unique to adult-onset BD.

  View details for DOI 10.1016/j.biopsych.2005.03.039

  View details for PubMedID 16084840

• Functional MRI of working memory in paediatric head injury BRAIN INJURY Williams, S. E., Rivera, S., Reiss, A. L. 2005; 19 (7): 549-553

  Abstract

  A case study examining the recovery of a 9 year old boy who sustained a severe head injury is reported. The subject sustained damage to the left parietal-occipital and right frontal-parietal regions. Structural and functional imaging and cognitive data were collected at the time of injury and 1 year post-injury. Cognitive assessment revealed improvement over time. Functional imaging at the time of injury revealed minimal activation in the right posterior temporal region. Imaging 1 year post-injury revealed increased activation in the right pre-frontal cortex, bilateral pre-motor cortex and bilateral posterior parietal cortex. This activation pattern is consistent with the performance of unaffected individuals on working memory tasks. These findings differ from those in the adult literature and suggest an alternative pattern of recovery of function in children.

  View details for DOI 10.1080/02699050400013576

  View details for Web of Science ID 000229622500010

  View details for PubMedID 16134743

• Reduced amygdalar gray matter volume in familial pediatric bipolar disorder 50th Annual Meeting of the American-Academy-of-Child-and-Adolescent-Psychiatry Chang, K., Karchemskiy, A., Barnea-Goraly, N., Garrett, A., Simeonova, D. I., Reiss, A. LIPPINCOTT WILLIAMS & WILKINS. 2005: 565–73

  Abstract

  Subcortical limbic structures have been proposed to be involved in the pathophysiology of adult and pediatric bipolar disorder (BD). We sought to study morphometric characteristics of these structures in pediatric subjects with familial BD compared with healthy controls.Twenty children and adolescents with BD I (mean age = 14.6 years, four females) and 20 healthy age, gender, and IQ-matched controls underwent high-resolution magnetic resonance imaging at 3 T. Patients were mostly euthymic and most were taking medications. Amygdala, hippocampus, thalamus, and caudate volumes were determined by manual tracings from researchers blinded to diagnosis. Analyses of covariance were performed, with total brain volume, age, and gender as covariates.No differences were found in the volumes of hippocampus, caudate, and thalamus between subjects with BD and controls. Subjects with BD had smaller volumes in the left and right amygdala, driven by reductions in gray matter volume. Exploratory analyses revealed that subjects with BD with past lithium or valproate exposure tended to have greater amygdalar gray matter volume than subjects with BD without such exposure.Children and adolescents with early-onset BD may have reduced amygdalar volumes, consistent with other studies in this population. Prolonged medication exposure to lithium or valproate may account for findings in adults with BD of increased amygdalar volume relative to controls.

  View details for DOI 10.1097/01.chi.0000159948.75136.0d

  View details for PubMedID 15908839

• Abnormal cortical complexity and thickness profiles mapped in Williams syndrome JOURNAL OF NEUROSCIENCE Thompson, P. M., Lee, A. D., Dutton, R. A., Geaga, J. A., Hayashi, K. M., Eckert, M. A., Bellugi, U., Galaburda, A. M., Korenberg, J. R., Mills, D. L., Toga, A. W., Reiss, A. L. 2005; 25 (16): 4146-4158

  Abstract

  We identified and mapped an anatomically localized failure of cortical maturation in Williams syndrome (WS), a genetic condition associated with deletion of approximately 20 contiguous genes on chromosome 7. Detailed three-dimensional (3D) maps of cortical thickness, based on magnetic resonance imaging (MRI) scans of 164 brain hemispheres, identified a delimited zone of right hemisphere perisylvian cortex that was thicker in WS than in matched controls, despite pervasive gray and white matter deficits and reduced total cerebral volumes. 3D cortical surface models were extracted from 82 T1-weighted brain MRI scans (256 x 192 x 124 volumes) of 42 subjects with genetically confirmed WS (mean +/- SD, 29.2 +/- 9.0 years of age; 19 males, 23 females) and 40 age-matched healthy controls (27.5 +/- 7.4 years of age; 16 males, 24 females). A cortical pattern-matching technique used 72 sulcal landmarks traced on each brain as anchors to align cortical thickness maps across subjects, build group average maps, and identify regions with altered cortical thickness in WS. Cortical models were remeshed in frequency space to compute their fractal dimension (surface complexity) for each hemisphere and lobe. Surface complexity was significantly increased in WS (p < 0.0015 and p < 0.0014 for left and right hemispheres, respectively) and correlated with temporoparietal gyrification differences, classified via Steinmetz criteria. In WS, cortical thickness was increased by 5-10% in a circumscribed right hemisphere perisylvian and inferior temporal zone (p < 0.002). Spatially extended cortical regions were identified with increased complexity and thickness; cortical thickness and complexity were also positively correlated in controls (p < 0.03). These findings visualize cortical zones with altered anatomy in WS, which merit additional study with techniques to assess function and connectivity.

  View details for DOI 10.1523/JNEUROSCI.0165-05.2005

  View details for Web of Science ID 000228542600018

  View details for PubMedID 15843618

• Relative sparing of primary auditory cortex in Williams Syndrome BRAIN RESEARCH Holinger, D. P., Bellugi, U., Mills, D. L., Korenberg, J. R., Reiss, A. L., Sherman, G. F., Galaburda, A. M. 2005; 1037 (1-2): 35-42

  Abstract

  Williams Syndrome (WS) is a neurodevelopment disorder associated with a hemizygous deletion on chromosome 7. WS is characterized with mental retardation, severe visual-spatial deficits, relative language preservation, and excellent facial recognition. Distinctive auditory features include musical ability, heightened sound sensitivity, and specific patterns of auditory evoked potentials. These features have led to the hypothesis that the dorsal forebrain is more affected than the ventral. Previously, we reported primary visual area 17 abnormalities in rostral striate cortex, a region contributing to the dorsal visual pathway. Based on the dorsal-ventral hypothesis, and language and auditory findings, we predicted a more normal histometric picture in auditory area 41. We used an optical dissector method to measure neurons in layers II-VI of area 41 in right and left hemispheres of the same 3 WS and 3 control brains used in the area 17 study. There was a hemisphere by diagnosis interaction in cell packing density (CPD) in layer IV and in cell size in layer III between WS and control brains. Post hoc analysis disclosed in control brains, but not WS, a layer IV left > right asymmetry in CPD, and a layer III left < right asymmetry in cell size. WS brains showed more large neurons bilaterally in layer II and in left layer VI. Histometric alterations in area 41 were less widespread than rostral visual cortex. Also, there was less asymmetry in the WS brain. We interpret layers II and VI differences as reflecting increased limbic connectivity in primary auditory cortex of WS.

  View details for DOI 10.1016/j.brainres.2004.11.038

  View details for Web of Science ID 000228251400005

  View details for PubMedID 15777750

• From research to practice: Teacher and pediatrician awareness of phenotypic traits in neurogenetic syndromes AMERICAN JOURNAL ON MENTAL RETARDATION Lee, T. H., Blasey, C. M., Dyer-Friedman, J., Glaser, B., Reiss, A. L., Eliez, S. 2005; 110 (2): 100-106

  Abstract

  Pediatricians' and teachers' knowledge of physical, cognitive, and behavioral features associated with three genetic syndromes were assessed and the effectiveness of information sources about these syndromes evaluated. The surveyed sample included 53 pediatricians and 69 teachers from Northern and Central California. Respondents demonstrated limited knowledge regarding the physical phenotype of fragile X syndrome and significantly less knowledge of velo-cardio-facial syndrome (VCFS). In the cognitive and behavioral domains, significantly more was known about Down and fragile X syndromes than VCFS. Pediatricians and teachers make critical treatment and education decisions for children with these syndromes and would benefit from continued professional development about these syndromes through conferences, professional/association publications, in-service teacher training, and journals.

  View details for Web of Science ID 000227920600003

  View details for PubMedID 15762820

• Evidence for superior parietal impairment in Williams syndrome NEUROLOGY Eckert, M. A., Hu, D., Eliez, S., Bellugi, U., Galaburda, A., Korenberg, J., Mills, D., Reiss, A. L. 2005; 64 (1): 152-153

  Abstract

  Parietal lobe impairment is hypothesized to contribute to the dramatic visual-spatial deficits in Williams syndrome (WS). The authors examined the superior and inferior parietal lobule in 17 patients with WS and 17 control female adults (CNLs). The right and left superior parietal lobule gray matter volumes were significantly smaller in patients with WS than in CNLs, even after controlling for total cerebral gray matter. Impaired superior parietal function could explain WS visual-spatial and visual-motor problems.

  View details for Web of Science ID 000226216000032

  View details for PubMedID 15642924

• The contribution of novel brain imaging techniques to understanding the neurobiology of mental retardation and developmental disabilities MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Gothelf, D., Furfaro, J. A., Penniman, L. C., Glover, G. H., Reiss, A. L. 2005; 11 (4): 331-339

  Abstract

  Studying the biological mechanisms underlying mental retardation and developmental disabilities (MR/DD) is a very complex task. This is due to the wide heterogeneity of etiologies and pathways that lead to MR/DD. Breakthroughs in genetics and molecular biology and the development of sophisticated brain imaging techniques during the last decades have facilitated the emergence of a field called Behavioral Neurogenetics. Behavioral Neurogenetics focuses on studying genetic diseases with known etiologies that are manifested by unique cognitive and behavioral phenotypes. In this review, we describe the principles of magnetic resonance imaging (MRI) techniques, including structural MRI, functional MRI, and diffusion tensor imaging (DTI), and how they are implemented in the study of Williams (WS), velocardiofacial (VCFS), and fragile X (FXS) syndromes. From WS we learn that dorsal stream abnormalities can be associated with visuospatial deficits; VCFS is a model for exploring the molecular and brain pathways that lead to psychiatric disorders for which subjects with MR/DD are at increased risk; and finally, findings from multimodal imaging techniques show that aberrant frontal-striatal connections are implicated in the executive function and attentional deficits of subjects with FXS. By deciphering the molecular pathways and brain structure and function associated with cognitive deficits, we will gain a better understanding of the pathophysiology of MR/DD, which will eventually make possible more specific treatments for this population.

  View details for DOI 10.1002/mrdd.20089

  View details for Web of Science ID 000232943600008

  View details for PubMedID 16240408

• Event-related fMRI evidence of frontotemporal involvement in aberrant response inhibition and task switching in attention-deficit/hlyperactivity disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Tamm, L., Menon, V., Ringel, J., Reiss, A. L. 2004; 43 (11): 1430-1440

  Abstract

  Response inhibition deficits are characteristic of individuals with attention-deficit/hyperactivity disorder (ADHD). Previous functional magnetic resonance imaging (fMRI) studies investigating the neural correlates of this dysfunction have used block designs, making it difficult to disentangle activation differences specifically related to response inhibition from activation differences related to subprocesses involved in task performance. The current study was designed to further enhance our understanding of this critical function in individuals with ADHD using event-related fMRI.Ten adolescent boys diagnosed with ADHD, combined type, and 12 typically developing controls completed a Go/NoGo task modified to control for novelty processing.The ADHD group made significantly more errors of omission and more errors of commission than the control group. Further, compared with controls, individuals with ADHD showed marked abnormalities in brain activation during response inhibition, including hypoactivation of the anterior/mid-cingulate cortex extending to the supplementary motor area and hyperactivation of the left temporal gyrus.The authors suggest that underactivation in frontal regions reflects core deficits in response/task-switching abilities for the ADHD group.

  View details for DOI 10.1097/01.chi.0000140452.51205.8d

  View details for Web of Science ID 000224630900021

  View details for PubMedID 15502603

• Voxel-based morphometry elucidates structural neuroanatomy of high-functioning autism and Asperger syndrome DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Kwon, H., Ow, A. W., Pedatella, K. E., Lotspeich, L. J., Reiss, A. L. 2004; 46 (11): 760-764

  Abstract

  Efforts to examine the structural neuroanatomy of autism by using traditional methods of imaging analysis have led to variable findings, often based on methodological differences in image acquisition and analysis. A voxel-based computational method of whole-brain anatomy allows examination of small patterns of tissue differences between groups. High-resolution structural magnetic resonance images were acquired for nine males with high-functioning autism (HFA; mean age 14y [SD3y 4mo]), 11 with Asperger syndrome (ASP; mean age 13y 6mo [SD2y 5mo]), and 13 comparison (COM) participants (mean age 13y 7mo [SD 3y 1mo]). Using statistical parametric mapping, we examined contrasts of gray matter differences between the groups. Males with HFA and ASP had a pattern of decreased gray matter density in the ventromedial regions of the temporal cortex in comparison with males from an age-matched comparison group. Examining contrasts revealed that the COM group had increased gray matter density compared with the ASP or combined HFA and ASP group in the right inferior temporal gyrus, entorhinal cortex, and rostral fusiform gyrus. The ASP group had less gray matter density in the body of the cingulate gyrus in comparison with either the COM or HFA group. The findings of decreased gray matter density in ventromedial aspects of the temporal cortex in individuals with HFA and ASP lends support to theories suggesting an involvement of these areas in the pathophysiology of autism, particularly in the integration of visual stimuli and affective information.

  View details for DOI 10.1017/S0012162204001306

  View details for Web of Science ID 000225066000007

  View details for PubMedID 15540637

• Volumetric analysis of regional cerebral development in preterm children PEDIATRIC NEUROLOGY Kesler, S. R., Ment, L. R., Vohr, B., Pajot, S. K., Schneider, K. C., Katz, K. H., Ebbitt, T. B., Duncan, C. C., Makuch, R. W., Reiss, A. L. 2004; 31 (5): 318-325

  Abstract

  Preterm birth is frequently associated with both neuropathologic and cognitive sequelae. This study examined cortical lobe, subcortical, and lateral ventricle development in association with perinatal variables and cognitive outcome. High-resolution volumetric magnetic resonance imaging scans were acquired and quantified using advanced image processing techniques. Seventy-three preterm and 33 term control children ages 7.3-11.4 years were included in the study. Results indicated disproportionately enlarged parietal and frontal gray matter, occipital horn, and ventricular body, as well as reduced temporal and subcortical gray volumes in preterm children compared with control subjects. Birth weight was negatively correlated with parietal and frontal gray, as well as occipital horn volumes. Intraventricular hemorrhage was associated with reduced subcortical gray matter. Ventricular cerebrospinal fluid was negatively correlated with subcortical gray matter volumes but not with white matter volumes. Maternal education was the strongest predictor of cognitive function in the preterm group. Preterm birth appears to be associated with disorganized cortical development, possibly involving disrupted synaptic pruning and neural migration. Lower birth weight and the presence of intraventricular hemorrhage may increase the risk for neuroanatomic abnormality.

  View details for DOI 10.1016/j.pediatrneurol.2004.06.008

  View details for Web of Science ID 000225313400002

  View details for PubMedID 15519112

  View details for PubMedCentralID PMC3061618

• A volumetric study of parietal lobe subregions in Turner syndrome DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Brown, W. E., Kesler, S. R., Eliez, S., Warsofsky, I. S., Haberecht, M., Reiss, A. L. 2004; 46 (9): 607-609

  Abstract

  Turner syndrome, a genetic disorder that results from the complete or partial absence of an X chromosome in females, has been associated with specific impairment in visuospatial cognition. Previous studies have demonstrated a relationship between parietal lobe abnormalities and visuospatial deficits in Turner syndrome. We used high-resolution magnetic resonance imaging to measure parietal lobe subdivisions in 14 participants with Turner syndrome (mean age 13 years 5 months, SD 5 years) and 14 age-matched controls (mean age 13 years 5 months, SD 4 years 7 months) to localize neuroanatomical variations more closely. Scans were acquired and analyzed for 14 females with Turner syndrome. Analyses of variance were used to investigate differences in regional parietal lobes. Females with Turner syndrome showed a bilateral parietal lobe reduction, specifically in the superior parietal and postcentral gyri. Full-scale IQ scores were significantly positively correlated with postcentral tissue volume in the Turner syndrome group. Structural differences in the parietal lobe are localized specifically to the anterior and superior parietal lobe and might be related to the visuospatial and visuomotor deficits associated with Turner syndrome.

  View details for DOI 10.1017/S0012162204001021

  View details for PubMedID 15344520

• Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder - A functional magnetic resonance imaging investigation 49th Annual Meeting of the American-Academy-of-Child-and-Adolescent-Psychiatry Chang, K., Adleman, N. E., Dienes, K., Simeonova, D. I., Menon, V., Reiss, A. AMER MEDICAL ASSOC. 2004: 781–92

  Abstract

  The neurobiological features of pediatric bipolar disorder (BD) are largely unknown. Children and adolescents with BD may be important to study with functional neuroimaging techniques because of their unique status of early-onset BD and high familial loading for the disorder. Neuroimaging studies of adults with BD have implicated the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in the development of this disorder.To study children and adolescents with BD via functional magnetic resonance imaging using cognitive and affective tasks and to examine possible abnormalities in the DLPFC and ACC, as well as selected subcortical areas, in pediatric familial BD.We evaluated 12 male subjects aged 9 to 18 years with BD who had at least 1 parent with BD as well as 10 age- and IQ-matched healthy male controls. Stimulants were discontinued for at least 24 hours; other medications were continued. Subjects underwent functional magnetic resonance imaging at 3 T while performing a 2-back visuospatial working memory task and an affective task involving the visualization of positively, neutrally, or negatively valenced pictures.An academic referral setting, drawing from the Bay Area of San Francisco, Calif.Compared with controls, for the visuospatial working memory task, subjects with BD had greater activation in several areas including the bilateral ACC, left putamen, left thalamus, left DLPFC, and right inferior frontal gyrus. Controls had greater activation in the cerebellar vermis. In viewing negatively valenced pictures, subjects with BD had greater activation in the bilateral DLPFC, inferior frontal gyrus, and right insula. Controls had greater activation in the right posterior cingulate gyrus. For positively valenced pictures, subjects with BD had greater activation in the bilateral caudate and thalamus, left middle/superior frontal gyrus, and left ACC, whereas controls had no areas of greater activation.Children and adolescents with BD may have underlying abnormalities in the regulation of prefrontal-subcortical circuits. Further functional magnetic resonance imaging studies of attention and mood with greater sample sizes are needed.

  View details for PubMedID 15289277

• Sex differences in cerebral volumes of 8-year-olds born preterm JOURNAL OF PEDIATRICS Reiss, A. L., Kesler, S. R., Vohr, B., Duncan, C. C., Katz, K. H., Pajot, S., Schneider, K. C., Makuch, R. W., Ment, L. R. 2004; 145 (2): 242-249

  Abstract

  We investigate sex-associated effects of preterm birth on cerebral gray matter (GM) and white matter (WM) volumes. Preterm children (n=65) and 31 healthy, term control children had usable magnetic resonance imaging (MRI) data acquired at 8 years of age. Both GM and WM volumes were significantly reduced in the preterm group compared with controls. However, only males with preterm birth had significantly reduced WM compared with term males (P=.021), whereas WM volumes were equivalent in the female groups. Lower birth weight was associated with reduced WM in both boys and girls with preterm birth, whereas intraventricular hemorrhage (IVH) was associated with reduced GM in girls only. Positive correlations between GM and cognitive outcome were observed in girls with preterm birth but not boys. We conclude that preterm birth has a significant impact on brain development with increased risk for smaller GM and WM cerebral volumes. Males appear particularly vulnerable to adverse effects of preterm birth on WM development. However, girls with preterm birth show stronger correlations between neuro-anatomical variables and both neonatal risk factors and cognitive outcome, compared with boys. These findings indicate that the sex of the very preterm newborn influences the mechanisms by which the developing brain is affected.

  View details for DOI 10.1016/j.jpeds.2004.04.031

  View details for Web of Science ID 000223406200024

  View details for PubMedID 15289777

• Reduced basal forebrain and hippocampal activation during memory encoding in girls with fragile X syndrome NEUROREPORT Greicius, M. D., Boyett-Anderson, J. M., Menon, V., Reiss, A. L. 2004; 15 (10): 1579-1583

  Abstract

  Fragile X syndrome (FraX), the most common heritable cause of developmental disability, is associated with IQ, memory, and visuospatial processing deficits. The fragile X gene (FMR1) is prominently transcribed in two regions critical to memory encoding and attention: the hippocampus and the basal forebrain. To probe functional MRI activation abnormalities associated with the disorder, girls with FraX and age-matched, normally-developing girls were scanned during a test of visual memory encoding. While there were considerable similarities in activation patterns between the two groups, the girls with FraX showed significantly less activation in the hippocampus and the basal forebrain. This is the first study, to our knowledge, demonstrating functional deficits in FraX subjects in brain regions known to have the highest FMR1 transcription.

  View details for DOI 10.1097/01.wnr.0000134472.44362.be

  View details for Web of Science ID 000225140700010

  View details for PubMedID 15232287

• The amygdala is enlarged in children but not adolescents with autism; The hippocampus is enlarged at all ages JOURNAL OF NEUROSCIENCE Schumann, C. M., Hamstra, J., Goodlin-Jones, B. L., Lotspeich, L. J., Kwon, H., Buonocore, M. H., Lammers, C. R., Reiss, A. L., Amaral, D. G. 2004; 24 (28): 6392-6401

  Abstract

  Autism is a neurodevelopmental disorder characterized by impairments in reciprocal social interaction, deficits in verbal and nonverbal communication, and a restricted repertoire of activities or interests. We performed a magnetic resonance imaging study to better define the neuropathology of autistic spectrum disorders. Here we report findings on the amygdala and the hippocampal formation. Borders of the amygdala, hippocampus, and cerebrum were defined, and their volumes were measured in male children (7.5-18.5 years of age) in four diagnostic groups: autism with mental retardation, autism without mental retardation, Asperger syndrome, and age-matched typically developing controls. Although there were no differences between groups in terms of total cerebral volume, children with autism (7.5-12.5 years of age) had larger right and left amygdala volumes than control children. There were no differences in amygdala volume between the adolescent groups (12.75-18.5 years of age). Interestingly, the amygdala in typically developing children increases substantially in volume from 7.5 to 18.5 years of age. Thus, the amygdala in children with autism is initially larger, but does not undergo the age-related increase observed in typically developing children. Children with autism, with and without mental retardation, also had a larger right hippocampal volume than typically developing controls, even after controlling for total cerebral volume. Children with autism but without mental retardation also had a larger left hippocampal volume relative to controls. These cross-sectional findings indicate an abnormal program of early amygdala development in autism and an abnormal pattern of hippocampal development that persists through adolescence. The cause of amygdala and hippocampal abnormalities in autism is currently unknown.

  View details for DOI 10.1523/JNEUROSCI.1297-04.2004

  View details for Web of Science ID 000222650000018

  View details for PubMedID 15254095

• Anomalous brain activation during face and gaze processing in Williams syndrome NEUROLOGY Mobbs, D., Garrett, A. S., Menon, V., Rose, F. E., Bellugi, U., Reiss, A. L. 2004; 62 (11): 2070-2076

  Abstract

  To investigate the discrete neural systems that underlie relatively preserved face processing skills in Williams syndrome (WS).The authors compared face and eye-gaze direction processing abilities in 11 clinically and genetically diagnosed WS subjects with 11 healthy age- and sex-matched controls, using functional MRI (fMRI).Compared to controls, WS subjects showed a strong trend toward being less accurate in determining the direction of gaze and had significantly longer response latencies. Significant increases in activation were observed in the right fusiform gyrus (FuG) and several frontal and temporal regions for the WS group. By comparison, controls showed activation in the bilateral FuG, occipital, and temporal lobes. Between-group analysis showed WS subjects to have more extensive activation in the right inferior, superior, and medial frontal gyri, anterior cingulate, and several subcortical regions encompassing the anterior thalamus and caudate. Conversely, controls had greater activation in the primary and secondary visual cortices.The observed patterns of activation in WS subjects suggest a preservation of neural functioning within frontal and temporal regions, presumably resulting from task difficulty or compensatory mechanisms. Persons with WS may possess impairments in visual cortical regions, possibly disrupting global-coherence and visuospatial aspects of face and gaze processing.

  View details for Web of Science ID 000221890400030

  View details for PubMedID 15184616

• An experiment of nature: Brain anatomy parallels cognition and behavior in Williams syndrome JOURNAL OF NEUROSCIENCE Reiss, A. L., Eckert, M. A., Rose, F. E., Karchemskiy, A., Kesler, S., Chang, M., Reynolds, M. F., Kwon, H., Galaburda, A. 2004; 24 (21): 5009-5015

  Abstract

  Williams syndrome (WS) is a neurogenetic-neurodevelopmental disorder characterized by a highly variable and enigmatic profile of cognitive and behavioral features. Relative to overall intellect, affected individuals demonstrate disproportionately severe visual-spatial deficits and enhanced emotionality and face processing. In this study, high-resolution magnetic resonance imaging data were collected from 43 individuals with WS and 40 age- and gender-matched healthy controls. Given the distinct cognitive-behavioral dissociations associated with this disorder, we hypothesized that neuroanatomical integrity in WS would be diminished most in regions comprising the visual-spatial system and most "preserved" or even augmented in regions involved in emotion and face processing. Both volumetric analysis and voxel-based morphometry were used to provide convergent approaches for detecting the hypothesized WS neuroanatomical profile. After adjusting for overall brain volume, participants with WS showed reduced thalamic and occipital lobe gray matter volumes and reduced gray matter density in subcortical and cortical regions comprising the human visual-spatial system compared with controls. The WS group also showed disproportionate increases in volume and gray matter density in several areas known to participate in emotion and face processing, including the amygdala, orbital and medial prefrontal cortices, anterior cingulate, insular cortex, and superior temporal gyrus. These findings point to specific neuroanatomical correlates for the unique topography of cognitive and behavioral features associated with this disorder.

  View details for DOI 10.1523/JNEUROSCI.5272-03.2004

  View details for Web of Science ID 000221654400013

  View details for PubMedID 15163693

  View details for PubMedCentralID PMC3061615

• Cognitive correlates of white matter growth and stress hormones in female squirrel monkey adults JOURNAL OF NEUROSCIENCE Lyons, D. M., Yang, C., Eliez, S., Reiss, A. L., Schatzberg, A. F. 2004; 24 (14): 3655-3662

  Abstract

  Neurobiological studies of stress and cognitive aging seldom consider white matter despite indications that complex brain processes depend on networks and white matter interconnections. Frontal and temporal lobe white matter volumes increase throughout midlife adulthood in humans, and this aspect of aging is thought to enhance distributed brain functions. Here, we examine spatial learning and memory, neuroendocrine responses to psychological stress, and regional volumes of gray and white matter determined by magnetic resonance imaging in 31 female squirrel monkeys between the ages of 5 and 17 years. This period of lifespan development corresponds to the years 18-60 in humans. Older adults responded to stress with greater increases in plasma levels of adrenocorticotropic hormone and modest reductions in glucocorticoid feedback sensitivity relative to young adults. Learning and memory did not differ with age during the initial cognitive test sessions, but older adults more often failed to inhibit the initial learned response after subsequent spatial reversals. Impaired cognitive response inhibition correlated with the expansion of white matter volume statistically controlling for age, stress hormones, gray matter, and CSF volumes. These results indicate that instead of enhancing cognitive control during midlife adulthood, white matter volume expansion contributes to aspects of cognitive decline. Cellular and molecular research combined with brain imaging is needed to determine the basis of white matter growth in adults, elucidate its functions during lifespan development, and provide potential new targets for therapies aimed at maintaining in humans cognitive vitality with aging.

  View details for DOI 10.1523/JNEUROSCI.0324-04.2004

  View details for Web of Science ID 000220715400022

  View details for PubMedID 15071114

• Emotional attribution in high-functioning individuals with autistic spectrum disorder: A functional imaging study JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Piggot, J., Kwon, H., Mobbs, D., Blasey, C., Lotspeich, L., Menon, V., Bookheimer, S., Reiss, A. L. 2004; 43 (4): 473-480

  Abstract

  To determine whether expertise in the attribution of emotion from basic facial expressions in high-functioning individuals with autistic spectrum disorder (ASD) is supported by the amygdala, fusiform, and prefrontal regions of interest (ROI) and is comparable to that of typically developing individuals.Functional magnetic resonance imaging scans were acquired from 14 males with ASD and 10 matched adolescent controls while performing emotion match (EM) (perceptual), emotion label (EL) (linguistic), and control tasks. Accuracy, response time, and average activation were measured for each ROI.There was no significant difference in accuracy, response time, or ROI activation between groups performing the EL task. The ASD group was as accurate as the control group performing the EM task but had a significantly longer response time and lower average fusiform activation.Expertise in the attribution of emotion from basic facial expressions was task-dependent in the high-functioning ASD group. The hypothesis that the high-functioning ASD group would be less expert and would have reduced fusiform activation was supported in the perceptual task but not the linguistic task. The reduced fusiform activation in the perceptual task was not explained by reduced expertise; it is therefore concluded that reduced fusiform activation is associated with the diagnosis of ASD.

  View details for DOI 10.1097/01.chi.0000111363.94169.37

  View details for Web of Science ID 000220384300014

  View details for PubMedID 15187808

• Default-mode network activity distinguishes Alzheimer's disease from healthy aging: Evidence from functional MRI PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Greicius, M. D., Srivastava, G., Reiss, A. L., Menon, V. 2004; 101 (13): 4637-4642

  Abstract

  Recent functional imaging studies have revealed coactivation in a distributed network of cortical regions that characterizes the resting state, or default mode, of the human brain. Among the brain regions implicated in this network, several, including the posterior cingulate cortex and inferior parietal lobes, have also shown decreased metabolism early in the course of Alzheimer's disease (AD). We reasoned that default-mode network activity might therefore be abnormal in AD. To test this hypothesis, we used independent component analysis to isolate the network in a group of 13 subjects with mild AD and in a group of 13 age-matched elderly controls as they performed a simple sensory-motor processing task. Three important findings are reported. Prominent coactivation of the hippocampus, detected in all groups, suggests that the default-mode network is closely involved with episodic memory processing. The AD group showed decreased resting-state activity in the posterior cingulate and hippocampus, suggesting that disrupted connectivity between these two regions accounts for the posterior cingulate hypometabolism commonly detected in positron emission tomography studies of early AD. Finally, a goodness-of-fit analysis applied at the individual subject level suggests that activity in the default-mode network may ultimately prove a sensitive and specific biomarker for incipient AD.

  View details for DOI 10.1073/pnas.0308627101

  View details for Web of Science ID 000220648700056

  View details for PubMedID 15070770

  View details for PubMedCentralID PMC384799

• Frontostriatal deficits in fragile X syndrome: Relation to FMR1 gene expression PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Menon, V., Leroux, J., White, C. D., Reiss, A. L. 2004; 101 (10): 3615-3620

  Abstract

  Fragile X syndrome (fraX) is the most common known cause of inherited developmental disability. fraX is associated with a CGG expansion in the FMR1 gene on the long arm of the X chromosome. Behavioral deficits, including problems with impulse control and distractibility, are common in fraX. We used functional brain imaging with a Go/NoGo task to examine the neural substrates of response inhibition in females with fraX (ages 10-22) and age- and gender-matched typically developing subjects. Although subjects with fraX had significantly lower IQ scores, as a group their performance on the Go/NoGo task was equivalent to that of the typically developing group. However, females with fraX showed abnormal activation patterns in several cortical and subcortical regions, with significantly reduced activation in the supplementary motor area, anterior cingulate and midcingulate cortex, basal ganglia, and hippocampus. An important finding of our study is that neural responses in the right ventrolateral prefrontal cortex (PFC) and the left and right striatum were correlated with the level of FMR1 gene expression. Our findings support the hypothesis that frontostriatal regions typically associated with response inhibition are dysfunctional in females with fraX. In addition to task-related activation deficits, reduced levels of "deactivation" were observed in the ventromedial PFC, and, furthermore, these reductions were correlated with the level of FMR1 gene expression. The ventromedial PFC is a key node in a "default mode" network that monitors mental and physiological states; we suggest that self-monitoring processes may be aberrant in fraX.

  View details for DOI 10.1073/pnas.0304544101

  View details for Web of Science ID 000220163800053

  View details for PubMedID 14993603

  View details for PubMedCentralID PMC373511

• Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism AMERICAN JOURNAL OF PSYCHIATRY Kates, W. R., Burnette, C. P., Eliez, S., Strunge, L. A., Kaplan, D., Landa, R., Reiss, A. L., Pearlson, G. D. 2004; 161 (3): 539-546

  Abstract

  The broader autism phenotype includes relatives of individuals with autism who display social and language deficits that are qualitatively similar to those of autism but less severe. In previous studies of monozygotic twins discordant for autism, more than 75% of the twins without autism displayed the broader phenotype. Differences in neuroanatomy between discordant monozygotic twins might be associated with the narrow and broader behavioral phenotypes. The authors examined the relationship of twin pair differences in clinical phenotype to differences in neuroanatomic phenotype.The subjects were 16 monozygotic twin pairs between the ages of 5 and 14 years and 16 matched singleton comparison subjects. Seven twin pairs were clinically concordant and nine twin pairs were clinically discordant for strictly defined autism. After magnetic resonance imaging, a semiautomated procedure was applied to images in which the brain tissue was subdivided into neurofunctional regions and segmented into gray, white, and ventricular compartments.Both the concordant and discordant twin pairs exhibited concordance in cerebral gray and white matter volumes. However, only the clinically concordant pairs exhibited concordance in cerebellar gray and white matter volumes. Within the discordant twin pairs, both the twins with autism and their co-twins exhibited frontal, temporal, and occipital white matter volumes that were lower than those of the comparison subjects.These findings support the role and the limits of genetic liability in autism. Continuing to clarify the neuroanatomic pathways in autistic spectrum disorders could illuminate the etiology of autism and, ultimately, contribute to treatments.

  View details for Web of Science ID 000221276000021

  View details for PubMedID 14992981

• 22q11 deletion syndrome in childhood onset schizophrenia: an update MOLECULAR PSYCHIATRY Sporn, A., Addington, A., Reiss, A. L., Dean, M., Gogtay, N., Potocnik, U., Greenstein, D., Hallmayer, J., Gochman, P., Lenane, M., Baker, N., Tossell, J., Rapoport, J. L. 2004; 9 (3): 225-226

  View details for DOI 10.1038/sj.mp.4001477

  View details for Web of Science ID 000220129200001

  View details for PubMedID 14699434

• Here's looking at you, kid - Neural systems underlying face and gaze processing in fragile X syndrome ARCHIVES OF GENERAL PSYCHIATRY Garrett, A. S., Menon, V., MacKenzie, K., Reiss, A. L. 2004; 61 (3): 281-288

  Abstract

  Children with fragile X syndrome (fraX) are at risk for manifesting abnormalities in social function that overlap with features of autism and social anxiety disorder. In this study, we analyzed brain activation in response to face and gaze stimuli to better understand neural functioning associated with social perception in fraX.Eleven female subjects with fraX, aged 10 to 22 years, were compared with age-matched female control subjects. Photographs of forward-facing and angled faces, each having direct and averted gaze (4 types of stimuli), were presented in an event-related design during functional magnetic resonance imaging. Subjects were instructed to determine the direction of gaze for each photograph. Activation in brain regions known to respond to face and gaze stimuli, the fusiform gyrus (FG) and superior temporal sulcus (STS), were compared between groups to isolate neural abnormalities in the perception of directed social stimuli.The fraX subjects had decreased accuracy in determining the direction of gaze compared with controls. Region of interest analysis of the FG revealed a significant interaction between diagnostic group and face orientation. Specifically, control subjects had greater FG activation to forward than to angled faces, whereas fraX subjects had no difference in FG activation to forward and angled faces. Controls showed greater left STS activation to all stimuli compared with fraX subjects.Our results suggest that gaze aversion in fraX subjects is related to decreased specialization of the FG in the perception of face orientation. Decreased STS activation in fraX suggests aberrant processing of gaze. These data suggest that gaze aversion in fraX may be related to dysfunction of neural systems underlying both face and gaze processing.

  View details for Web of Science ID 000220064800009

  View details for PubMedID 14993116

• Investigation of neuroanatomical differences between autism and Asperger syndrome ARCHIVES OF GENERAL PSYCHIATRY Lotspeich, L., Kwon, H., Schumann, C. M., Fryer, S. L., Goodlin-Jones, B. L., Buonocore, M. H., Lammers, C. R., AMARAL, D. G., Reiss, A. L. 2004; 61 (3): 291-298

  Abstract

  Autism and Asperger syndrome (ASP) are neurobiological conditions with overlapping behavioral symptoms and of unknown etiologies. Results from previous autism neuroimaging studies have been difficult to replicate, possibly owing to site differences in subject samples, scanning procedures, and image-processing methods. We sought (1) to determine whether low-functioning autism (LFA; IQ<70), high-functioning autism (HFA; IQ>or=70), and ASP constitute distinct biological entities as evidenced by neuroanatomical measures, and (2) to assess for intersite differences.Case-control study examining coronally oriented 124-section spoiled gradient echo images acquired on 3 magnetic resonance imaging (MRI) systems, and processed by BrainImage 5.X. Participants were recruited and underwent scanning at 2 academic medicine departments. Participants included 4 age-matched groups of volunteer boys aged 7.8 to 17.9 years (13 patients with LFA, 18 with HFA, 21 with ASP, and 21 control subjects), and 3 volunteer adults for neuroimaging reliability. Main outcome measures included volumetric measures of total, white, and gray matter for cerebral and cerebellar tissues.Intersite differences were seen for subject age, IQ, and cerebellum measures. Cerebral gray matter volume was enlarged in both HFA and LFA compared with controls (P =.009 and P =.04, respectively). Cerebral gray matter volume in ASP was intermediate between that of HFA and controls, but nonsignificant. Exploratory analyses revealed a negative correlation between cerebral gray matter volume and performance IQ within HFA but not ASP. A positive correlation between cerebral white matter volume and performance IQ was observed within ASP but not HFA.Lack of replication between previous autism MRI studies could be due to intersite differences in MRI systems and subjects' age and IQ. Cerebral gray tissue findings suggest that ASP is on the mild end of the autism spectrum. However, exploratory assessments of brain-IQ relationships reveal differences between HFA and ASP, indicating that these conditions may be neurodevelopmentally different when patterns of multiple measures are examined. Further investigations of brain-behavior relationships are indicated to confirm these findings.

  View details for Web of Science ID 000220064800010

  View details for PubMedID 14993117

• White matter structure in autism: Preliminary evidence from diffusion tensor imaging BIOLOGICAL PSYCHIATRY Barnea-Goraly, N., Kwon, H., Menon, V., Eliez, S., Lotspeich, L., Reiss, A. L. 2004; 55 (3): 323-326

  Abstract

  Individuals with autism have severe difficulties in social communication and relationships. Prior studies have suggested that abnormal connections between brain regions important for social cognition may contribute to the social deficits seen in autism.In this study, we used diffusion tensor imaging to investigate white matter structure in seven male children and adolescents with autism and nine age-, gender-, and IQ-matched control subjects.Reduced fractional anisotropy (FA) values were observed in white matter adjacent to the ventromedial prefrontal cortices and in the anterior cingulate gyri as well as in the temporoparietal junctions. Additional clusters of reduced FA values were seen adjacent to the superior temporal sulcus bilaterally, in the temporal lobes approaching the amygdala bilaterally, in occipitotemporal tracts, and in the corpus callosum.Disruption of white matter tracts between regions implicated in social functioning may contribute to impaired social cognition in autism.

  View details for DOI 10.1016/j.biopsych.2003.10.022

  View details for Web of Science ID 000188434000019

  View details for PubMedID 14744477

• Functional neuroanatomy of spatial orientation processing in Turner syndrome CEREBRAL CORTEX Kesler, S. R., Haberecht, M. F., Menon, V., Warsofsky, I. S., Dyer-Friedman, J., Neely, E. K., Reiss, A. L. 2004; 14 (2): 174-180

  Abstract

  Turner syndrome (TS), a neurogenetic disorder characterized by the absence of one X chromosome in a phenotypic female, is frequently associated with visuospatial impairments. We investigated the neural mechanisms underlying deficits in spatial orientation processing in TS. Thirteen subjects with TS and 13 age-matched typically developing controls underwent neuropsychological assessments and were scanned using functional MRI while they performed easy and difficult versions of a judgment of line orientation (JLO) task. Controls and subjects with TS activated parietal-occipital regions involved in spatial orientation during the JLO task. However, activation was significantly less in the TS group. Control subjects responded to increased task difficulty by recruiting executive frontal areas whereas subjects with TS did not activate alternate brain regions to meet increased task demands. Subjects with TS demonstrate activation deficits in parietal-occipital and frontal areas during the JLO task. Activation, and possibly deactivation, deficits in these areas may be responsible for the visuospatial deficits observed in females with TS.

  View details for DOI 10.1093/cercor/bhg116

  View details for PubMedID 14704214

• The neuroanatomy and neuroendocrinotogy of fragile X syndrome MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Hessl, D., Rivera, S. M., Reiss, A. L. 2004; 10 (1): 17-24

  Abstract

  Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene-brain-behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical features that are unique to this syndrome. In this article, we summarize studies focused on the neuroanatomy and neuroendocrinology of FXS. A review of structural imaging studies of individuals with the full mutation shows that several brain regions are enlarged, including the hippocampus, amygdala, caudate nucleus, and thalamus, even after controlling for overall brain volume. These regions mediate several cognitive and behavioral functions known to be aberrant in FXS such as memory and learning, information and sensory processing, and social and emotional behavior. Two regions, the cerebellar vermis, important for a variety of cognitive tasks and regulation of motor behavior, and the superior temporal gyrus, involved in processing complex auditory stimuli, are reported to be reduced in size relative to controls. Functional imaging, typically limited to females, has emphasized that individuals with FXS do not adequately recruit brain regions that are normally utilized by unaffected individuals to carry out various cognitive tasks, such as arithmetic processing or visual memory tasks. Finally, we review a number of neuroendocrine studies implicating hypothalamic dysfunction in FXS, including abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis. These studies may help to explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. In the future, innovative longitudinal studies to investigate development of neurobiologic and behavioral features over time, and ultimately empirical testing of pharmacological, behavioral, and even molecular genetic interventions using MRI are likely to yield significant positive changes in the lives of persons with FXS, as well as increase our understanding of the development of psychiatric and learning problems in the general population.

  View details for DOI 10.1002/mrdd.20004

  View details for Web of Science ID 000221595900004

  View details for PubMedID 14994284

• Amygdala and hippocampal volumes in Turner syndrome: a high-resolution MRI study of X-monosomy NEUROPSYCHOLOGIA Kesler, S. R., Garrett, A., Bender, B., Yankowitz, J., Zeng, S. M., Reiss, A. L. 2004; 42 (14): 1971-1978

  Abstract

  Turner syndrome (TS) results from partial or complete X-monosomy and is characterized by deficits in visuospatial functioning as well as social cognition and memory. Neuroimaging studies have demonstrated volumetric differences in the parietal region of females with TS compared to controls. The present study examined amygdala and hippocampus morphology in an attempt to further understand the neural correlates of psychosocial and memory functioning in TS. Thirty females with TS age 7.6-33.3 years (mean = 14.7 +/- 6.4) and 29 age-matched controls (mean age = 14.8 +/- 5.9; range = 6.4-32.7) were scanned using high resolution MRI. Volumetric analyses of the MRI scans included whole brain segmentation and manual delineation of the amygdala and hippocampus. Compared to controls, participants with TS demonstrated significantly larger left amygdala gray matter volumes, irrespective of total cerebral tissue and age. Participants with TS also showed disproportionately reduced right hippocampal volumes, involving both gray and white matter. Amygdala and hippocampal volumes appear to be impacted by X-monosomy. Aberrant morphology in these regions may be related to the social cognition and memory deficits often experienced by individuals with TS. Further investigations of changes in medial temporal morphology associated with TS are warranted.

  View details for DOI 10.1016/j.neuropsychologia.2004.04.021

  View details for Web of Science ID 000224330500012

  View details for PubMedID 15381027

  View details for PubMedCentralID PMC3051368

• Humor modulates the mesolimbic reward centers NEURON Mobbs, D., Greicius, M. D., Abdel-Azim, E., Menon, V., Reiss, A. L. 2003; 40 (5): 1041-1048

  Abstract

  Humor plays an essential role in many facets of human life including psychological, social, and somatic functioning. Recently, neuroimaging has been applied to this critical human attribute, shedding light on the affective, cognitive, and motor networks involved in humor processing. To date, however, researchers have failed to demonstrate the subcortical correlates of the most fundamental feature of humor-reward. In an effort to elucidate the neurobiological substrate that subserves the reward components of humor, we undertook a high-field (3 Tesla) event-related functional MRI study. Here we demonstrate that humor modulates activity in several cortical regions, and we present new evidence that humor engages a network of subcortical regions including the nucleus accumbens, a key component of the mesolimbic dopaminergic reward system. Further, the degree of humor intensity was positively correlated with BOLD signal intensity in these regions. Together, these findings offer new insight into the neural basis of salutary aspects of humor.

  View details for Web of Science ID 000187042200020

  View details for PubMedID 14659102

• Interactive specification of regions of interest on brain surfaces NEUROIMAGE Shiffman, S., Ng, Y. R., Brosnan, T. J., Eliez, S., Links, J. M., Kelkar, U. V., Reiss, A. L. 2003; 20 (3): 1811-1816

  Abstract

  We describe Surface Editor-a tool for interactive specification of regions of interest (ROIs) on brain surfaces. The tool allows users to define subsurfaces by tracing around areas within a triangle-mesh brain surface. The input to the program is a triangle-mesh representation of a brain volume and a set of user-defined input points on the mesh. The program connects each pair of successive input points with a polyline that results from the intersection of the mesh with a plane that is approximately normal to the mesh. The polyline comprises coplanar line segments. The boundary of an ROI is a connected set of polylines that intersects triangle edges to form a continuous path. To validate Surface Editor we demonstrated that the program could be used to interactively delineate gyri on brain surfaces, and we showed that paths that the program generated were comparable to paths that a user generated and to shortest paths.

  View details for DOI 10.1016/j.neuroimage.2003.06.001

  View details for Web of Science ID 000186723800034

  View details for PubMedID 14642490

• Williams Syndrome: evidence from atypical deletions links GTF21 and GTF2IRD1, but not FZD9, with posterior cortical structure and neural functions 53rd Annual Meeting of the American-Society-of-Human-Genetics Simon, A. F., Yao, G. M., Chen, X. N., Mills, D., Rose, F. E., Salandanan, L. S., Reiss, A., Bellugi, U., Korenberg, J. R. CELL PRESS. 2003: 514–14

  View details for Web of Science ID 000185599702022

• The behavioral neurogenetics of fragile X syndrome: Analyzing gene-brain-behavior relationships in child developmental psychopathologies DEVELOPMENT AND PSYCHOPATHOLOGY Reiss, A. L., Dant, C. C. 2003; 15 (4): 927-968

  Abstract

  Analyzing gene-brain-behavior linkages in childhood neurodevelopmental disorders, a research approach called "behavioral neurogenetics," has provided new insights into understanding how both genetic and environmental factors contribute to complex variations in typical and atypical human development. Research into etiologically more homogeneous disorders, such as fragile X syndrome, in particular, allows the use of more precise metrics of genetic risk so that we can more fully understand the complex pathophysiology of childhood onset neurodevelopmental disorders. In this paper, we review our laboratory's behavioral neurogenetics research by examining gene-brain-behavior relationships in fragile X syndrome, a single-gene disorder that has become a well-characterized model for studying neurodevelopmental dysfunction in childhood. Specifically, we examine genetic influences, trajectories of cognition and behavior, variation in brain structure and function, and biological and environmental factors that influence developmental and cognitive outcomes of children with fragile X. The converging approaches across these multilevel scientific domains indicate that fragile X, which arises from disruption of a single gene leading to the loss of a specific protein, is associated with a cascade of aberrations in neurodevelopment, resulting in a central nervous system that is suboptimal with respect to structure and function. In turn, structural and functional brain alterations lead to early disruption in emotion, cognition, and behavior in the child with fragile X. The combination of molecular genetics, neuroimaging, and behavioral research have advanced our understanding of the linkages between genetic variables, neurobiological measures, IQ, and behavior. Our research and that of others demonstrates that neurobehavior and neurocognition, genetics, and neuroanatomy are all different views of the same intriguing biological puzzle, a puzzle that today is rapidly emerging into a more complete picture of the intricate linkages among gene, brain, and behavior in developing children. Understanding the complex multilevel scientific perspective involved in fragile X will also contribute to our understanding of normal development by highlighting developmental events throughout the life span, thereby helping us to delineate the boundaries of pathology.

  View details for DOI 10.1017/S0954579403000464

  View details for Web of Science ID 000187321100006

  View details for PubMedID 14984133

• Towards effective and rewarding data sharing NEUROINFORMATICS Gardner, D., Toga, A. W., Ascoli, G. A., Beatty, J. T., Brinkley, J. F., Dale, A. M., Fox, P. T., Gardner, E. P., George, J. S., Goddard, N., Harris, K. M., Herskovits, E. H., Hines, M. L., Jacobs, G. A., Jacobs, R. E., Jones, E. G., Kennedy, D. N., Kimberg, D. Y., Mazziotta, J. C., Miller, P. L., Mori, S., MOUNTAIN, D. C., Reiss, A. L., Rosen, G. D., Rottenberg, D. A., Shepherd, G. M., Smalheiser, N. R., Smith, K. P., Strachan, T., Van Essen, D. C., Williams, R. W., Wong, S. T. 2003; 1 (3): 289-295

  View details for Web of Science ID 000186095000007

  View details for PubMedID 15046250

• Investigation of white matter structure in velocardiofacial syndrome: A diffusion tensor imaging study AMERICAN JOURNAL OF PSYCHIATRY Barnea-Goraly, N., Menon, V., Krasnow, B., Ko, A., Reiss, A., Eliez, S. 2003; 160 (10): 1863-1869

  Abstract

  Velocardiofacial syndrome, caused by a deletion on chromosome 22q11.2, is often accompanied by cognitive, behavioral, and psychiatric impairments. Specifically, velocardiofacial syndrome has been proposed as a disease model for a genetically mediated subtype of schizophrenia. Velocardiofacial syndrome is also known to affect brain structure. The most prominent structural findings in velocardiofacial syndrome are reduced white matter volumes. However, the structure of white matter and extent of specific regional involvement in this syndrome have never been investigated. The current study used diffusion tensor imaging to investigate white matter structure in children and young adults with velocardiofacial syndrome.Nineteen participants with velocardiofacial syndrome and 19 age- and gender-matched comparison subjects underwent diffusion-weighted magnetic resonance imaging scans. Whole brain voxel-by-voxel analyses were conducted to investigate white matter fractional anisotropy differences between the groups.Relative to the comparison group, the velocardiofacial syndrome group had reduced white matter anisotropy in the frontal, parietal, and temporal regions as well as in tracts connecting the frontal and temporal lobes.This study demonstrates that alterations of white matter tract structure occur in velocardiofacial syndrome. Reduced white matter anisotropy was observed in individuals with velocardiofacial syndrome in areas previously implicated in the neurocognitive phenotype of velocardiofacial syndrome. The finding of aberrant parietal white matter tracts as well as aberrant frontotemporal connectivity in velocardiofacial syndrome and in previous schizophrenia studies may be associated with increased vulnerability for development of psychotic symptoms.

  View details for Web of Science ID 000185880300024

  View details for PubMedID 14514502

• Effects of X-monosomy and X-linked imprinting on superior temporal gyrus morphology in Turner syndrome BIOLOGICAL PSYCHIATRY Kesler, S. R., Blasey, C. M., Brown, W. E., Yankowitz, J., Zeng, S. M., Bender, B. G., Reiss, A. L. 2003; 54 (6): 636-646

  Abstract

  Turner syndrome (TS) results from complete or partial monosomy X. The cognitive phenotype of TS involves preservation of verbal skills with visuospatial functioning deficits. The superior temporal gyrus (STG), which is involved in language capacities, has not been investigated in TS.The STG was measured in 30 female subjects (mean age = 14.73 +/- 6.41; range = 7.56-33.30) with TS and 30 age-matched control subjects (mean age = 14.63 +/- 5.90; range = 6.35-32.65) using volumetric magnetic resonance imaging analyses.-Right STG, including both gray and white matter volumes, was significantly larger in TS compared with control subjects. Overall left STG volume was not significantly different between groups, although left white matter volume was increased in the TS subjects. The TS subgroup with a maternally derived X chromosome (Xm) demonstrated more aberrant STG volumes compared with subjects with a paternally (Xp) derived X and control subjects. The difference in STG volumes between Xm and control subjects involved both white and gray matter. The Xm subjects differed from Xp subjects only in terms of gray matter.These findings suggest that X-monosomy and X-linked imprinting negatively affect STG development, possibly by disrupting neural pruning mechanisms.

  View details for DOI 10.1016/S0006-3223(03)00289-0

  View details for Web of Science ID 000185264700007

  View details for PubMedID 13129659

  View details for PubMedCentralID PMC3061621

• Functional brain imaging of olfactory processing in monkeys NEUROIMAGE Boyett-Anderson, J. M., Lyons, D. M., Reiss, A. L., Schatzberg, A. F., Menon, V. 2003; 20 (1): 257-264

  Abstract

  As a step toward bridging the gap between human and animal studies of olfactory brain systems, we report results from an fMRI study of olfaction in squirrel monkeys. High-resolution fMRI images at 3 T with 1.25 x 1.25 x 1.2 mm(3) voxels were obtained covering the whole brain using an 8-cm-diameter birdcage coil and a gradient-echo spiral pulse sequence. Data were acquired from six sedated adult males using a standard block design. All fMRI data were spatially normalized to a common template and analyzed at the individual and group levels with statistical parametric and nonparametric methods. Robust odorant-induced activations were detected in several brain regions previously implicated in conscious human olfactory processing, including the orbitofrontal cortex, cerebellum, and piriform cortex. Consistent with human data, no stimulus intensity effects were observed in any of these regions. Average signal changes in these regions exceeded 0.6%, more than three times the expected signal change based on human fMRI studies of olfaction adjusting for differences in voxel size. These results demonstrate the feasibility of studying olfaction in sedated monkeys with imaging techniques commonly used at 3 T in humans and help promote direct comparisons between humans and nonhuman primates. Our findings, for example, provide novel support for the hypothesis that the cerebellum is involved in sensory acquisition. More broadly, this study suggests that olfactory processing in sedated monkeys and nonsedated humans shares similar neural substrates both within and beyond the primary olfactory system.

  View details for DOI 10.1016/S1053-8119(03)00288-X

  View details for Web of Science ID 000185746400022

  View details for PubMedID 14527586

• Effect of head orientation on gaze processing in fusiform gyrus and superior temporal sulcus NEUROIMAGE Pageler, N. M., Menon, V., Merin, N. M., Eliez, S., Brown, W. E., Reiss, A. L. 2003; 20 (1): 318-329

  Abstract

  We used functional MRI with an event-related design to dissociate the brain activation in the fusiform gyrus (FG) and posterior superior temporal sulcus (STS) for multiple face and gaze orientations. The event-related design allowed for concurrent behavioral analysis, which revealed a significant effect of both head and gaze orientation on the speed of gaze processing, with the face and gaze forward condition showing the fastest reaction times. In conjunction with this behavioral finding, the FG responded with the greatest activation to face and gaze forward, perhaps reflecting the unambiguous social salience of congruent face and gaze directed toward the viewer. Random effects analysis showed greater activation in both the FG and posterior STS when the subjects viewed a direct face compared to an angled face, regardless of gaze direction. Additionally, the FG showed greater activation for forward gaze compared to angled gaze, but only when the face was forward. Together, these findings suggest that head orientation has a significant effect on gaze processing and these effects are manifest not only in the STS, but also the FG.

  View details for DOI 10.1016/S1053-8119(03)00229-5

  View details for Web of Science ID 000185746400028

  View details for PubMedID 14527592

• Factors associated with parenting stress in mothers of children with fragile X syndrome JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Johnston, C., Hessl, D., Blasey, C., Eliez, S., Erba, H., Dyer-Friedman, J., Glaser, B., Reiss, A. L. 2003; 24 (4): 267-275

  Abstract

  Whereas previous research has demonstrated elevated levels of parenting stress in parents of children with general developmental disability, there has been little investigation of stress in parents of children specifically affected by the common neurogenetic disorder fragile X syndrome (FraX). This study elucidates stress profiles in mothers of children with FraX and delineates the contribution of child characteristics, home environment, and maternal psychological functioning to specific dimensions of parental stress. Data on child, home, and family characteristics were collected from 75 families with a child affected by FraX. These characteristics were entered into multiple regression analyses with a domain or subscale of the Parenting Stress Index as the dependent variable in each analysis. The results demonstrated that aspects of child behavior, family cohesion, household income, and maternal psychopathology differentially correlate with specific dimensions of parenting stress. Determining the relative contribution of factors associated with stress will assist in the development of interventions to improve parental well-being in mothers of children with FraX.

  View details for Web of Science ID 000184777800007

  View details for PubMedID 12915799

• Amygdalar activation associated with happy facial expressions in adolescents: A 3-T functional MRI study JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Yang, T. T., Menon, V., Reid, A. J., Gotlib, I. H., Reiss, A. L. 2003; 42 (8): 979-985

  Abstract

  To study the possible role of the amygdala in the recognition of happy and sad facial expressions in adolescents aged 13 to 17 years.Twelve healthy adolescents (6 females and 6 males) underwent noninvasive 3-Tesla functional magnetic resonance imaging while viewing pictures of happy, sad, and neutral facial expressions.Happy faces produced significant bilateral amygdalar activation when compared with neutral faces (p <.05, corrected). Sad faces relative to neutral did not produce significant amygdalar activation.These results extend the role of the amygdala in adolescents to include the recognition of happy facial expressions. They demonstrate the feasibility of using happy facial expressions to noninvasively study amygdalar function in adolescents and establish a baseline against which the amygdalar response to emotional stimuli in several psychiatric conditions may be compared.

  View details for DOI 10.1097/01.CHI.0000046886.27264.BA

  View details for Web of Science ID 000184302700016

  View details for PubMedID 12874501

• Decreased N-acetylaspartate in children with familial bipolar disorder BIOLOGICAL PSYCHIATRY Chang, K., Adleman, N., Dienes, K., Barnea-Goraly, N., Reiss, A., Ketter, T. 2003; 53 (11): 1059-1065

  Abstract

  Relatively low levels of brain N-acetylaspartate, as measured by magnetic resonance spectroscopy, may indicate decreased neuronal density or viability. Dorsolateral prefrontal levels of N-acetylaspartate have been reported to be decreased in adults with bipolar disorder. We used proton magnetic resonance spectroscopy to investigate dorsolateral prefrontal N-acetylaspartate levels in children with familial bipolar disorder.Subjects were 15 children and adolescents with bipolar disorder, who each had at least one parent with bipolar disorder, and 11 healthy controls. Mean age was 12.6 years for subjects and controls. Subjects were allowed to continue current medications. Proton magnetic resonance spectroscopy at 3-Tesla was used to study 8 cm(3) voxels placed in left and right dorsolateral prefrontal cortex.Bipolar subjects had lower N-acetylaspartate/Creatine ratios only in the right dorsolateral prefrontal cortex (p <.02). No differences in myoinositol or choline levels were found.Children and adolescents with bipolar disorder may have decreased dorsolateral prefrontal N-acetylaspartate, similar to adults with BD, indicating a common neuropathophysiology. Longitudinal studies of at-risk children before the onset and during the early course of bipolar disorder are needed to determine the role of prefrontal N-acetylaspartate as a possible risk marker and/or indication of early bipolar illness progression.

  View details for DOI 10.1016/S0006-3223(02)01744-4

  View details for PubMedID 12788251

• Corpus callosum and posterior fossa development in monozygotic females: a morphometric MRI study of Turner syndrome DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Fryer, S. L., Kwon, H., Eliez, S., Reiss, A. L. 2003; 45 (5): 320-324

  Abstract

  Previous neuroimaging research in Turner syndrome (TS) has indicated parietal lobe anomalies, while anomalies in other brain loci have been less well-substantiated. This study focused on potential cerebellar abnormalities and possible disruptions of interhemispheric (parietal) callosal connections in individuals with TS. Twenty-seven female children and adolescents with TS (mean age 13 years, SD 4 years 2 months) and 27 age-matched female control individuals (mean age 13 years 2 months, SD 4 years 1 month) underwent MRI. Age range of all participants was 7 to 20 years. Morphometric analyses of midline brain structures were conducted using standardized, reliable methods. When compared with control participants, females with TS showed reduced areas of the genu of the corpus callosum, the pons, and vermis lobules VI-VII, and an increased area of the fourth ventricle. No group difference in intracranial area measurements was observed. The reduced area of the genu in TS may reflect compromised connectivity between inferior parietal regions. Further, cerebellar vermis hypoplasia associated with TS agrees with literature that suggests the posterior fossa as a region prone to structural alterations in the face of early developmental insult.

  View details for DOI 10.1017/S0012162203000604

  View details for Web of Science ID 000182624300007

  View details for PubMedID 12729146

• Functional imaging of brain responses to affective facial expressions in adolescent bipolar disorder 58th Annual Convention of the Society-of-Biological-Psychiatry Garrett, A. S., Chang, K. D., Menon, V., Chang, M. Y., Reiss, A. L. ELSEVIER SCIENCE INC. 2003: 36S–37S

  View details for Web of Science ID 000182436000099

• Investigation of white matter structure in velocardiofacial syndrome: A diffusion tensor imaging study 58th Annual Convention of the Society-of-Biological-Psychiatry Barnea-Goraly, N., Menon, V., Krasnow, B., Ko, A., Reiss, A., Eliez, S. ELSEVIER SCIENCE INC. 2003: 76S–76S

  View details for Web of Science ID 000182436000212

• Comparison of fMRI activation at 3 and 1.5 T during perceptual, cognitive, and affective processing NEUROIMAGE Krasnow, B., Tamm, L., Greicius, M. D., Yang, T. T., Glover, G. H., Reiss, A. L., Menon, V. 2003; 18 (4): 813-826

  Abstract

  Previous studies comparing fMRI data acquired at 1.5 T and higher field strengths have focused on examining signal increases in the visual and motor cortices. No information is, however, available on the relative gain, or the comparability of data, obtained at higher field strengths for other brain regions such as the prefrontal and other association cortices. In the present study, we investigated fMRI activation at 1.5 and 3 T during visual perception, visuospatial working memory, and affect-processing tasks. A 23% increase in striate and extrastriate activation volume was observed at 3 T compared with that for 1.5 T during the visual perception task. During the working memory task significant increases in activation volume were observed in frontal and parietal association cortices as well as subcortical structures, including the caudate, globus pallidus, putamen, and thalamus. Increases in working memory-related activation volume of 82, 73, 83, and 36% were observed in the left frontal, right frontal, left parietal, and right parietal lobes, respectively, for 3 T compared with 1.5 T. These increases were characterized by increased activation at 3 T in several prefrontal and parietal cortex regions that showed activation at 1.5 T. More importantly, at 3 T, activation was detected in several regions, such as the ventral aspects of the inferior frontal gyrus, orbitofrontal gyrus, and lingual gyrus, which did not show significant activation at 1.5 T. No difference in height or extent of activation was detected between the two scanners in the amygdala during affect processing. Signal dropout in the amygdala from susceptibility artifact was greater at 3 T, with a 12% dropout at 3 T compared with a 9% dropout at 1.5 T. The spatial smoothness of T2* images was greater at 3 T by less than 1 mm, suggesting that the greater extent of activation at 3 T beyond these spatial scales was not due primarily to increased intrinsic spatial correlations at 3 T. Rather, the increase in percentage of voxels activated reflects increased sensitivity for detection of brain activation at higher field strength. In summary, our findings suggest that functional imaging of prefrontal and other association cortices can benefit significantly from higher magnetic field strength.

  View details for DOI 10.1016/S1053-8119(03)00002-8

  View details for Web of Science ID 000182606000001

  View details for PubMedID 12725758

• White matter tract alterations in fragile X syndrome: Preliminary evidence from diffusion tensor imaging AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Barnea-Goraly, N., Eliez, S., Hedeus, M., Menon, V., White, C. D., Moseley, M., Reiss, A. L. 2003; 118B (1): 81-88

  Abstract

  Fragile X syndrome, the most common form of hereditary mental retardation, causes disruption in the development of dendrites and synapses, the targets for axonal growth in the central nervous system. This disruption could potentially affect the development, wiring, and targeting of axons. The current study utilized diffusion tensor imaging (DTI) to investigate whether white matter tract integrity and connectivity are altered in fragile X syndrome. Ten females with a diagnosis of fragile X syndrome and ten, age matched, female control subjects underwent diffusion weighted MRI scans. A whole brain analysis of fractional anisotropy (FA) values was performed using statistical parametric mapping (SPM). A follow-up, regions-of-interest analysis also was conducted. Relative to controls, females with fragile X exhibited lower FA values in white matter in fronto-striatal pathways, as well as in parietal sensory-motor tracts. This preliminary study suggests that regionally specific alterations of white matter integrity occur in females with fragile X. Aberrant white matter connectivity in these regions is consistent with the profile of cognitive and behavioral features of fragile X syndrome, and potentially provide additional insight into the detrimental effects of suboptimal levels of FMRP in the developing brain.

  View details for DOI 10.1002/ajmg.b.10035

  View details for Web of Science ID 000182401800017

  View details for PubMedID 12627472

• A prospective test of the association between hyperarousal and emotional numbing in youth with a history of traumatic stress JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY Weems, C. F., Saltzman, K. M., Reiss, A. L., Carrion, V. G. 2003; 32 (1): 166-171

  Abstract

  Investigated the hypothesis that emotional numbing may develop as a result of hyperarousal using a prospective design. Forty-two children between the ages of 7 and 14 with a history of trauma and posttraumatic stress disorder (PTSD) symptoms were assessed with the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA; Nader et al., 1996) and were reassessed 1 year later. Results indicated that hyperarousal symptoms were concurrently positively correlated with emotional numbing at both time points. Moreover, Time 1 hyperarousal symptoms were associated with emotional numbing at Time 2 and predicted Time 2 emotional numbing even when controlling for each of the other symptom clusters of PTSD at Time 1 as well as other concurrent (i.e., Time 2) PTSD symptoms. Results are discussed in terms of the implications of the findings for enhancing the understanding of PTSD symptoms in youth.

  View details for Web of Science ID 000180579800015

  View details for PubMedID 12573941

• Biological and environmental contributions to adaptive behavior in fragile X syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Glaser, B., Hessl, D., Dyer-Friedman, J., Johnston, C., Wisbeck, J., Taylor, A., Reiss, A. 2003; 117A (1): 21-29

  Abstract

  Fragile X syndrome is the most common cause of inherited developmental disability. The purpose of the present study is to understand how both biological and environmental influences affect the development of adaptive behavior in children with fragile X. In-home assessments were conducted on 120 children (80 boys and 40 girls) with the fragile X full mutation and their unaffected siblings (58 boys and 62 girls). Hierarchical multiple regression analyses were utilized. Independent variables included biological or demographic variables specific to the child (age, gender, full-scale IQ, and FMRP percentage), as well as factors specific to his/her environment (household income, home environment, maternal psychopathology, and effectiveness of educational/therapeutic services). Results of these analyses showed that for both boys with fragile X and the control sibling group, adaptive behavior was predicted by IQ, age, gender, and home environment. For girls with fragile X, adaptive behavior was most strongly associated with IQ. Adaptive behavior was not significantly associated with FMRP in boys or girls with fragile X. By examining the relative influences of biological and environmental factors on adaptive behavior in children with fragile X, we begin to lay the foundation for the development of more specific treatment studies in children with this disorder.

  View details for DOI 10.1002/ajmg.a.10549

  View details for Web of Science ID 000182400900005

  View details for PubMedID 12548736

• [Williams syndrome. A summary of cognitive, electrophysiological, anatomofunctional, microanatomical and genetic findings]. Revista de neurologia Galaburda, A. M., HOLINGER, D., Mills, D., Reiss, A., Korenberg, J. R., Bellugi, U. 2003; 36: S132-7

  Abstract

  Williams syndrome (WS) is the result of a hemideletion of about 17 genes in the q11.22-23 region of chromosome 7. Patients with WS show unique phenotypic features that include elfin face, heart malformations, calcium metabolism problems and learning disorders. The latter consist of mental retardation that is characterised by serious difficulties with processing visuospatial tasks, a striking ability to easily recognise faces, a relatively developed linguistic capacity and sensitiveness to sound, a strong need to establish affective ties with other people and a fondness for music. Anatomical studies show a decrease in the postero-dorsal parts of both hemispheres of the brain, malformation in the central dorsal region and an expansion of the superior temporal gyrus, of the amygdala and of the frontal lobe. These macroscopic anomalies are accompanied by microscopic anomalies, which consist of changes in the number and size of the neurons. Studies on evoked potentials show acoustic hyperexcitability and abnormal waves related to language and to faces. Genetic studies in our laboratories show that the exact size of the deletion can vary, which means partial cases also exist and have partial phenotypes. Combining behavioural, electrophysiological, anatomical and genetic reports suggests a problem with the posterior dorsal region of the brain, possibly resulting from mistakes in establishing the dorsoventral and caudorostral genetico-molecular gradients, which specify the cortical regions during development.

  View details for PubMedID 12599114

• Abnormal prefrontal cortex function during response inhibition in Turner syndrome: Functional magnetic resonance imaging evidence BIOLOGICAL PSYCHIATRY Tamm, L., Menon, V., Reiss, A. L. 2003; 53 (2): 107-111

  Abstract

  Turner syndrome (TuS) arises from the partial or complete absence of one X chromosome. Although neuropsychological studies report impaired attentional function and response inhibition in TuS, the neural correlates of these cognitive problems are unknown.Eleven female subjects with TuS and 11 individually matched normal control subjects were imaged using functional magnetic resonance imaging while performing a Go/NoGo task.Groups did not differ on accuracy or reaction time; however, the TuS group activated more in the bilateral superior and middle frontal gyri than control subjects. Control subjects did not activate more than the TuS group in any region.These findings suggest that female subjects with TuS compensate for executive dysfunction via recruitment of additional prefrontal cortex regions involved in inhibition, attention, and working memory, functions necessary for successful performance of Go/NoGo tasks. Elucidating brain function in TuS will advance our understanding of the influence of X-chromosome genes on neurodevelopment and brain function and contribute to planning future intervention strategies.

  View details for DOI 10.1016/S0006-3223(02)01488-9

  View details for Web of Science ID 000180518900001

  View details for PubMedID 12547465

• Functional connectivity in the resting brain: A network analysis of the default mode hypothesis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Greicius, M. D., Krasnow, B., Reiss, A. L., Menon, V. 2003; 100 (1): 253-258

  Abstract

  Functional imaging studies have shown that certain brain regions, including posterior cingulate cortex (PCC) and ventral anterior cingulate cortex (vACC), consistently show greater activity during resting states than during cognitive tasks. This finding led to the hypothesis that these regions constitute a network supporting a default mode of brain function. In this study, we investigate three questions pertaining to this hypothesis: Does such a resting-state network exist in the human brain? Is it modulated during simple sensory processing? How is it modulated during cognitive processing? To address these questions, we defined PCC and vACC regions that showed decreased activity during a cognitive (working memory) task, then examined their functional connectivity during rest. PCC was strongly coupled with vACC and several other brain regions implicated in the default mode network. Next, we examined the functional connectivity of PCC and vACC during a visual processing task and show that the resultant connectivity maps are virtually identical to those obtained during rest. Last, we defined three lateral prefrontal regions showing increased activity during the cognitive task and examined their resting-state connectivity. We report significant inverse correlations among all three lateral prefrontal regions and PCC, suggesting a mechanism for attenuation of default mode network activity during cognitive processing. This study constitutes, to our knowledge, the first resting-state connectivity analysis of the default mode and provides the most compelling evidence to date for the existence of a cohesive default mode network. Our findings also provide insight into how this network is modulated by task demands and what functions it might subserve.

  View details for DOI 10.1073/pnas.0135058100

  View details for Web of Science ID 000180307100046

  View details for PubMedID 12506194

  View details for PubMedCentralID PMC140943

• Neural correlates of auditory perception in Williams syndrome: An fMRI study NEUROIMAGE Levitin, D. J., Menon, V., Schmitt, J. E., Eliez, S., White, C. D., Glover, G. H., Kadis, J., Korenberg, J. R., Bellugi, U., Reiss, A. L. 2003; 18 (1): 74-82

  Abstract

  Williams syndrome (WS), a neurogenetic developmental disorder, is characterized by a rare fractionation of higher cortical functioning: selective preservation of certain complex faculties (language, music, face processing, and sociability) in contrast to marked and severe deficits in nearly every other cognitive domain (reasoning, spatial ability, motor coordination, arithmetic, problem solving). WS people are also known to suffer from hyperacusis and to experience heightened emotional reactions to music and certain classes of noise. We used functional magnetic resonance imaging to examine the neural basis of auditory processing of music and noise in WS patients and age-matched controls and found strikingly different patterns of neural organization between the groups. Those regions supporting music and noise processing in normal subjects were found not to be consistently activated in the WS participants (e.g., superior temporal and middle temporal gyri). Instead, the WS participants showed significantly reduced activation in the temporal lobes coupled with significantly greater activation in the right amygdala. In addition, WS participants (but not controls) showed a widely distributed network of activation in cortical and subcortical structures, including the brain stem, during music processing. Taken together with previous ERP and cytoarchitectonic studies, this first published report of WS using fMRI provides additional evidence of a different neurofunctional organization in WS people than normal people, which may help to explain their atypical reactions to sound. These results constitute an important first step in drawing out the links between genes, brain, cognition, and behavior in Williams syndrome.

  View details for DOI 10.1006/nimg.2002.1297

  View details for Web of Science ID 000180015200007

  View details for PubMedID 12507445

• Regional analysis of hippocampal activation during memory encoding and retrieval: fMRI study HIPPOCAMPUS Greicius, M. D., Krasnow, B., Boyett-Anderson, J. M., Eliez, S., Schatzberg, A. F., Reiss, A. L., Menon, V. 2003; 13 (1): 164-174

  Abstract

  Investigators have recently begun to examine the differential role of subregions of the hippocampus in episodic memory. Two distinct models have gained prominence in the field. One model, outlined by Moser and Moser (Hippocampus 1998;8:608-619), based mainly on animal studies, has proposed that episodic memory is subserved by the posterior two-thirds of the hippocampus alone. A second model, derived by Lepage et al. (Hippocampus 1998;8:313-322) from their review of 52 PET studies, has suggested that the anterior hippocampus is activated by memory encoding while the posterior hippocampus is activated by memory retrieval. Functional magnetic resonance imaging (fMRI) studies have tended to show limited activation in the anteriormost regions of the hippocampus, providing support for the Moser and Moser model. A potential confounding factor in these fMRI studies, however, is that susceptibility artifact may differentially reduce signal in the anterior versus the posterior hippocampus. In the present study, we examined activation differences between hippocampal subregions during encoding and retrieval of words and interpreted our findings within the context of these two models. We also examined the extent to which susceptibility artifact affects the analysis and interpretation of hippocampal activation by demonstrating its differential effect on the anterior versus the posterior hippocampus. Both voxel-by-voxel and region-of-interest analyses were conducted, allowing us to quantify differences between the anterior and posterior aspects of the hippocampus. We detected significant hippocampal activation in both the encoding and retrieval conditions. Our data do not provide evidence for regional anatomic differences in activation between encoding and retrieval. The data do suggest that, even after accounting for susceptibility artifact, both encoding and retrieval of verbal stimuli activate the middle and posterior hippocampus more strongly than the anterior hippocampus. Finally, this study is the first to quantify the effects of susceptibility-induced signal loss on hippocampal activation and suggests that this artifact has significantly biased the interpretation of earlier fMRI studies.

  View details for DOI 10.1002/hipo.10064

  View details for Web of Science ID 000181005800014

  View details for PubMedID 12625466

• Brain development in Turner syndrome: a magnetic resonance imaging study PSYCHIATRY RESEARCH-NEUROIMAGING Brown, W. E., Kesler, S. R., Eliez, S., Warsofsky, I. S., Haberecht, M., Patwardhan, A., Ross, J. L., Neely, E. K., Zeng, S. M., Yankowitz, J., Reiss, A. L. 2002; 116 (3): 187-196

  Abstract

  Turner syndrome (TS) results from the absence of an X chromosome in females. This genetic condition is associated with specific cognitive deficits and variations in brain volumes. The goal of this study was to use high-resolution magnetic resonance imaging (MRI) to determine morphological variations in TS and to investigate the effects of parental origin of the X chromosome on brain development in TS. MRI brain scans were acquired from 26 girls with TS and 26 age- and gender-matched controls. Seventeen of the TS subjects had a maternally inherited X chromosome (Xm), and nine of the subjects had a paternally inherited X chromosome (Xp). Rater-blind morphometric analyses were conducted to compare tissue volume differences between girls with TS and controls. Three-way analyses were used to compare subgroups and controls. Subjects with TS demonstrated bilateral decreases in parietal gray and occipital white matter accompanied by increased cerebellar gray matter. Subjects with Xm showed decreased occipital white matter and increased cerebellar gray matter compared to controls. No differences were found in comparisons between subjects with Xp and controls or between subjects with Xm and Xp. Results suggest that X monosomy affects posterior cerebral and cerebellar anatomy in TS. While differences between comparisons of Xm and Xp to controls might suggest an imprinting effect, no significant differences were found when the two subgroups were directly compared to each other. Further investigation into the possible role of genomic imprinting is therefore warranted.

  View details for PubMedID 12477602

• Incidental findings on pediatric MR images of the brain AMERICAN JOURNAL OF NEURORADIOLOGY Kim, B. S., Illes, J., Kaplan, R. T., Reiss, A., Scott, W. 2002; 23 (10): 1674-1677

  Abstract

  Previous studies have addressed the prevalence of incidental findings in symptomatic and healthy adult populations. Our study aims to elucidate the prevalence of incidental findings in a healthy pediatric population.We retrospectively reviewed 225 conventional brain MR imaging studies obtained during structural and functional brain imaging research in a cohort of neurologically healthy children (100 boys [44%] and 125 girls [56%]) ranging in age from younger than 1 month to 18 years. All MR images were reviewed, and two board-certified neuroradiologists categorized the findings by consensus.Incidental abnormalities were detected in 47 subjects (21%), while 79% of the images were normal. Of the 47 abnormalities detected, 17 (36%) required routine clinical referral; a single lesion (2%) required urgent referral. The occurrence of these findings in the male cohort was twice that of the female cohort; however, the percentage of subjects requiring either routine or urgent referral did not differ by sex (male subjects, 34%; female subjects, 39%).Although the frequency of clinically important incidental abnormalities was not high in the sample of children studied, the presence and variety of findings in any pediatric group is particularly important for both the welfare of the subject and for research in which knowledge of the subject's neurologic status is vital to the interpretation of the results. Despite the limitations of the study in terms of the age and ethnic distribution, this work highlights the need for the routine involvement of trained radiologists in these studies to ensure that such incidental findings are detected and that appropriate follow-up is provided.

  View details for Web of Science ID 000179199000017

  View details for PubMedID 12427622

• Amygdalar activation associated with positive and negative facial expressions NEUROREPORT Yang, T. T., Menon, V., Eliez, S., Blasey, C., White, C. D., Reid, A. J., Gotlib, I. H., Reiss, A. L. 2002; 13 (14): 1737-1741

  Abstract

  Most theories of amygdalar function have underscored its role in fear. One broader theory suggests that neuronal activation of the amygdala in response to fear-related stimuli represents only a portion of its more widespread role in modulating an organism's vigilance level. To further explore this theory, the amygdalar response to happy, sad, angry, fearful, and neutral faces in 17 subjects was characterized using 3 T fMRI. Utilizing a random effects model and hypothesis-driven analytic strategy, it was observed that each of the four emotional faces was associated with reliable bilateral activation of the amygdala compared with neutral. These findings suggest a broader role for the amygdala in modulating the vigilance level during the perception of several negative and positive facial emotions.

  View details for Web of Science ID 000179156600009

  View details for PubMedID 12395114

• Cortisol and behavior in fragile X syndrome PSYCHONEUROENDOCRINOLOGY Hessl, D., Glaser, B., Dyer-Friedman, J., Blasey, C., Hastie, T., Gunnar, M., Reiss, A. L. 2002; 27 (7): 855-872

  Abstract

  The purpose of this study was to determine if children with fragile X syndrome, who typically demonstrate a neurobehavioral phenotype that includes social anxiety, withdrawal, and hyper-arousal, have increased levels of cortisol, a hormone associated with stress. The relevance of adrenocortical activity to the fragile X phenotype also was examined.One hundred and nine children with the fragile X full mutation (70 males and 39 females) and their unaffected siblings (51 males and 58 females) completed an in-home evaluation including a cognitive assessment and a structured social challenge task. Multiple samples of salivary cortisol were collected throughout the evaluation day and on two typical non-school days. Measures of the fragile X mental retardation (FMR1) gene, child intelligence, the quality of the home environment, parental psychopathology, and the effectiveness of educational and therapeutic services also were collected. Linear mixed-effects analyses were used to examine differences in cortisol associated with the fragile X diagnosis and gender (fixed effects) and to estimate individual subject and familial variation (random effects) in cortisol hormone levels. Hierarchical multiple regression analyses were conducted to determine whether adrenocortical activity is associated with behavior problems after controlling for significant genetic and environmental factors.Results showed that children with fragile X, especially males, had higher levels of salivary cortisol on typical days and during the evaluation. Highly significant family effects on salivary cortisol were detected, consistent with previous work documenting genetic and environmental influences on adrenocortical activity. Increased cortisol was significantly associated with behavior problems in boys and girls with fragile X but not in their unaffected siblings.These results provide evidence that the function of the hypothalamic-pituitary-adrenal axis may have an independent association with behavioral problems in children with fragile X syndrome.

  View details for Web of Science ID 000178462800008

  View details for PubMedID 12183220

• Detection of occult y mosaicism in 45, X Turner syndrome: Quantitation of Y chromosome material by real time PCR. Zeng, S. M., Reiss, A. L., Yankowitz, J. UNIV CHICAGO PRESS. 2002: 170

  View details for Web of Science ID 000178025800034

• Neural basis of protracted developmental changes in visuo-spatial working memory PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kwon, H., Reiss, A. L., Menon, V. 2002; 99 (20): 13336-13341

  Abstract

  Developmental studies have shown that visuo-spatial working memory (VSWM) performance improves throughout childhood and adolescence into young adulthood. The neural basis of this protracted development is poorly understood. In this study, we used functional MRI (fMRI) to examine VSWM function in children, adolescents, and young adults, ages 7-22. Subjects performed a 2-back VSWM experiment that required dynamic storage and manipulation of spatial information. Accuracy and response latency on the VSWM task improved gradually, extending into young adulthood. Age-related increases in brain activation were observed in focal regions of the left and right dorsolateral prefrontal cortex, left ventrolateral prefrontal cortex (including Broca's area), left premotor cortex, and left and right posterior parietal cortex. Multiple regression analysis was used to examine the relative contributions of age, accuracy, and response latency on activation. Our analysis showed that age was the most significant predictor of activation in these brain regions. These findings provide strong evidence for a process of protracted functional maturation of bilateral fronto-parietal neural networks involved in VSWM development. At least two neural systems involved in VSWM mature together: (i) a right hemisphere visuo-spatial attentional system, and (ii) a left hemisphere phonological storage and rehearsal system. These observations suggest that visually and verbally mediated mnemonic processes, and their neural representations, develop concurrently during childhood and adolescence and into young adulthood.

  View details for DOI 10.1073/pnas.162486399

  View details for Web of Science ID 000178391700150

  View details for PubMedID 12244209

  View details for PubMedCentralID PMC130634

• Maturation of brain function associated with response inhibition JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Tamm, L., Menon, V., Reiss, A. L. 2002; 41 (10): 1231-1238

  Abstract

  To investigate the developmental trajectory of response inhibition and, more specifically, whether there is a dissociation of function in the prefrontal cortex over the course of development of executive function and associated response inhibition abilities.Nineteen typically developing subjects, ranging in age from 8 to 20, performed a Go/NoGo task while behavioral and functional magnetic resonance imaging (fMRI) data were collected.All subjects performed the task with few errors of omission and commission. No relationship between accuracy and age emerged, but the ability to inhibit responses significantly improved with age. Analyses of fMRI data revealed a positive correlation between activation and age in the left inferior frontal gyrus/insula/orbitofrontal gyrus, and a negative correlation between activation and age in the left middle/superior frontal gyri.These data provide the first evidence of dissociable processes occurring in the prefrontal cortex during development of executive functions associated with response inhibition: (1) Younger subjects activate more extensively than older subjects in discrete regions of the prefrontal cortex, presumably due to increased demands and inefficient recruitment of brain regions subserving executive functions including working memory. (2) Older subjects show increasingly focal activation in specific regions thought to play a more critical role in response inhibition.

  View details for DOI 10.1097/00004583-200210000-00013

  View details for Web of Science ID 000178203700013

  View details for PubMedID 12364845

• Future of genetics of mood disorders research. Biological psychiatry Merikangas, K. R., Chakravarti, A., Moldin, S. O., Araj, H., Blangero, J. C., Burmeister, M., Crabbe, J., Depaulo, J. R., Foulks, E., Freimer, N. B., Koretz, D. S., Lichtenstein, W., Mignot, E., Reiss, A. L., Risch, N. J., Takahashi, J. S. 2002; 52 (6): 457-477

  Abstract

  This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research.

  View details for PubMedID 12361664

• Workgroup reports: NIMH strategic plan for mood disorders research - Future of genetics of mood disorders research BIOLOGICAL PSYCHIATRY Merikangas, K. R., Chakravarti, A., Moldin, S. O., Araj, H., Blangero, J., Burmeister, M., Crabbe, J. C., DePaulo, J. R., Foulks, E., Freimer, N. B., Koretz, D. S., Lichtenstein, W., Mignot, E., Reiss, A. L., Risch, N. J., Takahashi, J. S. 2002; 52 (6): 457-477

  Abstract

  This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research.

  View details for Web of Science ID 000178297000002

• Functional brain activation during arithmetic processing in females with fragile X Syndrome is related to FMRI protein expression HUMAN BRAIN MAPPING Rivera, S. M., Menon, V., White, C. D., Glaser, B., Reiss, A. L. 2002; 16 (4): 206-218

  Abstract

  Arithmetic processing deficits in persons with fragile X Syndrome (fraX), the most common heritable cause of mental retardation, are well known. In this study, we characterize the neural underpinnings of these performance deficits using functional MRI. Given that a single gene defect (FMR1) is known to be responsible for this disorder, we also assess whether brain activation in arithmetic processing areas is related to amount of FMR1 protein expression (FMRP). Subjects included 16 females with fraX, and 16 female age-matched controls. Subjects viewed arithmetic equations with two (1 + 3 = 4) or three (2 + 3 - 1 = 5) operands, and were asked to judge whether the results were correct or not. Subjects with fraX showed significant impairment in behavioral performance on the 3-operand but not the 2-operand arithmetic equations. Significant brain activation was observed bilaterally in the prefrontal and parietal cortices for unaffected subjects, and bilateral prefrontal and left angular gyrus for subjects with fraX, for both trial types. Subjects with fraX exhibited less overall activation than did unaffected subjects in both types of trials; and, unlike the unaffected group, did not show increased extent of activation in association with greater task difficulty. During the 3-operand trials, activation in bilateral prefrontal and motor/premotor, and left supramarginal and angular gyri were positively correlated with FMRP, suggesting that decreased FMR1 protein expression underlies deficits in math performance in persons with fraX. More broadly, this investigation demonstrates a unique bridging of cognitive and molecular neuroscience and represents a useful approach for the study of brain development and function.

  View details for DOI 10.1002/hbm.10048

  View details for Web of Science ID 000177176900002

  View details for PubMedID 12112763

• Increased basal ganglia volumes in velo-cardio-facial syndrome (deletion 22q11.2) BIOLOGICAL PSYCHIATRY Eliez, S., Barnea-Goraly, N., Schmitt, J. E., Liu, Y., Reiss, A. L. 2002; 52 (1): 68-70

  Abstract

  This study evaluated differences in caudate volumes in subjects with velo-cardio-facial syndrome due to a 22q11.2 (22qDS) deletion. Because psychosis is observed in 30% of adult subjects with 22qDS, this neurogenetic disorder could represent a putative model for a genetically mediated subtype of schizophrenia.Caudate volumes were measured on high-resolution magnetic resonance images in 30 children and adolescents with 22qDS and 30 gender- and age-matched normal comparison subjects.Caudate head volumes were increased in the 22qDS group independent of neuroleptic medications. Subjects with 22qDS also displayed an abnormal pattern of asymmetry in the anterior caudate, with left side greater than right.Alterations in the basal ganglia circuitry have been implicated in learning, cognitive, and behavioral problems in children and therefore could be involved in the expression of the neurobehavioral phenotype expressed by subjects with 22qDS. Abnormal caudate volume is a neurodevelopmental feature shared with schizophrenia, further establishing 22qDS as a potential neurodevelopmental model for this disorder.

  View details for Web of Science ID 000176340700009

  View details for PubMedID 12079732

• Prefrontal cortex involvement in processing incorrect arithmetic equations: Evidence from event-related fMRI HUMAN BRAIN MAPPING Menon, V., MacKenzie, K., Rivera, S. M., Reiss, A. L. 2002; 16 (2): 119-130

  Abstract

  The main aim of this study was to investigate the differential processing of correct and incorrect equations to gain further insight into the neural processes involved in arithmetic reasoning. Electrophysiological studies in humans have demonstrated that processing incorrect arithmetic equations (e.g., 2 + 2 = 5) elicits a prominent event-related potential (ERP) compared to processing correct equations (e.g., 2 + 2 = 4). In the present study, we investigated the neural substrates of this process using event-related functional magnetic resonance imaging (fMRI). Subjects were presented with arithmetic equations and asked to indicate whether the solution displayed was correct or incorrect. We found greater activation to incorrect, compared to correct equations, in the left dorsolateral prefrontal cortex (DLPFC, BA 46) and the left ventrolateral prefrontal cortex (VLPFC, BA 47). Our results provide the first brain imaging evidence for differential processing of incorrect vs. correct equations. The prefrontal cortex activation observed in processing incorrect equations overlaps with brain areas known to be involved in working memory and interference processing. The DLPFC region differentially activated by incorrect equations was also involved in overall arithmetic processing, whereas the VLPFC was activated only during the differential processing of incorrect equations. Differential response to correct and incorrect arithmetic equations was not observed in parietal cortex regions such as the angular gyrus and intra-parietal sulcus, which are known to play a specific role in performing arithmetic computations. The pattern of brain response observed is consistent with the hypothesis that processing incorrect equations involves detection of an incorrect answer and resolution of the interference between the internally computed and externally presented incorrect answer. More specifically, greater activation during processing of incorrect equations appears to reflect additional operations involved in maintaining the results in working memory, while subjects attempt to resolve the conflict and select a response. These findings allow us to further delineate and dissociate the contributions of prefrontal and parietal cortices to arithmetic reasoning.

  View details for DOI 10.1002/hbm.10035

  View details for PubMedID 11954061

• Language skills in children with velocardiofacial syndrome (deletion 22q11.2) JOURNAL OF PEDIATRICS Glaser, B., Mumme, D. L., Blasey, C., Morris, M. A., Dahoun, S. P., Antonarakis, S. E., Reiss, A. L., Eliez, S. 2002; 140 (6): 753-758

  Abstract

  To further define the language profile of children with velocardiofacial syndrome (VCFS) and explore the influence of parental origin of the deletion on language.Children and adolescents with VCFS (n = 27) were group-matched for sex, age, and IQ with 27 children and adolescents with idiopathic developmental delay. Fifty-four typically developing control subjects were also included in the analyses investigating word association abilities.Children with VCFS had significantly lower receptive than expressive language skills, a unique finding when compared with IQ-matched control subjects. However, no significant differences in word association were detected. Children with a deletion of paternal origin score significantly higher on receptive language when compared with children with a deletion of maternal origin.The Clinical Evaluation of Language Fundamentals-III results suggest that children with VCFS show more severe deficits in receptive than expressive language abilities. Language skills of children with VCFS could be influenced by parental origin of the deletion and thus related to neuroanatomic alterations at the deletion site.

  View details for DOI 10.1067/mpd.2002.124774

  View details for Web of Science ID 000176520300021

  View details for PubMedID 12072882

• Family environment and cognitive abilities in girls with fragile-X syndrome JOURNAL OF INTELLECTUAL DISABILITY RESEARCH Kuo, A. Y., Reiss, A. L., Freund, L. S., Huffman, L. C. 2002; 46: 328-339

  Abstract

  There remains some variance in cognitive ability that is unexplained in children with fragile-X syndrome (FXS). Studies in typically developing children suggest that family environment might be one contributor to this unexplained variance. However, the effect of family environment in relation to cognition in atypical children with FXS has been relatively unexplored to date.The present authors examined the putative genetic and environmental factors associated with cognition in a group of age-matched children consisting of 26 females with FXS and 31 typically developing children. All subjects were administered the Wechsler Intelligence Scale for Children-Revised; and the subjects' parents were administered the Wechsler Adult Intelligence Scale-Revised, and completed the Hollingshead Index of Social Status and the Moos & Moos Family Environment Scale.Using a multiple regression analytic strategy, the present authors found that family environment contributed significantly to cognitive abilities in typically developing girls, but did not have a unique contribution to cognitive abilities in girls with FXS. There was a suggestion that, for girls with FXS, socio-economic status, a measure of sociocultural environment, was correlated with IQ.The present study provides a basis for future research on the environmental contributions to cognitive abilities, particularly work related to verbal cognition.

  View details for Web of Science ID 000175531500005

  View details for PubMedID 12000584

• A developmental fMRI study of the stroop color-word task NEUROIMAGE Adleman, N. E., Menon, V., Blasey, C. M., White, C. D., Warsofsky, I. S., Glover, G. H., Reiss, A. L. 2002; 16 (1): 61-75

  Abstract

  We used fMRI to investigate developmental changes in brain activation during a Stroop color-word interference task. A positive correlation was observed between age and Stroop-related activation (n = 30) in the left lateral prefrontal cortex, the left anterior cingulate, and the left parietal and parieto-occipital cortices. No regions showed a negative correlation between activation and age. We further investigated age-related differences by stratifying the sample into three age groups: children (ages 7-11), adolescents (ages 12-16), and young adults (ages 18-22). Young adult subjects (n = 11) displayed significant activation in the inferior and middle frontal gyri bilaterally, the left anterior cingulate, and bilateral inferior and superior parietal lobules. Between-group comparisons revealed that young adults had significantly greater activation than adolescent subjects (n = 11) in the left middle frontal gyrus and that young adults showed significantly greater activation than children (n = 8) in the anterior cingulate and left parietal and parieto-occipital regions, as well as in the left middle frontal gyrus. Compared to children, both adult and adolescent subjects exhibited significantly greater activation in the parietal cortex. Adult and adolescent groups, however, did not differ in activation for this region. Together, these data suggest that Stroop task-related functional development of the parietal lobe occurs by adolescence. In contrast, prefrontal cortex function contributing to the Stroop interference task continues to develop into adulthood. This neuromaturational process may depend on increased ability to recruit focal neural resources with age. Findings from this study, the first developmental fMRI investigation of the Stroop interference task, provide a template with which normal development and neurodevelopmental disorders of prefrontal cortex function can be assessed.

  View details for DOI 10.1006/nimg.2001.1046

  View details for Web of Science ID 000176624700007

  View details for PubMedID 11969318

• Increased gyrification in Williams syndrome: evidence using 3D MRI methods DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Schmitt, J. E., Watts, K., Eliez, S., Galaburda, A. M., Reiss, A. L. 2002; 44 (5): 292-295

  Abstract

  Understanding patterns of gyrification in neurogenetic disorders helps to uncover the neurodevelopmental etiology underlying behavioral phenotypes. This is particularly true in Williams syndrome (WS), a condition caused by de novo deletion of approximately 1 to 2 Mb in the 7q11.23 region. Individuals with WS characteristically possess an unusual dissociation between deficits in visual-spatial ability and relative preservations in language, music, and social drive. A preliminary postmortem study reported anomalous gyri and sulci in individuals with WS. The present study examined gyrification patterns in 17 participants with WS (10 females, 7 males; mean age 28 years 11 months, SD 8 years 6 months) and 17 age- and sex-matched typically developing control participants (mean age 29 years 1 month, SD 8 years 1 month) using new automated techniques in MRI. Significantly increased cortical gyrification was found globally with abnormalities being more marked in the right parietal (p=0.0227), right occipital (p=0.0249), and left frontal (p=0.0086) regions. These results suggest that one or more genes in the 7q11.23 region are involved during the critical period when cortical folding occurs, and may be related to the hypothesized dorsal/ventral dissociation in this condition.

  View details for Web of Science ID 000175692600002

  View details for PubMedID 12033713

• Diurnal salivary cortisol in pediatric posttraumatic stress disorder BIOLOGICAL PSYCHIATRY Carrion, V. G., Weems, C. F., Ray, R. D., Glaser, B., Hessl, D., Reiss, A. L. 2002; 51 (7): 575-582

  Abstract

  The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). Additional information on basal cortisol levels in children exposed to trauma and experiencing PTSD symptoms may contribute to the understanding of the role of this axis in PTSD.Fifty-one children (30 boys and 21 girls, mean age 10.7 years) with a history of exposure to trauma and PTSD symptoms were compared with 31 age- and gender-matched healthy control subjects. Salivary cortisol was obtained from participants during home measurements and was collected four times a day (prebreakfast, prelunch, predinner, and prebed) for up to 3 consecutive days.The clinical group demonstrated significantly elevated cortisol levels when compared with the control group. In addition, exploratory analyses revealed that girls with PTSD symptoms had significantly elevated cortisol levels when compared with boys with PTSD symptoms.The physiologic response of children with history of trauma and with PTSD symptoms may be characterized by heightened adrenal activity.

  View details for PubMedID 11950459

• Relating semantic and episodic memory systems COGNITIVE BRAIN RESEARCH Menon, V., Boyett-Anderson, J. M., Schatzberg, A. F., Reiss, A. L. 2002; 13 (2): 261-265

  Abstract

  Episodic and semantic memory are two forms of declarative memory which appear to function in distinct yet interdependent ways. Here we provide direct evidence for a functional relationship between these two memory systems by showing that left lateral temporal lobe regions involved in semantic memory play an important role in accurate episodic memory retrieval.

  View details for Web of Science ID 000174786000014

  View details for PubMedID 11958970

• Genetic and environmental influences on the cognitive outcomes of children with fragile X syndrome JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Dyer-Friedman, J., Glaser, B., Hessl, D., Johnston, C., Huffman, L. C., Taylor, A., Wisbeck, J., Reiss, A. L. 2002; 41 (3): 237-244

  Abstract

  To measure the genetic and environmental factors influencing the cognitive outcomes in children with fragile X, a common genetic disorder causing cognitive impairments.In-home evaluations were conducted on 120 children (80 boys and 40 girls) with the fragile X full mutation and their unaffected siblings.Multiple regression analyses show that the cognitive outcomes for girls with fragile X are most strongly predicted by the mean IQ of their parents, with a small proportion of the variance accounted for by the quality of their home environment. FMR1 protein (FMRP) was associated with girls' levels of distractibility. Mean parental IQ was associated only with boys' Performance IQs, while FMRP was associated with boys' Full Scale IQs. The quality of boys' home environments accounted for more of the variance in their cognitive outcomes than it did for affected girls.Both biological/genetic factors and environmental factors are significant predictors of IQ in children with fragile X syndrome; however, the influence of specific factors differs between girls and boys. These findings lay the foundation for further investigation into biological and environmental interventions.

  View details for PubMedID 11886017

• fMRI study of cognitive interference processing in females with fragile X syndrome JOURNAL OF COGNITIVE NEUROSCIENCE Tamm, L., Menon, V., Johnston, C. K., Hessl, D. R., Reiss, A. L. 2002; 14 (2): 160-171

  Abstract

  Females with fragile X syndrome, the most common form of inherited developmental and learning problems, are known to be impaired in executive function. The current study is the first to investigate the performance of females with fragile X on a cognitive interference task utilizing functional magnetic resonance imaging (fMRI). Fourteen females with fragile X and 14 age-matched healthy controls were imaged while they performed a counting Stroop interference task. Compared to controls, females with fragile X appeared to have longer reaction times during the interference condition of the task, and adopted a strategy trading speed for accuracy. Females with fragile X also had a significantly different pattern of activation than controls. Whereas controls showed significant activation in the inferior/middle frontal gyrus and inferior/superior parietal lobe, females with fragile X showed more extensive activation in the anterior region of the prefrontal cortex, and failed to show expected activation in the inferior/superior parietal lobe. Further, between-group analyses revealed that females with fragile X had reduced activation in the left orbitofrontal gyrus, thought to be involved in modulating goal-directed behavior. Females with fragile X also demonstrated a markedly different pattern of deactivation from controls. These findings suggest that deficits in cognitive interference processing during the counting Stroop task observed in females with fragile X may arise from inability to appropriately recruit and modulate lateral prefrontal and parietal resources.

  View details for Web of Science ID 000173652000003

  View details for PubMedID 11970783

• Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: Usefulness as phenotypic indicators of schizophrenia risk BIOLOGICAL PSYCHIATRY Feinstein, C., Eliez, S., Blasey, C., Reiss, A. L. 2002; 51 (4): 312-318

  Abstract

  Velocardiofacial syndrome (VCFS), a genetic deletion condition with numerous cognitive sequelae, is associated with a high rate of psychiatric disorders in childhood. More recently, VCFS has been identified as a high-risk factor for developing adult onset schizophrenia. However, it has never been demonstrated that the childhood psychiatric disorders found in children with VCFS differ from those found in children with a similar degree of cognitive impairment. Identification of a specific behavioral (psychiatric) phenotype in childhood VCFS offers the potential for elucidating the symptomatic precursors of adult onset schizophrenia.Twenty-eight children with VCFS and 29 age- and cognitively matched control subjects received a standardized assessment of childhood psychiatric disorders and behaviors measured by the Child Behavior Checklist (CBCL). Findings from the two groups were compared.The rates and types of psychiatric disorder and behavior problems in VCFS and cognitively matched control subjects were very high, but showed no significant differences.Psychopathology in children with VCFS may not differ from that found in cognitively matched control subjects. Another explanation is that subtle phenotypic differences in behavior found in VCFS can not be observed using standard symptom inventories. The high rate of psychopathology in children with VCFS is not a useful phenotypic indicator of high risk for adult onset schizophrenia.

  View details for Web of Science ID 000174281200006

  View details for PubMedID 11958782

• Toward an empirical definition of pediatric PTSD: The phenomenology of PTSD symptoms in youth JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Carrion, V. G., Weems, C. F., Ray, R., Reiss, A. L. 2002; 41 (2): 166-173

  Abstract

  To examine the frequency and intensity of posttraumatic stress disorder (PTSD) symptoms and their relation to clinical impairment, to examine the requirement of meeting all DSM-IV symptom cluster criteria (i.e., criteria B, C, D), and to examine the aggregation of PTSD symptom clusters across developmental stages.Fifty-nine children between the ages of 7 and 14 years with a history of trauma and PTSD symptoms were assessed with the Clinician-Administered PTSD Scale for Children and Adolescents.Data support the utility of distinguishing between the frequency and the intensity of symptoms in the investigation of the phenomenology of pediatric PTSD. Children fulfilling requirements for two symptom clusters did not differ significantly from children meeting all three cluster criteria with regard to impairment and distress. Reexperience (cluster B) showed increased aggregation with avoidance and numbing (cluster C) and hyperarousal (cluster D) in the later stages of puberty.Frequency and intensity of symptoms may both contribute to the phenomenology of pediatric PTSD. Children with subthreshold criteria for PTSD demonstrate substantial functional impairment and distress.

  View details for PubMedID 11837406

• Reduced size of the amygdala in individuals with 47,XXY and 47,XXX Karyotypes AMERICAN JOURNAL OF MEDICAL GENETICS Patwardhan, A. J., Brown, W. E., Bender, B. G., Linden, M. G., Eliz, S., Reiss, A. L. 2002; 114 (1): 93-98

  Abstract

  The excess of 47,XXX and 47,XXY karyotypes found in cytogenetic screening studies of individuals with schizophrenia has given support for an increased risk of psychiatric illness among men and women with sex chromosomal aneuploidy (SCA). Mesial temporal lobe structures, including the amygdala and hippocampus, are thought to be associated with abnormalities of mood and behavior in humans and in the neurobiology of schizophrenia. This study focuses on variations in volumes of mesial temporal lobe structures in men and women with SCA. Utilizing an unselected birth cohort of subjects with SCA and high-resolution magnetic resonance imaging (MRI), we investigated the neuroanatomical consequences of a supernumerary X chromosome on the morphology of the amygdala and hippocampus. Regional and total brain volumes were measured in 10 subjects with 47,XXY, 10 subjects with 47,XXX, and 20 euploid controls. Amygdala volumes were significantly reduced in men with 47,XXY, compared to control men, while the decrease in women with 47,XXX was not as pronounced. Hippocampus volumes were preserved in both groups, compared to same-gender controls. Longitudinal studies of SCA individuals have shown an increased incidence of mild psychopathology and behavioral dysfunction in men with 47,XXY and more overt psychiatric illness in women with 47,XXX, compared to control populations. The alteration in amygdala volumes in individuals with a supernumerary X chromosome may provide a neuroanatomic basis for these findings.

  View details for Web of Science ID 000173133600015

  View details for PubMedID 11840512

• Attenuation of frontal asymmetry in pediatric posttraumatic stress disorder BIOLOGICAL PSYCHIATRY Carrion, V. G., Weems, C. F., Eliez, S., Patwardhan, A., BROWN, W., Ray, R. D., Reiss, A. L. 2001; 50 (12): 943-951

  Abstract

  Volumetric imaging research has shown abnormal brain morphology in adults with posttraumatic stress disorder (PTSD) when compared with matched control subjects. In this article, we present brain imaging findings from a study of children with PTSD symptoms.Twenty-four children between the ages of 7 and 14 with a history of trauma and PTSD symptoms were assessed with the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA). The sample underwent magnetic resonance imaging in a 1.5 T scanner. Brain images were analyzed by raters blind to diagnostic status using well-standardized methods, and images were compared with age- and gender-matched healthy control subjects.The clinical group demonstrated attenuation of frontal lobe asymmetry and smaller total brain and cerebral volumes when compared with the control group. There were no statistically significant differences in hippocampal volume between clinical and control subjects.Frontal lobe abnormalities may occur as a result of PTSD in children or, alternatively, be a risk factor for the development of the syndrome in this age group. The implications of the findings and their consistency with previous research are discussed.

  View details for PubMedID 11750890

• No widespread psychological effect of the fragile X premutation in childhood: Evidence from a preliminary controlled study JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Myers, G. F., Mazzocco, M. M., Maddalena, A., Reiss, A. L. 2001; 22 (6): 353-359

  Abstract

  This study was designed to examine the effect of the fragile X premutation (pM) on cognitive function and behavior. Participants included 14 children (7 males, 7 females) with the fragile X pM and 14 children without the fragile X pM (and without the fragile X full mutation [fM]), each of whom was matched by age and gender with one of the participants from the pM group. The children ranged in age from 3 years, 1 month, to 17 years, 11 months. Participants were individually administered measures of intellectual functioning, academic achievement, and visual motor integration. Parent rating scales of problem behaviors were completed. Group differences were examined using nonparametric statistics. No statistically significant differences were found between the premutation and nonpremutation groups. The results from this study are consistent with the hypothesis that the premutation does not, in general, have an effect on a child's development. However, this does not preclude cases where specific factors may lead to a specific phenotype.

  View details for Web of Science ID 000172745700001

  View details for PubMedID 11773799

• The influence of environmental and genetic factors on behavior problems and autistic symptoms in boys and girls with fragile X syndrome PEDIATRICS Hessl, D., Dyer-Friedman, J., Glaser, B., Wisbeck, J., Barajas, R. G., Taylor, A., Reiss, A. L. 2001; 108 (5)

  Abstract

  Fragile X syndrome, caused by mutations in a single gene of the X chromosome (FMR1), is associated with neurobehavioral characteristics including social deficits with peers, social withdrawal, gaze aversion, inattention, hyperactivity, anxiety, depression, and autistic behavior. However, there is considerable variability in the behavioral and psychiatric problems among children with this condition. The purpose of this study was to measure genetic and environmental factors influencing behavior problems and autistic symptoms in children with fragile X syndrome.We conducted an in-home evaluation of 120 children (80 boys and 40 girls) with the fragile X full mutation and their unaffected siblings, including measurements of the FMR1 protein (FMRP), quality of the home environment, maternal and paternal psychopathology, effectiveness of educational and therapeutic services, and child behavior problems.Results of multiple regression analyses showed that for boys with fragile X, effectiveness of educational and therapeutic services and parental psychological problems predicted internalizing and externalizing types of problems, while the quality of the home environment predicted autistic behavior. For girls with fragile X, the results emphasized significant effects of FMRP on behavior, in particular social withdrawal and anxious/depressed behavior.These findings are among the first to link FMRP expression to behavior. They also emphasize the significance of home- and school-based environmental variables in the neurobehavioral phenotype and help to lay the foundation for studies designed to identify specific interventions for reducing problem behavior in children with fragile X syndrome.

  View details for Web of Science ID 000171925200011

  View details for PubMedID 11694672

• Dorsal forebrain anomaly in Williams syndrome ARCHIVES OF NEUROLOGY Galaburda, A. M., Schmitt, J. E., Atlas, S. W., Eliez, S., Bellugi, U., Reiss, A. L. 2001; 58 (11): 1865-1869

  Abstract

  Williams syndrome (WMS) is a rare neurogenetic condition with a behavioral phenotype that suggests a dorsal and/or ventral developmental dissociation, with deficits in dorsal but not the ventral hemispheric visual stream. A shortened extent of the dorsal central sulcus has been observed in autopsy specimens.To compare gross anatomical features between the dorsal and ventral portions of the cerebral hemispheres by examining the dorsal extent of the central sulcus in brain magnetic resonance images from a sample of subjects with WMS and age- and sex-matched control subjects.Twenty-one subjects having clinically and genetically diagnosed WMS (mean +/- SD age, 28.9 +/- 7.9 years) were compared with 21 age- and sex-matched typically developing controls (mean +/- SD age, 28.8 +/- 7.9 years).High-resolution structural magnetic resonance images were acquired. The extent of the central sulcus was qualitatively assessed via surface projections of the cerebral cortex.The dorsal central sulcus is less likely to reach the interhemispheric fissure in subjects with WMS than in controls for both left (P< .001, chi(2) = 15.79) and right (P< .001, chi(2) = 12.95) hemispheres. No differences between the groups were found in the ventral extent of the central sulcus.Anomalies in the dorsal region in patients with WMS are indicative of early neurodevelopmental problems affecting the development of the dorsal forebrain and are most likely related to the deficits in visuospatial ability and behavioral timing often observed in this condition.

  View details for Web of Science ID 000172055300021

  View details for PubMedID 11708996

• Neurobehavioral phenotype in carriers of the fragile X premutation AMERICAN JOURNAL OF MEDICAL GENETICS Johnston, C., Eliez, S., Dyer-Friedman, J., Hessl, D., Glaser, B., Blasey, C., Taylor, A., Reiss, A. 2001; 103 (4): 314-319

  Abstract

  There have been contradictory findings in the fragile X (fraX) literature about possible neurocognitive and psychological symptoms due to the fraX premutation (pM). The purpose of the present study was to investigate the relationship between CGG repeat length and neurobehavioral functioning in carriers of the fraX pM. Eighty-five female carriers of the pM with allele sizes ranging from 59-166 were administered a comprehensive IQ test (WAIS-III) and completed a questionnaire designed to measure psychopathology (Symptom Checklist (SCL)-90-R). No relationship between allele size and cognition was identified. A significant negative relationship between allele size and age was found, as well as a positive relationship between allele size and depression. Follow-up analyses separating small and large allele sizes (below and above 100 CGG repeats) indicated that individuals with larger allele sizes scored significantly higher on the Interpersonal Sensitivity and Depression subscales of the SCL-90-R. Despite the limitation of few individuals with high CGG repeat lengths, our findings suggest that females with larger premutated alleles (> or = 100 repeats) display some clinical manifestations of fraX syndrome.

  View details for Web of Science ID 000171752600009

  View details for PubMedID 11746012

• Neuroanatomy of Down's syndrome: A high-resolution MRI study AMERICAN JOURNAL OF PSYCHIATRY Pinter, J. D., Eliez, S., Schmitt, J. E., Capone, G. T., Reiss, A. L. 2001; 158 (10): 1659-1665

  Abstract

  Down's syndrome, the most common genetic cause of mental retardation, results in characteristic physical and neuropsychological findings, including mental retardation and deficits in language and memory. This study was undertaken to confirm previously reported abnormalities of regional brain volumes in Down's syndrome by using high-resolution magnetic resonance imaging (MRI), determine whether these volumetric abnormalities are present from childhood, and consider the relationship between neuroanatomic abnormalities and the cognitive profile of Down's syndrome.Sixteen children and young adults with Down's syndrome (age range=5-23 years) were matched for age and gender with 15 normal comparison subjects. High-resolution MRI scans were quantitatively analyzed for measures of overall and regional brain volumes and by tissue composition.Consistent with prior imaging studies, subjects with Down's syndrome had smaller overall brain volumes, with disproportionately smaller cerebellar volumes and relatively larger subcortical gray matter volumes. Also noted was relative preservation of parietal lobe gray and temporal lobe white matter in subjects with Down's syndrome versus comparison subjects. No abnormalities in pattern of brain asymmetry were noted in Down's syndrome subjects.The results largely confirm findings of previous studies with respect to overall patterns of brain volumes in Down's syndrome and also provide new evidence for abnormal volumes of specific regional tissue components. The presence of these abnormalities from an early age suggests that fetal or early postnatal developmental differences may underlie the observed pattern of neuroanatomic abnormalities and contribute to the specific cognitive and developmental deficits seen in individuals with Down's syndrome.

  View details for Web of Science ID 000171374500020

  View details for PubMedID 11578999

• Functional neuroanatomy of visuo-spatial working memory in Turner syndrome HUMAN BRAIN MAPPING Haberecht, M. F., Menon, V., Warsofsky, I. S., White, C. D., Dyer-Friedman, J., Glover, G. H., Neely, E. K., Reiss, A. L. 2001; 14 (2): 96-107

  Abstract

  Turner syndrome (TS), a genetic disorder characterized by the absence of an X chromosome in females, has been associated with cognitive and visuo-spatial processing impairments. We utilized functional MRI (fMRI) to investigate the neural substrates that underlie observed deficits in executive functioning and visuo-spatial processing. Eleven females with TS and 14 typically developing females (ages 7-20) underwent fMRI scanning while performing 1-back and 2-back versions of a standard visuo-spatial working memory (WM) task. On both tasks, TS subjects performed worse than control subjects. Compared with controls, TS subjects showed increased activation in the left and right supramarginal gyrus (SMG) during the 1-back task and decreased activation in these regions during the 2-back task. In addition, decreased activation in the left and right dorsolateral prefrontal cortex (DLPFC) and caudate nucleus was observed during the 2-back task in TS subjects. Activation differences localized to the SMG, in the inferior parietal lobe, may reflect deficits in visuo-spatial encoding and WM storage mechanisms in TS. In addition, deficits in the DLPFC and caudate may be related to deficits in executive function during WM performance. Together these findings point to deficits in frontal-striatal and frontal-parietal circuits subserving multiple WM functions in TS.

  View details for PubMedID 11500993

• BrainImageJ: a Java-based framework for interoperability in neuroscience, with specific application to neuroimaging. Journal of the American Medical Informatics Association Ng, Y. R., Shiffman, S., Brosnan, T. J., Links, J. M., Beach, L. S., Judge, N. S., Xu, Y., Kelkar, U. V., Reiss, A. L. 2001; 8 (5): 431-442

  Abstract

  The Human Brain Project consortium continues to struggle with effective sharing of tools. To facilitate reuse of its tools, the Stanford Psychiatry Neuroimaging Laboratory (SPNL) has developed BrainImageJ, a new software framework in Java. The framework consists of two components-a set of four programming interfaces and an application front end. The four interfaces define extension pathways for new data models, file loaders and savers, algorithms, and visualization tools. Any Java class that implements one of these interfaces qualifies as a BrainImageJ plug-in-a self-contained tool. After automatically detecting and incorporating new plug-ins, the application front end transparently generates graphical user interfaces that provide access to plug-in functionality. New plug-ins interoperate with existing ones immediately through the front end. BrainImageJ is used at the Stanford Psychiatry Neuroimaging Laboratory to develop image-analysis algorithms and three-dimensional visualization tools. It is the goal of our development group that, once the framework is placed in the public domain, it will serve as an interlaboratory platform for designing, distributing, and using interoperable tools.

  View details for PubMedID 11522764

• A java-based framework for interoperability in neuroscience, with specific application to neuroimaging Spring Meeting of the Human Brain Project Ng, Y. R., Shiffman, S., Brosnan, T. J., Links, J. M., Beach, L. S., Judge, N. S., Xu, Y. R., Kelkar, U. V., Reiss, A. L. ELSEVIER SCIENCE INC. 2001: 431–42

  Abstract

  The Human Brain Project consortium continues to struggle with effective sharing of tools. To facilitate reuse of its tools, the Stanford Psychiatry Neuroimaging Laboratory (SPNL) has developed BrainImageJ, a new software framework in Java. The framework consists of two components-a set of four programming interfaces and an application front end. The four interfaces define extension pathways for new data models, file loaders and savers, algorithms, and visualization tools. Any Java class that implements one of these interfaces qualifies as a BrainImageJ plug-in-a self-contained tool. After automatically detecting and incorporating new plug-ins, the application front end transparently generates graphical user interfaces that provide access to plug-in functionality. New plug-ins interoperate with existing ones immediately through the front end. BrainImageJ is used at the Stanford Psychiatry Neuroimaging Laboratory to develop image-analysis algorithms and three-dimensional visualization tools. It is the goal of our development group that, once the framework is placed in the public domain, it will serve as an interlaboratory platform for designing, distributing, and using interoperable tools.

  View details for Web of Science ID 000171031300002

  View details for PubMedCentralID PMC131041

• Brain anatomy, gender and IQ in children and adolescents with fragile X syndrome BRAIN Eliez, S., Blasey, C. M., Freund, L. S., Hastie, T., Reiss, A. L. 2001; 124: 1610-1618

  Abstract

  This study utilized MRI data to describe neuroanatomical morphology in children and adolescents with fragile X syndrome, the most common inherited cause of developmental disability. The syndrome provides a model for understanding how specific genetic factors can influence both neuroanatomy and cognitive capacity. Thirty-seven children and adolescents with fragile X syndrome received an MRI scan and cognitive testing. Scanning procedures and analytical strategies were identical to those reported in an earlier study of 85 typically developing children, permitting a comparison with a previously published template of normal brain development. Regression analyses indicated that there was a normative age-related decrease in grey matter and an increase in white matter. However, caudate and ventricular CSF volumes were significantly enlarged, and caudate volumes decreased with age. Rates of reduction of cortical grey matter were different for males and females. IQ scores were not significantly correlated with volumes of cortical and subcortical grey matter, and these relationships were statistically different from the correlational patterns observed in typically developing children. Children with fragile X syndrome exhibited several typical neurodevelopmental patterns. Aberrations in volumes of subcortical nuclei, gender differences in rates of cortical grey matter reduction and an absence of correlation between grey matter and cognitive performance provided indices of the deleterious effects of the fragile X mutation on the brain's structural organization.

  View details for Web of Science ID 000170453400013

  View details for PubMedID 11459752

• Enlarged cerebellar vermis in Williams syndrome JOURNAL OF PSYCHIATRIC RESEARCH Schmitt, J. E., Eliez, S., Warsofsky, I. S., Bellugi, U., Reiss, A. L. 2001; 35 (4): 225-229

  Abstract

  Williams syndrome (WMS) is a rare genetic disorder characterized by relative preservations of language ability and facial processing despite deficits in overall intelligence, problem solving, and visuospatial processing. Subjects with WMS also display hypersocial behavior and excessive linguistic affect during conversations and when giving narratives. Neuroimaging studies have shown global reductions in the brain volumes of subjects with WMS compared with normal controls, but with preservations in cerebellar volume. This study examines the neuroanatomic structure of the cerebellar vermis in 20 subjects with WMS and 20 age- and gender-matched controls via high-resolution magnetic resonance imaging. The vermis was divided into lobules I-V, VI-VII, and VIII-X. Lobules VI-VII and VIII-X were both relatively enlarged in the WMS group, and after adjusting for the smaller size of the WMS brain, the posterior vermis was significantly larger in WMS (Mann-Whitney z-value=4.27; P<0.001). Given that reductions in posterior vermis size have been implicated in flattened affect and autistic features, increased vermis size in subjects with WMS may be related to the hypersociality and heightened affective expression characteristic of individuals with this genetic condition.

  View details for Web of Science ID 000171268700003

  View details for PubMedID 11578640

• Functional neuroanatomy of visuospatial working memory in fragile X syndrome: Relation to behavioral and molecular measures AMERICAN JOURNAL OF PSYCHIATRY Kwon, H., Menon, V., Eliez, S., Warsofsky, I. S., White, C. D., Dyer-Friedman, J., Taylor, A. K., Glover, G. H., Reiss, A. L. 2001; 158 (7): 1040-1051

  Abstract

  Fragile X syndrome is a neurogenetic disorder that is the most common known heritable cause of neurodevelopmental disability. This study examined the neural substrates of working memory in female subjects with fragile X syndrome. Possible correlations among behavioral measures, brain activation, and the FMR1 gene product (FMRP expression), as well as between IQ and behavioral measures, were investigated.Functional magnetic resonance imaging was used to examine visuospatial working memory in 10 female subjects with fragile X syndrome and 15 typically developing female subjects (ages 10-23 years). Subjects performed standard 1-back and 2-back visuospatial working memory tasks. Brain activation was examined in four regions of the cortex known to play a critical role in visuospatial working memory. Correlations between behavioral, neuroimaging, and molecular measures were examined.Relative to the comparison group, subjects with fragile X syndrome performed significantly worse on the 2-back task but not on the 1-back task. In a region-of-interest analysis focused on the inferior frontal gyrus, middle frontal gyrus, superior parietal lobule, and supramarginal gyrus, comparison subjects showed significantly increased brain activation between the 1-back and 2-back tasks, but subjects with fragile X syndrome showed no change in activation between the two tasks. Significant correlations were found in comparison subjects between activation in the frontal and parietal regions and the rate of correct responses on the 2-back task, but not on the 1-back task. In subjects with fragile X syndrome, significant correlations were found during the 2-back task between FMRP expression and activation in the right inferior and bilateral middle frontal gyri and the bilateral supramarginal gyri.Subjects with fragile X syndrome are unable to modulate activation in the prefrontal and parietal cortex in response to an increasing working memory load, and these deficits are related to a lower level of FMRP expression in fragile X syndrome subjects than in normal comparison subjects. The observed correlations between biological markers and brain activation provide new evidence for links between gene expression and cognition.

  View details for Web of Science ID 000169773000009

  View details for PubMedID 11431225

• Effects of image orientation on the comparability of pediatric brain volumes using three-dimensional MR data JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Patwardhan, A. J., Eliez, S., Warsofsky, I. S., Glover, G. H., White, C. D., Giedd, J. N., Peterson, B. S., Rojas, D. C., Reiss, A. L. 2001; 25 (3): 452-457

  Abstract

  The purpose of this study was to examine the comparability of morphometric measurements made on pediatric data sets collected at five scanner locations, each using variations on a 3D spoiled gradient-recalled echo (SPGR) pulse sequence.Archived MR data from 60 typically developing children were collected and separated into seven groups based on the pulse sequence used. A highly automated image-processing procedure was used to segment the brain data into white tissue, gray tissue, and CSF compartments and into various neuroanatomic regions of interest.Volumetric comparisons between groups revealed differences in areas of the temporal and occipital lobes. These differences were observed when comparing data sets with different image orientations and appeared to be due to partial volume averaging (PVA) and susceptibility-induced geometric distortions.Our results indicate that slice selection and image resolution should be controlled in volumetric studies using aggregated data from multiple centers to minimize the effects of PVA and susceptibility-induced geometric distortions.

  View details for Web of Science ID 000168573200020

  View details for PubMedID 11351198

• Proton MRS of bipolar offspring with bipolar disorder Chang, K. D., Adleman, N., Sachs, N., Dienes, K., Reiss, A., Ketter, T. A. ELSEVIER SCIENCE INC. 2001: 91S–92S

  View details for Web of Science ID 000168163000313

• fMRI of a spatial working memory task in bipolar offspring with bipolar disorder Chang, K. D., Adleman, N., Dienes, K., Ketter, T. A., Reiss, A. ELSEVIER SCIENCE INC. 2001: 25S–26S

  View details for Web of Science ID 000168163000089

• Amygdala and hippocampal volumes in children with Down syndrome: A high-resolution MRI study NEUROLOGY Pinter, J. D., Brown, W. E., Eliez, S., Schmitt, J. E., Capone, G. T., Reiss, A. L. 2001; 56 (7): 972-974

  Abstract

  The objective of this study was to use high-resolution MRI techniques to determine whether children with Down syndrome exhibit decreases in hippocampal and amygdala volumes similar to those demonstrated in recent studies of adults with this condition. When corrected for overall brain volumes, amygdala volumes did not differ between groups but hippocampal volumes were significantly smaller in the Down syndrome group. These findings suggest that the hippocampal volume reduction seen in adults with Down syndrome may be primarily due to early developmental differences rather than neurodegenerative changes.

  View details for Web of Science ID 000167961500026

  View details for PubMedID 11294940

• Preliminary evidence of widespread morphological variations of the brain in dyslexia NEUROLOGY Brown, W. E., Eliez, S., Menon, V., Rumsey, J. M., White, C. D., Reiss, A. L. 2001; 56 (6): 781-783

  Abstract

  The MR images of 16 men with dyslexia and 14 control subjects were compared using a voxel-based analysis. Evidence of decreases in gray matter in dyslexic subjects, most notably in the left temporal lobe and bilaterally in the temporoparietooccipital juncture, but also in the frontal lobe, caudate, thalamus, and cerebellum, was found. Widely distributed morphologic differences affecting several brain regions may contribute to the deficits associated with dyslexia.

  View details for Web of Science ID 000167697100018

  View details for PubMedID 11274316

• A quantitative MRI study of posterior fossa development in velocardiofacial syndrome BIOLOGICAL PSYCHIATRY Eliez, S., Schmitt, J. E., White, C. D., Wellis, V. G., Reiss, A. L. 2001; 49 (6): 540-546

  Abstract

  Velocardiofacial syndrome (VCFS) has been identified as a risk factor for developing schizophrenia. Qualitative neuroimaging studies indicated that VCFS was frequently associated with abnormal development of structures in the posterior fossa of the brain. The objective of this investigation was to identify the specific structures affected in the posterior fossa and investigate the association of these neuroanatomic variations with behaviors potentially related to later-onset psychiatric disorders.Twenty-four children and adolescents with VCFS individually matched for age and gender with 24 control subjects received magnetic resonance imaging scans. Analysis of covariance models were used to investigate regional brain differences. Association between brain areas and behaviors measured on the Child Behavior Checklist (CBCL) were assessed using simple regression models.Children with VCFS had significantly smaller size of vermal lobules VI--VII and the pons after adjusting for overall brain size. There were no significant associations between scores on the CBCL and measures of neuroanatomic variation within the VCFS group.Structural alterations of the posterior fossa in VCFS are specifically limited to cerebellar vermis lobules VI--VII and pons. Previous literature has suggested that the vermis is involved in social cognition, and alteration of lobules VI--VII could therefore partially explain the neurobehavioral profile associated with VCFS.

  View details for Web of Science ID 000167516400007

  View details for PubMedID 11257239

• Velocardiofacial syndrome: Are structural changes in the temporal and mesial temporal regions related to schizophrenia? AMERICAN JOURNAL OF PSYCHIATRY Eliez, S., Blasey, C. M., Schmitt, E. J., White, C. D., Hu, D., Reiss, A. L. 2001; 158 (3): 447-453

  Abstract

  Velocardiofacial syndrome results from a microdeletion on chromosome 22 (22q11.2). Clinical studies indicate that more than 30% of children with the syndrome will develop schizophrenia. The authors sought to determine whether neuroanatomical features in velocardiofacial syndrome are similar to those reported in the literature on schizophrenia by measuring the volumes of the temporal lobe, superior temporal gyrus, and mesial temporal structures in children and adolescents with velocardiofacial syndrome.Twenty-three children and adolescents with velocardiofacial syndrome and 23 comparison subjects, individually matched for age and gender, received brain magnetic resonance imaging (MRI) scans. Analysis of covariance models were used to compare regional brain volumes. Correlations between residualized brain volumes and age were standardized and compared with the Fisher r-to-z transformation.Children with velocardiofacial syndrome had significantly smaller average temporal lobe, superior temporal gyrus, and hippocampal volumes than normal comparison children, although these differences were commensurate with a lower overall brain size in the affected children. In a cross-sectional analysis, children with velocardiofacial syndrome exhibited aberrant volumetric reductions with age that were localized to the temporal lobe and left hippocampal regions.Abnormal temporal lobe and hippocampal development in velocardiofacial syndrome is potentially concordant with MRI findings in the schizophrenia literature. Temporal lobe and mesial temporal structures may represent a shared substrate for the effects of the 22q11.2 deletion and for the complex etiological pathways that lead to schizophrenia. Longitudinal research may help determine which children with velocardiofacial syndrome are at risk for serious psychiatric illness in adulthood.

  View details for Web of Science ID 000167323000017

  View details for PubMedID 11229987

• Corpus callosum morphology of Williams syndrome: relation to genetics and behavior DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Schmitt, J. E., Eliez, S., Warsofsky, I. S., Bellugi, U., Reiss, A. L. 2001; 43 (3): 155-159

  Abstract

  As the largest interhemispheric commissure in the brain, the corpus callosum is of particular interest in disorders that may preferentially affect white matter development such as Williams syndrome (WS). Individuals with WS possess a remarkable array of neurobehavioral peaks and valleys, including deficits in visuospatial ability, mathematics, and attention, but with relative preservation of language and affect. Our study measured the corpus callosum and its primary subdivisions using high-resolution MRI in 20 individuals with WS (13 females and seven males; mean age 28.5, SD 8.3 years; range 19 to 44 years) and 20 age- and sex-matched control participants (mean age 28.5, SD 8.2 years; range 19 to 48 years). Total midsagittal corpus callosum area was reduced (F=4.5, p=0.04, df=36) in the WS population. The area of the splenium (F=12.4, p=0.001, df=36) and isthmus (F=9.4, p=0.004, df=36) were disproportionately reduced in WS beyond the absolute reduction of the entire corpus callosum. These reductions are in concordance with other neuroanatomical findings of decreased parietooccipital volumes as well as the observed visuospatial problems associated with WS.

  View details for Web of Science ID 000167705000003

  View details for PubMedID 11263684

• Error-related brain activation during a Go/NoGo response inhibition task HUMAN BRAIN MAPPING Menon, V., Adleman, N. E., White, C. D., Glover, G. H., Reiss, A. L. 2001; 12 (3): 131-143

  Abstract

  Inhibitory control and performance monitoring are critical executive functions of the human brain. Lesion and imaging studies have shown that the inferior frontal cortex plays an important role in inhibition of inappropriate response. In contrast, specific brain areas involved in error processing and their relation to those implicated in inhibitory control processes are unknown. In this study, we used a random effects model to investigate error-related brain activity associated with failure to inhibit response during a Go/NoGo task. Error-related brain activation was observed in the rostral aspect of the right anterior cingulate (BA 24/32) and adjoining medial prefrontal cortex, the left and right insular cortex and adjoining frontal operculum (BA 47) and left precuneus/posterior cingulate (BA 7/31/29). Brain activation related to response inhibition and competition was observed bilaterally in the dorsolateral prefrontal cortex (BA 9/46), pars triangularis region of the inferior frontal cortex (BA 45/47), premotor cortex (BA 6), inferior parietal lobule (BA 39), lingual gyrus and the caudate, as well as in the right dorsal anterior cingulate cortex (BA 24). These findings provide evidence for a distributed error processing system in the human brain that overlaps partially, but not completely, with brain regions involved in response inhibition and competition. In particular, the rostal anterior cingulate and posterior cingulate/precuneus as well as the left and right anterior insular cortex were activated only during error processing, but not during response competition, inhibition, selection, or execution. Our results also suggest that the brain regions involved in the error processing system overlap with brain areas implicated in the formulation and execution of articulatory plans.

  View details for Web of Science ID 000167259000001

  View details for PubMedID 11170305

• Analysis of cerebral shape in Williams syndrome ARCHIVES OF NEUROLOGY Schmitt, J. E., Eliez, S., Bellugi, U., Reiss, A. L. 2001; 58 (2): 283-287

  Abstract

  As a neurobehavioral disorder with a specific neurocognitive profile and a well-defined genetic etiology, Williams syndrome (WMS) provides an exceptional opportunity to examine associations among measures of behavior, neuroanatomy, and genetics. This study was designed to determine how cerebral shape differs between the brains of subjects with WMS and those of normal controls.Twenty adults with clinically and genetically diagnosed WMS (mean +/- SD age, 28.5 +/- 8.3 years) and 20 healthy, age- and sex-matched controls (mean +/- SD age, 28.5 +/- 8.2 years).High-resolution structural magnetic resonance imaging data were used for shape-based morphological analysis of the right and left cerebral hemispheres and the corpus callosum. Statistical analyses were performed to examine group differences.Both right and left cerebral hemispheres of subjects with WMS bend to a lesser degree in the sagittal plane than normal controls (P<.001). The corpus callosum also bends less in subjects with WMS (P =.05). In addition, subjects with WMS have decreased cerebral (P<.001) and corpus callosum (P<.001) midline lengths.Subjects with WMS have significantly different cerebral shape from normal controls, perhaps due to decreased parieto-occipital lobe volumes relative to frontal regions. The similar observation in the corpus callosum may be associated with a decreased size of the splenium in WMS. These findings may provide important clues to the effect of genes in the WMS-deleted region on brain development.

  View details for Web of Science ID 000166899800015

  View details for PubMedID 11176967

• Parental origin of the deletion 22q11.2 and brain development in velocardiofacial syndrome - A preliminary study ARCHIVES OF GENERAL PSYCHIATRY Eliez, S., Antonarakis, S. E., Morris, M. A., Dahoun, S. P., Reiss, A. L. 2001; 58 (1): 64-68

  Abstract

  As children with velocardiofacial syndrome (VCFS) develop, they are at increased risk for psychopathology; one third will eventually develop schizophrenia. Because VCFS and the concomitant symptomatology result from a known genetic origin, the biological and behavioral characteristics of the syndrome provide an optimal framework for conceptualizing the associations among genes, brain development, and behavior. The purpose of this study was to investigate the effect of the parental origin of the 22q11.2 microdeletion on the brain development of children and adolescents with VCFS.Eighteen persons with VCFS and 18 normal control subjects were matched individually for age and sex. Results of DNA polymorphism analyses determined the parental origin of the deletion. Nine persons with VCFS had a deletion on the maternally derived chromosome 22; 9 persons, on the paternally derived chromosome 22. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of gray and white matter brain tissue.Total brain volume was approximately 11% smaller in the VCFS group than in controls. Comparisons between VCFS subgroups (maternal vs paternal microdeletion 22q11.2) indicated a significant 9% volumetric difference in total volume of cerebral gray matter (volume was greater in patients with paternal microdeletion) but not cerebral white matter. Significant age-related changes in gray matter were detected for subjects whose 22q11.2 deletion was on the maternal chromosome.Children and adolescents with VCFS experience major alterations in brain volumes. Significant reduction in gray matter development is attributable to presence of 22q11.2 microdeletion on the maternal chromosome.

  View details for Web of Science ID 000166349500007

  View details for PubMedID 11146759

• Functional brain imaging study of mathematical reasoning abilities in velocardiofacial syndrome (del22q11.2) GENETICS IN MEDICINE Eliez, S., Blasey, C. M., Menon, V., White, C. D., Schmitt, J. E., Reiss, A. L. 2001; 3 (1): 49-55

  Abstract

  Children with velocardiofacial syndrome (VCFS) often have deficits in mathematical reasoning. Previous research has suggested that structural abnormalities in the parietal lobe region might underlie these deficits. The present study utilized functional magnetic resonance imaging (fMRI) to explore the relationship between brain function and mathematical performance in VCFS.Eight children with VCFS and eight comparison subjects underwent fMRI scanning and completed an arithmetic computation task.In the VCFS group, increased activation was observed in the left supramarginal gyrus (LSMG) as the task difficulty increased.Aberrant LSMG activation, possibly due to structural deficits of the left parietal lobe, may explain decrements in arithmetic performance observed in VCFS.

  View details for Web of Science ID 000167393400011

  View details for PubMedID 11339378

• Enfants et adolescents atteints du syndrome vélo-cardio-facial. Une étude quantitative du développement cérébral à l'aide de l'imagerie par résonance magnétique nucléaire Médecine et hygiène Eliez, S., Schmitt, JE, White CD, Reiss AL 2001; 59: 414-418
• Dissociating prefrontal and parietal cortex activation during arithmetic processing NEUROIMAGE Menon, V., Rivera, S. M., White, C. D., Glover, G. H., Reiss, A. L. 2000; 12 (4): 357-365

  Abstract

  Lesion and brain-imaging studies have implicated the prefrontal and parietal cortices in arithmetic processing, but do not exclude the possibility that these brain areas are also involved in nonarithmetic operations. In the present study, we used functional magnetic resonance imaging to explore which brain areas contribute uniquely to numeric computation. Task difficulty was manipulated in a factorial design by varying the number of operands and the rate of stimulus presentation. Both manipulations increased the number of operations to be performed in unit time. Manipulating the number of operands allowed us to investigate the specific effect of calculation, while manipulating the rate of presentation allowed us to increase task difficulty independent of calculation. We found quantitative changes in activation patterns in the prefrontal and parietal cortices as well as the recruitment of additional brain regions, including the caudate and midcerebellar cortex, with increasing task difficulty. More importantly, the main effect of arithmetic complexity was observed in the left and right angular gyrus, while the main effect of rate of stimulus presentation was observed in the left insular/orbitofrontal cortex. Our findings indicate a dissociation in prefrontal and parietal cortex function during arithmetic processing and further provide the first evidence for a specific role for the angular gyrus in arithmetic computation independent of other processing demands.

  View details for Web of Science ID 000089737000001

  View details for PubMedID 10988030

• Williams syndrome: Genes and pathways responsible for human cognition. Korenberg, J. R., Chen, X. N., Shi, Z. Y., Schmidt, E., Lai, Z., Bellugi, U., Reiss, A., Mills, D., Galaburda, A. CELL PRESS. 2000: 14–14

  View details for Web of Science ID 000089400700021

• Does imprinting influence brain development in X monosomy? Zeng, S. M., Haberecht, M., Eliez, S., Brown, W. E., Warsofsky, I., Yankowitz, J., Reiss, A. L. CELL PRESS. 2000: 112–12

  View details for Web of Science ID 000089400700560

• Analysis of a distributed neural system involved in spatial information, novelty, and memory processing HUMAN BRAIN MAPPING Menon, V., White, C. D., Eliez, S., Glover, G. H., Reiss, A. L. 2000; 11 (2): 117-129

  Abstract

  Perceiving a complex visual scene and encoding it into memory involves a hierarchical distributed network of brain regions, most notably the hippocampus (HIPP), parahippocampal gyrus (PHG), lingual gyrus (LNG), and inferior frontal gyrus (IFG). Lesion and imaging studies in humans have suggested that these regions are involved in spatial information processing as well as novelty and memory encoding; however, the relative contributions of these regions of interest (ROIs) are poorly understood. This study investigated regional dissociations in spatial information and novelty processing in the context of memory encoding using a 2 x 2 factorial design with factors Novelty (novel vs. repeated) and Stimulus (viewing scenes with rich vs. poor spatial information). Greater activation was observed in the right than left hemisphere; however, hemispheric effects did not differ across regions, novelty, or stimulus type. Significant novelty effects were observed in all four regions. A significant ROI x Stimulus interaction was observed - spatial information processing effects were largest effects in the LNG, significant in the PHG and HIPP and nonsignificant in the IFG. Novelty processing was stimulus dependent in the LNG and stimulus independent in the PHG, HIPP, and IFG. Analysis of the profile of Novelty x Stimulus interaction across ROIs provided evidence for a hierarchical independence in novelty processing characterized by increased dissociation from spatial information processing. Despite these differences in spatial information processing, memory performance for novel scenes with rich and poor spatial information was not significantly different. Memory performance was inversely correlated with right IFG activation, suggesting the involvement of this region in strategically flawed encoding effort. Stepwise regression analysis revealed that memory encoding accounted for only a small fraction of the variance (< 16%) in medial temporal lobe activation. The implications of these results for spatial information, novelty, and memory processing in each stage of the distributed network are discussed.

  View details for Web of Science ID 000089712000005

  View details for PubMedID 11061338

• Functional brain activation during cognition is related to FMR1 gene expression BRAIN RESEARCH Menon, V., Kwon, H., Eliez, S., Taylor, A. K., Reiss, A. L. 2000; 877 (2): 367-370

  Abstract

  Fragile X syndrome, the most common known cause of inherited mental retardation, is caused by alterations of the FMR1 gene encoding the FMRP protein. We investigated the relation between FMRP protein levels and functional brain activation during a working memory task. Our study provides the first evidence for a relation between FMR1 gene expression and neural activity during higher-order cognition. More broadly, our findings provide the first demonstration of how gene-brain-behavior investigations can help to bridge the gap between molecular and systems neuroscience.

  View details for Web of Science ID 000089388500029

  View details for PubMedID 10986352

• MRI neuroimaging of childhood psychiatric disorders: a selective review. Journal of child psychology and psychiatry, and allied disciplines Eliez, S., Reiss, A. L. 2000; 41 (6): 679-694

  Abstract

  Over the past 10 years, innovations in physics and computer science have promoted magnetic resonance imaging (MRI) as an essential tool for investigating the biological substrates of psychiatric disorders. Requiring no radiation exposure, MRI is now the preferred imaging technique for pediatric populations. However, the rapid technical advances in MRI pulse sequences, data processing, and analysis have made it increasingly complex for clinicians to compare and critically evaluate MRI research studies. This paper selectively reviews MRI research on five psychiatric conditions occurring in childhood or adolescence: ADHD, autism, childhood-onset schizophrenia, Tourette syndrome, and early-onset depression. The selection of papers reviewed was based on four criteria: the originality of the idea underlying the paper, the quality of the sample and methodologies used, the presence of controversial findings in the paper, and whether the paper was a clear illustration of specific methodological strengths or weaknesses. The two goals of this review paper are to update clinicians on morphometric brain imaging in child psychiatry and the methodological issues pertaining to image acquisition and analysis, and to promote critical reading of future MRI studies.

  View details for PubMedID 11039681

• Annotation: MRI neuroimaging of childhood psychiatric disorders: A selective review JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Eliez, S., Reiss, A. L. 2000; 41 (6): 679-694

  Abstract

  Over the past 10 years, innovations in physics and computer science have promoted magnetic resonance imaging (MRI) as an essential tool for investigating the biological substrates of psychiatric disorders. Requiring no radiation exposure, MRI is now the preferred imaging technique for pediatric populations. However, the rapid technical advances in MRI pulse sequences, data processing, and analysis have made it increasingly complex for clinicians to compare and critically evaluate MRI research studies. This paper selectively reviews MRI research on five psychiatric conditions occurring in childhood or adolescence: ADHD, autism, childhood-onset schizophrenia, Tourette syndrome, and early-onset depression. The selection of papers reviewed was based on four criteria: the originality of the idea underlying the paper, the quality of the sample and methodologies used, the presence of controversial findings in the paper, and whether the paper was a clear illustration of specific methodological strengths or weaknesses. The two goals of this review paper are to update clinicians on morphometric brain imaging in child psychiatry and the methodological issues pertaining to image acquisition and analysis, and to promote critical reading of future MRI studies.

  View details for Web of Science ID 000089630300002

• Realizing the potential of behavioral neurogenetics research in childhood onset neuropsychiatric disorders. Reiss, A. L. WILEY-LISS. 2000: 472–73

  View details for Web of Science ID 000088565900070

• Cortisol and social stressors in children with fragile X: A pilot study JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Wisbeck, J. M., Huffman, L. C., Freund, L., Gunnar, M. R., Davis, E. P., Reiss, A. L. 2000; 21 (4): 278-282

  Abstract

  Evidence of neuroendocrine dysfunction, behavioral features of social anxiety and avoidance, and neuroanatomical abnormalities suggest that abnormal hypothalamic-pituitary-adrenal (HPA) function may be a component of the fragile X (fra X) syndrome. In this preliminary study, salivary cortisol levels of males (n = 8, mean age = 13.5 yr) and females (n = 7, mean age = 13.9 yr) with the fra X full mutation were studied for 3 days. Day 1 was an experimental day, during which subjects experienced a Social Stressor task midmorning. Days 2 and 3 were routine days, during which the subjects were engaged in their typical activities. Saliva samples were collected before breakfast, lunch, dinner, and bedtime. On the experimental day, the prelunch sample collection occurred 30 and 90 minutes after the Social Stressor task. Compared with children's norms, the combined group of males and females with fra X had significantly higher cortisol levels in the prelunch and the prebedtime samples for the routine days. Comparisons between the two fra X groups for the experimental day revealed similar diurnal patterns for cortisol level. However, compared with females with fra X, males with fra X had significantly higher cortisol levels at two points during the day: 30 minutes after the social stressor and at bedtime. These preliminary data suggest that individuals with fra X have abnormal HPA function. Understanding the relations among HPA dysfunction, abnormalities in brain structure and/or function, and maladaptive behavior and cognition in fra X could inform the design of early interventions using pharmacological or environmental measures designed to normalize neuroendocrine function.

  View details for PubMedID 10972251

• Morphological alteration of temporal lobe gray matter in dyslexia: An MRI study JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Eliez, S., Rumsey, J. M., Giedd, J. N., Schmitt, J. E., Patwardhan, A. J., Reiss, A. L. 2000; 41 (5): 637-644

  Abstract

  Functional imaging studies of developmental dyslexia have reported reduced task-related neural activity in the temporal and inferior parietal cortices. To examine the possible contribution of subtle anatomic deviations to these reductions, volumes were measured for the major lobes of the brain, the subcortical nuclei, cerebellum, and lateral ventricles on magnetic resonance imaging (MRI) scans from 16 right-handed dyslexic men, ages 18 to 40, and 14 matched controls, most of whom had previously undergone PET imaging. A specific decrease in tissue volume was localized to the temporal lobes and was particularly prominent on the left (p < .01). An analysis of tissue composition revealed that this reduction was primarily attributable to decreased gray matter within the left temporal lobe (p < .002). Further segmentation of the temporal lobe showed that this reduction was not confined to the superior temporal gyrus, the primary location of primary auditory cortex. Reductions of temporal lobe gray matter may reflect a regional decrease in neuronal number or neuropil, which in turn may result in reading impairment.

  View details for Web of Science ID 000088318300010

  View details for PubMedID 10946755

• Brain morphology in Klinefelter syndrome - Extra X chromosome and testosterone supplementation NEUROLOGY Patwardhan, A. J., Eliez, S., Bender, B., Linden, M. G., Reiss, A. L. 2000; 54 (12): 2218-2223

  Abstract

  This study focuses on variation in brain morphology associated with supernumerary X chromosome and Klinefelter syndrome (KS). Using an unselected birth cohort of KS subjects and high-resolution MRI, the authors investigated the neuroanatomic consequences of the 47,XXY karyotype in the presence and absence of exogenous testosterone supplementation.Regional brain volumes were measured in 10 subjects with KS and 10 age-matched control men. Five of the KS subjects had received testosterone supplementation since puberty (KS+T) and five had not (KS-T).KS subjects showed significant (p < 0.01) reduction in left temporal lobe gray matter volumes compared with normal control subjects. Differences in left temporal gray volumes were also significant between the KS+T and KS-T groups (p < 0.01). Verbal fluency scores were significantly different between the KS+T and KS-T groups as well.Supernumerary X chromosome material in men is associated with a reduction in left temporal lobe gray matter, a finding that is consistent with the verbal and language deficits associated with KS. Also, relative preservation of gray matter in the left temporal region is associated with exposure to exogenous androgen during development. A history of testosterone supplementation also appears to be associated with increased verbal fluency scores in KS patients.

  View details for Web of Science ID 000087804600007

  View details for PubMedID 10881243

• Functional optimization of arithmetic processing in perfect performers COGNITIVE BRAIN RESEARCH Menon, V., Rivera, S. M., White, C. D., Eliez, S., Glover, G. H., Reiss, A. L. 2000; 9 (3): 343-345

  Abstract

  Lesion and imaging studies to date have not clarified which sub-regions of the parietal lobe are specialized for arithmetic processing, and which perform supporting functions. We used functional magnetic resonance imaging to investigate parietal lobe function during arithmetic processing. Functional optimization was examined by analyzing regional differences in brain activation between perfect (100% accuracy) and imperfect performers. Perfect performers had significantly less activation only in the left angular gyrus, a finding that may be associated with skill mastery and long-term practice effects. The present results provide the first direct evidence of localized functional optimization for arithmetic processing in the human brain.

  View details for Web of Science ID 000087193400013

  View details for PubMedID 10808145

• Children and adolescents with velocardiofacial syndrome: A volumetric MRI study AMERICAN JOURNAL OF PSYCHIATRY Eliez, S., Schmitt, J. E., White, C. D., Reiss, A. L. 2000; 157 (3): 409-415

  Abstract

  Velocardiofacial syndrome is a common genetic condition often accompanied by mild cognitive impairment. Children and adolescents with velocardiofacial syndrome also are at greater risk for developing serious neuropsychiatric disorders in adulthood, particularly schizophrenia-like disorders. The purpose of this preliminary study was to 1) elucidate through brain imaging the neurobiological basis of cognitive and neuropsychiatric problems in velocardiofacial syndrome, and 2) consider the association between variations in neuroanatomy in velocardiofacial syndrome subjects and the associated neurobehavioral phenotype.Fifteen children and adolescents with velocardiofacial syndrome were matched by age and gender with 15 comparison subjects. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of specified brain tissues and regions. Rater-blind morphometric analyses were conducted to examine tissue volumes of the four lobes and the cerebellum.Total brain volume was approximately 11% smaller in the children with velocardiofacial syndrome. Gray matter volume was reduced to a lesser extent (7.5%) than white matter volume (16.3%). Multivariate analyses of variance indicated a distinct pattern of regional morphological variation among the children with velocardiofacial syndrome. Specifically, frontal lobe tissue tended to be enlarged relative to the overall reduction in brain volume. Normal symmetry of parietal lobe tissue observed in the comparison group was not evident in the velocardiofacial syndrome group. This loss of symmetry was attributable to a significant reduction of gray matter in the left parietal lobe.Aberrant brain morphology is associated with velocardiofacial syndrome. These changes are potentially related to the language and learning deficits associated with the syndrome and may provide clues about neurodevelopmental pathways associated with schizophrenia.

  View details for Web of Science ID 000085731200014

  View details for PubMedID 10698817

• Generics of childhood disorders: XI. Fragile X syndrome JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Eliez, S., Reiss, A. L. 2000; 39 (2): 264-266

  View details for Web of Science ID 000085031900028

  View details for PubMedID 10673840

• Survey of the fragile X syndrome CGG repeat and the short-tendem-repeat and single-nucleotide-polymorphism haplotypes in an African American population AMERICAN JOURNAL OF HUMAN GENETICS Crawford, D. C., Schwartz, C. E., Meadows, K. L., Newman, J. L., Taft, L. F., Gunter, C., Brown, W. T., Carpenter, N. J., Howard-Peebles, P. N., Monaghan, K. G., Nolin, S. L., Reiss, A. L., Feldman, G. L., Rohlfs, E. M., WARREN, S. T., Sherman, S. L. 2000; 66 (2): 480-493

  Abstract

  Previous studies have shown that specific short-tandem-repeat (STR) and single-nucleotide-polymorphism (SNP)-based haplotypes within and among unaffected and fragile X white populations are found to be associated with specific CGG-repeat patterns. It has been hypothesized that these associations result from different mutational mechanisms, possibly influenced by the CGG structure and/or cis-acting factors. Alternatively, haplotype associations may result from the long mutational history of increasing instability. To understand the basis of the mutational process, we examined the CGG-repeat size, three flanking STR markers (DXS548-FRAXAC1-FRAXAC2), and one SNP (ATL1) spanning 150 kb around the CGG repeat in unaffected (n=637) and fragile X (n=63) African American populations and compared them with unaffected (n=721) and fragile X (n=102) white populations. Several important differences were found between the two ethnic groups. First, in contrast to that seen in the white population, no associations were observed among the African American intermediate or "predisposed" alleles (41-60 repeats). Second, two previously undescribed haplotypes accounted for the majority of the African American fragile X population. Third, a putative "protective" haplotype was not found among African Americans, whereas it was found among whites. Fourth, in contrast to that seen in whites, the SNP ATL1 was in linkage equilibrium among African Americans, and it did not add new information to the STR haplotypes. These data indicate that the STR- and SNP-based haplotype associations identified in whites probably reflect the mutational history of the expansion, rather than a mutational mechanism or pathway.

  View details for Web of Science ID 000088373100015

  View details for PubMedID 10677308

  View details for PubMedCentralID PMC1288101

• Neuroanatomy of Williams syndrome: A high-resolution MRI study JOURNAL OF COGNITIVE NEUROSCIENCE Reiss, A. L., Eliez, S., Schmitt, J. E., Straus, E., Lai, Z., Jones, W., Bellugi, U. 2000; 12: 65-73

  Abstract

  Williams syndrome (WMS), a genetic condition resulting from a contiguous deletion on the long arm of chromosome 7, is associated with a relatively consistent profile of neurocognitive and neurobehavioral features. The distinctiveness and regularity of the profile of learning and behavioral characteristics in this genetic condition suggests that underlying neurobiological correlates may be identifiable. In this initial study, we report findings derived from a high-resolution neuroimaging study of 14 young adult subjects with WMS and an individually matched normal control group. Compared to controls, subjects with WMS were noted to have decreased overall brain and cerebral volumes, relative preservation of cerebellar and superior temporal gyrus (STG) volumes, and disproportionate volume reduction of the brainstem. Analyses also suggested that the pattern of cerebral lobe proportions in WMS may be altered compared to normal controls with a greater ratio of frontal to posterior (parietal+occipital) tissue. Assessment of tissue composition indicated that, relative to controls, individuals with WMS have relative preservation of cerebral gray matter volume and disproportionate reduction in cerebral white matter volume. However, within the cerebral gray matter tissue compartment, the right occipital lobe was noted to have excess volume loss. Combined with our growing knowledge of the function of genes in the commonly deleted region for WMS, more detailed information regarding the structure and function of the WMS brain will provide a unique opportunity for elucidating meaningful correlations amongst genetic, neurobiological, and neurobehavioral factors in humans.

  View details for Web of Science ID 000087725700005

  View details for PubMedID 10953234

• Dissociating prefrontal and parietal cortex activation during arithmetic processing Rivera, S., Menon, V., White, C. D., Reiss, A. L. MIT PRESS. 2000: 104–104

  View details for Web of Science ID 000085813800475

• Functional neuroanatomy of visuospatial working memory in fragile X syndrome: Relation to behavior and FMR-1 protein expression Kwon, H., Menon, V., Eliez, S., Dyer-Friedman, J., Glover, G. H., Reiss, A. L. MIT PRESS. 2000: 146–146

  View details for Web of Science ID 000085813800692

• Gaze processing deficits in fragile X syndrome investigated using fMRI Merin, N. M., Menon, V., White, C. D., Glover, G. H., Reiss, A. L. MIT PRESS. 2000: 57–57

  View details for Web of Science ID 000085813800224

• Brain imaging in neurogenetic conditions: Realizing the potential of behavioral neurogenetics research MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Reiss, A. L., Eliez, S., Schmitt, J. E., Patwardhan, A., Haberecht, M. 2000; 6 (3): 186-197

  Abstract

  Behavioral neurogenetics research is a new method of scientific inquiry that focuses on investigation of neurodevelopmental dysfunction associated with specific genetic conditions. This research method provides a powerful tool for scientific inquiry into human gene-brain-behavior linkages that complements more traditional research approaches. In particular, the use of specific genetic conditions as models of common behavioral and cognitive disorders occurring in the general population can reveal insights into neurodevelopmental pathways that might otherwise be obscured or diluted when investigating more heterogeneous, behaviorally defined subject groups. In this paper, we review five genetic conditions that commonly give rise to identifiable neurodevelopmental and neuropsychiatric disability in children: fragile X syndrome, velo-cardio-facial syndrome, Williams syndrome, Turner syndrome, and Klinefelter syndrome. While emphasis is placed on describing the brain morphology associated with these conditions as revealed by neuroimaging studies, we also include information pertaining to molecular genetic, postmortem, and neurobehavioral investigations to illustrate how behavioral neurogenetics research can contribute to an improved understanding of brain disorders in childhood.

  View details for Web of Science ID 000089075600006

  View details for PubMedID 10982496

• Children's participation in genetic prevalence research: Influences on enrollment and reports of parent satisfaction JOURNAL OF APPLIED SOCIAL PSYCHOLOGY MAZZOCCO, M. M., Myers, G. F., Harum, K. H., Reiss, A. L. 1999; 29 (11): 2308-2327

  View details for Web of Science ID 000084603600006

• Automated Talairach atlas-based parcellation and measurement of cerebral lobes in children PSYCHIATRY RESEARCH-NEUROIMAGING Kates, W. R., Warsofsky, I. S., Patwardhan, A., Abrams, M. T., Liu, A. M., Naidu, S., Kaufmann, W. E., Reiss, A. L. 1999; 91 (1): 11-30

  Abstract

  This study applied a Talairach-based automated parcellation method, originally proposed for adults, to the measurement of lobar brain regions in pediatric study groups. Manual measures of lobar brain regions in a sample of 15 healthy boys, girls and adults were used initially to revise the original Talairach-based grid to increase its applicability to pediatric brains. The applicability of the revised Talairach grid was then tested on an independent sample of five girls with Rett syndrome. As Tables 3 and 4 in the text demonstrate, sensitivity, specificity and positive predictive values either remained unchanged or increased as a result of revising the sectors to fit the brains of children. High levels of sensitivity and specificity were achieved for all revised Talairach-based calculations in relation to the manual measures. Both positive predictive values and intraclass correlations between volumetric measures produced by the revised automated and manual methods varied with the relative size of the brain region. Values were relatively low for smaller structures such as the brainstem and subcortical region, and high for lobar regions. These results suggest that the automated Talairach atlas-based parcellation method can produce sensitive and specific volumetric measures of lobar brain regions in both normal children and children with brain disorders. Accordingly, the method holds much promise for facilitating quantitative pediatric neuroimaging research.

  View details for Web of Science ID 000082458000002

  View details for PubMedID 10496689

• Maximizing the sensitivity of a screening questionnaire for determining fragile X at-risk status 8th International Workshop on the Fragile X Syndrome and X-Linked Mental Retardation Teisl, J. T., Reiss, A. L., MAZZOCCO, M. M. WILEY-LISS. 1999: 281–85

  Abstract

  Parents of 55 preschool and school-aged children with the FMR1 full mutation (fM) completed a brief screening questionnaire. Parents of 55 additional children, each of whom was individually matched for sex, age, and IQ to one of the 55 children with Fragile X syndrome, also completed a questionnaire. Items on the questionnaire concerned behavior, rather than physical features or family history, associated with Fragile X syndrome. Children with the fM were more likely than controls to be on prescription medication, to have poor eye contact, to be described as nervous or anxious, and to regularly engage in repetitive movements and/or repetitive speech. Moreover, children with the fM received higher total scores on the questionnaire than their matched controls. These results suggest that questions about behavior are useful in the diagnostic evaluation of Fragile X syndrome, especially in the absence of the recognizable physical features associated with this condition.

  View details for Web of Science ID 000079339300009

  View details for PubMedID 10208162

• Genotype, molecular phenotype, and cognitive phenotype: Correlations in fragile X syndrome 8th International Workshop on the Fragile X Syndrome and X-Linked Mental Retardation Kaufmann, W. E., Abrams, M. T., Chen, W. M., Reiss, A. L. WILEY-LISS. 1999: 286–95

  Abstract

  The study of the neurobehavioral consequences of mutations of FMR1, the gene responsible for fragile X syndrome (FraX), has been based largely on correlations between mutation patterns and cognitive profile. Following the characterization of FMRP, the FMR1 gene product, preliminary correlations between FMRP levels, and neurologic phenotype have been established. However, most of these investigations have focused on individuals at both ends of the genetic and cognitive spectra of FraX, subjects with normal or premutation (PM) alleles or males with the FMR1 full mutation (FM). The present study is designed to characterize FMRP expression and to correlate it with IQ, in a sample representing a wide spectrum of FMR1 mutations. For this purpose we developed a highly sensitive immunoblotting assay using peripheral leukocytes. Three distinct patterns of FMRP immunoreactivity (-ir) emerged. Individuals with normal (n = 28) and PM (n = 8) alleles as well as most females with the FM (n = 14) showed the highest levels with multiple approximately 70-80 kDa FMRP-ir bands. Males with the FM (n = 10) demonstrated only a 70 kDa FMRP-ir band, and had significantly lower levels when compared with any previous groups. Males with mosaicism and three of 14 females with FM displayed a doublet with equal amounts of the highest and lowest molecular weight FMRP-ir bands. Multiple regression models that adjust for the effect of parental IQ indicated that both activation ratio and FMRP-ir are significantly correlated to subject IQ. We conclude that FMRP-ir offers promise as an indicator of the impact of FMR1 mutations upon neurologic function. Furthermore, our unexpected finding of FMRP-ir in all males with FM suggests that most of them are not transcriptionally silent.

  View details for Web of Science ID 000079339300010

  View details for PubMedID 10208163

• Molecular and cellular genetics of fragile X syndrome AMERICAN JOURNAL OF MEDICAL GENETICS Kaufmann, W. E., Reiss, A. L. 1999; 88 (1): 11-24

  View details for Web of Science ID 000078397400003

  View details for PubMedID 10050961

• Normal Variation in Size of the FMR2next term Gene Is Not Associated With Variation In Intellectual Performance Intelligence Mazzocco, M., Reiss, AL 1999; 27 (2): 175-182
• Normal variation in size of the FMR2 gene is not associated with variation in intellectual performance INTELLIGENCE MAZZOCCO, M. M., Reiss, A. L. 1999; 27 (2): 175-182

  View details for Web of Science ID 000084158400006

• FMR1 gene expression in olfactory neuroblasts from two males with fragile X syndrome AMERICAN JOURNAL OF MEDICAL GENETICS Abrams, M. T., Kaufmann, W. E., Rousseau, F., Oostra, B. A., Wolozin, B., Taylor, C. V., Lishaa, N., Morel, M. L., Hoogeveen, A., Reiss, A. L. 1999; 82 (1): 25-30

  Abstract

  The fragile X mental retardation 1 gene (FMR1) mutation is strongly correlated with specific and marked neurobehavioral and neuroanatomical abnormalities. The protein product, FMRP, is highly expressed in neurons of the normal mammalian brain, and absent or in low levels in leukocytes from individuals with fragile X (FraX)-associated mental impairment. Inferences which arise from these findings are that FMRP has a critical role in the development and functioning of the brain, and that leukocyte-derived molecular assessments provide a good indicator of FMR1 expression in that organ. This latter conclusion appears true in most cases even though the typical FMR1 mutation is an unstable triplet repeat expansion which demonstrates somatic heterogeneity within and across tissues. Blood to brain correspondence in FraX patients has only rarely been confirmed by the direct study of human brain specimens and, to our knowledge, it has never been studied in living individuals with the FMR1 mutation. In this report, we describe the FMR1 patterns in olfactory neuroblasts (ON) from two living brothers with expansion mutations in their leukocytes who are mentally retarded and autistic. ON were chosen for study because they are accessible neurons closely linked to the brain. In both subjects, the ON genotype was highly, but not perfectly, consistent with that observed in leukocytes. Protein phenotypes across tissues were completely consistent showing the absence of FMRP-immunoreactivity (-ir). These results augment the limited amount of direct evidence which indicates that FMR1 mutation patterns in leukocytes are a good, albeit potentially fallible, reflection of such patterns in the brain. This report further demonstrates the feasibility of using ON samples to evaluate the FMR1 mutation in humans in vivo.

  View details for Web of Science ID 000078009200005

  View details for PubMedID 9916838

• Children's Participation in Genetic Prevalence Research: Influences on Enrollment and Reports of Parent Satisfaction Journal of Applied Social Psychology Mazzocco, M., Myers GF, Harum K, Reiss AL 1999; 29 (11): 2308-2327
• Social functioning among girls with fragile X or Turner syndrome and their sisters JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS MAZZOCCO, M. M., Baumgardner, T., Freund, L. S., Reiss, A. L. 1998; 28 (6): 509-517

  Abstract

  Social behaviors among two genetically homogeneous groups--girls with fragile X (fraX) or Turner syndrome (TS)--were examined to address the role of family environment versus biological determinants of social dysfunction in girls with these disorders. Using a sibling pair design, girls with fraX or TS were compared with their own sisters on measures of IQ and social functioning. The 8 girls with fraX and the 9 girls with TS had lower FSIQ scores and higher ratings of social and attention problems relative to their own sisters. Girls with fraX also had higher ratings of withdrawn behaviors, relative to their own sisters. The unaffected sisters were not rated as demonstrating any difficulties in these areas, relative to controls. Correlations between problem ratings and FSIQ were not statistically significant. Although these preliminary findings do not indicate a lack of familial impact on social development in girls with either disorder, the results provide preliminary evidence that social dysfunction reported for girls with fraX or TS cannot be attributed solely, nor primarily, to global aspects of the family environment.

  View details for Web of Science ID 000078364400006

  View details for PubMedID 9932237

• Early detection of social interaction problems: Development of a social interaction instrument in young children JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Ghuman, J. K., Freund, L., Reiss, A., Serwint, J., Folstein, S. 1998; 19 (6): 411-419

  Abstract

  Children with developmental or psychiatric disorders often have problems with social interaction. This study reports on the development of the Ghuman-Folstein Screen for Social Interaction (SSI), a parent/caregiver questionnaire designed to measure the capacity for basic social interaction skills across a variety of contexts in preschool children. The SSI was administered to 51 clinically referred children with a high probability of deficits in social interaction and 60 healthy control subjects to establish reliability and validity. The children were 24 to 61 months of age, with diverse ethnic and socioeconomic backgrounds. Strong internal consistency, significant correlation for test/retest reliability, moderate correlation for interrater reliability and support for external validity of the SSI was established. The SSI scores differentiated between the clinically referred subjects and healthy control subjects and between children with pervasive developmental disorder (PDD) of the autistic type and other non-PDD developmental disorders. The SSI is a relatively simple, efficient, reliable, and valid measure for the capacity for basic social interaction skills in children 24 months to 5 years of age. The SSI has a potential to be useful in primary health care settings to identify children at risk who may need tracking and/or further evaluation and treatment services.

  View details for Web of Science ID 000077469700004

  View details for PubMedID 9866088

• Autism: The point of view from fragile X studies JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Feinstein, C., Reiss, A. L. 1998; 28 (5): 393-405

  Abstract

  The relationship between the fragile X syndrome (FXS) and autism is reviewed. Shortly after the FXS was first described, it was noted that certain behaviors commonly found in afflicted individuals resemble certain features of autism. Research concerning a possible relationship between these conditions is summarized. The outcome of this research indicates that FXS is not a common cause of autism, although the number of individuals with FXS who meet diagnostic criteria for autism is higher than can be accounted for by chance. The major focus of this paper highlights that FXS is a well-defined neurogenetic disease that includes a cognitive behavioral phenotype, and has both a known biological cause and an increasing well-delineated pathogenesis. Autism is a behaviorally defined syndrome whose syndromic boundaries and biological causes are not known. These profound differences complicate comparisons and causal discussions. However, the behavioral neurogenetic information available about FXS suggests certain pathways for future research directed at elucidating the syndrome of autism.

  View details for Web of Science ID 000076763600004

  View details for PubMedID 9813775

• Evaluation of cerebellar size in attention-deficit hyperactivity disorder JOURNAL OF CHILD NEUROLOGY Mostofsky, S. H., Reiss, A. L., Lockhart, P., Denckla, M. B. 1998; 13 (9): 434-439

  Abstract

  Evidence from animal and human research suggests that the cerebellum may play a role in cognition. This includes domains of executive function that are normally attributed to the prefrontal cortex and are typically deficient in individuals with attention-deficit hyperactivity disorder (ADHD). To investigate cerebellar structure in ADHD, magnetic resonance imaging morphometry was used to measure the area of the cerebellar vermis in 12 males with ADHD and 23 male controls matched for age and Wechsler Full-Scale IQ. Analyses were conducted to evaluate group differences, as well as differences between matched pairs of subjects with ADHD and those without ADHD. All measurements were corrected for overall brain size. Both analyses revealed that the size of the posterior vermis was significantly decreased in males with ADHD (P < .05 in both analyses), and that within the posterior vermis, the inferior posterior lobe (lobules VIII-X) was involved in this reduction (P < .05 for group analysis, P < .005 for matched pair analysis), while the superior posterior lobe (lobules VI/VII) was not involved in the reduction. The finding of abnormal inferior posterior vermal size suggests that dysfunction within this region of the cerebellum may underlie clinical deficits seen in individuals with ADHD.

  View details for Web of Science ID 000075512900004

  View details for PubMedID 9733289

• Neuroanatomical and neurocognitive differences in a pair of monozygous twins discordant for strictly defined autism ANNALS OF NEUROLOGY Kates, W. R., Mostofsky, S. H., Zimmerman, A. W., MAZZOCCO, M. M., Landa, R., Warsofsky, I. S., Kaufmann, W. E., Reiss, A. L. 1998; 43 (6): 782-791

  Abstract

  In this study, we investigated the neuroanatomical similarities and differences between a pair of monozygotic, 7.5-year-old twin boys discordant for strictly defined autism, to identify neuroanatomical pathways that are impaired in individuals with autism. Although the unaffected twin did not fulfill the traditional diagnostic criteria for autism, he displayed constrictions in social interaction and play that were consistent with the broader phenotype for autism that has been described in nonautistic co-twins. Magnetic resonance imaging scans were obtained for each brother and compared with the scans of 5 age- and sex-matched unaffected peers. Quantitative analysis of brain anatomy revealed that the affected twin had markedly smaller caudate, amygdaloid, and hippocampal volumes, and smaller cerebellar vermis lobules VI and VII, in comparison with his brother. Both twins evidenced disproportionately reduced volumes of the superior temporal gyrus and the frontal lobe relative to the comparison sample. The results suggest the dysfunction of two separate but overlapping neuroanatomical pathways, ie, one subcortical network differentiating the twins from each other that may underlie the traditional neurobehavioral phenotype for strictly defined autism, and a second cortical network differentiating the twins from the comparison sample that may lead to the broader phenotype for autism.

  View details for Web of Science ID 000074023800012

  View details for PubMedID 9629848

• Edge complexity and partial volume effects JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Links, J. M., Beach, L. S., Subramaniam, B., Rubin, M. A., Hennessey, J. G., Reiss, A. L. 1998; 22 (3): 450-458

  Abstract

  The accuracy of MR brain image segmentation is limited by so-called partial volume effects. We hypothesized that "edge complexity" (i.e., tissue class interface border complexity) significantly influences the magnitude of such effects.To investigate partial volume effects and provide a vehicle for validation of segmentation algorithm accuracy in brain MRI. We developed a computer simulation, the "gigabrain." The simulation is based on interpolated (supersampled) data from actual MR studies. The voxels are assigned to one of five compartments (gray matter, white matter, CSF, fat, or "background"), the compartment interfaces are "jittered" to add high frequency "signal" or "edge complexity," and the voxels are populated with appropriate values determined from human data, low pass filtered (based on the MR scanner's point spread function), and subsampled back to the sampling and voxel size of the original MR data set.In comparison studies with actual phantoms and human MR data, our simulation approach was able to produce images whose appearance and quantitative values were comparable with the actual data, but only when edge complexity was added to the original MR data.Edge complexity is a significant source of partial volume effects. MR simulations must include edge complexity to adequately test segmentation algorithms.

  View details for Web of Science ID 000073590700019

  View details for PubMedID 9606389

• The prevalence of the FMR1 and FMR2 mutations among preschool children with language delay JOURNAL OF PEDIATRICS MAZZOCCO, M. M., Myers, G. F., Hamner, J. L., Panoscha, R., Shapiro, B. K., Reiss, A. L. 1998; 132 (5): 795-801

  Abstract

  We examined the prevalence of the fragile X mental retardation (FMR1) full mutation and fragile X E mutation (FMR2) among preschoolers evaluated for language delay. A total of 534 preschoolers recruited from a Developmental Pediatric or Speech and Language Disorders clinic were tested with Southern blot and polymerase chain reaction DNA analyses; 3 were found to have the FMR1 full mutation. None of the 534 children tested positive for the FMR2 full mutation; however, 3 children had unusually small FMR2 alleles suggestive of FMR2 deletions. Screening for fragile X among language-delayed preschoolers is warranted, particularly when there is a family history of mental retardation, but regardless of sex or the presence of behavioral or physical features associated with the fragile X phenotype. The potential benefit of screening for FMR2 alterations is an unexpected implication of the study and is worthy of continued exploration.

  View details for Web of Science ID 000073610400012

  View details for PubMedID 9602188

• Reliability and validity of an algorithm for fuzzy tissue segmentation of MRI JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Reiss, A. L., Hennessey, J. G., Rubin, M., Beach, L., Abrams, M. T., Warsofsky, I. S., Liu, A. M., Links, J. M. 1998; 22 (3): 471-479

  Abstract

  A new multistep, volumetric-based tissue segmentation algorithm that results in fuzzy (or probabilistic) voxel description is described. This algorithm is designed to accurately segment gray matter, white matter, and CSF and can be applied to both single channel high resolution and multispectral (multiecho) MR images.The reliability and validity of this method are evaluated by assessing (a) the stability of the algorithm across time, rater, and pulse sequence; (b) the accuracy of the method when applied to both real and synthetic image datasets; and (c) differences in specific tissue volumes between individuals with a specific genetic condition (fragile X syndrome) and normal control subjects.The algorithm was found to have high reliability, accuracy, and validity. The finding of increased caudate gray matter volume associated with the fragile X syndrome is replicated in this sample.Since this segmentation approach incorporates "fuzzy" or probabilistic methods, it has the potential to more accurately address partial volume effects, anatomical variation within "pure" tissue compartments, and more subtle changes in tissue volumes as a result of disease and treatment. The method is a component of software that is available in the public domain and has been implemented on an inexpensive personal computer thus offering an attractive and promising method for determining the status and progression of both normal development and pathology of the CNS.

  View details for Web of Science ID 000073590700021

  View details for PubMedID 9606391

• Examination of posterior vermis size in young males with fragile X syndrome Mostofsky, S. H., Reiss, A. L., Freund, L. LIPPINCOTT WILLIAMS & WILKINS. 1998: A86

  View details for Web of Science ID 000073240900244

• Decreased cerebellar posterior vermis size in fragile X syndrome - Correlation with neurocognitive performance NEUROLOGY Mostofsky, S. H., MAZZOCCO, M. M., Aakalu, G., Warsofsky, I. S., Denckla, M. B., Reiss, A. L. 1998; 50 (1): 121-130

  Abstract

  We examined whether posterior vermis size is smaller in individuals with fragile X syndrome (fra X) than in control subjects and whether this decreased size is associated with cognitive performance. Cognitive and behavioral dysfunctions have been identified in fra X; however, underlying neuropathogenic mechanisms remain unclear. MRI was used to investigate the posterior fossa in 32 males with fra X, 28 males with other causes of cognitive disability (CD), and 38 males with normal development (ND) as well as and in 37 females with fra X and 53 female control subjects. Among females with fra X, neurocognitive correlates of posterior vermis size were examined. Posterior vermis size (cross-sectional area) in males with fra X was significantly smaller compared with CD and ND groups, particularly when corrected for intracranial area. Posterior vermis size corrected for intracranial area was significantly smaller in females with fra X compared with control subjects. Compared with males with fra X and non-fra X control subjects, posterior vermis size in females with fra X was intermediate. After statistically removing the effect of mean parental IQ, posterior vermis size predicted a significant proportion of the variance (10 to 23%) of performance on full-scale, verbal, and performance IQ; block design; categories achieved on the Wisconsin Card Sorting Test; and the Rey inventory score. The size of the posterior vermis is significantly decreased in fra X, more so in males than in females. In females with fra X, posterior vermis size predicts performance on selected cognitive measures.

  View details for Web of Science ID 000071486900024

  View details for PubMedID 9443468

• Effective Procedures for Conducting Genetic Prevalence Studies With Children Journal of Applied Social Psychology Mazzocco, M., Sonna NL, Shapiro BK, Pinit A, Reiss AL 1998; 28 (1): 23-40
• Effective procedures for conducting genetic prevalence studies with children JOURNAL OF APPLIED SOCIAL PSYCHOLOGY Mazzocco, M. M., Sonna, N. L., Shapiro, B. K., Pinit, A., Reiss, A. L. 1998; 28 (1): 23-40

  View details for Web of Science ID 000071911200002

• The FMR1 and FMR2 mutations are not common etiologies of academic difficulty among school-age children JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Mazzocco, M. M., Sonna, N. L., Teisl, J. T., Pinit, A., Shapiro, B. K., Shah, N., Reiss, A. L. 1997; 18 (6): 392-398

  Abstract

  The prevalence of the fragile X mental retardation (FMR) 1 and FMR2 full mutations (fM) was examined among 1014 school-age children with academic difficulties but without mental retardation. Both Southern blot and polymerase chain reaction analyses for FMR1 and FMR2 were performed on samples obtained from these children. No fM genes were found, and one FMR1 premutation was identified. The distribution of allele sizes for both genes was comparable to those reported for other clinical and normal population samples. These results suggest that neither the FMR1 nor the FMR2 mutation is a common etiology of academic failure among school-age children without mental retardation and that the prevalence of the FMR1 premutation is no more frequent in children with academic failure than it is in the general population.

  View details for Web of Science ID 000071027400004

  View details for PubMedID 9431501

• Application of an automated parcellation method to the analysis of pediatric brain volumes PSYCHIATRY RESEARCH-NEUROIMAGING Kaplan, D. M., Liu, A. M., Abrams, M. T., Warsofsky, I. S., Kates, W. R., White, C. D., Kaufmann, W. E., Reiss, A. L. 1997; 76 (1): 15-27

  Abstract

  New techniques in quantitative imaging are needed to accelerate understanding of brain development and function in children. In this study we evaluate the reliability and validity of an automated parcellation method for the measurement of large and small brain regions in normal and developmentally disabled children. We utilized an adaptation of the Talairach atlas to semi-automatically quantify brain volumes from 10 children with fragile X syndrome, 10 age- and gender-matched controls and 10 adult controls comparing them to 'gold standard' manually delineated regions. Excellent sensitivity, specificity, intra-class correlation and positive predictive value were achieved for large structures although results were less satisfactory for smaller structures, illustrating the limits of resolution of the method. Statistically significant differences in regional brain volumes were shown between males and females, children and adults, and individuals with fragile X and matched controls. This study demonstrates an automated method which rapidly and accurately quantifies large neuroanatomical structures, but not smaller structures. This method is sufficiently accurate to demonstrate some known anatomical differences in individuals with fragile X; the results suggest that this method could be applied to the assessment of brain volume in other neurodevelopmental disabilities.

  View details for Web of Science ID 000071897300002

  View details for PubMedID 9498306

• Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome PSYCHIATRY RESEARCH-NEUROIMAGING Kates, W. R., Abrams, M. T., Kaufmann, W. E., Breiter, S. N., Reiss, A. L. 1997; 75 (1): 31-48

  Abstract

  Evidence from numerous structural magnetic resonance imaging (MRI) studies has converged to implicate mesial temporal lobe structures in the pathophysiology of several developmental and psychiatric disorders. Efforts to integrate the results of these studies are challenged, however, by the lack of consistency, detail and precision in published protocols for the manual measurement of the amygdala and hippocampus. In this study, we describe a highly detailed, standardized protocol for measuring the amygdala and the hippocampus. Within the context of this protocol, we tested the inter- and intra-rater reliability of two frequently cited methods for normalizing the anatomical position of the amygdala and hippocampus prior to measurement. One method consisted of creating a coronal data set in which images are rotated in a plane perpendicular to the long axis of the hippocampus. The second method consisted of creating a coronal data set in which images are rotated in a plane perpendicular to the axis connecting the anterior and posterior commissures. Inter- and intra-rater reliability coefficients (using the intraclass correlation) ranged from 0.80 to 0.98, indicating that both methods for positional normalization are highly reliable. In addition, we tested the validity of each method by comparing the temporal lobe anatomy of children with fragile X syndrome to a group of unaffected children matched by age and gender. We found that hippocampal volumes in children with fragile X were significantly increased when either rotational method was used. These results replicated previous findings, suggesting that either method can be validly applied to neuronanatomic studies of pediatric populations.

  View details for Web of Science ID A1997XT98400004

  View details for PubMedID 9287372

• Autistic behaviors among girls with fragile X syndrome 4th Consensus for Biological Bases and Clinical Perspectives on Autism MAZZOCCO, M. M., Kates, W. R., Baumgardner, T. L., Freund, L. S., Reiss, A. L. PLENUM PUBL CORP. 1997: 415–35

  Abstract

  Reports of autistic behaviors were examined for 30 school-age girls with fragile X (fraX) and 31 age- and IQ-matched controls through a structured interview administered to each girl's parent(s). IQ scores were obtained for each participant; anxiety, neuroanatomical, and molecular-genetic data were derived for girls with fraX. Girls with fraX had significantly more autistic behaviors than controls. These behaviors were qualitatively similar to those reported for boys with fraX, but were not correlated with IQ. Anxiety in girls with fraX was positively correlated with abnormal social and communication behaviors; posterior cerebellar vermis area was negatively correlated with measures of communication and stereotypic/restricted behaviors. Severity of stereotypic/restricted behaviors was negatively correlated with the prevalence of active non-fraX chromosomes. Thus anxiety and posterior cerebellar area measures had distinct associations with subsets of autistic behaviors; these associations may have important implications for understanding the neurobiology of autism.

  View details for Web of Science ID A1997XP25800006

  View details for PubMedID 9261667

• A Tourette-like syndrome following cardiopulmonary bypass and hypothermia: MRI volumetric measurements MOVEMENT DISORDERS Singer, H. S., DELACRUZ, P. S., Abrams, M. T., BEAN, S. C., Reiss, A. L. 1997; 12 (4): 588-592

  Abstract

  We present the case of an adolescent boy who developed a variety of simple and complex motor and vocal tics (Tourette-like syndrome), along with inattentiveness and obsessive-compulsive behaviors after cardiac surgery with cardiopulmonary bypass and profound hypothermia. A single photon emission computed tomography study 2 months after surgery showed reduced uptake in the left hemisphere and 2 years later a perfusion defect in the basal ganglia. Serial magnetic resonance imaging (MRI) studies were normal. Volumetric MRI studies were obtained 4 years after surgery and compared with published values for normal individuals and children with Tourette syndrome (TS), including subsets matched for age, sex, and handedness. Measurement of basal ganglia structures showed a right-dominant asymmetry of the caudate and putamen, in part similar to findings previously reported in patients with TS. Other volumetric abnormalities included a > 2-SD reduction of cortical gray matter, a small decrease of total cerebral volume, and increase in cerebral white matter. Although a variety of neurological problems may occur after cardiopulmonary bypass, to our knowledge this case represents the first report of a chronic tic disorder following cardiac surgery with cardiopulmonary bypass and hypothermia.

  View details for Web of Science ID A1997XM20000016

  View details for PubMedID 9251079

• Neuroimaging of developmental and genetic disorders CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA Kates, W. R., Kaufmann, W. E., Reiss, A. L. 1997; 6 (2): 283-?

  View details for Web of Science ID A1997WX10900005

• Cognitive, behavioral, and neuroanatomical assessment of two unrelated male children expressing FRAXE AMERICAN JOURNAL OF MEDICAL GENETICS MAZZOCCO, M. M., Knight, S. J., Abrams, M. T., Doheny, K. F., Baumgardner, T. L., Freund, L. S., Davies, K. E., Reiss, A. L. 1997; 74 (1): 73-81

  Abstract

  Standardized cognitive, behavioral, and neuroanatomical data are presented on 2 unrelated boys with the FRAXE (FMR2) GCC expansion mutation. In the context of normal IQ, both boys had a history of developmental delay, including significant problems with communication, attention, and overactivity. Additionally, one child was diagnosed with autistic disorder. Data from these 2 cases are compared to analogous information from previous reports about individuals with the FRAXE or FRAXA (FMR1) mutation. These comparisons support the idea that FRAXE is associated with nonspecific developmental delay and possibly high-functioning autism.

  View details for Web of Science ID A1997WG27300016

  View details for PubMedID 9034011

• Neuroanatomy in Rett syndrome: Cerebral cortex and posterior fossa NEUROLOGY Subramaniam, B., Naidu, S., Reiss, A. L. 1997; 48 (2): 399-407

  Abstract

  Rett syndrome (RS), a neurodevelopmental disorder of unknown etiology occurring almost exclusively in females, is characterized by autistic-like behavior, motor dysfunction, loss of language skills, dementia, and microcephaly. This study is a follow-up and extension of a previously reported neuroimaging study of patients with RS. We replicated previously reported findings with a larger patient population, and the volumetric MRI analysis was extended to include an analysis of neuroanatomy of the posterior fossa. Twenty girls with RS were compared with individually age- and gender-matched normal controls. Patients with RS showed global reduction in gray- and white-matter volumes. The prefrontal, posterior-frontal, and anterior-temporal regions showed the largest bilateral decrease in gray-matter volume, whereas white-matter volume was uniformly reduced throughout the brain. We found confirmation for the preferential reduction in caudate nucleus volume. However, we observed no preferential reduction in midbrain volume despite a preferential reduction in the midsagittal area of this region. We also present an individual case comparison between monozygotic twins discordant for RS.

  View details for Web of Science ID A1997WH53500020

  View details for PubMedID 9040729

• Neurogenetic and Neurodevelopmental Pathways to Learning Disabilities. Learning Disabilities 1997; 8 (1): 31-43
• Normal variation in size of the FMR1 gene is not associated with variation in intellectual performance INTELLIGENCE MAZZOCCO, M. M., Reiss, A. L. 1997; 24 (2): 355-366

  View details for Web of Science ID 000071767400004

• Normal variation in size of the FMR1 gene is not associated with variation in intellectual performance Intelligence Mazzocco, M., Reiss, AL 1997; 24 (2): 355-366
• Brain development, gender and IQ in children - A volumetric imaging study BRAIN Reiss, A. L., Abrams, M. T., Singer, H. S., Ross, J. L., Denckla, M. B. 1996; 119: 1763-1774

  Abstract

  Normal brain development during childhood is a complex and dynamic process for which detailed scientific information is lacking. MRI techniques, combined with methods for advanced image analysis, offer the potential to begin to construct a quantitative map of normal paediatric brain development in vivo. In this study we utilize volumetric analysis of high resolution brain images obtained from MRI to describe cerebral development and morphology in 85 normal children and adolescents ranging in age from 5 to 17 years. The results show that total cerebral volume is 10% larger in boys compared with girls. However, both boys and girls show little change in total cerebral volume after the age of 5 years. Increased cortical grey matter is the primary contributor to larger brain volume in boys, thus supporting the hypothesis that gender associated differences in brain size are related to differences in cortical neuronal density. Prominent, age-related changes in grey matter, white matter and CSF volumes are evident during childhood and appear to reflect ongoing maturation and remodelling of the CNS. Both boys and girls show a similar pattern of cerebral asymmetry; a rightward prominence of cortical and subcortical grey matter and a leftward prominence of CSF is observed. IQ is positively correlated with total cerebral volume in children, in particular, with the volume of cortical grey matter in the prefrontal region of the brain. Subcortical grey matter also contributes to the variance in IQ, although to a lesser extent than cortical grey volume. Quantitative knowledge of the developing human brain will play an increasingly greater role in improving sensitivity and specificity in the interpretation of brain abnormalities in patients within the clinical environment, as well as in groups of children with suspected brain dysfunction in the research setting.

  View details for Web of Science ID A1996VX51400030

  View details for PubMedID 8931596

• Psychiatric disorder in mentally retarded children and adolescents - The challenges of meaningful diagnosis CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA Feinstein, C., Reiss, A. L. 1996; 5 (4): 827-?

  View details for Web of Science ID A1996VP55800007

• Bupropion hydrochloride in attention deficit disorder with hyperactivity JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Conners, C. K., Casat, C. D., GUALTIERI, C. T., Weller, E., Reader, M., Reiss, A., Weller, R. A., Khayrallah, M., Ascher, J. 1996; 35 (10): 1314-1321

  Abstract

  This is a multisite, double-blind, placebo-controlled trial to determine the safety and efficacy of bupropion in the treatment of children with attention deficit disorder with hyperactivity (ADDH).In a four-center, double-blind comparison of bupropion (n = 72) and placebo (n = 37), children aged 6 to 12 years meeting DSM-III criteria for ADDH were randomized to receive bupropion 3 to 6 mg/kg per day or placebo, administered twice daily, at 7 A.M. and 7 P.M. Measures of efficacy included the Conners Parent and Teacher Questionnaires (93-item, 39-item, and 10 item), Clinical Global Impressions Scales of Severity and Improvement, the Sternberg Short-Term Memory Task, and the Continuous Performance Test. Screen and posttreatment physical examinations, electrocardiograms, electroencephalograms, and clinical laboratory evaluations were performed. Height, weight, and vital signs were measured and adverse experiences were assessed weekly.A significant treatment effect, apparent as early as day 3, was present for both conduct problems and hyperactivity on the Conners 10-item and 39-item teacher's checklist, and at day 28 for conduct problems and restless-impulsive behavior on the 93-item parent questionnaire. Findings were of smaller magnitude for parent ratings than teacher ratings. Significant treatment effects were present on both the Continuous Performance Test and memory retrieval test. Effect sizes of bupropion/placebo differences for teacher and parent ratings in this study were somewhat smaller than for standard stimulant drugs used to treat ADDH. Bupropion appeared to be well tolerated in most children. Dermatological reactions were twice as frequent in the drug group as the placebo group, with four reactions involving rash and urticaria that were serious enough to require discontinuation of medication.Bupropion may be a useful addition to available treatments for ADDH. Comparative trials with such standard drugs as methylphenidate are warranted to determine the relative clinical merits of bupropion.

  View details for Web of Science ID A1996VK05500018

  View details for PubMedID 8885585

• Corpus callosum morphology in children with Tourette syndrome and attention deficit hyperactivity disorder NEUROLOGY Baumgardner, T. L., Singer, H. S., Denckla, M. B., Rubin, M. A., Abrams, M. T., COLLI, M. J., Reiss, A. L. 1996; 47 (2): 477-482

  Abstract

  The aim of this study was to investigate the morphology of the corpus callosum (CC) in Tourette syndrome (TS) and attention deficit hyperactivity disorder (ADHD) to determine whether these conditions affect distinct regional differences. Seventy-seven children and adolescents, aged 6 to 16 years, comprised the four research groups--16 patients with TS, 21 patients with TS plus ADHD, 13 patients with ADHD, and 27 unaffected control subjects. A semiautomated, computer-assisted procedure was used to measure the total area, five subregions, centerline length, perimeter, and bending angle of the CC. MRI data were analyzed using several statistical methods, primarily two-tailed analysis of variance to test the effects of TS and ADHD status, while controlling for the influence of age, gender, and total intracranial area (an estimate of brain size). TS was associated with significant increases in the area of four of five subdivisions, the total area, and the perimeter of the CC. ADHD was associated with a significant decrease in the area of the rostral body. There were no interactions between TS and ADHD factors. These findings suggest that the area of the CC is larger in children with TS, and that this difference is independent of age, handedness, intracranial area, and the diagnosis of ADHD. Our findings support hypotheses that the neurobiologic mechanisms in TS and ADHD involve frontal/subcortical circuits.

  View details for Web of Science ID A1996VC63400027

  View details for PubMedID 8757024

• Differential response of psychotic and obsessive symptoms to risperidone in an adolescent JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY DrydenEdwards, R. C., Reiss, A. L. 1996; 6 (2): 139-145

  Abstract

  A 13-year-old boy with psychotic, depressive, and obsessive-compulsive symptoms initially presented with auditory and visual hallucinations and a lifetime of excessive worries about contamination. Family history was significant for schizophrenia and compulsive behavior. When treated with clomipramine 100 mg daily (plasma level 85 ng/mL), obsessive-compulsive symptoms but not the hallucinations improved significantly, and racing thoughts and grandiosity developed later. Haloperidol 0.5 mg daily reduced the psychotic symptoms but was poorly tolerated, and then trifluoperazine 3 mg daily was ineffective, so clomipramine was discontinued (without worsening of OCD symptoms). Trifluoperazine in combination with lithium 1500 mg daily (0.9 meq/L), and then with the addition of carbamazepine 250 mg daily (3.7 micrograms/mL), was only partially helpful. Dose reductions in any medication led to increased psychotic symptoms within days. Trifluoperazine was then replaced by risperidone 3 mg twice daily. Within 2 weeks of starting risperidone, psychotic symptoms ceased but the patient experienced an incapacitating exacerbation of obsessive-compulsive symptoms, experiencing the most severe symptoms in his illness. Sertraline 50 mg reduced the OCD symptoms only briefly. After 5 months on risperidone, risperidone and sertraline were discontinued, and the obsessive-compulsive symptoms significantly decreased within 2 weeks. These clinical observations suggest that even when risperidone has a therapeutic antipsychotic effect, it may exacerbate obsessive-compulsive symptoms in predisposed adolescents.

  View details for Web of Science ID A1996VD56200005

  View details for PubMedID 9231306

• Trajectories and profiles of adaptive behavior in males with fragile X syndrome: Multicenter studies JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Dykens, E., Ort, S., Cohen, I., Finucane, B., Spiridigliozzi, G., Lachiewicz, A., Reiss, A., Freund, L., Hagerman, R., OCONNOR, R. 1996; 26 (3): 287-301

  Abstract

  We conducted two multicenter studies on adaptive trajectories and profiles in males with fragile X syndrome. Study 1 longitudinally assessed 29 males ages 1-20 years using age-equivalent scores from the Vineland Adaptive Behavior Scales. Fragile X boys ages 1-10 years showed significant gains in adaptive skills from first to second testing; males ages 11-20 years were stable in their adaptive development. Study 2 cross-sectionally examined 132 males ages 1-20 years. Significant age-related gains were found in boys ages 1-10, particularly in preschool children. Subjects ages 11-20 showed increased variability and nonsignificant relations between age and adaptive skills. Preliminary findings from 26 young adults with fragile X syndrome ages 21-40 years showed stable age-equivalent adaptive scores during these years. Relative strengths in daily living skills and weaknesses in communication were only evident among older subjects. Significant relations were found between adaptive behavior standard scores and IQ; these two scores also showed age-related declines that likely parallel one another. Findings are related to adaptive features in other genetic syndromes, and to directions for future adaptive behavior research.

  View details for Web of Science ID A1996UP76200002

  View details for PubMedID 8792261

• Neuropsychological status of children with Tourette's syndrome with and without attention deficit hyperactivity disorder NEUROLOGY Schuerholz, L. J., Baumgardner, T. L., Singer, H. S., Reiss, A. L., Denckla, M. B. 1996; 46 (4): 958-965

  Abstract

  To determine the frequency of learning disabilities (LD) and describe the neuropsychological profile of children with Tourette's syndrome (TS) with and without attention deficit hyperactivity disorder (ADHD), we analyzed psychosocial, psychoeducational, and neuropsychological data from 65 children between the ages of 6 and 14 years selected from a larger study of LD. Three groups were formed: TS only, TS+ADHD, and TS +/- ADHD. The third group was composed of children whose ADHD status was not as strongly confirmed by the three different instruments used for ADHD diagnosis. From other (non-TS) research projects in the Center, a comparison group of 27 unaffected siblings who had no diagnosis of ADHD was formed. All children were unmedicated at the time of assessment and had the full set of data available for analysis. LDs were present in 23% of the total TS sample, but LD was not present in the TS-only group. All TS groups had scores at or below 1 SD from the mean on measures of choice reaction time, but the TS-only group was significantly poorer on a measure of executive function (letter word fluency). We discuss the implication of the finding in the TS-only group in terms of a slowing of linguistic productivity.

  View details for Web of Science ID A1996UG63500014

  View details for PubMedID 8780072

• Basal ganglia volumes in children with attention-deficit hyperactivity disorder JOURNAL OF CHILD NEUROLOGY Aylward, E. H., Reiss, A. L., READER, M. J., Singer, H. S., Brown, J. E., Denckla, M. B. 1996; 11 (2): 112-115

  Abstract

  Previous research has demonstrated volume reduction of the left globus pallidus in children with the codiagnoses of Tourette syndrome and attention-deficit hyperactivity disorder (ADHD), in comparison with children who have Tourette syndrome alone and with normal controls. The purpose of this study was to determine whether children with ADHD alone also had volume reduction of the globus pallidus or other basal ganglia structures. Subjects were 10 boys with ADHD, 16 boys with Tourette syndrome and ADHD, and 11 normal control boys. Groups were matched for age. Boys with ADHD were individually matched for age, handedness, and IQ to 10 of the 16 boys with Tourette syndrome and ADHD. Volumes of caudate, putamen, and globus pallidus were measured and corrected for brain volume. The boys with ADHD had significantly smaller left globus pallidus volume and total globus pallidus volume (corrected for brain volume) than the normal controls. The Tourette syndrome plus ADHD group did not differ from the ADHD group on any of the measures. We conclude that small globus pallidus volume, particularly on the left side, is associated with ADHD.

  View details for Web of Science ID A1996UB13300008

  View details for PubMedID 8881987

• Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1 AMERICAN JOURNAL OF MEDICAL GENETICS Denckla, M. B., Hofman, K., MAZZOCCO, M. M., Melhem, E., Reiss, A. L., Bryan, R. N., Harris, E. L., Lee, J., Cox, C. S., Schuerholz, L. J. 1996; 67 (1): 98-102

  Abstract

  To address the controversy regarding the relationship between cognitive impairment (lowering of IQ) and magnetic resonance imaging (MRI) characteristics (T2-weighted hyperintensities or unidentified bright objects [UBOs]) in children with neurofibromatosis-1 (NF-1), we used a pairwise NF-1/ sibling design; we set out to predict the lowering of IQ in each child with NF-1 as a discrepancy from the IQ of an unaffected sibling (D-SIQ). Our multiple regression model included the age of the child with NF-1, familial or sporadic nature of the NF-1, number of locations in the child's brain occupied by T2-weighted hyperintensities (UBOs), and the volumetric percentage of brain tissue occupied by T2-weighted hyperintensities (UBOs). Only the number of locations occupied by UBOs accounted for IQ lowering (D-SIQ) in children with NF-1 (42% of the variance in D-SIQ). This is the first report to confirm that a continuum of lowered IQs in NF-1-affected children exists in relation to the distribution of UBOs (range 0-7), not just presence (vs. absence) of any UBOs.

  View details for Web of Science ID A1996TY40300018

  View details for PubMedID 8678124

• CONTRIBUTION OF THE FMR1 GENE MUTATION TO HUMAN INTELLECTUAL DYSFUNCTION NATURE GENETICS Reiss, A. L., Freund, L. S., Baumgardner, T. L., Abrams, M. T., Denckla, M. B. 1995; 11 (3): 331-334

  Abstract

  The degree to which genetic factors influence human intelligence remains a matter of some controversy. However, there is little doubt that single gene mutations can significantly alter brain development and function. For example, mutations affecting the FMR1 gene cause the fragile X syndrome, the most prevalent known inherited cause of intellectual dysfunction. The most common mutation occurring in the FMR1 locus involves expansion of a trinucleotide (CGG)n repeat sequence within the promoter region of the gene. Between 6 and 54 repeats are typically observed in individuals from the general population. When > or = 200 CGG repeats are present, the expanded repeat sequence and an adjacent CpG island are usually hypermethylated, Aa phenomenon associated with transcriptional silencing of the gene and commonly referred to as the FMR1 full mutation. The intermediate range of repeats (approximately 50 to 200 CGGs), referred to as the premutation, is characterized by the absence of hypermethylation within the promoter region and normal phenotype. Some individuals have a combination of methylated and unmethylated alleles of differing size and are referred to as having mosaic status. Most males with the FMR1 full mutation function in the mentally retarded range of intelligence; in contrast, females with the FMR1 full mutation show a broader range of intelligence, from mental retardation to normal IQ.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1995TC63900025

  View details for PubMedID 7581460

• NEURODEVELOPMENTAL EFFECTS OF X-MONOSOMY - A VOLUMETRIC IMAGING STUDY ANNALS OF NEUROLOGY Reiss, A. L., MAZZOCCO, M. M., Greenlaw, R., Freund, L. S., Ross, J. L. 1995; 38 (5): 731-738

  Abstract

  Thirty girls with Turner syndrome (TuS) were compared with 30 individually age-matched controls on volumetric brain measures derived from magnetic resonance imaging and on measures of psychological functioning. As expected, girls with TuS performed more poorly on visual-spatial and intellectual measures relative to controls, and were rated by their parents as having more significant problems in attention and social behaviors. Although no group differences in overall cerebral or subcortical volumes were observed, the regional distribution of gray and white matter differed across groups in both right and left parietal regions. Differences in total tissue volume ratios were seen for both right and left parietal areas, but differences in individual gray and white matter ratios were seen exclusively in the right parietal regions. In general, girls with TuS had a smaller proportion of tissue (gray and white) within the right and left parietal regions, and a larger proportion of tissue within the right inferior parietal-occipital region relative to girls in the control group. These data suggest a potentially important role for X chromosome genes and/or sex steroids in the development and specialization of brain structure and function.

  View details for Web of Science ID A1995TE95500006

  View details for PubMedID 7486864

• NEUROPSYCHOLOGICAL AND PSYCHOSOCIAL EFFECTS OF THE FMR-1 FULL MUTATION - CASE-REPORT OF MONOZYGOTIC TWINS DISCORDANT FOR THE FRAGILE-X SYNDROME NEUROPSYCHOLOGY MAZZOCCO, M. M., Freund, L. S., Baumgardner, T. L., Forman, L., Reiss, A. L. 1995; 9 (4): 470-480

  View details for Web of Science ID A1995TA64400006

• Preliminary report on cognitive and adaptive behaviors of preschool-aged males with fragile X DEVELOPMENTAL BRAIN DYSFUNCTION Freund, L. S., Peebles, C. D., Aylward, E., Reiss, A. L. 1995; 8 (4-6): 242-251

  View details for Web of Science ID A1995UB47700008

• Quantitative brain imaging studies of fragile X syndrome DEVELOPMENTAL BRAIN DYSFUNCTION Abrams, M. T., Reiss, A. L. 1995; 8 (4-6): 187-198

  View details for Web of Science ID A1995UB47700003

• SPECIFICATION OF THE NEUROBEHAVIORAL PHENOTYPE IN MALES WITH FRAGILE-X SYNDROME PEDIATRICS Baumgardner, T. L., Reiss, A. L., Freund, L. S., Abrams, M. T. 1995; 95 (5): 744-752

  Abstract

  A controlled clinical study was designed to identify the neurobehavioral profile that is specific to males with fragile X syndrome.Thirty-one males with fragile X syndrome and 30 age and IQ-matched male controls were evaluated with instruments that assess multiple domains of adaptive functioning and problem behaviors. The Vineland Adaptive Behavior Scales and the Aberrant Behavior Checklist were selected for their dimensional scaling of behavioral ratings.Parent and Teacher versions of the Aberrant Behavior Checklist demonstrated a profile of behaviors specific to males with fragile X syndrome characterized by significantly higher levels of hyperactivity, stereotypic movements, and unusual speech. The Vineland Adaptive Behavior Scales revealed no fragile X-specific profile of adaptive skills development.The distinct pattern of aberrant behavior observed among males with fragile X emphasizes the importance of drawing subtype distinctions within the classification of individuals with mental retardation on the basis of underlying etiology. For clinical research, specifying the fragile X phenotype is a vital part in the effort to elucidate the neurodevelopmental pathways of normal behavior and psychopathology. Understanding the fragile X symptom pattern is essential for designing symptom-specific treatment interventions, as well as for research into the efficacy of interventions strategies.

  View details for Web of Science ID A1995QW47900023

  View details for PubMedID 7724315

• NEURODEVELOPMENTAL EFFECTS OF THE FMR-1 FULL MUTATION IN HUMANS NATURE MEDICINE Reiss, A. L., Abrams, M. T., Greenlaw, R., Freund, L., Denckla, M. B. 1995; 1 (2): 159-167

  Abstract

  Brain dysfunction is the most important sequelae of the fragile X (FMR-1) mutation, the most common heritable cause of developmental disability. Using magnetic resonance imaging (MRI) and quantitative morphometry, we have compared the neuroanatomy of 51 individuals with an FMR-1 mutation with matched controls and showed that subjects with an FMR-1 mutation have increased volume of the caudate nucleus and, in males, the lateral ventricle. Both caudate and lateral ventricular volumes are correlated with IQ. Caudate volume is also correlated with the methylation status of the FMR-1 gene. Neuroanatomical differences between two monozygotic twins with an FMR-1 mutation who are discordant for mental retardation are localized to the cerebellum, lateral ventricles and subcortical nuclei. These findings suggest that the FMR-1 mutation causing the fragile X syndrome leads to observable changes in neuroanatomy that may be relevant to the neurodevelopmental disability and behavioural problems observed in affected individuals.

  View details for Web of Science ID A1995QX55800028

  View details for PubMedID 7585014

• The neurobiology of fragile X syndrome Mental Retardation and Developmental Disabilities Research Reviews Abrams MT, Reiss AL 1995; 1: 269-275
• Neuropsychological and Psychosocial Effects of the FMR-1 Full Mutation: Case Report of Monozygotic Twins Discordant for the Fragile X Syndrome Neuropsychology Mazzocco, M., Freund LS, Baumgardner TL, Forman F, Reiss AL 1995; 9 (4)
• AN ANALYSIS OF 2 DISCREPANCY-BASED MODELS AND A PROCESSING-DEFICIT APPROACH IN IDENTIFYING LEARNING-DISABILITIES JOURNAL OF LEARNING DISABILITIES Schuerholz, L. J., Harris, E. L., Baumgardner, T. L., Reiss, A. L., Freund, L. S., Church, R. P., Mohr, J., Denckla, M. B. 1995; 28 (1): 18-29

  Abstract

  The incidence of learning disabilities (LD) in a research center sample of 107 boys and 103 girls between 6 and 12 years of age was calculated using Wechsler IQ and Woodcock-Johnson cluster scores in a regression model (REG) and a reliability model (REL). The REL method identified LD three times more often than the REG method, and all those identified by REG were also identified by REL. When stratified by IQ, REG and REL identified similar percentages in the lowest IQ group; however, REG identified at a lower rate as IQ increased. All 87 children identified with reading disabilities (both REL-RD and REG-RD) were weak to a similar extent on phonemic awareness. Comorbid elevated attention ratings were found in 62% of children with RD; 26% had elevated attention ratings but no linguistic processing deficits, and 21% had at least one linguistic processing deficit but no attentionally suspect rating.

  View details for Web of Science ID A1995PY84100003

  View details for PubMedID 7844483

• Preliminary report on cognitive and adaptive behaviors of preschool-aged males with fragile X Developmental Brain Dysfunction Freund LS, Peebles CD, Aylward E, Reiss AL 1995; 8: 242-251
• MAGNETIC-RESONANCE-IMAGING MEASUREMENT OF POSTERIOR-FOSSA STRUCTURES IN SCHIZOPHRENIA AMERICAN JOURNAL OF PSYCHIATRY Aylward, E. H., Reiss, A., Barta, P. E., Tien, A., Han, W., Lee, J., Pearlson, G. D. 1994; 151 (10): 1448-1452

  Abstract

  Previous research has yielded conflicting results regarding the hypothesis that structural abnormalities of the cerebellar vermis and other posterior fossa structures are associated with schizophrenia. The purpose of this study was to apply techniques of measuring posterior fossa structures from magnetic resonance imaging scans that have proven reliable in identifying structural abnormalities in other patient populations.Midsagittal areas of cerebellar vermis and its subsections (anterior vermis, lobules VI-VII, and lobules VIII-X), brainstem (pons, medulla, and midbrain), and fourth ventricle, as well as intracranial area and cortical area, were measured. Subjects included 36 schizophrenic patients and 51 normal comparison subjects. Groups were matched on age, sex, race, and family socioeconomic status.No significant group differences were detected for any posterior fossa structure. When corrected for intracranial area, fourth ventricle area was significantly larger in patients than in the comparison group. Fourth ventricle area was not, however, correlated with any measures of symptom severity.The size of posterior fossa structures is not abnormal in schizophrenia.

  View details for Web of Science ID A1994PJ93700008

  View details for PubMedID 8092338

• LENGTH OF UNINTERRUPTED CGG REPEATS DETERMINES INSTABILITY IN THE FMR1 GENE NATURE GENETICS Eichler, E. E., Holden, J. J., Popovich, B. W., Reiss, A. L., Snow, K., Thibodeau, S. N., Richards, C. S., Ward, P. A., Nelson, D. L. 1994; 8 (1): 88-94

  Abstract

  Analysis of 84 human X chromosomes for the presence of interrupting AGG trinucleotides within the CGG repeat tract of the FMR1 gene revealed that most alleles possess two interspersed AGGs and that the longest tract of uninterrupted CGG repeats is usually found at the 3' end. Variation in the length of the repeat appears polar. Alleles containing between 34 and 55 repeats, with documented unstable transmissions, were shown to have lost one or both AGG interruptions. These comparisons define an instability threshold of 34-38 uninterrupted CGG repeats. Analysis of premutation alleles in Fragile X syndrome carriers reveals that 70% of these alleles contain a single AGG interruption. These data suggest that the loss of an AGG is an important mutational event in the generation of unstable alleles predisposed to the Fragile X syndrome.

  View details for Web of Science ID A1994PE15700021

  View details for PubMedID 7987398

• MOLECULAR-NEUROBEHAVIORAL ASSOCIATIONS IN FEMALES WITH THE FRAGILE-X FULL MUTATION Sixth International Workshop on the Fragile X and X-Linked Mental Retardation Abrams, M. T., Reiss, A. L., Freund, L. S., Baumgardner, T. L., Chase, G. A., Denckla, M. B. WILEY-LISS. 1994: 317–27

  Abstract

  In this study, young females with the fragile X [fra(X)] full mutation (fM) were assessed using quantitative measures of mutation amplification size (Amp) as well as the ratio of active normal X chromosome to total normal X chromosome (activation ratio-AR). Neurobehavioral assessments of females with the fM were performed and included specific and general measures of cognitive and behavioral/developmental functioning. To investigate molecular-behavioral associations, Amp and AR were used as independent variables, while cognitive and behavioral scores were used as dependent variables. Significant correlations were observed between both molecular variables (Amp and AR) and measures of cognitive functioning, with AR showing the most consistent and robust correlations. As AR increased, overall IQ and specific subtest and area scores from the cognitive tests increased. Conversely, as Amp increased, the overall IQ and specific subtest and area cognitive scores decreased. No significant associations were observed between AR or Amp and measures of behavior or development. The molecular-cognitive associations were generally consistent with the cognitive profile previously described in studies comparing females with fra(X) to age-matched controls. Amp and AR were not associated with one another, nor were they associated with the same cluster of cognitive measures. Though this report does not conclusively show that AR and Amp can be used to clinically assess the risk of a female with the fM for cognitive disability, the evidence presented does suggest that these molecular variables, especially AR, reflect important underlying genetic factors contributing to the fra(X) phenotype.

  View details for Web of Science ID A1994NV28200006

  View details for PubMedID 7942994

• NEUROANATOMY OF FRAGILE-X SYNDROME - THE TEMPORAL-LOBE NEUROLOGY Reiss, A. L., Lee, J., Freund, L. 1994; 44 (7): 1317-1324

  Abstract

  Fragile X syndrome, an X-linked genetic disorder caused by a mutation in the FMR-1 gene, is associated with a particular profile of abnormalities of behavior, learning, language, and memory, suggesting temporal lobe dysfunction. We undertook a quantitative neuroimaging study investigating the neuroanatomy of the temporal lobe in individuals with the fragile X mutation. The temporal lobe neuroanatomy of 15 young fragile X subjects was quantified and compared with that of 26 age- and IQ-matched control subjects. Analyses showed the right and left hippocampal volumes to be significantly larger in the fragile X group compared with the control group. Subjects with the fragile X mutation showed an age-related increase in volume of the hippocampus an age-related decrease in volume of the superior temporal gyrus. Along with the findings of previous imaging studies of fragile X subjects, the results of the present investigation are consistent with studies showing a nonrandom distribution of expression of the FMR-1 gene in the developing brain, with increased expression in the cerebellum, hippocampus, and specific cortical regions. The results also suggest involvement of temporal lobe regions in the behavioral and cognitive abnormalities associated with fragile X syndrome.

  View details for Web of Science ID A1994NX63200025

  View details for PubMedID 8035938

• FOLIC-ACID IN NEURODEVELOPMENT AND CHILD-PSYCHIATRY PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Greenblatt, J. M., Huffman, L. C., Reiss, A. L. 1994; 18 (4): 647-660

  Abstract

  1. Folic acid deficiency has been associated with diverse neuropsychiatric symptoms. 2. This paper discusses the impact of folate on brain development, maturation and function and reviews the role of folate in psychiatric disorders, particularly childhood disorders. 3. A brief case report examines the use of folate in the treatment of attentional problems in a child with fragile X syndrome.

  View details for Web of Science ID A1994NX41900002

  View details for PubMedID 7938557

• A BEHAVIORAL NEUROGENETICS APPROACH TO DEVELOPMENTAL-DISABILITIES - GENE-BRAIN-BEHAVIOR ASSOCIATIONS CURRENT OPINION IN NEUROLOGY Baumgardner, T. L., Green, K. E., Reiss, A. L. 1994; 7 (2): 172-178

  Abstract

  This review provides a discussion of behavioral neurogenetics' contribution to understanding neurodevelopmental pathways in learning and developmental disabilities. A brief overview is given of several common neurogenetic disorders with various genetic etiologies including Down syndrome, Turner syndrome, Prader-Willi syndrome, Angelman syndrome, and Tourette's syndrome. Special emphasis is placed on fragile X syndrome as representative of a newly-discovered class of genetic conditions characterized by an unstable trinucleotide repeat. A spectrum of cognitive, behavioral, and social-emotional phenotypic features associated with fragile X syndrome is examined. Also included are findings from recent neuroimaging research and a discussion of the need for the classification of symptoms on the basis of underlying genetic/medical conditions.

  View details for Web of Science ID A1994ND72400013

  View details for PubMedID 8019664

• FREQUENCY AND STABILITY OF THE FRAGILE-X PREMUTATION HUMAN MOLECULAR GENETICS Reiss, A. L., Kazazian, H. H., KREBS, C. M., MCAUGHAN, A., Boehm, C. D., Abrams, M. T., Nelson, D. L. 1994; 3 (3): 393-398

  Abstract

  Although considered the most common heritable cause of neurodevelopmental disability, precise prevalence figures for the FMR1 mutation in the general population are lacking. Since no fragile X premutation alleles have yet been observed to originate from FMR1 alleles within the normal size range, there is also little information available about the origin of the fragile X premutation and mechanisms leading to instability of the FMR1 trinucleotide repeat region. In this study, 977 genetically unrelated individuals from families unselected for mental retardation or fragile X were analyzed with Southern blot analysis for the presence of FMR1 mutations. A subgroup of subjects with evidence of a large CGG repeat number, and any available relatives, were further studied with PCR to investigate the stability of the trinucleotide repeat segment of FMR1. One subject had a 75 repeat length which was unstable (increased in size) when passed to subsequent generations. This includes one male descendent who had a premutation/full mutation mosaic pattern. Two other alleles with > or = 46 repeats from different subjects were also found to be unstable and increased in size in subsequent generations. Considering all three unstable alleles to be indicative of an evolving or actual premutation, the estimated frequency of the fragile X premutation is one in 510 X chromosomes. However, since 11 other alleles with > or = 46 repeats were found to be stable through at least one meiotic transmission, repeat length appears to be an important but not sufficient condition leading to instability of the FMR1 gene.

  View details for Web of Science ID A1994NA58300001

  View details for PubMedID 8012350

• MRI measurement of posterior fossa structures in schizophrenia American Journal of Psychiatry Aylward E, Reiss AL, Barta PE, Tien A, Han W, Lee J, Pearlson GD 1994; 151: 1448-1452
• Genetic disorders and advances Current Opinion in Psychiatry Mazzocco, M., Reiss, AL 1994; 7 (5): 392-396
• NEUROANATOMY OF RETT-SYNDROME - A VOLUMETRIC IMAGING STUDY ANNALS OF NEUROLOGY Reiss, A. L., Faruque, F., Naidu, S., Abrams, M., Beaty, T., Bryan, R. N., Moser, H. 1993; 34 (2): 227-234

  Abstract

  Rett syndrome is a pediatric neurological disorder of unknown etiology defined by the presence of severe neurodevelopment decline, acquired microcephaly, dementia, abnormalities of movement, autistic behavior, and seizures in young female children. In this study, the neuroanatomy of 11 females with Rett syndrome and 15 age- and gender-matched control subjects was investigated in vivo with quantitative neuroimaging techniques. Compared to control subjects, the patients with Rett syndrome were found to have significantly reduced cerebral volume; evidence of greater loss of gray matter in comparison to white matter; regional variation in cortical gray matter, with the frontal regions showing the largest decrease; and reduced volume of the caudate nucleus and midbrain, even when taking into account general reduction in the size of the brain. In addition, there was no evidence of an ongoing degenerative process in this sample of girls with Rett syndrome. The consistency of these data with results from neuropathological investigations points to the need for continued quantitative neuroimaging studies of children with this condition. In particular, research employing serial longitudinal scans of very young children manifesting early signs of the clinical syndrome holds promise for helping to elucidate the neuropathological pathways leading to the debilitating clinical manifestations of Rett syndrome.

  View details for Web of Science ID A1993LR02400018

  View details for PubMedID 8338347

• DNA METHYLATION OF THE FRAGILE-X LOCUS IN SOMATIC AND GERM-CELLS DURING FETAL DEVELOPMENT - RELEVANCE TO THE FRAGILE-X SYNDROME AND X-INACTIVATION SOMATIC CELL AND MOLECULAR GENETICS Luo, S. Y., Robinson, J. C., Reiss, A. L., Migeon, B. R. 1993; 19 (4): 393-404

  Abstract

  To obtain insights into mechanisms responsible for methylation of CpG islands on the inactive X chromosome of normal females, we examined methylation of the fragile X (FraX) locus in a variety of tissues from normal fetuses and adults, and from males with the FraX syndrome. We identified 20 CCGG sites (MspI-HpaII sites M1-M20) within a 12-kb BglII fragment that includes the CpG island. Sites M3-M18, within the 1.2-kb CpG island are unmethylated on the active X in normal males and females at all ages and in all tissues studied. In contrast, these sites are at least partially methylated on the inactive X chromosome in a variety of tissues from normal females by six weeks from conception. The exceptional tissues are chorionic villi and gonads, which are significantly undermethylated. In addition, fetal germ cells are unmethylated at site M3, which is methylated on the inactive X in other tissues; thus, the methylation imprint of the inactive X has been erased. Methylation of the locus on the fragile X chromosome is similar to that of the normal inactive X but is more extensive and less heterogeneous. This suggests that the expansion of the island and the greater number of CpGs that result from amplification of the CGG repeat enhance the methylatibility of the island. Additional studies show that the chromatin of the CpG island is nuclease hypersensitive on the active X but insensitive on both inactive and FraX.

  View details for Web of Science ID A1993LZ82100008

  View details for PubMedID 8211380

• THE EFFECTS OF X-MONOSOMY ON BRAIN-DEVELOPMENT - MONOZYGOTIC TWINS DISCORDANT FOR TURNERS-SYNDROME ANNALS OF NEUROLOGY Reiss, A. L., Freund, L., Plotnick, L., Baumgardner, T., Green, K., SOZER, A. C., Reader, M., BOEHM, C., Denckla, M. B. 1993; 34 (1): 95-107

  Abstract

  Monosomy for the X chromosome is the most frequent cause of Turner's syndrome, a common clinical syndrome associated with particular physical and neurobehavioral features. The results from comprehensive assessment of prepubertal monozygotic female twins discordant for X monosomy are presented. Zygosity was established with DNA Fingerprinting and no evidence of chromosomal mosaicism was seen in either child. Physical features in the affected twin were relatively mild with respect to the full spectrum of physical malformations and disabilities associated with Turner's syndrome. The neurobehavioral phenotypes of the twins were compared. Although both sisters scored in the superior range of intelligence, the affected twin's Performance IQ was 18 points less than her sister, whereas Verbal IQ showed only a 3-point difference between the sisters. Other relative differences were noted within the executive, visuospatial, and visuomotor domains of function. Behavioral evaluation indicated greater problems with attention, hyperactivity, and anxiety in the affected twin. Quantitative analysis of brain anatomy revealed evidence of both general and regional effects of X monosomy on neurodevelopment. Cerebrospinal fluid volume was increased by 25% in the affected twin compared with her sister with a corresponding decrease in gray matter volume. The right frontal, right parietal-occipital, and left parietal-perisylvian regions showed the greatest discrepancy between the sisters with respect to increased cerebrospinal fluid and decreased gray matter volumes in twin with X monosomy. Differences in the posterior fossa were also noted with a 50% relative increase in the volumes of the fourth ventricle and cisterna magna and a 10 to 15% relative reduction in size of the cerebellar vermis, pons, and medulla in the affected twin. The association between the neurobehavioral and neuroanatomical findings in the affected twin is discussed. The unique nature of the naturally occurring genetic phenomenon seen in this twin pair provides an opportunity to more fully elucidate the neurobehavioral phenotype associated with X monosomy and Turner's syndrome.

  View details for Web of Science ID A1993LK40400015

  View details for PubMedID 8517687

• DUAL DIAGNOSES - PSYCHIATRIC-DISORDERS IN DEVELOPMENTAL-DISABILITIES PEDIATRIC CLINICS OF NORTH AMERICA Lovell, R. W., Reiss, A. L. 1993; 40 (3): 579-592

  Abstract

  A high prevalence of psychiatric illness exists in persons with mental retardation. Among children with mild to moderate retardation, psychiatric illnesses resemble those seen in the general population. Major affective disorders, ADHD, and conduct disorder are common and respond to the same interventions used in children without mental retardation. Persons with severe to profound retardation are more likely to engage in stereotypies and self-injurious behaviors. In addition, certain specific syndromes associated with mental retardation present with particular neurocognitive, behavioral, and psychiatric profiles. Common examples are fetal alcohol syndrome, Down syndrome, fragile X syndrome, and Rett syndrome. Specific challenges exist for pediatricians who diagnose and treat patients with mental retardation and psychiatric illness. The child's impaired ability to communicate his or her thoughts and feelings with words makes clinical history taking difficult. The clinician must frequently rely on the observation of family members and teachers. An understanding of developmental profiles and interpersonal, peer, and family dynamics is important. Specific behaviors must be targeted and realistic objectives set in treatment planning, which may include psychotherapy, medication, behavior management techniques, and rehabilitation therapy.

  View details for Web of Science ID A1993LD17300010

  View details for PubMedID 7684122

• NEUROBEHAVIORAL EFFECTS OF THE FRAGILE-X PREMUTATION IN ADULT WOMEN - A CONTROLLED-STUDY AMERICAN JOURNAL OF HUMAN GENETICS Reiss, A. L., Freund, L., Abrams, M. T., BOEHM, C., Kazazian, H. 1993; 52 (5): 884-894

  Abstract

  Although previous studies have suggested that the fragile X premutation (fra [X] pM) does not cause deleterious effects, methodological constraints have prevented more definitive conclusions from being reached. In this report, we describe the neuropsychiatric and cognitive-neuropsychological status of 34 adult women with the fra (X) pM, as compared with a well-matched control group of 41 mothers of fra (X)-negative children with developmental disability. The results indicate that there are no meaningful differences between adult women with the fra (X) pM and control subjects with respect to cognitive abilities or profile, neuropsychological function, psychiatric diagnoses or symptoms, and self-rated personality profile. No measure for either group showed evidence of functioning outside the normal range except for a high lifetime prevalence of major depression in both groups. Additional exploratory analyses within the fra (X) group showed no significant effect of either the size of the fra (X) insert or X chromosome inactivation pattern in leukocytes, on any measure of neurobehavioral function. These findings provide additional information to professionals providing genetic counseling to, and assessment of, fra (X) families.

  View details for Web of Science ID A1993LB88900005

  View details for PubMedID 8488838

• VOLUMETRIC MRI CHANGES IN BASAL GANGLIA OF CHILDREN WITH TOURETTES-SYNDROME NEUROLOGY Singer, H. S., Reiss, A. L., Brown, J. E., Aylward, E. H., Shih, B., Chee, E., Harris, E. L., READER, M. J., Chase, G. A., Bryan, R. N., Denckla, M. B. 1993; 43 (5): 950-956

  Abstract

  To define the site of pathology in Tourette's syndrome (TS), we performed a volumetric MRI study of basal ganglia structures and lateral ventricles on 37 children with this disorder and 18 controls. There were no statistically significant differences in the size of the right or left caudate, putamen, globus pallidus, or ventricles in these populations. In contrast, there were significant differences for measures of symmetry in the putamen and the lenticular region. Virtually all controls (17 right- and one left-handed) had a left-sided predominance of the putamen, whereas in 13 of 37 TS subjects, a right predominance exceeded that of any control. Statistical comparisons among TS patients, with (n = 18) or without (n = 19) attention-deficit hyperactivity disorder (ADHD), and controls showed significant differences for the volume of the left globus pallidus and for lenticular asymmetry. Post hoc evaluations showed that in the TS + ADHD group, the volume of the left globus pallidus was significantly smaller than the volume of the right and that lenticular asymmetry was due to a greater right-sided predominance in the TS+ADHD group. This study lends further support to proposals that claim the basal ganglia is involved in the pathogenesis of TS and also suggests that the comorbid problem of ADHD is related to regional changes that differ from those primarily associated with tics.

  View details for Web of Science ID A1993LC36300020

  View details for PubMedID 8492951

• PSYCHIATRIC-DISORDERS ASSOCIATED WITH FRAGILE-X IN THE YOUNG FEMALE PEDIATRICS Freund, L. S., Reiss, A. L., Abrams, M. T. 1993; 91 (2): 321-329

  Abstract

  Seventeen females with the fragile X mutation and 17 non-fragile X females group-matched on age (range 4 to 27 years), IQ (range 34 to 126), and socioeconomic status were compared on Diagnostic and Statistical Manual of Mental Disorders (3rd ed, revised) criteria for selected psychiatric disorders. Additional comparisons were made on level of social development and parent and teacher ratings of maladaptive behaviors. Correlations of genetic testing data with psychiatric and behavioral variables were investigated. Consistent with hypotheses, females with the fragile X mutation showed a greater frequency of avoidant disorder and mood disorders compared with control subjects. Females with the fragile X mutation also showed greater frequency of stereotypy/habit disorder when compared with control subjects. Contrary to predictions, females with the fragile X mutation did not show higher frequencies of attention deficit hyperactivity disorder or undifferentiated attention deficit. They showed greater deficits in their interpersonal socialization skills and were rated by their parents and teachers as significantly more withdrawn and depressed when compared with control subjects. The size of the DNA insertion associated with the genetic abnormality was correlated with IQ, severity of attention problems, and anxiety/withdrawal symptoms. Evidence from this study points to an association between a specific genetic syndrome and characteristic developmental and psychiatric difficulties. Implications for the clinician are discussed.

  View details for Web of Science ID A1993KK57800008

  View details for PubMedID 8380924

• BIPOLAR SPECTRUM DISORDER AND FRAGILE-X SYNDROME - A FAMILY STUDY BIOLOGICAL PSYCHIATRY JEFFRIES, F. M., Reiss, A. L., Brown, W. T., Meyers, D. A., GLICKSMAN, A. C., Bandyopadhyay, S. 1993; 33 (3): 213-216

  View details for Web of Science ID A1993KR26300012

  View details for PubMedID 8448271

• NEUROCOGNITIVE FUNCTION AND BRAIN IMAGING IN TURNER SYNDROME - PRELIMINARY-RESULTS HORMONE RESEARCH Ross, J. L., Reiss, A. L., Freund, L., Roeltgen, D., Cutler, G. B. 1993; 39: 65-69

  Abstract

  Girls with Turner syndrome were investigated in order to determine the anatomical differences in their brains compared with those of normal age-matched female controls, and to relate these differences to deficits in neurocognitive function with a view to understanding the abnormal brain development in Turner syndrome. During the 2-year study period, it is planned to evaluate 50 girls with Turner syndrome and 50 age-matched controls. A wide range of authentic neurocognitive tests will be applied to establish the neurocognitive profile, and brain anatomy will be studied by magnetic resonance imaging (MRI). Ten patients with Turner syndrome have been evaluated by neurocognitive testing to date, and 8 girls with Turner syndrome and 13 controls have had MRI scans performed. There is preliminary evidence of both specific and generalized processes affecting brain development and cognitive function in Turner syndrome. The evidence of a role for sex hormones in socio-behavioural and cognitive abilities in Turner syndrome is discussed.

  View details for Web of Science ID A1993LN15200016

  View details for PubMedID 8359792

• BRIEF SCREENING QUESTIONNAIRE FOR DETERMINING AFFECTED STATE IN FRAGILE-X SYNDROME - A CONSENSUS RECOMMENDATION AMERICAN JOURNAL OF MEDICAL GENETICS Reiss, A. L., Cianchetti, C., Cohen, I. L., DeVries, B., Hagerman, R., Hinton, V., Froster, U., Lachiewicz, A., Mazzocco, M., Sobesky, W., Sudhalter, V. 1992; 43 (1-2): 61-64

  Abstract

  New molecular research has provided strong evidence for different forms of the fragile X mutation. These findings suggest the need to develop a more standardized and sensitive method for determining neurobehavioral effects of the fragile X gene(s), particularly for molecular studies of patients who do not have obvious mental retardation. This report describes a brief screening questionnaire designed to increase the detection of neurobehavioral dysfunction in individuals from fragile X families who are included in new molecular studies. Improved detection of the affected state in fragile X syndrome will allow more valid clinical data to be correlated with the important molecular information currently being collected.

  View details for Web of Science ID A1992HT25900008

  View details for PubMedID 1605236

• BEHAVIORAL-PHENOTYPE OF FRAGILE-X SYNDROME - DSM-III-R AUTISTIC BEHAVIOR IN MALE-CHILDREN AMERICAN JOURNAL OF MEDICAL GENETICS Reiss, A. L., Freund, L. 1992; 43 (1-2): 35-46

  Abstract

  Comparison of 34 fragile X [(fra(X)] male children (age 3-18 years) with 32 IQ- and age-matched, non-fra(X) male control children was conducted using specific DSM-III-R criteria for autism. Statistical analyses supported predictions that fra(X) males show increased dysfunction in peer social play, nonverbal communication (e.g., gaze aversion, gesturing), verbal communication (e.g., rate, volume, word/phrase perseveration), and repetitive motor behaviors (e.g., handflapping, rocking). There was a trend for fra(X) children to show abnormal responsivity to sensory stimuli as well such as oversensitivity to sound and increased mouthing or smelling of objects. The investigation supports the contention that fra(X) males manifest a specific subset of behaviors from the autistic spectrum. Implications for treatment are discussed.

  View details for Web of Science ID A1992HT25900005

  View details for PubMedID 1605210

• THE MESIAL-TEMPORAL LOBE AND AUTISM - CASE-REPORT AND REVIEW DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Hoon, A. H., Reiss, A. L. 1992; 34 (3): 252-259

  Abstract

  Human and non-human primate research has shown that pathological processes affecting the temporal lobe, particularly the amygdala and hippocampus, are related to the development of the autistic syndrome. This case report describes a young male child with left temporal oligodendroglioma, who demonstrated a constellation of autistic behaviors meeting DSM-III-R criteria for pervasive developmental disorder. Abnormalities in social interaction, affective expression and communication were particularly evident. Some of the symptoms improved after tumor resection, while other signs of qualitative abnormalities in development emerged or persisted. This case adds evidence to the hypothesis that damage to mesial-temporal structures at an early developmental period may lead to the autistic syndrome.

  View details for Web of Science ID A1992HE19600009

  View details for PubMedID 1559605

• CHROMOSOMAL DISORDERS - BACKGROUND AND NEURORADIOLOGY AMERICAN JOURNAL OF NEURORADIOLOGY Kumar, A. J., Naidich, T. P., Stetten, G., Reiss, A. L., Wang, H., Thomas, G. H., Hurko, O. 1992; 13 (2): 577-593

  View details for Web of Science ID A1992HH84800012

  View details for PubMedID 1533086

• CLINICAL, BIOCHEMICAL, AND NEUROPSYCHIATRIC EVALUATION OF A PATIENT WITH A CONTIGUOUS GENE SYNDROME DUE TO A MICRODELETION XP11.3 INCLUDING THE NORRIE DISEASE LOCUS AND MONOAMINE-OXIDASE (MAOA AND MAOB) GENES AMERICAN JOURNAL OF MEDICAL GENETICS Collins, F. A., Murphy, D. L., Reiss, A. L., Sims, K. B., Lewis, J. G., Freund, L., Karoum, F., Zhu, D. P., Maumenee, I. H., Antonarakis, S. E. 1992; 42 (1): 127-134

  Abstract

  Norrie disease is a rare X-linked recessive disorder characterized by blindness from infancy. The gene for Norrie disease has been localized to Xp11.3. More recently, the genes for monoamine oxidase (MAOA, MAOB) have been mapped to the same region. This study evaluates the clinical, biochemical, and neuropsychiatric data in an affected male and 2 obligate heterozygote females from a single family with a submicroscopic deletion involving Norrie disease and MAO genes. The propositus was a profoundly retarded, blind male; he also had neurologic abnormalities including myoclonus and stereotopy-habit disorder. Both obligate carrier females had a normal IQ. The propositus' mother met diagnostic criteria for "chronic hypomania and schizotypal features." The propositus' MAO activity was undetectable and the female heterozygotes had reduced levels comparable to patients receiving MAO inhibiting antidepressants. MAO substrate and metabolite abnormalities were found in the propositus' plasma and CSF. This study indicates that subtle biochemical and possibly neuropsychiatric abnormalities may be detected in some heterozygotes with the microdeletion in Xp11.3 due to loss of the gene product for the MAO genes; this deletion can also explain some of the complex phenotype of this contiguous gene syndrome in the propositus.

  View details for Web of Science ID A1992GW60700025

  View details for PubMedID 1308352

• The psychological effects associated with fragile x syndrome Current Opinion in Pediatrics Baumgardner T, Green K, Reiss AL 1992; 4 (4): 609-615
• CHROMOSOME FRAGILITY AND PSYCHOPATHOLOGY IN OBLIGATE FEMALE CARRIERS OF THE FRAGILE X-CHROMOSOME ARCHIVES OF GENERAL PSYCHIATRY Freund, L. S., Reiss, A. L., Hagerman, R., Vinogradov, S. 1992; 49 (1): 54-60

  Abstract

  The relationship between fragility (the percentage of cells exhibiting the fragile X chromosome abnormality) and psychopathological conditions was investigated in a sample of 40 obligate female carriers of the fragile X chromosome. Subjects were categorized by those with positive fragility greater than 0% (n = 19) and those with 0% fragility (n = 21). Compared with women with 0% fragility, it was expected that women with positive fragility would have a higher likelihood of manifesting a spectrum of social and psychological disability previously shown to be associated with fragile X syndrome in women. It was also expected that within the group with positive fragility, degree of fragility would be related to severity of symptoms. Results partially supported the hypotheses: women with fragility over 0% were more likely to be assigned a diagnosis of schizotypal features, were rated higher on symptoms associated with the schizophrenia spectrum, and scored lower on IQ, level of healthiest functioning, education, and socioeconomic status than women with 0% fragility. Subsequent comparisons with a control group indicated that the group with 0% fragility and normal controls did not differ on these variables. Within the group with positive fragility, increasing fragility was related to greater severity of symptoms and lower IQ, education, socioeconomic status, and levels of adaptive functioning, as predicted. Contrary to expectations, positive fragility was not associated with proportion of affective disorder diagnoses or ratings on affective disorder symptoms. The results of the study provide evidence that degree of fragility is a potentially important predictor of psychopathology among women with normal IQ who are carriers of the fragile X chromosome abnormality.

  View details for Web of Science ID A1992GY80000006

  View details for PubMedID 1728251

• 49,XXXXY SYNDROME - BEHAVIORAL AND DEVELOPMENTAL PROFILES JOURNAL OF MEDICAL GENETICS LOMELINO, C. A., Reiss, A. L. 1991; 28 (9): 609-612

  Abstract

  Behavioural, psychological, and cognitive profiles of three cases, including a 5 year old male with a 49,XXXXY karyotype and a (3;15) translocation, a 9 year old male with a 49,XXXXY karyotype, and a 32 year old male with 48,XXXY/49,XXXXY mosaicism, are presented. Significant behavioural problems were seen in the two older patients. The degree of mental retardation and impairment of language abilities were shown to be more severe in the older subjects as well. These findings are discussed with respect to the effects of the X chromosome on brain development.

  View details for Web of Science ID A1991GE98800007

  View details for PubMedID 1956059

• NEUROANATOMY IN FRAGILE-X FEMALES - THE POSTERIOR-FOSSA AMERICAN JOURNAL OF HUMAN GENETICS Reiss, A. L., Freund, L., Tseng, J. E., Joshi, P. K. 1991; 49 (2): 279-288

  Abstract

  The relative homogeneity of the neuropsychiatric phenotype in individuals with fragile (fra) X syndrome suggests that there are consistent central nervous system (CNS) abnormalities underlying the observed cognitive and behavioral abnormalities. In this study, the neuroanatomy of the posterior fossa and other selected CNS regions in 12 young fra X females were compared with those of a group of 12 age-, sex-, and IQ-matched females without evidence of the fra X syndrome. Fra X females were shown to have decreased size of the posterior cerebellar vermis and increased size of the fourth ventricle, findings that are identical to those previously reported for fra X males. When compared with fra X male and nonfra X control groups, the distribution of the posterior-vermis and fourth-ventricle variables for the fra X female group was intermediate. These results support the hypothesis that the fra X genetic abnormality leads to hypoplasia of the posterior cerebellar vermis, a neuroanatomical variation of potential importance to both developmental and neuropsychiatric syndromes.

  View details for Web of Science ID A1991GA86600004

  View details for PubMedID 1867191

• COGNITIVE PROFILES ASSOCIATED WITH THE FRA(X) SYNDROME IN MALES AND FEMALES AMERICAN JOURNAL OF MEDICAL GENETICS Freund, L. S., Reiss, A. L. 1991; 38 (4): 542-547

  Abstract

  Twenty-three fragile X [fra(X)] males (mean IQ 50, mean age 10 years) and 11 fra(X) females (mean IQ 84, mean age 11.3 years) were administered the Stanford-Binet Intelligence Scale, 4th ed. (S-B). The cognitive profiles generated from the S-B indicated a pattern of subtest strengths and weaknesses that was similar for both groups. Consistent weaknesses in both groups were found in quantitative skills and short-term memory recall for visually presented, abstract stimuli, whereas a consistent strength was observed for short-term memory recall of visually presented, meaningful stimuli. Strengths in verbal labeling and comprehension and deficits in spatial visualization and visual-motor coordination were identified by the S-B for the male group but not for the female group. Fragility in the female group was negatively correlated with the S-B score for the short-term memory area and the combined S-B scores for the verbal reasoning and quantitative reasoning areas. The specific, S-B-identified cognitive strengths and weaknesses associated with the fra(X) condition are potentially useful indicators for investigation of specific cognitive process deficits associated with the fra(X) condition and the design of appropriate educational interventions for fra(X) children.

  View details for Web of Science ID A1991FA60200008

  View details for PubMedID 2063895

• AUTISTIC FEATURES IN JOUBERT SYNDROME - A GENETIC DISORDER WITH AGENESIS OF THE CEREBELLAR VERMIS BIOLOGICAL PSYCHIATRY Holroyd, S., Reiss, A. L., Bryan, R. N. 1991; 29 (3): 287-294

  Abstract

  Recent reports in the literature have suggested a link between abnormalities of the cerebellar vermis and the behavioral syndrome of autism. Joubert syndrome is an autosomal recessive disorder characterized by partial or complete agenesis of the cerebellar vermis. However, there is little behavioral or psychiatric description of patients with this genetic condition. In this report, the neuropsychiatric characteristics of two children with Joubert syndrome are described in detail. One child met DSM-III-R diagnostic criteria for autistic disorder, while the other displayed autistic features. The female child displayed stereotypic behavior and impairments in social interaction and communication, had a markedly restricted repertoire of interests, and showed distress over changes in the environment. The male child demonstrated perseveration and preoccupation with sounds and textures, but had no abnormalities in social interaction. Although both children showed developmental disabilities, the degree of cognitive delay was significantly less than that described in previous reports of children with Joubert syndrome. This report adds to the growing body of evidence implicating cerebellar involvement in developmental disabilities and autistic behavior.

  View details for Web of Science ID A1991EX03700011

  View details for PubMedID 2015333

• Area and volume measurement of posterior fossa structures in MRI Journal of Psychiatric Research Aylward E, Reiss AL 1991; 25: 159-168
• RATING PROBLEM BEHAVIORS IN OUTPATIENTS WITH MENTAL-RETARDATION - USE OF THE ABERRANT BEHAVIOR CHECKLIST RESEARCH IN DEVELOPMENTAL DISABILITIES Freund, L. S., Reiss, A. L. 1991; 12 (4): 435-451

  Abstract

  Parent and teacher ratings of behavior problems of an outpatient sample of 110 children, adolescents, and young adults with IQs ranging from severe mental retardation to borderline were obtained using a modified version of the Aberrant Behavior Checklist (ABC). Using factor analytic techniques, the five-factor structure of the parent data corresponded extremely well with the five factors originally obtained from staff ratings of mentally retarded inpatients (i.e., Irritability, Withdrawal, Hyperactivity, Stereotypies, and Inappropriate Speech). Factor content was virtually identical between the parent and original ABC data with differences involving only one or two items per scale. The teacher data also revealed a factor structure that corresponded to the same five factors as the parent and original data. Although the teacher and parent factors showed a high degree of similarity, the teacher data suggested that the Stereotypies and Inappropriate Speech factors of the parent and original analyses were not the same constructs for teacher respondents. Age was related to the withdrawal factor for parent data; level of intellectual functioning was the only subject characteristic related to factor scale scores in both parent and teacher data. Test-retest reliabilities were adequate to excellent for all factors for both parent and teacher data. Parent-teacher cross-informant reliabilities were adequate for at least four of the factors. The results of the report indicate that the ABC is a useful, reliable instrument for assessing maladaptive behaviors in young, developmentally disabled outpatients.

  View details for Web of Science ID A1991GX51700007

  View details for PubMedID 1792366

• NEUROANATOMY OF FRAGILE-X-SYNDROME - THE POSTERIOR-FOSSA ANNALS OF NEUROLOGY Reiss, A. L., Aylward, E., Freund, L. S., Joshi, P. K., Bryan, R. N. 1991; 29 (1): 26-32

  Abstract

  The occurrence and specificity of posterior fossa abnormalities as measured from magnetic resonance images of the brain were investigated in a group of 14 males with fragile X syndrome and comparison groups consisting of 17 males with other causes of developmental disability and 18 males with normal IQs. The size of the posterior cerebellar vermis was significantly decreased and the fourth ventricle significantly increased in the group of males with fragile X syndrome compared with males in both comparison groups. These neuroanatomical abnormalities appeared to be secondary to hypoplasia rather than atrophy.

  View details for Web of Science ID A1991ER08000005

  View details for PubMedID 1996876

• AREA AND VOLUME MEASUREMENT OF POSTERIOR-FOSSA STRUCTURES IN MRI JOURNAL OF PSYCHIATRIC RESEARCH Aylward, E. H., Reiss, A. 1991; 25 (4): 159-168

  Abstract

  This study was undertaken to determine the extent to which area measures of posterior fossa structures can be used confidently to represent structure volumes. MRI scans were obtained from three groups: fragile X males, males with other developmental disabilities, and males with normal IQ. The areas of the midbrain, pons, medulla, cerebellar vermis, and fourth ventricle were measured in midsagittal sections. Volumes of midbrain, pons, medulla, cerebellum, fourth ventricle, and third ventricle were obtained by measuring these structures in contiguous axial slices. In addition, the largest axial area for each structure was identified. Analysis revealed that midsagittal area measures for pons, medulla, and fourth ventricle were significantly correlated with structure volumes, and that all of the largest axial area measures were significantly correlated with structure volumes. However, only the midsagittal area measure of fourth ventricle and the largest axial area measures of fourth ventricle and cerebellum were correlated with volume measures with an r of .80 of greater. Results of this study suggest that area measures may not accurately represent three-dimensional structure size.

  View details for Web of Science ID A1991GV63000002

  View details for PubMedID 1723429

• Brain and behavior correlates of the fragile X syndrome Current Opinion in Psychiatry Freund L, Abrams M, Reiss AL 1991; 4: 667-673
• Rating problem behaviors in mentally retarded outpatients: Use of the Aberrant Behavior Checklist Research in Developmental Disabilities Freund L, Reiss AL 1991; 12: 435-451
• FRAGILE X SYNDROME, DSM-III-R, AND AUTISM JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Reiss, A. L., Freund, L. 1990; 29 (6): 885-891

  Abstract

  Although reports of autistic behavior in fragile X males have been published for 8 years, there is little information about specific behaviors shown by fragile X males that are suggestive of the diagnosis of autism. The new diagnostic criteria for autistic disorder contained in the DSM-III-R provided the opportunity for more closely investigating the topography of autistic behavior in 17 fragile X males and the effects of age and IQ on its occurrence. The criteria most frequently met by these subjects were related to deficits in social interaction with peers, abnormalities in verbal and nonverbal communication, stereotypic motor behavior, and unusual responses to sensory stimuli. Fragile X subjects did not frequently show abnormalities in attachment behaviors and reciprocal interaction with caregivers. There were no discernable age or IQ effects. The importance and implications of these findings are discussed and the need for greater exploration of autism "subtypes" is emphasized.

  View details for Web of Science ID A1990EJ19200007

  View details for PubMedID 2273015

• METHYLATION STATUS OF GENES FLANKING THE FRAGILE SITE IN MALES WITH THE FRAGILE-X SYNDROME - A TEST OF THE IMPRINTING HYPOTHESIS AMERICAN JOURNAL OF HUMAN GENETICS Khalifa, M. M., Reiss, A. L., Migeon, B. R. 1990; 46 (4): 744-753

  Abstract

  Laird has suggested that the mutation responsible for the fragile X (FraX) syndrome interferes with the process of X chromosome reactivation in oocytes, thus blocking the transcription of loci at or neighboring the fragile site (Xq27.3) and producing the clinical FraX phenotype; he has also suggested that the transcriptional block might result from inappropriate DNA methylation. We have explored the latter possibility by examining the methylation status of several genes flanking the fragile site in eight FraX males from seven unrelated families. These genes (HPRT, G6PD, P3, and GdX), contain 5' clusters of CpG dinucleotides which are differentially methylated in transcriptionally active and inactive loci. Using the methylation-sensitive restriction enzyme, HpaII, we observed no differences between FraX and normal males in the methylation either of CpG islands in any of these genes or in nonclustered CpGs within the body of the HPRT gene. The same was true for the CpG cluster in intron 22 of the clotting factor VIII gene. In each gene, the island is methylated on the inactive X chromosome and not on the active one, but in no case were these islands methylated in FraX males. The four anonymous loci (DXS98, DXS304, DXS52, and DXS15) that are closely linked to the FraX locus (the closest is within 5 centimorgans) are not differentially methylated on active and inactive X, nor are they unusually methylated in FraX males. Therefore, our observations provide no evidence that DNA methylation in the vicinity of the FraX locus has a role in producing the clinical phenotype of the FraX syndrome.

  View details for Web of Science ID A1990CW54900012

  View details for PubMedID 2316521

• FRAGILE X-SYNDROME BIOLOGICAL PSYCHIATRY Reiss, A. L., Freund, L. 1990; 27 (2): 223-240

  Abstract

  Fragile X syndrome is the most important X-linked etiology of mental retardation and developmental disability currently known. Accumulating evidence also indicates that male and female carriers of the fragile X genetic abnormality demonstrate a relatively specific pattern of psychiatric disturbance. Fragile X males frequently manifest behaviors from the autistic spectrum whereas females show dysfunction in social interaction, thought processes, and affective regulation. In this review, an overview of the fragile X syndrome is presented with a focus on the occurrence of particular neuropsychiatric characteristics in males and females. Relevant data from recent genetic and neurobiological research is also described. The ability to study individuals with a specific genetic cause of psychopathology such as fragile X syndrome makes this condition of particular interest to biological psychiatry.

  View details for Web of Science ID A1990CH93800012

  View details for PubMedID 2403814

• Neuroanatomy of fragile X syndrome: The posterior fossa Annals of Neurology Reiss AL, Aylward E, Freund L, Bryan N, Joshi P 1990; 29: 26-32
• The fragile X phenotype: Cognitive behavioral and neurobiological profiles Current Opinion in Psychiatry Simon VA, Abrams M, Freund L, Reiss AL 1990; 3: 581-586
• Neuropsychiatric aspects of fragile X syndrome Brain Dysfunction Reiss AL, Freund L 1990; 3: 9-22
• PARENTAL INHERITANCE AND PSYCHOLOGICAL DISABILITY IN FRAGILE-X FEMALES AMERICAN JOURNAL OF HUMAN GENETICS Reiss, A. L., Freund, L., Vinogradov, S., Hagerman, R., Cronister, A. 1989; 45 (5): 697-705

  Abstract

  Studies of adult female carriers of the fragile X chromosome indicate that certain psychological problems occur with a greater frequency and severity than expected. This study examines the association of parental origin of the fragile X chromosome and of fragility detected in the karyotype with measures of social, educational, and psychological functioning in a group of adult fragile X females of normal intelligence. The results show that, as a group, women who inherit the fragile X chromosome from their mother and who demonstrate positive fragility in the karyotype (MI+ group = [maternal inheritance with positive fragility]) manifest significantly more impairment of social, educational, and psychological functioning when compared with fragile X females with paternal inheritance or negative fragility or with a matched control group comprising non-fragile X women. In particular, MI+ women show lower levels of both educational achievement and socioeconomic status and a greater degree of disturbance in communication, socialization, affect, and thought processes. These clinical findings are consistent with the recently advanced hypothesis which proposes that a two-stage process leading to chromosome imprinting in a preoogonial cell causes the fragile X syndrome.

  View details for Web of Science ID A1989AZ04900006

  View details for PubMedID 2816940

  View details for PubMedCentralID PMC1683434

• EFFECTS OF FENFLURAMINE ON SOCIAL-BEHAVIOR IN AUTISTIC-CHILDREN JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Reiss, A. L., Egel, A. L., Feinstein, C., Goldsmith, B., BORENGASSERCARUSO, M. A. 1988; 18 (4): 617-625

  Abstract

  Deficit in social interaction is a primary component of infantile autism. However, in the majority of drug studies, social interaction has not been measured consistently over time. Therefore, we examined, in a crossover design, the effect of fenfluramine on the social interactions of seven autistic children. Social interaction was measured one to three times per week, while the children were in open placebo, placebo, or drug phases of the study. The results demonstrated that the effect of fenfluramine on social interaction was inconsistent across children, with two children possibly demonstrating a tolerance to the behavioral effects of the drug. The results are discussed with respect to genetic and pharmacologic factors.

  View details for Web of Science ID A1988R608100012

  View details for PubMedID 3215887

• PRELIMINARY COMMUNICATION - NEUROANATOMICAL VARIATIONS OF THE POSTERIOR-FOSSA IN MEN WITH THE FRAGILE-X (MARTIN-BELL) SYNDROME AMERICAN JOURNAL OF MEDICAL GENETICS Reiss, A. L., Patel, S., Kumar, A. J., Freund, L. 1988; 31 (2): 407-414

  Abstract

  Four men with fragile X (fra (X], or Martin-Bell, syndrome were studied by magnetic resonance imaging (MRI) to determine whether detectable abnormalities of the cerebellum were present. The cerebellum was chosen because of the apparently increased tendency for fra (X) patients to demonstrate autistic behavior and accumulating evidence implicating cerebellar abnormalities in autism. Compared with a control group of four normal men, fra (X) patients had a significantly decreased area of the cerebellar vermis, particularly the posterior portion, on planimetric analysis in the midsagittal plane. The pons and fourth ventricular areas also were decreased and increased, respectively, in the fra (X) men. Neuroanatomical and animal research increasingly implicates the cerebellar vermis as an important component in functional brain systems subserving sensory and motor integration, learning, and modulation of affect, motivation, and social behavior. Thus, vermis dysfunction could account for many of the behavioral and cognitive abnormalities observed in fra (X) males, particularly those which overlap with the behavioral syndrome of autism.

  View details for Web of Science ID A1988Q621500019

  View details for PubMedID 3232704

• CYTOGENETIC STUDIES OF MALES WITH SCHIZOPHRENIA - SCREENING FOR THE FRAGILE X-CHROMOSOME AND OTHER CHROMOSOMAL-ABNORMALITIES SCHIZOPHRENIA RESEARCH DeLisi, L. E., Reiss, A. L., White, B. J., Gershon, E. S. 1988; 1 (4): 277-281

  Abstract

  Genetic factors appear to play a role in the etiology of schizophrenia, although no specific genetic mechanism has yet been identified. As a preliminary measure in the search for the chromosomal location of a gene or genes relevant to this illness, cytogenetic screening of populations of patients might provide clues for further in depth molecular studies. Additionally, since the X chromosome has been implicated as a possible site, specific examinations aimed at identifying abnormalities in this chromosome including the presence of the fragile X site, could also be important. The following report reviews the previous literature on chromosomal aberrations in schizophrenia and presents data from a new survey of 46 unrelated male patients with schizophrenia. No chromosomal aberrations or folate-sensitive fragile sites were found in samples from these patients.

  View details for Web of Science ID A1988R262000004

  View details for PubMedID 3154515

• INPATIENT PSYCHIATRIC RESEARCH PSYCHIATRIC ANNALS Reiss, A. L., Harris, J. C., Stahl, S. M. 1988; 18 (2): 97-101

  View details for Web of Science ID A1988M013200006

• PSYCHIATRIC DISABILITY IN FEMALE CARRIERS OF THE FRAGILE X-CHROMOSOME ARCHIVES OF GENERAL PSYCHIATRY Reiss, A. L., Hagerman, R. J., Vinogradov, S., Abrams, M., KING, R. J. 1988; 45 (1): 25-30

  Abstract

  Fragile X syndrome, an X-linked genetic condition, is an important genetic cause of mental retardation in males. In addition to mental retardation, hemizygous males with fragile X syndrome appear to have a greater likelihood of displaying behaviors classified under the diagnostic category of pervasive developmental disorder than would be expected on the basis of mental retardation alone. Although the majority of female heterozygotes with the fragile X genetic defect are of normal intelligence, our clinical work with this population and a recent case report have suggested that females with fragile X syndrome have an increased rate of schizophrenia spectrum and affective disorders. In this study, the relationship of the fragile X genetic defect to psychopathology in female heterozygotes is investigated by psychiatric evaluation of 35 obligate female carriers of the fragile X chromosome and a comparison group of 24 fragile X-negative controls. Female fragile X carriers were found to have a greater frequency of psychopathology associated with schizophrenia spectrum diagnoses, particularly schizotypal features. A weaker association between the fragile X genetic defect and chronic affective disorders was detected. The specificity of the neuropsychiatric phenotype occurring in particular genetic conditions such as the fragile X syndrome adds a potentially valuable tool to the study of psychopathology in the general population.

  View details for Web of Science ID A1988L573900003

  View details for PubMedID 3337608

• Cerebellar hypoplasia and autism New England Journal of Medicine Reiss AL 1988; 319: 1152-1153
• Inpatient Psychiatric Research Annals of Psychiatry Reiss AL, Harris J, Stahl SM 1988; 18: 97-101
• THE EFFECTS OF PIRACETAM UPON VISUAL EVENT-RELATED POTENTIALS IN DYSLEXIC-CHILDREN PSYCHOPHYSIOLOGY Conners, C. K., Reader, M., Reiss, A., Caldwell, J., Caldwell, L., Adesman, A., Mayer, L., Berg, M., Clymer, R., Erwin, R. 1987; 24 (5): 513-521

  View details for Web of Science ID A1987J727200002

  View details for PubMedID 3685231

• DETERMINATION OF A REFERENCE RANGE FOR WHOLE-BLOOD SEROTONIN IN A PEDIATRIC POPULATION USING HIGH-PRESSURE LIQUID-CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION CLINICAL BIOCHEMISTRY Goldsmith, B. M., Feinstein, C., Munson, S., Reiss, A., BORENGASSERCARUSO, M. A. 1986; 19 (6): 359-363

  Abstract

  Whole blood serotonin (5HT) concentrations were measured in a group of children and adolescents to determine a reference range for this population. Blood was collected after at least a 6-hour fast, mixed with ascorbic acid and EDTA, and frozen at -70 degrees C until analysis. 5HT was determined by HPLC with electrochemical detection. Matrix-matched whole blood standards and controls were used to determine 5HT concentrations, and monitor performance of the assay. 5HT concentrations in boys ranged from 0.53 to 3.13 mumol/L (mean = 1.27, SD = 0.47) while the range for girls was 0.63 to 2.46 mumol/L (mean = 1.21, SD = 0.47). There was no significant difference in 5HT concentrations between boys and girls, nor was there any significant change in 5HT concentration with age. The nonparametric central 95 percent reference range for boys and girls was determined to be 0.64-2.45 mumol/L.

  View details for Web of Science ID A1986G214800009

  View details for PubMedID 3581469

• USE OF LORAZEPAM IN TREATMENT-RESISTANT CATATONIA JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Vinogradov, S., Reiss, A. L. 1986; 6 (5): 323-325

  View details for Web of Science ID A1986E228500019

  View details for PubMedID 3771823

• CLONIDINE THERAPY IN WITHDRAWAL FROM HIGH-DOSE ALPRAZOLAM TREATMENT AMERICAN JOURNAL OF PSYCHIATRY Vinogradov, S., Reiss, A. L., Csernansky, J. G. 1986; 143 (9): 1188-1188

  View details for Web of Science ID A1986D780700034

  View details for PubMedID 2875667

• Inpatient clinical research: its importance in psychiatry and psychopharmacology. Psychiatric medicine Reiss, A. L., Stahl, S. M. 1986; 4 (4): 407-416

  Abstract

  We have outlined the essential components found in an inpatient psychiatry research unit from the point of patient recruitment through discharge. In virtually every phase of a patient's hospitalization on the unit, there is the potential for significant tension between research and clinical goals. We conclude that, as Braff and associates have suggested, clinical and research interests are compatible when both receive appropriate support. We have also discussed the potential advantages of an inpatient research setting for patient care. Because of the washout period, there is greater opportunity for an extended diagnostic assessment and response to the therapeutic milieu alone. The attention and priority patients receive during the research phase can be of significant therapeutic benefit. Findings from research protocols can be used to help with diagnosis and clinical care. Working on an inpatient research unit provides residents and other trainees with special learning experiences. In particular, observational and diagnostic skills are sharpened. Techniques of non-pharmacologic behavioral management are added to the trainees' repertoire of therapeutic interventions. By nature, the research experience promotes creative thinking and problem solving. In this era of fiscal restrictions and cost accountability in medicine, potential advantages for immediate patient care and for staff training are only secondary reasons which justify the existence of inpatient research centers in psychiatry. We must also ask what specific and unique research information an inpatient research setting offers compared to less expensive outpatient research environments. The first factor to be considered is the ability to study individuals whose illness is so severe as to make outpatient management difficult or impossible. It is becoming increasingly clear that for many categories of psychiatric disorders, there is a spectrum of severity of possible behavioral manifestations seen in affected individuals. In depressive illness, for example, the spectrum of expression appears to range from dysthymic disorder to major depressive disorder with psychotic features. Individuals with more severe symptomatology tend to create the greater cost to society because of their correspondingly greater degree of dysfunctional behavior, need for repeated and extended hospitalization, requirement for social services, etc. Such individuals, therefore, need to be studied in a research setting at least as much as patients with milder manifestations of psychiatric illness. This would not be possible without the control, structure, and staffing found in an inpatient setting.(ABSTRACT TRUNCATED AT 400 WORDS)

  View details for PubMedID 3432583

• AUTISM AND GENETIC-DISORDERS SCHIZOPHRENIA BULLETIN Reiss, A. L., Feinstein, C., Rosenbaum, K. N. 1986; 12 (4): 724-738

  Abstract

  The syndrome of autism has been documented as occurring in association with a wide variety of genetic conditions. Autistic patients with a coexistent genetic condition, however, are not behaviorally or developmentally distinct from autistic patients for whom there is no known etiology or associated organic condition. This report reviews the literature linking autistic behavior with genetic conditions. Genetic, neurodevelopmental, and neuropathological findings in three genetic conditions which frequently give rise to autism are presented in detail. On the basis of this review, two hypotheses are supported: autism is a behaviorally defined phenotype which arises from diverse causes of central nervous system (CNS) damage, and the autistic phenotype represents only one point along a continuum of psychological dysfunction resulting from CNS damage. Current theories of genetic influences on brain development are reviewed, with emphasis on the relationships among qualitative, quantitative, and temporal abnormalities of CNS maturation and behavioral dysfunction. A hypothesis of abnormal brain development resulting from dysfunctional myelination is proposed as a potential etiologic factor in autism.

  View details for Web of Science ID A1986F065000014

  View details for PubMedID 3810072

• PSYCHIATRIC DISABILITY ASSOCIATED WITH THE FRAGILE-X CHROMOSOME AMERICAN JOURNAL OF MEDICAL GENETICS Reiss, A. L., Feinstein, C., Toomey, K. E., Goldsmith, B., Rosenbaum, K., Caruso, M. A. 1986; 23 (1-2): 393-401

  Abstract

  Fragile X (or Martin-Bell) syndrome, a common, genetic, mental retardation disorder is increasingly being recognized as a major cause of cognitive disability and psychiatric illness in boys. Here, we present a study in which relatives in 4 generations of a large family with the fra(X) chromosome were given comprehensive psychiatric evaluations in order to further describe the psychopathology associated with this condition. Three of 4 males with the fra(X) chromosome were found to have autistic behavior. An adult fra(X) male had a chronic schizoaffective disorder and mental retardation. In female relatives, a relationship was found between the fra(X) carrier status and psychopathology including schizoaffective and major affective disorders.

  View details for Web of Science ID A1986AYQ1600029

  View details for PubMedID 3953657

• DEVELOPMENTAL MANIFESTATIONS IN A BOY WITH PREPUBERTAL BIPOLAR DISORDER JOURNAL OF CLINICAL PSYCHIATRY Reiss, A. L. 1985; 46 (10): 441-443

  Abstract

  Bipolar affective disorder is not commonly reported in prepubertal children. This may be secondary to age-related variability in patterns of symptomatology, lack of appropriate diagnostic criteria, and/or confusion with other psychiatric disorders of childhood. A case of adult-type bipolar disorder in a prepubertal child is presented, with emphasis on developmental history, genetic influences, and response to pharmacologic intervention. Studies of children affected by, or at risk for, bipolar disorder are needed to identify biologic and developmental markers of this syndrome.

  View details for Web of Science ID A1985ATW3600010

  View details for PubMedID 4044536

• AUTISM ASSOCIATED WITH WILLIAMS SYNDROME JOURNAL OF PEDIATRICS Reiss, A. L., Feinstein, C., Rosenbaum, K. N., BORENGASSERCARUSO, M. A., Goldsmith, B. M. 1985; 106 (2): 247-249

  View details for Web of Science ID A1985ABV1300015

  View details for PubMedID 3968612

• CARBAMAZEPINE-INDUCED MANIA IN 2 CHILDREN - CASE-REPORT JOURNAL OF CLINICAL PSYCHIATRY Reiss, A. L., ODONNELL, D. J. 1984; 45 (6): 272-274

  Abstract

  Carbamazepine-induced mania is described in two case reports of prepubertal boys, one of whom also developed manic symptoms after receiving imipramine and dextroamphetamine. The structural and chemical similarities between carbamazepine and polycyclic antidepressants are discussed and it is suggested that caution and close observation be employed when using carbamazepine to treat children who have been identified as being at risk for developing this adverse effect.

  View details for Web of Science ID A1984SU48300010

  View details for PubMedID 6725221