Mira Raman

All Publications

• Impact of pathogenic variants of the Ras-mitogen-activated protein kinase pathway on major white matter tracts in the human brain. Brain communications Siqueiros-Sanchez, M., Dai, E., McGhee, C. A., McNab, J. A., Raman, M. M., Green, T. 2024; 6 (4): fcae274

  Abstract

  Noonan syndrome and neurofibromatosis type 1 are genetic conditions linked to pathogenic variants in genes of the Ras-mitogen-activated protein kinase signalling pathway. Both conditions hyper-activate signalling of the Ras-mitogen-activated protein kinase pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of Noonan syndrome and neurofibromatosis type 1 and human imaging studies show white matter abnormalities in both conditions. While these findings suggest Ras-mitogen-activated protein kinas pathway hyper-activation effects on white matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of Noonan syndrome and neurofibromatosis type 1 on human white matter's microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with Noonan syndrome (n = 24), neurofibromatosis type 1 (n = 28) and age- and sex-matched controls (n = 31). We contrasted the clinical groups (Noonan syndrome or neurofibromatosis type 1) and controls using voxel-wise, tract-based and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. Noonan syndrome and neurofibromatosis type 1 showed similar patterns of reduced fractional anisotropy and increased axial diffusivity, radial diffusivity, and mean diffusivity on white matter relative to controls and different spatial patterns. Noonan syndrome presented a more extensive spatial effect than neurofibromatosis type 1 on white matter integrity as measured by fractional anisotropy. Tract-based analysis also demonstrated differences in effect magnitude with overall lower fractional anisotropy in Noonan syndrome compared to neurofibromatosis type 1 (d = 0.4). At the tract level, Noonan syndrome-specific effects on fractional anisotropy were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; P < 0.012), and neurofibromatosis type 1-specific effects were detected in the corpus callosum (P < 0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-mitogen-activated protein kinase pathway are associated with white matter abnormalities as measured by diffusion in the developing brain. Overall, Noonan syndrome and neurofibromatosis type 1 show common effects on fractional anisotropy and diffusion scalars, as well as specific unique effects, namely, on temporoparietal-frontal tracts (intra-hemispheric) in Noonan syndrome and on the corpus callosum (inter-hemispheric) in neurofibromatosis type 1. The observed specific effects not only confirm prior observations from independent cohorts of Noonan syndrome and neurofibromatosis type 1 but also inform on syndrome-specific susceptibility of individual tracts. Thus, these findings suggest potential targets for precise, brain-focused outcome measures for existing medications, such as MEK inhibitors, that act on the Ras-mitogen-activated protein kinase pathway.

  View details for DOI 10.1093/braincomms/fcae274

  View details for PubMedID 39210910

  View details for PubMedCentralID PMC11358645

• RASopathies influences on neuroanatomical variation in children. Biological psychiatry. Cognitive neuroscience and neuroimaging McGhee, C. A., Honari, H., Siqueiros-Sanchez, M., Serur, Y., van Staalduinen, E. K., Stevenson, D., Bruno, J. L., Raman, M. M., Green, T. 2024

  Abstract

  RASopathies are a group of disorders characterized by pathogenic mutations in the Ras-mitogen-activated protein kinase (Ras/MAPK) signaling pathway. Distinct pathogenic variants in genes encoding proteins in the Ras/MAPK pathway cause Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), which are associated with increased risk for autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD).This study examines the effect RASopathies (NS and NF1) has on human neuroanatomy, specifically on surface area (SA), cortical thickness (CT), and subcortical volumes. We compared structural T1-weighted images, using vertex-based analysis for cortical measures and Desikan ROI parcellation for subcortical volumes on children with RASopathies (n=91, mean age = 8.81, SD = 2.12) to sex- and age-matched TD (n=74, mean age=9.07, SD = 1.77).Compared to TD, RASopathies had convergent effects on SA and CT, exhibiting increased SA in the precentral gyrus, decreased SA in occipital regions, and thinner CT in the precentral gyrus. RASopathies exhibit divergent effects on subcortical volumes, with syndrome-specific influences from NS and NF1. Overall children with NS display decreased volumes in striatal and thalamic structures and children with NF1 display increased volumes in the hippocampus, amygdala, and thalamus.Our study reveals the converging and diverging neuroanatomical effects of RASopathies on human neurodevelopment. The convergence of cortical effects on SA and CT indicates a shared influence of Ras/MAPK hyperactivation on the human brain. Therefore, considering these measures as objective outcome indicators for targeted treatments is imperative.

  View details for DOI 10.1016/j.bpsc.2024.04.003

  View details for PubMedID 38621478

• THE INTERACTIVE EFFECTS OF POLYGENIC RISK SCORES AND SINGLE GENE DISORDERS ON THE SUBCORTICAL STRUCTURE Serur, Y., Rai, B., Raman, M., McGee, C., Green, T. ELSEVIER. 2023: S256-S257

  View details for DOI 10.1016/j.euroneuro.2023.08.451

  View details for Web of Science ID 001089437400447

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• The moderating effects of sex on insula subdivision structure in youth with posttraumatic stress symptoms. Depression and anxiety Klabunde, M., Weems, C. F., Raman, M., Carrion, V. G. 2017; 34 (1): 51-58

  Abstract

  The insula is involved in interoceptive processing, emotion awareness, and attention to salient stimuli. Research suggests that these functions are specific-albeit overlapping-within insula subdivisions. Additional studies also imply that sexual dimorphism and different rates of development occur within these subdivisions in youth. The purpose of this study was to examine potential insula subdivision structure differences in youth with PTSD symptoms as compared to controls and test sex as a moderator of these differences.Insula structure (volume, surface area, and thickness) was measured with structural magnetic resonance imaging (sMRI) and calculated using Freesurfer software. We compared insula structure across age- and sex-matched boys and girls with (30 with and 29 without) PTSD symptoms while also controlling for age and whole brain measurements.Differences were specific to the insula's anterior circular sulcus. Within this subregion, boys with PTSD symptoms demonstrated larger volume and surface area than control boys, while girls with PTSD symptoms demonstrated smaller volume and surface area than control girls.Findings indicate a potential neurobiological explanation for sex differences in youth with PTSD symptoms.

  View details for DOI 10.1002/da.22577

  View details for PubMedID 27862643

• 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

• 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

• LONGITUDINAL THALAMIC NEUROANATOMY IN ADOLESCENTS WITH BIPOLAR I DISORDER Singh, M. K., Wei, M., Soudi, L., Raman, M., Foland-Ross, L., DeGeorge, D., Chang, K. D. ELSEVIER SCIENCE INC. 2016: S299

  View details for DOI 10.1016/j.jaac.2016.07.270

  View details for Web of Science ID 000541964302094

• 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 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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., 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

• 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

• 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

• 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

• Topological properties of large-scale structural brain networks in children with familial risk for reading difficulties NEUROIMAGE Hosseini, S. M., Black, J. M., Soriano, T., Bugescu, N., Martinez, R., Raman, M. M., Kesler, S. R., Hoeft, F. 2013; 71: 260-274

  Abstract

  Developmental dyslexia is a neurobiological deficit characterized by persistent difficulty in learning to read in children and adults who otherwise possess normal intelligence. Functional and structural connectivity data suggest that developmental dyslexia could be a disconnection syndrome. However, whether abnormalities in connectivity exist in beginning readers at-risk for reading difficulties is unknown. Using graph-theoretical analysis, we investigated differences in global and regional topological properties of structural brain networks in 42 beginning readers with (FH+) and without (FH-) familial risk for reading difficulties. We constructed separate structural correlation networks based on measures of surface area and cortical thickness. Results revealed changes in topological properties in brain regions known to be abnormal in dyslexia (left supramarginal gyrus, left inferior frontal gyrus) in the FH+ group mainly in the network constructed from measures of cortical surface area. We also found alterations in topological properties in regions that are not often advertised as dyslexia but nonetheless play important role in reading (left posterior cingulate, hippocampus, and left precentral gyrus). To our knowledge, this is the first report of altered topological properties of structural correlation networks in children at risk for reading difficulty, and motivates future studies that examine the mechanisms underlying how these brain networks may mediate the influences of family history on reading outcome.

  View details for DOI 10.1016/j.neuroimage.2013.01.013

  View details for Web of Science ID 000316154400026

  View details for PubMedID 23333415

  View details for PubMedCentralID PMC3655726

• 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

• 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

• 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

• 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

• 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

• BOLD and CBV-weighted functional magnetic resonance imaging of the rat somatosensory system MAGNETIC RESONANCE IN MEDICINE Keilholz, S. D., SILVA, A. C., Raman, M., Merkle, H., Koretsky, A. P. 2006; 55 (2): 316-324

  Abstract

  A multislice spin echo EPI sequence was used to obtain functional MR images of the entire rat brain with blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) contrast at 11.7 T. Maps of activation incidence were created by warping each image to the Paxinos rat brain atlas and marking the extent of the activated area. Incidence maps for BOLD and CBV were similar, but activation in draining veins was more prominent in the BOLD images than in the CBV images. Cerebellar activation was observed along the surface in BOLD images, but in deeper regions in the CBV images. Both effects may be explained by increased signal dropout and distortion in the EPI images after administration of the ferumoxtran-10 contrast agent for CBV fMRI. CBV-weighted incidence maps were also created for 10, 20, and 30 mg Fe/kg doses of ferumoxtran-10. The magnitude of the average percentage change during stimulation increased from 4.9% with the 10 mg Fe/kg dose to 8.7% with the 30-mg Fe/kg dose. Incidence of activation followed a similar trend.

  View details for DOI 10.1002/mrm.20744

  View details for Web of Science ID 000235326500013

  View details for PubMedID 16372281

• Functional MRI of the rodent somatosensory pathway using multislice echo planar imaging MAGNETIC RESONANCE IN MEDICINE Keilholz, S. D., SILVA, A. C., Raman, M., Merkle, H., Koretsky, A. P. 2004; 52 (1): 89-99

  Abstract

  A multislice EPI sequence was used to obtain functional MR images of the entire rat brain with BOLD contrast at 11.7 T. Ten to 11 slices covering the rat brain, with an in-plane resolution of 300 microm, provided enough sensitivity to detect activation in brain regions known to be involved in the somatosensory pathway during stimulation of the forelimbs. These regions were identified by warping a digitized rat brain atlas to each set of images. Data analysis was constrained to four major areas of the somatosensory pathway: primary and secondary somatosensory cortices, thalamus, and cerebellum. Incidence maps were generated. Electrical stimulation at 3 Hz led to significant activation in the primary sensory cortex in all rats. Activation in the secondary sensory cortex and cerebellum was observed in 70% of the studies, while thalamic activation was observed in 40%. The amplitude of activation was measured for each area, and average response time courses were calculated. Finally, the frequency dependence of the response to forepaw stimulation was measured in each of the activated areas. Optimal activation occurred in all areas at 3 Hz. These results demonstrate that whole-brain fMRI can be performed on rodents at 11.7 T to probe a well-defined neural network.

  View details for DOI 10.1002/mrm.20114

  View details for Web of Science ID 000222491700013

  View details for PubMedID 15236371

• Ultrasonic measurement of breast tissue motion and the implications for velocity estimation ULTRASOUND IN MEDICINE AND BIOLOGY ElFallah, A. I., Plantec, M. B., Ferrara, K. W. 1997; 23 (7): 1047-1057

  Abstract

  A high-resolution study of breast tissue motion during cardiac systole and respiration is presented. An experimental system was designed to achieve a velocity resolution on the order of 1 mm/s with high spatial resolution. The peak velocity of tissue motion estimated during cardiac systole ranged from 0.2 mm/s to 5.6 mm/s among the subjects studied. It is shown that motion due to the cardiac cycle is less significant when the subject is positioned on the side rather than supine. The mean tissue velocity among subjects in the supine position is 2.88 mm/s and drops to 0.81 mm/s for the side position, with a corresponding spatial displacement of 0.095 mm, dropping to 0.027 mm. The velocity profiles indicate that 100 ms is required for the entire ribcage contraction-relaxation process to occur. Experiments using a prone biopsy table show the almost complete elimination of tissue motion due to cardiac systole, suggesting that the use of the table eliminates this motion, thus allowing for high-resolution blood velocity estimates. Features resulting from respiratory motion are also presented. We found this motion to be of a much longer time duration, and of a much higher magnitude, with velocities as high as 29 mm/s. The implications of the study on the high-resolution estimation of blood velocity and high-resolution breast imaging are discussed.

  View details for PubMedID 9330448