Jennifer L. Bruno

All Publications

• 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

• Toward Personalized Cognitive Training in Older Adults: A Pilot Investigation of the Effects of Baseline Performance and Age on Cognitive Training Outcomes. Journal of Alzheimer's disease : JAD Bruno, J. L., Shaw, J. S., Hosseini, S. M. 2023

  Abstract

  Cognitive training holds potential as a non-pharmacological intervention to decrease cognitive symptoms associated with Alzheimer's disease (AD), but more research is needed to understand individual differences that may predict maximal training benefits.We conducted a pilot study using a six-month training regimen in healthy aging adults with no cognitive decline. We investigated the effects of baseline performance and age on training and transfer improvements.Out of 43 participants aged 65-84 years, 31 successfully completed cognitive training (BrainHQ) in one of three cognitive domains: processing speed (N = 13), inhibitory control (N = 9), or episodic memory (N = 9). We used standardized assessments to measure baseline performance and transfer effects.All 31 participants improved on the cognitive training regimen and age was positively associated with training improvement (p = 0.039). The processing speed group improved significantly across many near- and far-transfer tasks. In the inhibitory control group, individuals with lower baseline performance improved more on inhibitory control and cognitive flexibility tasks. In the episodic memory group, older individuals improved most on a memory task while younger individuals improved most on an executive function far-transfer task.Individual differences are predictive of cognitive training gains, and the impact of individual differences on training improvements is specific to the domain of training. We provide initial insight regarding how non-pharmacological interventions can be optimized to combat the onset of cognitive decline in older adults. With future research this work can inform the design of effective cognitive interventions for delaying cognitive decline in preclinical AD.

  View details for DOI 10.3233/JAD-230619

  View details for PubMedID 38043011

• 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

• 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

• 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

• Multidimensional Neuropsychiatric Phenotypes in Children With Noonan Syndrome Bruno, J., Naylor, P., Green, T. SPRINGERNATURE. 2022: 147-148

  View details for Web of Science ID 000897934700308

• Brief intensive social gaze training reorganizes functional brain connectivity in boys with fragile X syndrome. Cerebral cortex (New York, N.Y. : 1991) Saggar, M., Bruno, J. L., Hall, S. S. 2022

  Abstract

  Boys with fragile X syndrome (FXS), the leading known genetic cause of autism spectrum disorder (ASD), demonstrate significant impairments in social gaze and associated weaknesses in communication, social interaction, and other areas of adaptive functioning. Little is known, however, concerning the impact of behavioral treatments for these behaviors on functional brain connectivity in this population. As part of a larger study, boys with FXS (mean age 13.23±2.31years) and comparison boys with ASD (mean age 12.15±2.76years) received resting-state functional magnetic resonance imaging scans prior to and following social gaze training administered by a trained behavior therapist in our laboratory. Network-agnostic connectome-based predictive modeling of pretreatment resting-state functional connectivity data revealed a set of positive (FXS>ASD) and negative (FXS

  View details for DOI 10.1093/cercor/bhac411

  View details for PubMedID 36376964

• Neural resources shift under Methylphenidate: a computational approach to examine anxiety-cognition interplay. NeuroImage Saggar, M., Bruno, J., Gaillard, C., Claudino, L., Ernst, M. 2022: 119686

  Abstract

  The reciprocal interplay between anxiety and cognition is well documented. Anxiety negatively impacts cognition, while cognitive engagement can down-regulate anxiety. The brain mechanisms and dynamics underlying such interplay are not fully understood. To study this question, we experimentally and orthogonally manipulated anxiety (using a threat of shock paradigm) and cognition (using methylphenidate; MPH). The effects of these manipulations on the brain and behavior were evaluated in 50 healthy participants (25 MPH, 25 placebo), using an n-back working memory fMRI task (with low and high load conditions). Behaviorally, improved response accuracy was observed as a main effect of the drug across all conditions. We employed two approaches to understand the neural mechanisms underlying MPH-based cognitive enhancement in safe and threat conditions. First, we performed a hypothesis-driven computational analysis using a mathematical framework to examine how MPH putatively affects cognitive enhancement in the face of induced anxiety across two levels of cognitive load. Second, we performed an exploratory data analysis using Topological Data Analysis (TDA)-based Mapper to examine changes in spatiotemporal brain activity across the entire cortex. Both approaches provided converging evidence that MPH facilitated greater differential engagement of neural resources (brain activity) across low and high working memory load conditions. Furthermore, load-based differential management of neural resources reflects enhanced efficiency that is most powerful during higher load and induced anxiety conditions. Overall, our results provide novel insights regarding brain mechanisms that facilitate cognitive enhancement under MPH and, in future research, may be used to help mitigate anxiety-related cognitive underperformance.

  View details for DOI 10.1016/j.neuroimage.2022.119686

  View details for PubMedID 36273770

• Can Translational Social Neuroscience Research offer Insights to Mitigate Structural Racism in America? Biological psychiatry. Cognitive neuroscience and neuroimaging Singh, M. K., Nimarko, A., Bruno, J., Anand, K. J., Singh, S. P. 2022

  Abstract

  Social isolation and conflict due to structural racism may result in human suffering and loneliness across the lifespan. Given the rising prevalence of these problems in America, combined with disruptions experienced during the COVID-19 pandemic, the neurobiology of affiliative behaviors may offer practical solutions to the pressing challenges associated with structural racism. Controlled experiments across species demonstrate that social connections are critical to survival, although strengthening individual resilience is insufficient to address the magnitude and impact of structural racism. In contrast, the multi-level construct of social resilience, defined by the power of groups to cultivate, engage in, and sustain positive relationships that endure and recuperate from social adversities, offers unique insights that may have greater impact, reach, and durability than individual-level interventions. Here, we review the putative social resilience-enhancing interventions and, when available, their biological mediators, with the hope to stimulate discovery of novel approaches to mitigate structural racism. We will first explore the social neuroscience principles underlying psychotherapy and other psychiatric interventions. Then, we will explore translational efforts across species to tailor treatments that increase social resilience, with context and cultural sensitivity in mind. Finally, we will conclude with some practical future directions for understudied areas that may be essential for progress in biological psychiatry, including ethical ways to increase representation in research and developing social paradigms that inform dynamics toward or away from socially resilient outcomes.

  View details for DOI 10.1016/j.bpsc.2022.05.005

  View details for PubMedID 35609781

• 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

• Brief, Intense Social Gaze Training Normalizes Functional Brain Connectivity in Boys With Fragile X Syndrome Bruno, J., Saggar, M., Hall, S. ELSEVIER SCIENCE INC. 2022: S152

  View details for Web of Science ID 000789022200373

• 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

• Thalamic Structure and Function in Youth With and At Familial Risk for Bipolar Disorder Singh, M., Gorelik, A., Carta, K., Gorelik, M., Chang, K., Bruno, J., Nimarko, A. SPRINGERNATURE. 2021: 285-286

  View details for Web of Science ID 000725511401115

• Parent Cognition and Behavior Predict Variable Outcomes in Children With Ras/mitogen-Activated Protein Kinase (RMK) Pathway Pathogenic Mutations Bruno, J., Green, T. SPRINGERNATURE. 2021: 123-124

  View details for Web of Science ID 000725511400248

• 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

• Neurite Imaging Reveals Widespread Alterations in Gray and White Matter Neurite Morphology in Healthy Aging and Amnestic Mild Cognitive Impairment. Cerebral cortex (New York, N.Y. : 1991) Gozdas, E., Fingerhut, H., Dacorro, L., Bruno, J. L., Hosseini, S. M. 2021

  Abstract

  Aging is the major risk factor for neurodegenerative diseases and affects neurite distributions throughout the brain, yet underlying neurobiological mechanisms remain unclear. Multi-shell diffusion-weighted imaging and neurite orientation dispersion and density imaging (NODDI) now provide in vivo biophysical measurements that explain these biological processes in the cortex and white matter. In this study, neurite distributions were evaluated in the cortex and white matter in healthy older adults and patients with amnestic mild cognitive impairment (aMCI) that provides fundamental contributions regarding healthy aging and neurodegeneration. Older age was associated with reduced neurite density and neurite orientation dispersion (ODI) in widespread cortical regions. In contrast, increased ODI was only observed in the right thalamus and hippocampus with age. For the first time, we also reported a widespread age-associated decrease in neurite density along major white matter tracts correlated with decreased cortical neurite density in the tract endpoints in healthy older adults. We further examined alterations in cortical and white matter neurite microstructures in aMCI patients and found significant neurite morphology deficits in memory networks correlated with memory performance. Our findings indicate that neurite parameters provide valuable information regarding cortical and white matter microstructure and complement myeloarchitectural information in healthy aging and aMCI.

  View details for DOI 10.1093/cercor/bhab180

  View details for PubMedID 34313731

• 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

• Empathic Accuracy in Adolescent Girls with Turner Syndrome JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Klabunde, M., Piccirilli, A., Bruno, J., Gendron, M., Reiss, A. L. 2021

  Abstract

  To examine the potential mechanisms underlying social deficits in Turner Syndrome, we administered the empathic accuracy task (EAT) -a naturalistic social cognition task- and a (control) visual-motor line-tracking task to 14 girls with TS was compared to 12 age-matched typically developing girls (TD; ages 12 to 17). Empathic accuracy was compared across positive and negative emotionally valanced videos. We found that TS differs from TD on empathic accuracy ratings for negative videos; no differences were detected for the positive videos or for the control line tracking task. Thus, our findings suggest impaired detection of negatively valanced empathic interactions in TS and may help inform the future development of social-cognition treatment strategies for girls with TS.

  View details for DOI 10.1007/s10803-021-05089-3

  View details for Web of Science ID 000657605000003

  View details for PubMedID 34081302

• 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

• 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

• 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

• Examining the Neurocognitive Basis of Applied Creativity in Entrepreneurs and Managers Design Thinking Research. Understanding Innovation. Auernhammer, J., Sonalkar, N., Xie, H., Monlux, K., Bruno, J., Saggar, M. Springer, Cham. 2021

  View details for DOI 10.1007/978-3-030-76324-4_18

• 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

• 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 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

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

  View details for DOI 10.1093/cercor/bhw055

• 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

• 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

• 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

• Phonological processing is uniquely associated with neuro-metabolic concentration NEUROIMAGE Bruno, J. L., Lu, Z., Manis, F. R. 2013; 67: 175-181

  Abstract

  Reading is a complex process involving recruitment and coordination of a distributed network of brain regions. The present study sought to establish a methodologically sound evidentiary base relating specific reading and phonological skills to neuro-metabolic concentration. Single voxel proton magnetic resonance spectroscopy was performed to measure metabolite concentration in a left hemisphere region around the angular gyrus for 31 young adults with a range of reading and phonological abilities. Correlation data demonstrated a significant negative association between phonological decoding and normalized choline concentration and as well as a trend toward a significant negative association between sight word reading and normalized choline concentration, indicating that lower scores on these measures are associated with higher concentrations of choline. Regression analyses indicated that choline concentration accounted for a unique proportion of variance in the phonological decoding measure after accounting for age, cognitive ability and sight word reading skill. This pattern of results suggests some specificity for the negative relationship between choline concentration and phonological decoding. To our knowledge, this is the first study to provide evidence that choline concentration in the angular region may be related to phonological skills independently of other reading skills, general cognitive ability, and age. These results may have important implications for the study and treatment of reading disability, a disorder which has been related to deficits in phonological decoding and abnormalities in the angular gyrus.

  View details for DOI 10.1016/j.neuroimage.2012.10.092

  View details for Web of Science ID 000314144600017

  View details for PubMedID 23147236

• Cognitive outcomes in pediatric heart transplant recipients bridged to transplantation with ventricular assist devices JOURNAL OF HEART AND LUNG TRANSPLANTATION Stein, M. L., Bruno, J. L., Konopacki, K. L., Kesler, S., Reinhartz, O., Rosenthal, D. 2013; 32 (2): 212-220

  Abstract

  Ventricular assist devices (VADs) have been associated with high rates of neurologic injury in pediatric patients during the period of support, but the delayed consequences of this type of injury have not been described in the literature.In this study we assess cognitive outcomes with indices of general intellectual functioning, including working memory, processing speed, perceptual reasoning and verbal comprehension, for pediatric heart transplant recipients who required VAD support as a bridge to transplant (n = 9). We present an aggregate of these VAD patients combined with heart transplant recipients who did not require mechanical circulatory support (n = 11), and compare the performance of all transplant patients (n = 20) to typically developing, healthy comparators (n = 12). We also present a post hoc analysis of those transplant recipients with significant medical morbidity in the first year of life, referred to as the "high-risk" transplant group (n = 5), and compare them with the "low-risk" transplant group (n = 15) and the typically developing comparators (n = 12).The mean performance of the VAD patients was in the average range for each of the examined indices of cognitive functioning. A total of 11% of the VAD patients performed in the impaired range and 78% performed in the average range, with 11% in the superior range on measures of general intellectual functioning. The typically developing participants performed significantly better than the aggregated transplant recipients on all indices except verbal comprehension. Lower cognitive performance in the combined transplant group appears to be associated with medical morbidity in the first year of life.Despite significant neurologic risk factors, this cohort of pediatric patients who were bridged to transplant with VAD demonstrated resiliency in terms of cognitive outcomes. In this heterogeneous population, it is likely that multiple factors contributed to the cognitive outcomes. As VAD use becomes more common in pediatric patients, a prospective evaluation of cognitive outcomes is warranted.

  View details for DOI 10.1016/j.healun.2012.11.006

  View details for Web of Science ID 000314445800006

  View details for PubMedID 23352393

• Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors NEUROBIOLOGY OF DISEASE Bruno, J., Hosseini, S. M., Kesler, S. 2012; 48 (3): 329-338

  Abstract

  Many women with breast cancer, especially those treated with chemotherapy, experience cognitive decline due in part to neurotoxic brain injury. Recent neuroimaging studies suggest widespread brain structural abnormalities pointing to disruption of large-scale brain networks. We applied resting state functional magnetic resonance imaging and graph theoretical analysis to examine the connectome in breast cancer survivors treated with chemotherapy relative to healthy comparison women. Compared to healthy females, the breast cancer group displayed altered global brain network organization characterized by significantly decreased global clustering as well as disrupted regional network characteristics in frontal, striatal and temporal areas. Breast cancer survivors also showed significantly increased self-report of executive function and memory difficulties compared to healthy females. These results suggest that topological organization of both global and regional brain network properties may be disrupted following breast cancer and chemotherapy. This pattern of altered network organization is believed to result in reduced efficiency of parallel information transfer. This is the first report of alterations in large-scale functional brain networks in this population and contributes novel information regarding the neurobiologic mechanisms underlying breast cancer-related cognitive impairment.

  View details for DOI 10.1016/j.nbd.2012.07.009

  View details for Web of Science ID 000309694000007

  View details for PubMedID 22820143

  View details for PubMedCentralID PMC3461109

• Neuroimaging in Genetic Disorders Handbook of Neurodevelopmental and Genetic Disorders in Children Kesler, S., Wilde, E., Bruno, J., Bigler, E. Gilford Press. 2010; 2
• Sensitivity to orthographic familiarity in the occipito-temporal region NEUROIMAGE Bruno, J. L., Zumberge, A., Manis, F. R., Lu, Z., Goldman, J. G. 2008; 39 (4): 1988-2001

  Abstract

  The involvement of the left hemisphere occipito-temporal (OT) junction in reading has been established, yet there is current controversy over the region's specificity for reading and the nature of its role in the reading process. Recent neuroimaging findings suggest that the region is sensitive to orthographic familiarity [Kronbichler, M., Bergmann, J., Hutzler, F., Staffen, W., Mair, A., Ladurner, G., Wimmer, H. 2007. Taxi vs. Taksi: on orthographic word recognition in the left ventral occipito-temporal cortex. Journal of Cognitive Neuroscience 19, 1-11], and the present study tested that hypothesis. Using fMRI, the OT region and other regions in the reading network were localized in 28 adult, right-handed participants. The BOLD signal in these regions was measured during a phonological judgment task (i.e., "Does it sound like a word?"). Stimuli included words, pseudohomophones (phonologically familiar yet orthographically unfamiliar), and pseudowords (phonologically and orthographically unfamiliar) that were matched on lexical properties including sublexical orthography. Relative to baseline, BOLD signal in the OT region was greater for pseudohomophones than for words, suggesting that the region is sensitive to orthographic familiarity at the whole-word level. Further contrasts of orthographic frequency within the word condition revealed increased BOLD signal for low- than high-frequency words. Specialization in the OT region for recognition of frequent letter strings may support the development of reading expertise. Additionally, BOLD signal in the OT region correlates positively with reading efficiency, supporting the idea that this region is a skill zone for reading printed words. BOLD signal in the IFG and STG correlates negatively with reading efficiency, indicating that processing effort in these classic phonological regions is inversely related to reading efficiency.

  View details for DOI 10.1016/j.neuroimage.2007.10.044

  View details for Web of Science ID 000253241800047

  View details for PubMedID 18180168

• Auditory word identification in dyslexic and normally achieving readers JOURNAL OF EXPERIMENTAL CHILD PSYCHOLOGY Bruno, J. L., Manis, F. R., Keating, P., Sperling, A. J., Nakamoto, J., Seidenberg, M. S. 2007; 97 (3): 183-204

  Abstract

  The integrity of phonological representation/processing in dyslexic children was explored with a gating task in which children listened to successively longer segments (gates) of a word. At each gate, the task was to decide what the entire word was. Responses were scored for overall accuracy as well as the children's sensitivity to coarticulation from the final consonant. As a group, dyslexic children were less able than normally achieving readers to detect coarticulation present in the vowel portion of the word, particularly on the most difficult items, namely those ending in a nasal sound. Hierarchical regression and path analyses indicated that phonological awareness mediated the relation of gating and general language ability to word and pseudoword reading ability.

  View details for DOI 10.1016/j.jecp.2007.01.005

  View details for Web of Science ID 000247704900002

  View details for PubMedID 17359994