Bio

Clinical Focus


  • Neurodevelopmental and neurogenetic disorders
  • Psychiatry, Child and Adolescent
  • Psychiatry

Administrative Appointments


  • Vice Chair, Department of Psychiatry and Behavioral Sciences (2011 - Present)
  • Director, Center for Interdisciplinary Brain Sciences Research (1997 - Present)
  • Associate Chair, Department of Psychiatry and Behavioral Sciences (2002 - 2011)
  • Director, Division of Child and Adolescent Psychiatry (1997 - 2005)

Honors & Awards


  • Distinguished Professional Award, Turner Syndrome Society of the United States (2012)
  • Institute of Medicine, National Academies of Science (2009)
  • Ruane Prize, NARSAD (2005)
  • George Tarjan Award, American Academy of Child & Adolescent Psychiatry (2005)
  • Alpha Omega Alpha, George Washington University School of Medicine (1981)
  • Phi Beta Kappa, Swarthmore College (1977)
  • Spirit of Excellence Award for Lifetime Achievements, National Fragile X Foundation (2004)
  • Distinguished Alumni Achievement Award, George Washington University School of Medicine (1998)
  • B.A. "with Distinction", Swarthmore College (1977)
  • Merck Academic Achievement Award, George Washington University School of Medicine (1981)
  • Travel Award, American College of Neuropsychopharmacology (1988)
  • Faculty Teaching Award, Johns Hopkins University School of Medicine Division of Child Psychiatry (1990)
  • Clinician Scientist Award, Johns Hopkins University Shcool of Medicine (1987)

Professional Education


  • Medical Education:George Washington University Medical School (1981) DC
  • Residency:Stanford University School of Medicine (1986) CA
  • Board Certification: Psychiatry, American Board of Psychiatry and Neurology (1987)
  • Board Certification: Child and Adolescent Psychiatry, American Board of Psychiatry and Neurology (1988)
  • Residency:Children's Hospital National Medical Center (1984) DC
  • Internship:Univ Of CO Health Science Center (1982) CO
  • B.A., Swarthmore College, Psychobioogy (1977)
  • M.D., Geroge Washington University, Medicine (1981)

Research & Scholarship

Current Research and Scholarly Interests


Allan L. Reiss, M.D. is the Howard C. Robbins Professor in the Department of Psychiatry and Behavioral Sciences and Director of the Center for Interdisciplinary Brain Sciences Research (CIBSR) at Stanford University School of Medicine. Dr. Reiss uses advanced research methods and tools such as neuroimaging, genetic analyses and neurobehavioral assessment to focus on neurodevelopmental and neurogenetic disorders of childhood onset. In particular, he studies how genetic and environmental factors affect brain structure and function, and how this ultimately impacts the development and function of persons with these disorders. Dr. Reiss has worked extensively with individuals affected by neurogenetic disorders that increase risk for serious psychopathology including fragile X syndrome, Turner syndrome, Williams syndrome and velocardiofacial syndrome. A particularly important focus of this work is identifying gene-brain-behavior interactions that have relevance to the development of more specific and effective interventions.

A second major research focus of the CIBSR is on the neuroscience of human resilience. Work in this area includes studies of the brain basis of humor and territorial behavior. These studies are carried out in typically developing children and adults and are designed to advance our understanding of both biological and environmental influences on the development of human resilience.

Dr. Reiss’ laboratory and key collaborations serve as a model for interdisciplinary brain sciences collaboration. Research in the laboratory is carried out, or facilitated by faculty and staff from numerous fields including psychiatry, neurology, psychology, neuroscience, genetics, radiology, computer science, special education and statistics. The CIBSR is dedicated to the concept that direct interaction among individuals from these multiple disciplines will serve as the engine for substantive progress in our field.

Clinical Trials


  • Randomized Controlled Study of Donepezil in Fragile X Syndrome Not Recruiting

    Fragile X syndrome (FraX) is the most common known heritable cause of human intellectual disability. Though recent research has revealed much about the genetic and neurobiological bases of FraX, knowledge about specific and effective treatments for affected individuals is lacking. Based on information from both human and animal studies, one cause of intellectual disability in FraX may be related to deficits in a particular brain neurotransmitter system (the "cholinergic" system). Thus, the investigators propose to use a specific medication, donepezil, to augment cholinergic system in adolescents affected by FraX. If found to be effective, the knowledge generated by this research may also be relevant to other developmental disorders that share common disease pathways with FraX.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai K Manchanda, AB, 650-704-9763.

    View full details

  • Double-blind Placebo Controlled Study of Oxytocin in Fragile X Syndrome Not Recruiting

    The purpose of this study is to determine whether the medication oxytocin is an effective and tolerable treatment in adolescent males with fragile X syndrome (FraX) for improving socially appropriate behaviors and reducing social anxiety.

    Stanford is currently not accepting patients for this trial. For more information, please contact Scott Hall, (650) 498 - 4799.

    View full details

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


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

    Abstract

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

    View details for DOI 10.1073/pnas.1002762107

    View details for Web of Science ID 000277822600057

    View details for PubMedID 20439717

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

    Abstract

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

    View details for DOI 10.1523/JNEUROSCI.4268-09.2010

    View details for Web of Science ID 000277653600023

    View details for PubMedID 20463232

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

    Abstract

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

    View details for DOI 10.1523/JNEUROSCI.5324-08.2009

    View details for Web of Science ID 000262859000025

    View details for PubMedID 19176822

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

    Abstract

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

    View details for DOI 10.1371/journal.pone.0002225

    View details for Web of Science ID 000262258700033

    View details for PubMedID 18493621

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

    Abstract

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

    View details for DOI 10.1016/j.jpsychires.2007.11.010

    View details for Web of Science ID 000254137300001

    View details for PubMedID 18194807

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

    Abstract

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

    View details for DOI 10.1073/pnas.0408456102

    View details for Web of Science ID 000233283700066

    View details for PubMedID 16275931

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

    Abstract

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

    View details for DOI 10.1038/nn1572

    View details for Web of Science ID 000232966600023

    View details for PubMedID 16234808

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

    Abstract

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

    View details for DOI 10.1080/17470919.2013.794751

    View details for PubMedID 23672302

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

    Abstract

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

    View details for DOI 10.1016/j.neuroimage.2013.02.011

    View details for Web of Science ID 000317441300022

    View details for PubMedID 23435208

  • 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

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

    Abstract

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

    View details for DOI 10.1016/j.neures.2013.02.005

    View details for PubMedID 23471015

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

    Abstract

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

    View details for DOI 10.1080/09297049.2011.647900

    View details for Web of Science ID 000315675600004

    View details for PubMedID 22372383

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

    Abstract

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

    View details for DOI 10.1016/j.neurobiolaging.2012.06.006

    View details for Web of Science ID 000313117900001

    View details for PubMedID 22770543

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

    Abstract

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

    View details for DOI 10.1016/j.pscychresns.2012.06.008

    View details for Web of Science ID 000316828400004

    View details for PubMedID 23149036

  • Altered Microstructure Within Social-Cognitive Brain Networks During Childhood in Williams Syndrome. Cerebral cortex (New York, N.Y. : 1991) Haas, B. W., Barnea-Goraly, N., Sheau, K. E., Yamagata, B., Ullas, S., Reiss, A. L. 2013

    Abstract

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

    View details for PubMedID 23709644

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

    Abstract

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

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

    View details for PubMedID 23639144

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

    Abstract

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

    View details for DOI 10.1016/j.jaac.2012.10.004

    View details for Web of Science ID 000313143400008

    View details for PubMedID 23265635

  • Aberrant neurocognitive processing of fear in young girls with Turner syndrome. Social cognitive and affective neuroscience Hong, D. S., Bray, S., Haas, B. W., Hoeft, F., Reiss, A. L. 2013

    Abstract

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

    View details for PubMedID 23171616

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

    Abstract

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

    View details for DOI 10.1093/cercor/bhr355

    View details for Web of Science ID 000310965200005

    View details for PubMedID 22172580

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

    Abstract

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

    View details for DOI 10.1016/j.jaac.2012.09.001

    View details for Web of Science ID 000312046500012

    View details for PubMedID 23200289

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

    Abstract

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

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

    View details for Web of Science ID 000311288900021

    View details for PubMedID 23057627

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

    Abstract

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

    View details for DOI 10.2337/dc12-0017

    View details for Web of Science ID 000311424100015

    View details for PubMedID 22966090

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

    Abstract

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

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

    View details for Web of Science ID 000308872200003

    View details for PubMedID 22533667

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

    Abstract

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

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

    View details for Web of Science ID 000308286800002

    View details for PubMedID 22938166

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

    Abstract

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

    View details for DOI 10.1016/j.jaac.2012.07.003

    View details for Web of Science ID 000308054800010

    View details for PubMedID 22917205

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

    Abstract

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

    View details for DOI 10.1016/j.jaac.2012.06.005

    View details for Web of Science ID 000307128300010

    View details for PubMedID 22840553

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

    Abstract

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

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

    View details for Web of Science ID 000305231000009

    View details for PubMedID 21972117

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

    Abstract

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

    View details for DOI 10.1016/j.pscychresns.2012.04.001

    View details for Web of Science ID 000307424600009

    View details for PubMedID 22703620

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

    Abstract

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

    View details for PubMedID 22946281

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

    Abstract

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

    View details for DOI 10.1002/da.21892

    View details for Web of Science ID 000303440700010

    View details for PubMedID 22553009

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

    Abstract

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

    View details for DOI 10.1097/WCO.0b013e328351823c

    View details for Web of Science ID 000301288000003

    View details for PubMedID 22395002

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

    Abstract

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

    View details for DOI 10.1542/peds.2011-0719

    View details for Web of Science ID 000302541700057

    View details for PubMedID 22412026

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

    Abstract

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

    View details for DOI 10.1016/j.psyneuen.2011.07.020

    View details for Web of Science ID 000302044800007

    View details for PubMedID 21862226

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

    Abstract

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

    View details for DOI 10.1210/jc.2011-2916

    View details for Web of Science ID 000301229600020

    View details for PubMedID 22238395

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

    Abstract

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

    View details for DOI 10.1016/j.neuroimage.2011.09.003

    View details for Web of Science ID 000299494000044

    View details for PubMedID 21933717

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

    Abstract

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

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

    View details for Web of Science ID 000298989400006

    View details for PubMedID 21939500

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

    Abstract

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

    View details for DOI 10.1523/JNEUROSCI.4172-11.2012

    View details for Web of Science ID 000299977200024

    View details for PubMedID 22302817

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

    Abstract

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

    View details for DOI 10.1016/j.neuroimage.2011.10.024

    View details for Web of Science ID 000299494000100

    View details for PubMedID 22023744

  • 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 PubMedID 22806268

  • Aberrant functional network recruitment of posterior parietal cortex in turner syndrome. Human brain mapping Bray, S., Hoeft, F., Hong, D. S., Reiss, A. L. 2012

    Abstract

    Turner syndrome is a genetic disorder caused by the complete or partial absence of an X chromosome in affected women. Individuals with TS show characteristic difficulties with executive functions, visual-spatial and mathematical cognition, with relatively intact verbal skills, and congruent abnormalities in structural development of the posterior parietal cortex (PPC). The functionally heterogeneous PPC has recently been investigated using connectivity-based clustering methods, which sub-divide a given region into clusters of voxels showing similar structural or functional connectivity to other brain regions. In the present study, we extended this method to compare connectivity-based clustering between groups and investigate whether functional networks differentially recruit the PPC in TS. To this end, we parcellated the PPC into sub-regions based on temporal correlations with other regions of the brain. fMRI data were collected from 15 girls with TS and 14 typically developing (TD) girls, aged 7-14, while they performed a visual-spatial task. Temporal correlations between voxels in the PPC and a set of seed regions were calculated, and the PPC divided into clusters of voxels showing similar connectivity. It was found that in general the PPC parcellates similarly in TS and TD girls, but that regions in bilateral inferior parietal lobules, and posterior right superior parietal lobule, were reliably recruited by different networks in TS relative to TD participants. These regions showed weaker correlation in TS with a set of regions involved in visual processing. These results suggest that abnormal development of visuospatial functional networks in TS may relate to the well documented cognitive difficulties in this disorder. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.

    View details for PubMedID 22711287

  • Regionally specific increased volume of the amygdala in Williams syndrome: Evidence from surface-based modeling. Human brain mapping Haas, B. W., Sheau, K., Kelley, R. G., Thompson, P. M., Reiss, A. L. 2012

    Abstract

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

    View details for PubMedID 23152007

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

    Abstract

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

    View details for DOI 10.3389/fpsyg.2012.00186

    View details for PubMedID 22701108

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

    Abstract

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

    View details for DOI 10.1016/j.pscychresns.2011.03.006

    View details for Web of Science ID 000298522600016

    View details for PubMedID 22041532

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

    Abstract

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

    View details for DOI 10.1080/87565641.2011.584356

    View details for Web of Science ID 000296931600003

    View details for PubMedID 22004020

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

    Abstract

    Insulin resistance (IR) is the main pathological condition underlying vascular disorders, such as diabetes and cardiovascular disease, which are well established risk factors for cognitive decline and Alzheimer disease (AD). Hippocampal atrophy has been associated with cognitive decline, but little is known about the influence of IR on hippocampus integrity in non-diabetic, cognitively intact individuals. Herein, 50 women ages 50-65, current users of hormone therapy, underwent magnetic resonance imaging, cognitive testing, and homeostatic assessment of insulin resistance (HOMA-IR), as part of a longitudinal study examining brain structure and function in postmenopausal women at risk for AD. Results demonstrated a significant negative relationship between HOMA-IR and right and total hippocampal volume, overall cognitive performance, and selective tests of verbal and non-verbal memory. The main effect of HOMA-IR on brain structure and cognition was not altered by the presence of APOE-?4 allele or by reproductive history, such as duration of endogenous and exogenous estrogen exposure. These results suggest that IR in middle-aged individuals at risk for AD may be biomarker for dementia risk.

    View details for DOI 10.1016/j.neurobiolaging.2009.12.005

    View details for Web of Science ID 000295220700003

    View details for PubMedID 20031276

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

    Abstract

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

    View details for DOI 10.1016/j.biopsych.2011.05.038

    View details for Web of Science ID 000296228000012

    View details for PubMedID 21802660

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

    Abstract

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

    View details for DOI 10.1177/0956797611419521

    View details for Web of Science ID 000300826400015

    View details for PubMedID 22006060

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

    Abstract

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

    View details for DOI 10.1093/cercor/bhr017

    View details for Web of Science ID 000295413200005

    View details for PubMedID 21441396

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

    Abstract

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

    View details for DOI 10.1016/j.pscychresns.2011.06.008

    View details for Web of Science ID 000296544300003

    View details for PubMedID 21875781

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

    Abstract

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

    View details for DOI 10.1097/DBP.0b013e3182255301

    View details for Web of Science ID 000294421200004

    View details for PubMedID 21743350

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

    Abstract

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

    View details for DOI 10.2337/dc10-2164

    View details for Web of Science ID 000293261200003

    View details for PubMedID 21562318

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

    Abstract

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

    View details for DOI 10.1177/0883073810391904

    View details for Web of Science ID 000290961000012

    View details for PubMedID 21471553

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

    Abstract

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

    View details for DOI 10.1016/j.ijdevneu.2011.01.003

    View details for Web of Science ID 000291506000016

    View details for PubMedID 21291994

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

    Abstract

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

    View details for DOI 10.1523/JNEUROSCI.5899-10.2011

    View details for Web of Science ID 000290212100006

    View details for PubMedID 21543594

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

    Abstract

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

    View details for DOI 10.1089/cap.2010.0094

    View details for Web of Science ID 000289678800006

    View details for PubMedID 21486168

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

    Abstract

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

    View details for DOI 10.1016/j.neuroimage.2010.12.054

    View details for Web of Science ID 000287556200001

    View details for PubMedID 21195197

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

    Abstract

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

    View details for DOI 10.1016/j.jpsychires.2010.07.008

    View details for Web of Science ID 000288723800005

    View details for PubMedID 20817203

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

    Abstract

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

    View details for Web of Science ID 000288086900009

    View details for PubMedID 21041609

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

    Abstract

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

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

    View details for Web of Science ID 000288863500008

    View details for PubMedID 21443573

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

    Abstract

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

    View details for DOI 10.1016/j.neuroimage.2010.10.069

    View details for Web of Science ID 000286495800025

    View details for PubMedID 21047559

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

    Abstract

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

    View details for DOI 10.1016/j.neuroimage.2010.11.019

    View details for Web of Science ID 000286495800002

    View details for PubMedID 21073965

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

    Abstract

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

    View details for DOI 10.1176/appi.ajp.2010.09121718

    View details for Web of Science ID 000286972800011

    View details for PubMedID 21078708

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

    Abstract

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

    View details for DOI 10.1073/pnas.1008950108

    View details for Web of Science ID 000285915000067

    View details for PubMedID 21173250

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

    Abstract

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

    View details for DOI 10.1080/09602011.2011.578446

    View details for Web of Science ID 000299788700001

    View details for PubMedID 21714745

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

    Abstract

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

    View details for DOI 10.1176/appi.ajp.2010.10010056

    View details for Web of Science ID 000285868100010

    View details for PubMedID 21123315

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

    Abstract

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

    View details for DOI 10.1371/journal.pone.0015474

    View details for Web of Science ID 000284087800027

    View details for PubMedID 21085607

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

    Abstract

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

    View details for Web of Science ID 000282917400009

    View details for PubMedID 20921121

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

    Abstract

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

    View details for DOI 10.1016/j.biopsych.2010.05.010

    View details for Web of Science ID 000281126800013

    View details for PubMedID 20579974

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

    Abstract

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

    View details for DOI 10.1016/j.jaac.2010.07.001

    View details for Web of Science ID 000281331400006

    View details for PubMedID 20732628

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

    Abstract

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

    View details for PubMedID 20714036

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

    Abstract

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

    View details for DOI 10.1093/jpepsy/jsp112

    View details for Web of Science ID 000278614700012

    View details for PubMedID 19995868

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

    Abstract

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

    View details for DOI 10.1016/j.neuropsychologia.2010.03.032

    View details for Web of Science ID 000279023100025

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

    Abstract

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

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

    View details for Web of Science ID 000278580700004

    View details for PubMedID 21304831

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

    Abstract

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

    View details for DOI 10.1016/j.pscychresns.2010.01.003

    View details for Web of Science ID 000278701500013

    View details for PubMedID 20413280

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

    Abstract

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

    View details for DOI 10.1016/j.neuropsychologia.2009.12.030

    View details for Web of Science ID 000276770800013

    View details for PubMedID 20036269

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

    Abstract

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

    View details for DOI 10.1016/j.neuropsychologia.2009.12.002

    View details for Web of Science ID 000275933500023

    View details for PubMedID 20005238

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

    Abstract

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

    View details for DOI 10.1016/j.pscychresns.2009.10.004

    View details for Web of Science ID 000275009200004

    View details for PubMedID 20080394

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

    Abstract

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

    View details for DOI 10.1016/j.neuroimage.2009.11.050

    View details for Web of Science ID 000274064500016

    View details for PubMedID 19945536

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

    Abstract

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

    View details for DOI 10.1089/cap.2009.0004

    View details for Web of Science ID 000274636300003

    View details for PubMedID 20166792

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

    Abstract

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

    View details for DOI 10.1016/j.jpsychires.2009.07.001

    View details for Web of Science ID 000275071600004

    View details for PubMedID 19660766

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

    Abstract

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

    View details for DOI 10.1016/j.neuropsychologia.2009.10.003

    View details for Web of Science ID 000274371700012

    View details for PubMedID 19822162

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

    Abstract

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

    View details for DOI 10.1016/j.neuroscience.2009.04.033

    View details for Web of Science ID 000271609000022

    View details for PubMedID 19376197

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

    Abstract

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

    View details for DOI 10.1017/S1355617709990476

    View details for Web of Science ID 000272114500003

    View details for PubMedID 19703322

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

    Abstract

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

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

    View details for Web of Science ID 000270386000003

    View details for PubMedID 19277733

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

    Abstract

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

    View details for DOI 10.1176/appi.ajp.2009.08101538

    View details for Web of Science ID 000268638900014

    View details for PubMedID 19605538

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

    Abstract

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

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

    View details for Web of Science ID 000268029100006

    View details for PubMedID 19416325

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

    Abstract

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

    View details for DOI 10.1016/j.biopsych.2009.02.025

    View details for Web of Science ID 000267961600007

    View details for PubMedID 19389661

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

    Abstract

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

    View details for DOI 10.1016/j.pscychresns.2008.07.008

    View details for Web of Science ID 000266580800010

    View details for PubMedID 19349151

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

    Abstract

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

    View details for DOI 10.1038/jhg.2009.5

    View details for Web of Science ID 000266218800001

    View details for PubMedID 19282872

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

    Abstract

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

    View details for DOI 10.1901/jaba.2009.42-171

    View details for Web of Science ID 000263982700013

    View details for PubMedID 19721738

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

    Abstract

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

    View details for DOI 10.1097/CHI.0b013e318195bd15

    View details for Web of Science ID 000263742100011

    View details for PubMedID 19182690

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

    Abstract

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

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

    View details for Web of Science ID 000274727000008

    View details for PubMedID 19890439

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

    Abstract

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

    View details for DOI 10.1002/ajmg.a.32697

    View details for Web of Science ID 000264142300018

    View details for PubMedID 19215057

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

    Abstract

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

    View details for DOI 10.1093/brain/awn353

    View details for Web of Science ID 000264889000011

    View details for PubMedID 19158105

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

    Abstract

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

    View details for DOI 10.1109/TMI.2008.2004402

    View details for Web of Science ID 000263920500005

    View details for PubMedID 19244008

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

    Abstract

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

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

    View details for Web of Science ID 000274727000004

    View details for PubMedID 19865612

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

    Abstract

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

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

    View details for Web of Science ID 000274727000007

    View details for PubMedID 20700390

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

    Abstract

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

    View details for DOI 10.1542/peds.2008-0025

    View details for Web of Science ID 000262678700012

    View details for PubMedID 19171615

  • Effect of Divalproex on Brain Morphometry, Chemistry, and Function in Youth at High-Risk for Bipolar Disorder: A Pilot Study JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Chang, K., Karchemskiy, A., Kelley, R., Howe, M., Garrett, A., Adleman, N., Reiss, A. 2009; 19 (1): 51-59

    Abstract

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

    View details for DOI 10.1089/cap.2008.060

    View details for Web of Science ID 000263913500007

    View details for PubMedID 19232023

  • A solution to limitations of cognitive testing in children with intellectual disabilities: The case of fragile X syndrome Journal of Neurodevelopmental Disorders Hessl, D., Nguyen D, Green C, Chavez A, Tassone F, Hagerman R, Senturk D, Schneider A, Lightbody A, Reiss A, Hall S 2009; 1 (1): 33-45
  • The neural basis of auditory temporal discrimination in girls with fragile X syndrome. Journal of Neurodevelopmental Disorders Hall SS, Walter E, Sherman E, Hoeft F, Reiss AL 2009; 1 (1): 91-99
  • Teasing apart the heterogeneity of autism: Same behavior, different brains in toddlers with fragile X syndrome and autism Journal of Neurodevelopmental Disorders Hazlett HC, Poe MD, Lightbody AA. Gerig G, MacFall JR, Ross AK, Provenzale J, Martin A, Reiss AL, Piven J 2009; 1 (1): 81-90
  • STRUCTURAL AND FUNCTIONAL NEUROIMAGING IN KLINEFELTER (47,XXY) SYNDROME: A REVIEW OF THE LITERATURE AND PRELIMINARY RESULTS FROM A FUNCTIONAL MAGNETIC RESONANCE IMAGING STUDY OF LANGUAGE DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Steinman, K., Ross, J., Lai, S., Reiss, A., Hoeft, F. 2009; 15 (4): 295-308

    Abstract

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

    View details for DOI 10.1002/ddrr.84

    View details for Web of Science ID 000273207500005

    View details for PubMedID 20014370

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

    Abstract

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

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

    View details for Web of Science ID 000262889700012

    View details for PubMedID 19220592

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

    Abstract

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

    View details for DOI 10.1002/ddrr.77

    View details for Web of Science ID 000273207500010

    View details for PubMedID 20014368

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

    Abstract

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

    View details for DOI 10.1097/CHI.0b013e3181886e92

    View details for Web of Science ID 000261112200012

    View details for PubMedID 18981933

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

    Abstract

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

    View details for DOI 10.1097/CHI.0b013e318185d285

    View details for Web of Science ID 000260444800012

    View details for PubMedID 18827721

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

    Abstract

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

    View details for Web of Science ID 000260600300009

    View details for PubMedID 18981343

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

    Abstract

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

    View details for DOI 10.1002/ajmg.a.32507

    View details for Web of Science ID 000260985400008

    View details for PubMedID 18924169

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

    Abstract

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

    View details for DOI 10.1016/j.biopsycho.2008.02.005

    View details for Web of Science ID 000258738800005

    View details for PubMedID 18395317

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

    Abstract

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

    View details for Web of Science ID 000259089300014

    View details for PubMedID 18762595

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

    Abstract

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

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

    View details for Web of Science ID 000257726600010

    View details for PubMedID 18347972

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

    Abstract

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

    View details for DOI 10.1002/hbm.20537

    View details for Web of Science ID 000256674400012

    View details for PubMedID 18219620

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

    Abstract

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

    View details for DOI 10.1176/appi.ajp.2008.07081257

    View details for Web of Science ID 000257320100016

    View details for PubMedID 18450931

  • A preliminary functional magnetic resonance imaging study of prefrontal-amygdalar activation changes in adolescents with bipolar depression treated with lamotrigine BIPOLAR DISORDERS Chang, K. D., Wagner, C., Garrett, A., Howe, M., Reiss, A. 2008; 10 (3): 426-431

    Abstract

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

    View details for Web of Science ID 000254807600008

    View details for PubMedID 18402630

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

    Abstract

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

    View details for DOI 10.1016/j.jpeds.2007.08.009

    View details for Web of Science ID 000254543200024

    View details for PubMedID 18346506

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

    Abstract

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

    View details for DOI 10.1542/peds.2007-0414

    View details for Web of Science ID 000252877600011

    View details for PubMedID 18245422

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

    Abstract

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

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

    View details for Web of Science ID 000252160700001

    View details for PubMedID 17347882

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

    Abstract

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

    View details for Web of Science ID 000252702800004

    View details for PubMedID 18173299

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

    Abstract

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

    View details for DOI 10.1017/S0954579408000011

    View details for Web of Science ID 000252689300001

    View details for PubMedID 18211726

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

    Abstract

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

    View details for DOI 10.1002/ana.21243

    View details for Web of Science ID 000253008700007

    View details for PubMedID 17932962

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

    Abstract

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

    View details for DOI 10.1002/da.20346

    View details for Web of Science ID 000257017000007

    View details for PubMedID 17598145

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

    Abstract

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

    View details for DOI 10.1016/j.schres.2007.07.021

    View details for Web of Science ID 000250690900007

    View details for PubMedID 17804201

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

    Abstract

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

    View details for DOI 10.1176/appi.ajp.2007.06101754

    View details for Web of Science ID 000250811200020

    View details for PubMedID 17974939

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

    Abstract

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

    View details for DOI 10.1523/JNEUROSCI.3591-07.2007

    View details for Web of Science ID 000250577600025

    View details for PubMedID 17978036

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

    Abstract

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

    View details for DOI 10.1002/jts.20241

    View details for Web of Science ID 000250736400012

    View details for PubMedID 17955544

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

    Abstract

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

    View details for DOI 10.1002/ajmg.a.31928

    View details for Web of Science ID 000249829900013

    View details for PubMedID 17853486

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

    Abstract

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

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

    View details for Web of Science ID 000249130800007

    View details for PubMedID 17714375

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

    Abstract

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

    View details for DOI 10.1016/j.biopsych.2006.09.020

    View details for Web of Science ID 000249042800009

    View details for PubMedID 17210143

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

    Abstract

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

    View details for DOI 10.1016/j.biopsych.2006.05.041

    View details for Web of Science ID 000248208100010

    View details for PubMedID 16996488

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

    Abstract

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

    View details for DOI 10.1016/j.neuroimage.2007.04.024

    View details for Web of Science ID 000248152400005

    View details for PubMedID 17512756

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

    Abstract

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

    View details for DOI 10.1016/j.chc.2007.03.001

    View details for Web of Science ID 000247944400010

    View details for PubMedID 17562585

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

    Abstract

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

    View details for DOI 10.1037/0735-7044.121.3.602

    View details for Web of Science ID 000247359300017

    View details for PubMedID 17592952

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

    Abstract

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

    View details for Web of Science ID 000247346300010

    View details for PubMedID 17518929

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

    Abstract

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

    View details for DOI 10.1002/hbm.20406

    View details for Web of Science ID 000246628900009

    View details for PubMedID 17437282

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

    Abstract

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

    View details for DOI 10.1002/hbm.20405

    View details for Web of Science ID 000246628900008

    View details for PubMedID 17427209

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

    Abstract

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

    View details for DOI 10.1016/j.pscyhresns.2006.12.009

    View details for Web of Science ID 000246515400008

    View details for PubMedID 17395436

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

    Abstract

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

    View details for DOI 10.1109/TMI.2006.891481

    View details for Web of Science ID 000245599200009

    View details for PubMedID 17427738

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

    Abstract

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

    View details for Web of Science ID 000245402600022

    View details for PubMedID 17403981

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

    Abstract

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

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

    View details for Web of Science ID 000244692400009

    View details for PubMedID 17318637

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

    Abstract

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

    View details for DOI 10.1038/nn1865

    View details for Web of Science ID 000245228600023

    View details for PubMedID 17351637

  • Affect, social behavior, and the brain in Williams syndrome CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE Bellugi, U., Jarvinen-Pasley, A., Doyle, T. F., Reilly, J., Reiss, A. L., Korenberg, J. R. 2007; 16 (2): 99-104
  • Automated extraction of the cortical sulci based on a supervised learning approach IEEE TRANSACTIONS ON MEDICAL IMAGING Tu, Z., Zheng, S., Yuille, A. L., Reiss, A. L., Dutton, R. A., Lee, A. D., Galaburda, A. M., Dinov, I., Thompson, P. M., Toga, A. W. 2007; 26 (4): 541-552

    Abstract

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

    View details for DOI 10.1109/TMI.2007.892506

    View details for Web of Science ID 000245599200012

    View details for PubMedID 17427741

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

    Abstract

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

    View details for DOI 10.1073/pnas.0609399104

    View details for Web of Science ID 000244972400100

    View details for PubMedID 17360506

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

    Abstract

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

    View details for DOI 10.1542/peds.2006-2028

    View details for Web of Science ID 000244579800011

    View details for PubMedID 17332204

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

    Abstract

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

    View details for DOI 10.1523/JNEUROSCI.5587-06.2007

    View details for Web of Science ID 000244758500023

    View details for PubMedID 17329432

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

    Abstract

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

    View details for DOI 10.1016/j.neuroimage.2006.09.043

    View details for Web of Science ID 000243758700007

    View details for PubMedID 17161622

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

    Abstract

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

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

    View details for Web of Science ID 000244835500003

    View details for PubMedID 17165142

  • Joint sulci detection using graphical models and boosted priors. Information processing in medical imaging : proceedings of the ... conference Shi, Y., Tu, Z., Reiss, A. L., Dutton, R. A., Lee, A. D., Galaburda, A. M., Dinov, I., Thompson, P. M., Toga, A. W. 2007; 20: 98-109

    Abstract

    In this paper we propose an automated approach for joint sulci detection on cortical surfaces by using graphical models and boosting techniques to incorporate shape priors of major sulci and their Markovian relations. For each sulcus, we represent it as a node in the graphical model and associate it with a sample space of candidate curves, which is generated automatically using the Hamilton-Jacobi skeleton of sulcal regions. To take into account individual as well as joint priors about the shape of major sulci, we learn the potential functions of the graphical model using AdaBoost algorithm to select and fuse information from a large set of features. This discriminative approach is especially powerful in capturing the neighboring relations between sulcal lines, which are otherwise hard to be captured by generative models. Using belief propagation, efficient inferencing is then performed on the graphical model to estimate each sulcus as the maximizer of its final belief. On a data set of 40 cortical surfaces, we demonstrate the advantage of joint detection on four major sulci: central, precentral, postcentral and the sylvian fissure.

    View details for PubMedID 17633692

  • Affect, social behavior, and the brain in Williams syndrome. Current Directions in Psychological Science Bellugi U, Jarvinen-Pasley A, Doyle TF, Reilly J, Reiss AL, Korenberg J 2007; 16 (2): 99-104
  • Hippocampal size positively correlates with verbal IQ in male children HIPPOCAMPUS Schumann, C. M., Hamstra, J., Goodlin-Jones, B. L., Kwon, H., Reiss, A. L., Amaral, D. G. 2007; 17 (6): 486-493

    Abstract

    Historically, there have been numerous proposals that the size of the brain correlates with its capacity to process information. Little is known, however, about which specific brain regions contribute to this correlation in children and adolescents. This study evaluated the relationship between intelligence and the size of various brain structures in typically developing male children 8-18 yrs of age. Magnetic resonance imaging (MRI) scans were used to measure the volume of the cerebrum, cerebral gray and white matter, cerebellum, amygdala, and hippocampus. Gray matter and hippocampal volume significantly correlated with full scale and verbal IQ. Since the hippocampus strongly correlated with verbal but not performance IQ, our findings reinforce the hypothesis that the hippocampus is involved in declarative and semantic learning, which contributes more notably to verbal IQ, than to performance IQ. Given the substantial evidence for environmentally induced changes in hippocampal structure, an unresolved issue is whether this relationship reflects genetically determined individual variation or learning induced plasticity.

    View details for DOI 10.1002/hipo.20282

    View details for Web of Science ID 000246971100009

    View details for PubMedID 17407128

  • Anomalous sylvian fissure morphology in Williams syndrome NEUROIMAGE Eckert, M. A., Galaburda, A. M., Karchemskiy, A., Liang, A., Thompson, P., Dutton, R. A., Lee, A. D., Bellugi, U., Korenberg, J. R., Mills, D., Rose, F. E., Reiss, A. L. 2006; 33 (1): 39-45

    Abstract

    The unusual sensitivity and attraction to auditory stimuli in people with Williams syndrome (WS) has been hypothesized to be the consequence of atypical development of brain regions surrounding the Sylvian fissure. Planum temporale surface area, which is determined in part by Sylvian fissure patterning, was examined in 42 WS and 40 control participants to determine if anomalous Sylvian fissure morphology is present in WS. WS participants had significantly reduced leftward asymmetry of the planum temporale compared to control participants, due to a significant expansion in the size of the right planum temporale. The increased right planum temporale size was largely due to WS participants (24%) who had a right hemisphere Sylvian fissure that coursed horizontally and failed to ascend into the parietal lobe. This sulcal pattern is unusual in the right hemisphere and is more commonly found in the left hemisphere of typically developing individuals. There were no control participants with this type of right hemisphere Sylvian fissure pattern. The right hemisphere Sylvian fissure sulcal patterns were also related to a measure of cortical complexity and the amount of right hemisphere occipital lobe volume, suggesting that intrinsic genetic influences leading to anomalous visual system development in WS have widespread influences on cortical morphology that are similar in manner to extrinsic embryonic visual system lesions.

    View details for DOI 10.1016/j.neuroimage.2006.05.062

    View details for Web of Science ID 000241209800006

    View details for PubMedID 16876437

  • Increased local gyrification mapped in Williams syndrome NEUROIMAGE Gaser, C., Luders, E., Thompson, P. M., Lee, A. D., Dutton, R. A., Geaga, J. A., Hayashi, K. M., Bellugi, U., Galaburda, A. M., Korenberg, J. R., Mills, D. L., Toga, A. W., Reiss, A. L. 2006; 33 (1): 46-54

    Abstract

    Applying a recently developed method to analyze gyrification with excellent spatial resolution across thousands of points across the lateral and medial cortical surface, we mapped differences in cortical surface anatomy between subjects with Williams syndrome (WS; n=42) and an age-matched sample of healthy subjects (n=40). WS subjects showed increased gyrification bilaterally in occipital regions and over the cuneus. Differences were more pronounced in the left hemisphere than in the right, with additional regions of increased gyrification in WS in the left precuneus, posterior and anterior cingulate, paracentral and mesial frontal lobe. No cortical area was significantly more convoluted in healthy subjects relative to the WS subjects. On the lateral surfaces, the direction and pattern of gyrification asymmetries were similar in WS subjects and controls; posterior brain regions had greater gyrification in the left hemisphere, while anterior brain regions showed greater gyrification in the right hemisphere. On the medial surfaces, control subjects and WS individuals differed considerably with respect to the degree but also direction of gyrification asymmetry. Our findings confirm and extend previous studies measuring cortical complexity at the global whole-brain or hemispheric levels. The observed gyrification abnormalities in individuals with WS might be related to dysfunctions in neuronal circuits and consequently contribute to the distinct cognitive and behavioral profile accompanying the disorder.

    View details for DOI 10.1016/j.neuroimage.2006.06.018

    View details for Web of Science ID 000241209800007

    View details for PubMedID 16901723

  • Autism and the development of face processing CLINICAL NEUROSCIENCE RESEARCH Golarai, G., Grill-Spector, K., Reiss, A. L. 2006; 6 (3-4): 145-160

    Abstract

    Autism is a pervasive developmental condition, characterized by impairments in non-verbal communication, social relationships and stereotypical patterns of behavior. A large body of evidence suggests that several aspects of face processing are impaired in autism, including anomalies in gaze processing, memory for facial identity and recognition of facial expressions of emotion. In search of neural markers of anomalous face processing in autism, much interest has focused on a network of brain regions that are implicated in social cognition and face processing. In this review, we will focus on three such regions, namely the STS for its role in processing gaze and facial movements, the FFA in face detection and identification and the amygdala in processing facial expressions of emotion. Much evidence suggests that a better understanding of the normal development of these specialized regions is essential for discovering the neural bases of face processing anomalies in autism. Thus, we will also examine the available literature on the normal development of face processing. Key unknowns in this research area are the neuro-developmental processes, the role of experience and the interactions among components of the face processing system in shaping each of the specialized regions for processing faces during normal development and in autism.

    View details for DOI 10.1016/j.cnr.2006.08.001

    View details for Web of Science ID 000242486200006

  • Social escape behaviors in children with fragile X syndrome JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Hall, S., DeBernardis, M., Reiss, A. 2006; 36 (7): 935-947

    Abstract

    Social escape behavior is a common behavioral feature of individuals with fragile X syndrome (fraX). In this observational study, we examined the effect of antecedent social and performance demands on problem behaviors in four conditions: face-to-face interview, silent reading, oral reading and a singing task. Results showed that problem behaviors were significantly more likely to occur during the interview and singing conditions. Higher levels of salivary cortisol were predictive of higher levels of fidgeting behavior and lower levels of eye contact in male participants. There were no associations between level of FMRP expression and social escape behaviors. These data suggest that specific antecedent biological and environmental factors evoke social escape behaviors in fragile X syndrome.

    View details for DOI 10.1007/s10803-006-0132-z

    View details for Web of Science ID 000241171600011

    View details for PubMedID 16897394

  • The acquisition of stimulus equivalence in individuals with fragile X syndrome JOURNAL OF INTELLECTUAL DISABILITY RESEARCH Hall, S. S., DeBernardis, G. M., Reiss, A. L. 2006; 50: 643-651

    Abstract

    Few studies have employed stimulus equivalence procedures to teach individuals with intellectual disabilities (IDs) new skills. To date, no studies of stimulus equivalence have been conducted in individuals with fragile X syndrome (FXS), the most common known cause of inherited ID.Five adolescents with FXS were taught basic math and geography skills by using a computerized stimulus equivalence training programme administered over 2 days in 2-h sessions.Four of the five participants learned the math relations, with one participant demonstrating stimulus equivalence at post-test. Three of the five participants learned the geography relations, with all three of these participants demonstrating stimulus equivalence at post-test.These data indicate that computerized stimulus equivalence procedures, conducted in time-limited sessions, may help individuals with FXS learn new skills. Hypotheses concerning the failure of some participants to learn the training relations and to demonstrate stimulus equivalence at post-test are discussed.

    View details for DOI 10.1111/j.1365-2788.2006.00814.x

    View details for Web of Science ID 000239258100003

    View details for PubMedID 16901291

  • To modulate or not to modulate: Differing results in uniquely shaped Williams syndrome brains NEUROIMAGE Eckert, M. A., Tenforde, A., Galaburda, A. M., Bellugi, U., Korenberg, J. R., Mills, D., Reiss, A. L. 2006; 32 (3): 1001-1007

    Abstract

    Voxel based morphometry (VBM) studies of Williams syndrome (WS) have demonstrated remarkably consistent findings of reduced posterior parietal gray matter compared to typical controls. Other WS VBM findings have been inconsistent, however. In particular, different findings have been reported for hypothalamus and orbitofrontal gray matter regions. We examined a sample of 8 WS and 9 control adults and show that the hypothalamus and orbitofrontal cortex results depend on whether the images undergo Jacobian modulation. Deformation based morphometry (DBM) analysis demonstrated that major brain shape differences between the groups accounted for the Jacobian modulated gray matter findings. These results indicate that cautious interpretations of modulated gray matter findings are warranted when there are gross shape and size differences between experimental groups. This study demonstrates the importance of methodological choices towards understanding a disorder like WS, but also highlights the consistency of parietal lobe, orbitofrontal, and midbrain findings for this disorder across methodologies, participants, and research groups.

    View details for DOI 10.1016/j.neuroimage.2006.05.014

    View details for Web of Science ID 000240470300003

    View details for PubMedID 16806978

  • The neurobiology of Williams syndrome: Cascading influences of visual system impairment? CELLULAR AND MOLECULAR LIFE SCIENCES Eckert, M. A., Galaburda, A. M., Mills, D. L., Bellugi, U., Korenberg, J. R., Reiss, A. L. 2006; 63 (16): 1867-1875

    Abstract

    Williams syndrome (WS) is characterized by a unique pattern of cognitive, behavioral, and neurobiological findings that stem from a microdeletion of genes on chromosome 7. Visuospatial ability is particularly affected in WS and neurobiological studies of WS demonstrate atypical function and structure in posterior parietal, thalamic, and cerebellar regions that are important for performing space-based actions. This review summarizes the neurobiological findings in WS, and, based on these findings, we suggest that people with WS have a primary impairment in neural systems that support the performance of space-based actions. We also examine the question of whether impaired development of visual systems could affect the development of atypical social-emotional and language function in people with WS. Finally, we propose developmental explanations for the visual system impairments in WS. While hemizygosity for the transcription factor II-I gene family probably affects the development of visual systems, we also suggest that Lim-kinase 1 hemizygosity exacerbates the impairments in performing space-based actions.

    View details for DOI 10.1007/s00018-005-5553-x

    View details for Web of Science ID 000239928100006

    View details for PubMedID 16810457

  • Chronological age, but not FMRP levels, predicts neuropsychological performance in girls with fragile X syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Lightbody, A. A., Hall, S. S., Reiss, A. L. 2006; 141B (5): 468-472

    Abstract

    The effect of FMRP levels and chronological age on executive functioning, visual-spatial abilities ,and verbal fluency tasks were examined in 46 school-age girls with fragile X syndrome (FXS). Results indicated that FMRP levels were not predictive of outcome on the neuropsychological tests but that performance on the executive functioning task tended to worsen with chronological age. This age effect was not observed on the tests of visual-spatial abilities or verbal fluency. These data indicate that relative deficits in executive functioning in girls with FXS become more pronounced with age. In contrast, the relative deficits in spatial and verbal abilities of these girls did not appear to increase with age, suggesting that these abilities may be spared.

    View details for DOI 10.1002/ajmg.b.30307

    View details for Web of Science ID 000238622300006

    View details for PubMedID 16741913

  • Selective alterations of white matter associated with visuospatial and sensorimotor dysfunction in Turner syndrome JOURNAL OF NEUROSCIENCE Holzapfel, M., Barnea-Goraly, N., Eckert, M. A., Kesler, S. R., Reiss, A. L. 2006; 26 (26): 7007-7013

    Abstract

    Turner syndrome (TS) is a neurogenetic disorder characterized by impaired spatial, numerical, and motor functioning but relatively spared verbal ability. Results from previous neuroimaging studies suggest that gray matter alterations in parietal and frontal regions may contribute to atypical visuospatial and executive functioning in TS. Recent findings in TS also indicate variations in the shape of parietal gyri and white matter microstructural anomalies of the temporal lobe. Diffusion tensor imaging and structural imaging methods were used to determine whether 10 females with TS and 10 age- and gender-matched control subjects exhibited differences in fractional anisotropy, white matter density, and local brain shape. Relative to controls, females with TS had lower fractional anisotropy (FA) values in the deep white matter of the left parietal-occipital region extending anteriorly along the superior longitudinal fasciculus into the deep white matter of the frontal lobe. In addition, decreased FA values were located bilaterally in the internal capsule extending into the globus pallidus and in the right prefrontal region. Voxel-based morphometry (VBM) analysis showed corresponding white matter density differences in the internal capsules and left centrum semiovale. Tensor-based morphometry analysis indicated that the FA and VBM results were not attributable to differences in the local shape of brain structures. Compared with controls, females with TS had increases in FA values and white matter density in language-related areas of the inferior parietal and temporal lobes. These complementary analyses provide evidence for alterations in white matter pathways that subserve affected and preserved cognitive functions in TS.

    View details for DOI 10.1523/JNEUROSCI.1764-06.2006

    View details for Web of Science ID 000238804400014

    View details for PubMedID 16807330

  • Social behavior and cortisol reactivity in children with fragile X syndrome JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Hessl, D., Glaser, B., Dyer-Friedman, J., Reiss, A. L. 2006; 47 (6): 602-610

    Abstract

    To examine the association between limbic-hypothalamic-pituitary-adrenal (L-HPA) axis reactivity and social behavior in children with fragile X syndrome (FXS).Salivary cortisol changes and concurrent anxiety-related behaviors consistent with the behavioral phenotype of FXS were measured in 90 children with the fragile X full mutation and their 90 unaffected siblings during a social challenge task in the home.Boys and girls with FXS demonstrated more gaze aversion, task avoidance, behavioral signs of distress, and poorer vocal quality than the unaffected siblings. Multiple regression analyses showed that after accounting for effects of IQ, gender, age, quality of the home environment, and basal cortisol level, cortisol reactivity to the task was significantly associated with social gaze in children with FXS. The most gaze-aversive children with FXS had cortisol reductions, whereas those with more eye contact demonstrated the most cortisol reactivity. Unaffected siblings demonstrated an opposite pattern in which less eye contact was associated with increased cortisol reactivity.Results of the study suggest a unique relation between abnormal gaze behavior and L-HPA mediated stress reactivity in FXS.

    View details for DOI 10.1111/j.1469-7610.2005.01556.x

    View details for Web of Science ID 000237636900009

    View details for PubMedID 16712637

  • Parietal attentional system aberrations during target detection in adolescents with attention deficit hyperactivity disorder: Event-related fMRI evidence AMERICAN JOURNAL OF PSYCHIATRY Tamm, L., Menon, V., Reiss, A. L. 2006; 163 (6): 1033-1043

    Abstract

    Directed attention, the ability to allocate and direct attention toward a salient stimulus, is impaired in attention deficit hyperactivity disorder (ADHD). This construct is often assessed with target detection or oddball tasks, and individuals with ADHD perform poorly on such tasks. However, to date, the specific brain structures or neural mechanisms underlying target detection dysfunction in individuals with ADHD have not been identified. The authors' goal was to investigate neural correlates of target detection dysfunction in ADHD using event-related fMRI.Behavioral and brain activation data were collected while subjects performed a visual oddball task. Participants included 14 right-handed male adolescents with ADHD (combined type) and 12 typically developing age- and handedness-matched male comparison subjects.Individuals with ADHD made significantly more errors of commission than comparison subjects. Further, relative to comparison subjects, individuals with ADHD showed significantly less activation in the bilateral parietal lobes (including the superior parietal gyrus and supramarginal and angular gyri of the inferior parietal lobe), right precuneus, and thalamus.Adolescents with ADHD demonstrated significant impairments in their ability to direct and allocate attentional resources. These difficulties were associated with significant aberrations in the parietal attentional system, which is known to play a significant role in attention shifting and detecting specific or salient targets. Thus, dysfunction in the parietal attentional system may play a significant role in the behavioral phenotype of ADHD.

    View details for Web of Science ID 000237972300016

    View details for PubMedID 16741204

  • Neurofunctional differences associated with arithmetic processing in turner syndrome CEREBRAL CORTEX Kesler, S. R., Menon, V., Reiss, A. L. 2006; 16 (6): 849-856

    Abstract

    Turner syndrome (TS) is a neurogenetic disorder characterized by the absence of one X chromosome in a phenotypic female. Individuals with TS are at risk for impairments in mathematics. We investigated the neural mechanisms underlying arithmetic processing in TS. Fifteen subjects with TS and 15 age-matched typically developing controls were scanned using functional MRI while they performed easy (two-operand) and difficult (three-operand) versions of an arithmetic processing task. Both groups activated fronto-parietal regions involved in arithmetic processing during the math tasks. Compared with controls, the TS group recruited additional neural resources in frontal and parietal regions during the easier, two-operand math task. During the more difficult three-operand task, individuals with TS demonstrated significantly less activation in frontal, parietal and subcortical regions than controls. However, the TS group's performance on both math tasks was comparable to controls. Individuals with TS demonstrate activation differences in fronto-parietal areas during arithmetic tasks compared with controls. They must recruit additional brain regions during a relatively easy task and demonstrate a potentially inefficient response to increased task difficulty compared with controls.

    View details for DOI 10.1093/cercor/bhj028

    View details for Web of Science ID 000237525900008

    View details for PubMedID 16135780

  • Symmetry of cortical folding abnormalities in Williams syndrome revealed by surface-based analyses JOURNAL OF NEUROSCIENCE Van Essen, D. C., Dierker, D., Snyder, A. Z., Raichle, M. E., Reiss, A. L., Korenberg, J. 2006; 26 (20): 5470-5483

    Abstract

    We analyzed folding abnormalities in the cerebral cortex of subjects with Williams syndrome (WS), a genetically based developmental disorder, using surface-based analyses applied to structural magnetic resonance imaging data. Surfaces generated from each individual hemisphere were registered to a common atlas target (the PALS-B12 atlas). Maps of sulcal depth (distance from the cerebral hull) were combined across individuals to generate maps of average sulcal depth for WS and control subjects, along with depth-difference maps and t-statistic maps that accounted for within-group variability. Significant structural abnormalities were identified in 33 locations, arranged as 16 bilaterally symmetric pairs plus a lateral temporal region in the right hemisphere. Discrete WS folding abnormalities extended across a broad swath from dorsoposterior to ventroanterior regions of each hemisphere, in cortical areas associated with multiple sensory modalities as well as regions implicated in cognitive and emotional behavior. Hemispheric asymmetry in the temporal cortex is reduced in WS compared with control subjects. These findings provide insights regarding possible developmental mechanisms that give rise to folding abnormalities and to the spectrum of behavioral characteristics associated with WS.

    View details for DOI 10.1523/JNEUROSCI.4154-05.2006

    View details for Web of Science ID 000237608400020

    View details for PubMedID 16707799

  • Hippocampal volume, PTSD, and alcoholism in combat veterans AMERICAN JOURNAL OF PSYCHIATRY Woodward, S. H., Kaloupek, D. G., Streeter, C. C., Kimble, M. O., Reiss, A. L., Eliez, S., Wald, L. L., Renshaw, P. F., Frederick, B. B., Lane, B., Sheikh, J. I., Stegman, W. K., Kutter, C. J., Stewart, L. P., Prestel, R. S., Arsenault, N. J. 2006; 163 (4): 674-681

    Abstract

    Studies imposing rigorous control over lifetime alcohol intake have usually not found smaller hippocampal volumes in persons with posttraumatic stress disorder. Because the majority of negative studies have used adolescent samples, it has been suggested that chronicity is a necessary condition for such findings. To test the hypothesis that a smaller hippocampus in PTSD is unrelated to comorbid alcoholism or to chronicity, this study estimated hippocampal volume in a relatively large group (N=99) of combat veterans in which PTSD, lifetime alcohol abuse/dependence, and Vietnam versus Gulf War service were crossed. In subjects with histories of alcoholism, unadjusted hippocampal volume was 9% smaller in persons with PTSD than in those without PTSD. In nonalcoholic subjects, the PTSD-related difference in hippocampal volume was 3%. The failure to observe a strong association between PTSD and hippocampal volume in nonalcoholic subjects was not ascribable to younger age, reduced PTSD chronicity, or lower PTSD symptom severity. The possibility that smaller hippocampal volume is limited to groups in which PTSD is compounded by comorbid alcoholism is not necessarily incompatible with results suggesting a smaller hippocampus is predispositional to PTSD. Further examination of the role of alcoholism and other comorbid conditions in studies of brain structure and function in PTSD appears warranted.

    View details for Web of Science ID 000236541200020

    View details for PubMedID 16585443

  • Mixed lateral preference in posttraumatic stress disorder JOURNAL OF NERVOUS AND MENTAL DISEASE Saltzman, K. M., Weems, C. F., Reiss, A. L., Carrion, V. G. 2006; 194 (2): 142-144

    Abstract

    Recent research indicates that adults with posttraumatic stress disorder (PTSD) have a higher incidence of mixed laterality with respect to handedness than the rest of the population. To test if this relationship also occurs early in life, we evaluated children with history of interpersonal trauma. Fifty-nine traumatized children were evaluated with the Clinician Administered PTSD Scale for Children and Adolescents and the Edinburgh Handedness Inventory. Forty matched healthy controls were used for comparison. Increased mixed laterality was found in all children exhibiting symptoms of PTSD when compared with healthy controls, and children who met DSM-IV diagnostic criteria for PTSD had more mixed laterality than the subthreshold traumatized group (F = 7.71; df = 2,96; p = 0.001). Within the entire traumatized group, there was a positive correlation between PTSD symptom severity and mixed laterality. Mixed laterality was positively associated with PTSD symptoms in traumatized children, suggesting that neurological abnormalities may be related to degree of PTSD symptom expression.

    View details for DOI 10.1097/01.nmd.0000198201.59824.37

    View details for Web of Science ID 000235488700014

    View details for PubMedID 16477196

  • Use of 3-D cortical morphometry for mapping increased cortical gyrification and complexity in Williams syndrome IEEE International Symposium on Biomedical Imaging Tosun D, Reiss AL, Lee AD, Dutton RA, Geaga JA, Hayashi KM, Eckert MA, Bellugi U, Galaburda AM, Korenberg JR, Mills DL, Toga AW, Thompson PM 2006: 1172-1175
  • Regional differences of the prefrontal cortex in pediatric PTSD: an MRI study DEPRESSION AND ANXIETY Richert, K. A., Carrion, V. G., Karchemskiy, A., Reiss, A. L. 2006; 23 (1): 17-25

    Abstract

    Previous studies have revealed altered structural development of the frontal lobes and prefrontal cortex (PFC) in children with symptoms of posttraumatic stress disorder (PTSD). This study is the first to provide a detailed structural analysis of the PFC in children with and without PTSD symptoms. We compared gray and white matter volume in four subregions of the PFC between said groups, then explored whether volume was associated with PTSD symptom severity and functional impairment. PFC measurements were extracted from magnetic resonance imaging (MRI) data from a sample of 23 children (ages 7-14) with a history of trauma and symptoms of PTSD, who had undergone assessment for PTSD symptoms and functional impairment using the Child and Adolescent version of the Clinician-Administered PTSD Scale (CAPS-CA). These measurements were compared to data from an age-equivalent control group of 24 healthy children. Children with PTSD symptoms showed a significantly larger volume of gray matter in the delineated middle-inferior and ventral regions of the PFC than did control children. Decreased volume of gray matter in the dorsal PFC correlated with increased functional impairment scores. Results indicate that increased volume of the middle-inferior and ventral PFC may be associated with trauma and PTSD symptoms in children. Furthermore, the neuroanatomy of the dorsal PFC may influence the degree of functional impairment experienced by children with PTSD symptoms.

    View details for DOI 10.1002/da.20131

    View details for Web of Science ID 000235381900004

    View details for PubMedID 16247760

  • A learning based algorithm for automatic extraction of the cortical sulci. Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention Zheng, S., Tu, Z., Yuille, A. L., Reiss, A. L., Dutton, R. A., Lee, A. D., Galaburda, A. M., Thompson, P. M., Dinov, I., Toga, A. W. 2006; 9: 695-703

    Abstract

    This paper presents a learning based method for automatic extraction of the major cortical sulci from MRI volumes or extracted surfaces. Instead of using a few pre-defined rules such as the mean curvature properties, to detect the major sulci, the algorithm learns a discriminative model by selecting and combining features from a large pool of candidates. We used the Probabilistic Boosting Tree algorithm to learn the model, which implicitly discovers and combines rules based on manually annotated sulci traced by neuroanatomists. The algorithm almost has no parameters to tune and is fast because of the adoption of integral volume and 3D Haar filters. For a given approximately registered MRI volume, the algorithm computes the probability of how likely it is that each voxel lies on a major sulcus curve. Dynamic programming is then applied to extract the curve based on the probability map and a shape prior. Because the algorithm can be applied to MRI volumes directly, there is no need to perform preprocessing such as tissue segmentation or mapping to a canonical space. The learning aspect makes the approach flexible and it also works on extracted cortical surfaces.

    View details for PubMedID 17354951

  • Increased temporal lobe gyrification in preterm children NEUROPSYCHOLOGIA Kesler, S. R., Vohr, B., Schneider, K. C., Katz, K. H., Makuch, R. W., Reiss, A. L., Ment, L. R. 2006; 44 (3): 445-453

    Abstract

    Preterm birth often results in significant learning disability, and previous magnetic resonance imaging (MRI) studies of preterm children have demonstrated reduction in overall cortical tissue with particular vulnerability in the temporal lobe. We measured cortical gyrification in 73 preterm and 33 term control children at 8 years of age and correlated these findings with tests of language ability to determine the associations among preterm birth, neurodevelopment and functional outcome. Preterm children demonstrated significantly increased bilateral temporal lobe gyrification index compared to term controls. Left temporal gyrification index was significantly negatively correlated with left temporal lobe gray matter volume as well as reading recognition scores in the preterm group. Cortical development in the temporal lobe appears to be differentially vulnerable to preterm birth.

    View details for DOI 10.1016/j.neuropsychologia.2005.05.015

    View details for Web of Science ID 000235861600012

    View details for PubMedID 15985272

  • White matter development during childhood and adolescence: A cross-sectional diffusion tensor imaging study CEREBRAL CORTEX Barnea-Goraly, N., Menon, V., Eckert, M., Tamm, L., Bammer, R., Karchemskiy, A., Dant, C. C., Reiss, A. L. 2005; 15 (12): 1848-1854

    Abstract

    Maturation of brain white matter pathways is an important factor in cognitive, behavioral, emotional and motor development during childhood and adolescence. In this study, we investigate white matter maturation as reflected by changes in anisotropy and white matter density with age. Thirty-four children and adolescents aged 6-19 years received diffusion-weighted magnetic resonance imaging scans. Among these, 30 children and adolescents also received high-resolution T1-weighed anatomical scans. A linear regression model was used to correlate fractional anisotropy (FA) values with age on a voxel-by-voxel basis. Within the regions that showed significant FA changes with age, a post hoc analysis was performed to investigate white matter density changes. With increasing age, FA values increased in prefrontal regions, in the internal capsule as well as in basal ganglia and thalamic pathways, the ventral visual pathways, and the corpus callosum. The posterior limb of the internal capsule, intrathalamic connections, and the corpus callosum showed the most significant overlaps between white matter density and FA changes with age. This study demonstrates that during childhood and adolescence, white matter anisotropy changes in brain regions that are important for attention, motor skills, cognitive ability, and memory. This typical developmental trajectory may be altered in individuals with disorders of development, cognition and behavior.

    View details for DOI 10.1093/cercor/bhi062

    View details for Web of Science ID 000233217300002

    View details for PubMedID 15758200

  • N-acetylaspartate levels in bipolar offspring with and at high-risk for bipolar disorder BIPOLAR DISORDERS Gallelli, K. A., Wagner, C. M., Karchemskiy, A., Howe, M., Spielman, D., Reiss, A., Chang, K. D. 2005; 7 (6): 589-597

    Abstract

    Studies have reported decreased N-acetylaspartate (NAA) in dorsolateral prefrontal cortex (DLPFC) of adults and children with bipolar disorder (BD), suggesting decreased neuronal density in this area. However, it is unclear if this finding represents neurodegeneration after or a trait marker present before BD onset. To address this question, we used proton magnetic resonance spectroscopy ((1)H-MRS) to compare DLPFC levels of NAA among bipolar offspring with early-onset BD, bipolar offspring with subsyndromal symptoms of BD and healthy children.Participants were 9-18 years old, and included 60 offspring of parents with bipolar I or II disorder (32 with BD and 28 with subsyndromal symptoms of BD), and 26 healthy controls. (1)H-MRS at 3 T was used to study 8-cm(3) voxels placed in left and right DLPFC.There were no significant group differences in mean right or left DLPFC NAA/Cr ratios. Exploratory analyses of additional metabolites (myoinositol, choline) also yielded no significant group differences. NAA/Cr ratios were not correlated with age, duration of illness, or exposure to lithium or valproate.Our findings suggest that DLPFC NAA/Cr ratios cannot be used as a trait marker for BD. Although we did not find decreased DLPFC NAA/Cr ratios in children and adolescents with BD, it is still possible that such levels begin to decrease after longer durations of illness into adulthood. Longitudinal neuroimaging studies of patients with BD accounting for developmental and treatment factors are needed to further clarify the neurodegenerative aspects of BD.

    View details for Web of Science ID 000233818300012

    View details for PubMedID 16403184

  • Arithmetic ability and parietal alterations: A diffusion tensor imaging study in Velocardiofacial syndrome COGNITIVE BRAIN RESEARCH Barnea-Goraly, N., Eliez, S., Menon, V., Bammer, R., Reiss, A. L. 2005; 25 (3): 735-740

    Abstract

    Velocardiofacial syndrome (VCFS) is a congenital anomaly that causes somatic as well as cognitive and psychiatric impairments. Previous studies have found specific deficits in arithmetic abilities in subjects with VCFS. In this study, we investigated whether abnormalities in white matter pathways are correlated with reduced arithmetic ability. Nineteen individuals with VCFS aged 7-19 years received diffusion-weighted magnetic resonance imaging (MRI) scans. A linear regression model was used to correlate fractional anisotropy (FA) values with scores of the arithmetic subscale on the WISC/WAIS on a voxel-by-voxel basis, after covarying for any IQ- and age-related effects. There was a statistically significant positive correlation between the arithmetic score on the WISC/WAIS and FA values in white matter tracts adjacent to the left supramarginal and angular gyri, as well as along the left intraparietal sulcus. Inferior parietal lobe white matter structural aberrations may contribute to reduced arithmetic ability in VCFS.

    View details for DOI 10.1016/j.cogbrainres.2005.09.013

    View details for Web of Science ID 000234236500014

    View details for PubMedID 16260124

  • Personality predicts activity in reward and emotional regions associated with humor PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Mobbs, D., Hagan, C. C., Azim, E., Menon, V., Reiss, A. L. 2005; 102 (45): 16502-16506

    Abstract

    Previous research and theory suggest that two stable personality dimensions, extroversion and neuroticism, differentially influence emotional reactivity to a variety of pleasurable phenomena. Here, we use event-related functional MRI to address the putative neural and behavioral associations between humor appreciation and the personality dimensions of introversion-extroversion and emotional stability-neuroticism. Our analysis showed extroversion to positively correlate with humor-driven blood oxygenation level-dependent signal in discrete regions of the right orbital frontal cortex, ventrolateral prefrontal cortex, and bilateral temporal cortices. Introversion correlated with increased activation in several regions, most prominently the bilateral amygdala. Although neuroticism did not positively correlate with any whole-brain activation, emotional stability (i.e., the inverse of neuroticism) correlated with increased activation in the mesocortical-mesolimbic reward circuitry encompassing the right orbital frontal cortex, caudate, and nucleus accumbens. Our findings tie together existing neurobiological studies of humor appreciation and are compatible with the notion that personality style plays a fundamental role in the neurobiological systems subserving humor appreciation.

    View details for DOI 10.1073/pnas.0408457102

    View details for Web of Science ID 000233283700067

    View details for PubMedID 16275930

  • Developmental changes in mental arithmetic: Evidence for increased functional specialization in the left inferior parietal cortex CEREBRAL CORTEX Rivera, S. M., Reiss, A. L., Eckert, M. A., Menon, V. 2005; 15 (11): 1779-1790

    Abstract

    Arithmetic reasoning is arguably one of the most important cognitive skills a child must master. Here we examine neurodevelopmental changes in mental arithmetic. Subjects (ages 8-19 years) viewed arithmetic equations and were asked to judge whether the results were correct or incorrect. During two-operand addition or subtraction trials, for which accuracy was comparable across age, older subjects showed greater activation in the left parietal cortex, along the supramarginal gyrus and adjoining anterior intra-parietal sulcus as well as the left lateral occipital temporal cortex. These age-related changes were not associated with alterations in gray matter density, and provide novel evidence for increased functional maturation with age. By contrast, younger subjects showed greater activation in the prefrontal cortex, including the dorsolateral and ventrolateral prefrontal cortex and the anterior cingulate cortex, suggesting that they require comparatively more working memory and attentional resources to achieve similar levels of mental arithmetic performance. Younger subjects also showed greater activation of the hippocampus and dorsal basal ganglia, reflecting the greater demands placed on both declarative and procedural memory systems. Our findings provide evidence for a process of increased functional specialization of the left inferior parietal cortex in mental arithmetic, a process that is accompanied by decreased dependence on memory and attentional resources with development.

    View details for DOI 10.1093/cercor/bhi055

    View details for Web of Science ID 000232595700014

    View details for PubMedID 15716474

  • Maturation of medial temporal lobe response and connectivity during memory encoding COGNITIVE BRAIN RESEARCH Menon, V., Boyett-Anderson, J. M., Reiss, A. L. 2005; 25 (1): 379-385

    Abstract

    The medial temporal lobe (MTL) plays an important role in memory encoding. The development and maturation of MTL and other brain regions involved in memory encoding are, however, poorly understood. We used functional magnetic resonance imaging to examine activation and effective connectivity of the MTL in children and adolescents during encoding of outdoor visual scenes. Here, we show that MTL response decreases with age whereas its connectivity with the left dorsolateral prefrontal cortex (PFC) increases with age. Our findings provide evidence for dissociable maturation of local and distributed memory encoding processes involving the MTL and furthermore suggest that increased functional interactions between the MTL and the PFC may underlie the development of more effective memory encoding strategies.

    View details for DOI 10.1016/j.cogbrainres.2005.07.007

    View details for Web of Science ID 000232709600037

    View details for PubMedID 16122916

  • Development of anxiety disorders in a traumatized pediatric population: A preliminary longitudinal evaluation CHILD ABUSE & NEGLECT Cortes, A. M., Saltzman, K. M., Weems, C. F., Regnault, H. P., Reiss, A. L., Carrion, V. G. 2005; 29 (8): 905-914

    Abstract

    The current study was conducted to determine if post-traumatic stress disorder (PTSD) symptomatology predicted later development of non-PTSD anxiety disorders in children and adolescents victimized by interpersonal trauma.Thirty-four children with a history of interpersonal trauma and no initial diagnosis of anxiety disorder participated in the study. Children were assessed at time one (T1) and then 12-18 months later at time two (T2). At T1, the Clinician Administered PTSD Scale for Children and Adolescents (CAPS-CA) and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL) were used to evaluate children's PTSD symptoms and comorbid non-PTSD anxiety disorder diagnosis. At T2, the CAPS-CA and the K-SADS-PL were repeated.The diagnosis of PTSD and PTSD symptoms in children exposed to interpersonal trauma at T1, particularly the symptoms associated with avoidance and constricted emotional expression (criteria C) as well as physiological hyperarousal (criteria D), predicted the development of other anxiety disorders at T2.Traumatized children with initial PTSD symptomatology may be at risk of later development of other anxiety disorders.

    View details for DOI 10.1016/j.chiabu.2004.12.010

    View details for Web of Science ID 000231777500005

    View details for PubMedID 16125233

  • Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder BIOLOGICAL PSYCHIATRY Chang, K., Barnea-Goraly, N., Karchemskiy, A., Simeonova, D. I., Barnes, P., Ketter, T., Reiss, A. L. 2005; 58 (3): 197-203

    Abstract

    Morphometric magnetic resonance imaging (MRI) studies of pediatric bipolar disorder (BD) have not reported on gray matter volumes but have reported increased lateral ventricular size and presence of white matter hyperintensities (WMH). We studied gray matter volume, ventricular-to-brain ratios (VBR), and number of WMH in patients with familial, pediatric BD compared with control subjects.Twenty subjects with BD (aged 14.6 +/- 2.8 years; 4 female) according to the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia, each with a parent with BD, and 20 age-, gender-, and intelligence quotient-matched healthy control subjects (aged 14.1 +/- 2.8 years; 4 female) were scanned at 3 T. Most subjects were taking psychotropic medications. A high-resolution T1-weighted spoiled gradient echo three-dimensional MRI sequence was analyzed by BrainImage for volumetric measurements, and T2-weighted images were read by a neuroradiologist to determine presence of WMH.After covarying for age and total brain volume, there were no significant differences between subjects with BD and control subjects in volume of cerebral (p = .09) or prefrontal gray matter (p = .34). Subjects with BD did not have elevated numbers of WMH or greater VBR when compared with control subjects.Children and adolescents with familial BD do not seem to have decreased cerebral grey matter or increased numbers of WMH, dissimilar to findings in adults with BD. Gray matter decreases and development of WMH might be later sequelae of BD or unique to adult-onset BD.

    View details for DOI 10.1016/j.biopsych.2005.03.039

    View details for Web of Science ID 000231057100003

    View details for PubMedID 16084840

  • Functional MRI of working memory in paediatric head injury BRAIN INJURY Williams, S. E., Rivera, S., Reiss, A. L. 2005; 19 (7): 549-553

    Abstract

    A case study examining the recovery of a 9 year old boy who sustained a severe head injury is reported. The subject sustained damage to the left parietal-occipital and right frontal-parietal regions. Structural and functional imaging and cognitive data were collected at the time of injury and 1 year post-injury. Cognitive assessment revealed improvement over time. Functional imaging at the time of injury revealed minimal activation in the right posterior temporal region. Imaging 1 year post-injury revealed increased activation in the right pre-frontal cortex, bilateral pre-motor cortex and bilateral posterior parietal cortex. This activation pattern is consistent with the performance of unaffected individuals on working memory tasks. These findings differ from those in the adult literature and suggest an alternative pattern of recovery of function in children.

    View details for DOI 10.1080/02699050400013576

    View details for Web of Science ID 000229622500010

    View details for PubMedID 16134743

  • Reduced amygdalar gray matter volume in familial pediatric bipolar disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Chang, K., Karchemskiy, A., Barnea-Goraly, N., Garrett, A., Simeonova, D. I., Reiss, A. 2005; 44 (6): 565-573

    Abstract

    Subcortical limbic structures have been proposed to be involved in the pathophysiology of adult and pediatric bipolar disorder (BD). We sought to study morphometric characteristics of these structures in pediatric subjects with familial BD compared with healthy controls.Twenty children and adolescents with BD I (mean age = 14.6 years, four females) and 20 healthy age, gender, and IQ-matched controls underwent high-resolution magnetic resonance imaging at 3 T. Patients were mostly euthymic and most were taking medications. Amygdala, hippocampus, thalamus, and caudate volumes were determined by manual tracings from researchers blinded to diagnosis. Analyses of covariance were performed, with total brain volume, age, and gender as covariates.No differences were found in the volumes of hippocampus, caudate, and thalamus between subjects with BD and controls. Subjects with BD had smaller volumes in the left and right amygdala, driven by reductions in gray matter volume. Exploratory analyses revealed that subjects with BD with past lithium or valproate exposure tended to have greater amygdalar gray matter volume than subjects with BD without such exposure.Children and adolescents with early-onset BD may have reduced amygdalar volumes, consistent with other studies in this population. Prolonged medication exposure to lithium or valproate may account for findings in adults with BD of increased amygdalar volume relative to controls.

    View details for DOI 10.1097/01.chi.0000159948.75136.0d

    View details for Web of Science ID 000229245600011

    View details for PubMedID 15908839

  • Abnormal cortical complexity and thickness profiles mapped in Williams syndrome JOURNAL OF NEUROSCIENCE Thompson, P. M., Lee, A. D., Dutton, R. A., Geaga, J. A., Hayashi, K. M., Eckert, M. A., Bellugi, U., Galaburda, A. M., Korenberg, J. R., Mills, D. L., Toga, A. W., Reiss, A. L. 2005; 25 (16): 4146-4158

    Abstract

    We identified and mapped an anatomically localized failure of cortical maturation in Williams syndrome (WS), a genetic condition associated with deletion of approximately 20 contiguous genes on chromosome 7. Detailed three-dimensional (3D) maps of cortical thickness, based on magnetic resonance imaging (MRI) scans of 164 brain hemispheres, identified a delimited zone of right hemisphere perisylvian cortex that was thicker in WS than in matched controls, despite pervasive gray and white matter deficits and reduced total cerebral volumes. 3D cortical surface models were extracted from 82 T1-weighted brain MRI scans (256 x 192 x 124 volumes) of 42 subjects with genetically confirmed WS (mean +/- SD, 29.2 +/- 9.0 years of age; 19 males, 23 females) and 40 age-matched healthy controls (27.5 +/- 7.4 years of age; 16 males, 24 females). A cortical pattern-matching technique used 72 sulcal landmarks traced on each brain as anchors to align cortical thickness maps across subjects, build group average maps, and identify regions with altered cortical thickness in WS. Cortical models were remeshed in frequency space to compute their fractal dimension (surface complexity) for each hemisphere and lobe. Surface complexity was significantly increased in WS (p < 0.0015 and p < 0.0014 for left and right hemispheres, respectively) and correlated with temporoparietal gyrification differences, classified via Steinmetz criteria. In WS, cortical thickness was increased by 5-10% in a circumscribed right hemisphere perisylvian and inferior temporal zone (p < 0.002). Spatially extended cortical regions were identified with increased complexity and thickness; cortical thickness and complexity were also positively correlated in controls (p < 0.03). These findings visualize cortical zones with altered anatomy in WS, which merit additional study with techniques to assess function and connectivity.

    View details for DOI 10.1523/JNEUROSCI.0165-05.2005

    View details for Web of Science ID 000228542600018

    View details for PubMedID 15843618

  • Relative sparing of primary auditory cortex in Williams Syndrome BRAIN RESEARCH Holinger, D. P., Bellugi, U., Mills, D. L., Korenberg, J. R., Reiss, A. L., Sherman, G. F., Galaburda, A. M. 2005; 1037 (1-2): 35-42

    Abstract

    Williams Syndrome (WS) is a neurodevelopment disorder associated with a hemizygous deletion on chromosome 7. WS is characterized with mental retardation, severe visual-spatial deficits, relative language preservation, and excellent facial recognition. Distinctive auditory features include musical ability, heightened sound sensitivity, and specific patterns of auditory evoked potentials. These features have led to the hypothesis that the dorsal forebrain is more affected than the ventral. Previously, we reported primary visual area 17 abnormalities in rostral striate cortex, a region contributing to the dorsal visual pathway. Based on the dorsal-ventral hypothesis, and language and auditory findings, we predicted a more normal histometric picture in auditory area 41. We used an optical dissector method to measure neurons in layers II-VI of area 41 in right and left hemispheres of the same 3 WS and 3 control brains used in the area 17 study. There was a hemisphere by diagnosis interaction in cell packing density (CPD) in layer IV and in cell size in layer III between WS and control brains. Post hoc analysis disclosed in control brains, but not WS, a layer IV left > right asymmetry in CPD, and a layer III left < right asymmetry in cell size. WS brains showed more large neurons bilaterally in layer II and in left layer VI. Histometric alterations in area 41 were less widespread than rostral visual cortex. Also, there was less asymmetry in the WS brain. We interpret layers II and VI differences as reflecting increased limbic connectivity in primary auditory cortex of WS.

    View details for DOI 10.1016/j.brainres.2004.11.038

    View details for Web of Science ID 000228251400005

    View details for PubMedID 15777750

  • From research to practice: Teacher and pediatrician awareness of phenotypic traits in neurogenetic syndromes AMERICAN JOURNAL ON MENTAL RETARDATION Lee, T. H., Blasey, C. M., Dyer-Friedman, J., Glaser, B., Reiss, A. L., Eliez, S. 2005; 110 (2): 100-106

    Abstract

    Pediatricians' and teachers' knowledge of physical, cognitive, and behavioral features associated with three genetic syndromes were assessed and the effectiveness of information sources about these syndromes evaluated. The surveyed sample included 53 pediatricians and 69 teachers from Northern and Central California. Respondents demonstrated limited knowledge regarding the physical phenotype of fragile X syndrome and significantly less knowledge of velo-cardio-facial syndrome (VCFS). In the cognitive and behavioral domains, significantly more was known about Down and fragile X syndromes than VCFS. Pediatricians and teachers make critical treatment and education decisions for children with these syndromes and would benefit from continued professional development about these syndromes through conferences, professional/association publications, in-service teacher training, and journals.

    View details for Web of Science ID 000227920600003

    View details for PubMedID 15762820

  • Evidence for superior parietal impairment in Williams syndrome NEUROLOGY Eckert, M. A., Hu, D., Eliez, S., Bellugi, U., Galaburda, A., Korenberg, J., Mills, D., Reiss, A. L. 2005; 64 (1): 152-153

    Abstract

    Parietal lobe impairment is hypothesized to contribute to the dramatic visual-spatial deficits in Williams syndrome (WS). The authors examined the superior and inferior parietal lobule in 17 patients with WS and 17 control female adults (CNLs). The right and left superior parietal lobule gray matter volumes were significantly smaller in patients with WS than in CNLs, even after controlling for total cerebral gray matter. Impaired superior parietal function could explain WS visual-spatial and visual-motor problems.

    View details for Web of Science ID 000226216000032

    View details for PubMedID 15642924

  • The contribution of novel brain imaging techniques to understanding the neurobiology of mental retardation and developmental disabilities MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Gothelf, D., Furfaro, J. A., Penniman, L. C., Glover, G. H., Reiss, A. L. 2005; 11 (4): 331-339

    Abstract

    Studying the biological mechanisms underlying mental retardation and developmental disabilities (MR/DD) is a very complex task. This is due to the wide heterogeneity of etiologies and pathways that lead to MR/DD. Breakthroughs in genetics and molecular biology and the development of sophisticated brain imaging techniques during the last decades have facilitated the emergence of a field called Behavioral Neurogenetics. Behavioral Neurogenetics focuses on studying genetic diseases with known etiologies that are manifested by unique cognitive and behavioral phenotypes. In this review, we describe the principles of magnetic resonance imaging (MRI) techniques, including structural MRI, functional MRI, and diffusion tensor imaging (DTI), and how they are implemented in the study of Williams (WS), velocardiofacial (VCFS), and fragile X (FXS) syndromes. From WS we learn that dorsal stream abnormalities can be associated with visuospatial deficits; VCFS is a model for exploring the molecular and brain pathways that lead to psychiatric disorders for which subjects with MR/DD are at increased risk; and finally, findings from multimodal imaging techniques show that aberrant frontal-striatal connections are implicated in the executive function and attentional deficits of subjects with FXS. By deciphering the molecular pathways and brain structure and function associated with cognitive deficits, we will gain a better understanding of the pathophysiology of MR/DD, which will eventually make possible more specific treatments for this population.

    View details for DOI 10.1002/mrdd.20089

    View details for Web of Science ID 000232943600008

    View details for PubMedID 16240408

  • Event-related fMRI evidence of frontotemporal involvement in aberrant response inhibition and task switching in attention-deficit/hlyperactivity disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Tamm, L., Menon, V., Ringel, J., Reiss, A. L. 2004; 43 (11): 1430-1440

    Abstract

    Response inhibition deficits are characteristic of individuals with attention-deficit/hyperactivity disorder (ADHD). Previous functional magnetic resonance imaging (fMRI) studies investigating the neural correlates of this dysfunction have used block designs, making it difficult to disentangle activation differences specifically related to response inhibition from activation differences related to subprocesses involved in task performance. The current study was designed to further enhance our understanding of this critical function in individuals with ADHD using event-related fMRI.Ten adolescent boys diagnosed with ADHD, combined type, and 12 typically developing controls completed a Go/NoGo task modified to control for novelty processing.The ADHD group made significantly more errors of omission and more errors of commission than the control group. Further, compared with controls, individuals with ADHD showed marked abnormalities in brain activation during response inhibition, including hypoactivation of the anterior/mid-cingulate cortex extending to the supplementary motor area and hyperactivation of the left temporal gyrus.The authors suggest that underactivation in frontal regions reflects core deficits in response/task-switching abilities for the ADHD group.

    View details for DOI 10.1097/01.chi.0000140452.51205.8d

    View details for Web of Science ID 000224630900021

    View details for PubMedID 15502603

  • Voxel-based morphometry elucidates structural neuroanatomy of high-functioning autism and Asperger syndrome DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Kwon, H., Ow, A. W., Pedatella, K. E., Lotspeich, L. J., Reiss, A. L. 2004; 46 (11): 760-764

    Abstract

    Efforts to examine the structural neuroanatomy of autism by using traditional methods of imaging analysis have led to variable findings, often based on methodological differences in image acquisition and analysis. A voxel-based computational method of whole-brain anatomy allows examination of small patterns of tissue differences between groups. High-resolution structural magnetic resonance images were acquired for nine males with high-functioning autism (HFA; mean age 14y [SD3y 4mo]), 11 with Asperger syndrome (ASP; mean age 13y 6mo [SD2y 5mo]), and 13 comparison (COM) participants (mean age 13y 7mo [SD 3y 1mo]). Using statistical parametric mapping, we examined contrasts of gray matter differences between the groups. Males with HFA and ASP had a pattern of decreased gray matter density in the ventromedial regions of the temporal cortex in comparison with males from an age-matched comparison group. Examining contrasts revealed that the COM group had increased gray matter density compared with the ASP or combined HFA and ASP group in the right inferior temporal gyrus, entorhinal cortex, and rostral fusiform gyrus. The ASP group had less gray matter density in the body of the cingulate gyrus in comparison with either the COM or HFA group. The findings of decreased gray matter density in ventromedial aspects of the temporal cortex in individuals with HFA and ASP lends support to theories suggesting an involvement of these areas in the pathophysiology of autism, particularly in the integration of visual stimuli and affective information.

    View details for DOI 10.1017/S0012162204001306

    View details for Web of Science ID 000225066000007

    View details for PubMedID 15540637

  • Volumetric analysis of regional cerebral development in preterm children PEDIATRIC NEUROLOGY Kesler, S. R., Ment, L. R., Vohr, B., Pajot, S. K., Schneider, K. C., Katz, K. H., Ebbitt, T. B., Duncan, C. C., Makuch, R. W., Reiss, A. L. 2004; 31 (5): 318-325

    Abstract

    Preterm birth is frequently associated with both neuropathologic and cognitive sequelae. This study examined cortical lobe, subcortical, and lateral ventricle development in association with perinatal variables and cognitive outcome. High-resolution volumetric magnetic resonance imaging scans were acquired and quantified using advanced image processing techniques. Seventy-three preterm and 33 term control children ages 7.3-11.4 years were included in the study. Results indicated disproportionately enlarged parietal and frontal gray matter, occipital horn, and ventricular body, as well as reduced temporal and subcortical gray volumes in preterm children compared with control subjects. Birth weight was negatively correlated with parietal and frontal gray, as well as occipital horn volumes. Intraventricular hemorrhage was associated with reduced subcortical gray matter. Ventricular cerebrospinal fluid was negatively correlated with subcortical gray matter volumes but not with white matter volumes. Maternal education was the strongest predictor of cognitive function in the preterm group. Preterm birth appears to be associated with disorganized cortical development, possibly involving disrupted synaptic pruning and neural migration. Lower birth weight and the presence of intraventricular hemorrhage may increase the risk for neuroanatomic abnormality.

    View details for DOI 10.1016/j.pediatrneurol.2004.06.008

    View details for Web of Science ID 000225313400002

    View details for PubMedID 15519112

  • A volumetric study of parietal lobe subregions in Turner syndrome DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Brown, W. E., Kesler, S. R., Eliez, S., Warsofsky, I. S., Haberecht, M., Reiss, A. L. 2004; 46 (9): 607-609

    Abstract

    Turner syndrome, a genetic disorder that results from the complete or partial absence of an X chromosome in females, has been associated with specific impairment in visuospatial cognition. Previous studies have demonstrated a relationship between parietal lobe abnormalities and visuospatial deficits in Turner syndrome. We used high-resolution magnetic resonance imaging to measure parietal lobe subdivisions in 14 participants with Turner syndrome (mean age 13 years 5 months, SD 5 years) and 14 age-matched controls (mean age 13 years 5 months, SD 4 years 7 months) to localize neuroanatomical variations more closely. Scans were acquired and analyzed for 14 females with Turner syndrome. Analyses of variance were used to investigate differences in regional parietal lobes. Females with Turner syndrome showed a bilateral parietal lobe reduction, specifically in the superior parietal and postcentral gyri. Full-scale IQ scores were significantly positively correlated with postcentral tissue volume in the Turner syndrome group. Structural differences in the parietal lobe are localized specifically to the anterior and superior parietal lobe and might be related to the visuospatial and visuomotor deficits associated with Turner syndrome.

    View details for DOI 10.1017/S0012162204001021

    View details for Web of Science ID 000223720900005

    View details for PubMedID 15344520

  • Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder - A functional magnetic resonance imaging investigation ARCHIVES OF GENERAL PSYCHIATRY Chang, K., Adleman, N. E., Dienes, K., Simeonova, D. I., Menon, V., Reiss, A. 2004; 61 (8): 781-792

    Abstract

    The neurobiological features of pediatric bipolar disorder (BD) are largely unknown. Children and adolescents with BD may be important to study with functional neuroimaging techniques because of their unique status of early-onset BD and high familial loading for the disorder. Neuroimaging studies of adults with BD have implicated the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in the development of this disorder.To study children and adolescents with BD via functional magnetic resonance imaging using cognitive and affective tasks and to examine possible abnormalities in the DLPFC and ACC, as well as selected subcortical areas, in pediatric familial BD.We evaluated 12 male subjects aged 9 to 18 years with BD who had at least 1 parent with BD as well as 10 age- and IQ-matched healthy male controls. Stimulants were discontinued for at least 24 hours; other medications were continued. Subjects underwent functional magnetic resonance imaging at 3 T while performing a 2-back visuospatial working memory task and an affective task involving the visualization of positively, neutrally, or negatively valenced pictures.An academic referral setting, drawing from the Bay Area of San Francisco, Calif.Compared with controls, for the visuospatial working memory task, subjects with BD had greater activation in several areas including the bilateral ACC, left putamen, left thalamus, left DLPFC, and right inferior frontal gyrus. Controls had greater activation in the cerebellar vermis. In viewing negatively valenced pictures, subjects with BD had greater activation in the bilateral DLPFC, inferior frontal gyrus, and right insula. Controls had greater activation in the right posterior cingulate gyrus. For positively valenced pictures, subjects with BD had greater activation in the bilateral caudate and thalamus, left middle/superior frontal gyrus, and left ACC, whereas controls had no areas of greater activation.Children and adolescents with BD may have underlying abnormalities in the regulation of prefrontal-subcortical circuits. Further functional magnetic resonance imaging studies of attention and mood with greater sample sizes are needed.

    View details for Web of Science ID 000223140400004

    View details for PubMedID 15289277

  • Sex differences in cerebral volumes of 8-year-olds born preterm JOURNAL OF PEDIATRICS Reiss, A. L., Kesler, S. R., Vohr, B., Duncan, C. C., Katz, K. H., Pajot, S., Schneider, K. C., Makuch, R. W., Ment, L. R. 2004; 145 (2): 242-249

    Abstract

    We investigate sex-associated effects of preterm birth on cerebral gray matter (GM) and white matter (WM) volumes. Preterm children (n=65) and 31 healthy, term control children had usable magnetic resonance imaging (MRI) data acquired at 8 years of age. Both GM and WM volumes were significantly reduced in the preterm group compared with controls. However, only males with preterm birth had significantly reduced WM compared with term males (P=.021), whereas WM volumes were equivalent in the female groups. Lower birth weight was associated with reduced WM in both boys and girls with preterm birth, whereas intraventricular hemorrhage (IVH) was associated with reduced GM in girls only. Positive correlations between GM and cognitive outcome were observed in girls with preterm birth but not boys. We conclude that preterm birth has a significant impact on brain development with increased risk for smaller GM and WM cerebral volumes. Males appear particularly vulnerable to adverse effects of preterm birth on WM development. However, girls with preterm birth show stronger correlations between neuro-anatomical variables and both neonatal risk factors and cognitive outcome, compared with boys. These findings indicate that the sex of the very preterm newborn influences the mechanisms by which the developing brain is affected.

    View details for DOI 10.1016/j.jpeds.2004.04.031

    View details for Web of Science ID 000223406200024

    View details for PubMedID 15289777

  • Reduced basal forebrain and hippocampal activation during memory encoding in girls with fragile X syndrome NEUROREPORT Greicius, M. D., Boyett-Anderson, J. M., Menon, V., Reiss, A. L. 2004; 15 (10): 1579-1583

    Abstract

    Fragile X syndrome (FraX), the most common heritable cause of developmental disability, is associated with IQ, memory, and visuospatial processing deficits. The fragile X gene (FMR1) is prominently transcribed in two regions critical to memory encoding and attention: the hippocampus and the basal forebrain. To probe functional MRI activation abnormalities associated with the disorder, girls with FraX and age-matched, normally-developing girls were scanned during a test of visual memory encoding. While there were considerable similarities in activation patterns between the two groups, the girls with FraX showed significantly less activation in the hippocampus and the basal forebrain. This is the first study, to our knowledge, demonstrating functional deficits in FraX subjects in brain regions known to have the highest FMR1 transcription.

    View details for DOI 10.1097/01.wnr.0000134472.44362.be

    View details for Web of Science ID 000225140700010

    View details for PubMedID 15232287

  • The amygdala is enlarged in children but not adolescents with autism; The hippocampus is enlarged at all ages JOURNAL OF NEUROSCIENCE Schumann, C. M., Hamstra, J., Goodlin-Jones, B. L., Lotspeich, L. J., Kwon, H., Buonocore, M. H., Lammers, C. R., Reiss, A. L., Amaral, D. G. 2004; 24 (28): 6392-6401

    Abstract

    Autism is a neurodevelopmental disorder characterized by impairments in reciprocal social interaction, deficits in verbal and nonverbal communication, and a restricted repertoire of activities or interests. We performed a magnetic resonance imaging study to better define the neuropathology of autistic spectrum disorders. Here we report findings on the amygdala and the hippocampal formation. Borders of the amygdala, hippocampus, and cerebrum were defined, and their volumes were measured in male children (7.5-18.5 years of age) in four diagnostic groups: autism with mental retardation, autism without mental retardation, Asperger syndrome, and age-matched typically developing controls. Although there were no differences between groups in terms of total cerebral volume, children with autism (7.5-12.5 years of age) had larger right and left amygdala volumes than control children. There were no differences in amygdala volume between the adolescent groups (12.75-18.5 years of age). Interestingly, the amygdala in typically developing children increases substantially in volume from 7.5 to 18.5 years of age. Thus, the amygdala in children with autism is initially larger, but does not undergo the age-related increase observed in typically developing children. Children with autism, with and without mental retardation, also had a larger right hippocampal volume than typically developing controls, even after controlling for total cerebral volume. Children with autism but without mental retardation also had a larger left hippocampal volume relative to controls. These cross-sectional findings indicate an abnormal program of early amygdala development in autism and an abnormal pattern of hippocampal development that persists through adolescence. The cause of amygdala and hippocampal abnormalities in autism is currently unknown.

    View details for DOI 10.1523/JNEUROSCI.1297-04.2004

    View details for Web of Science ID 000222650000018

    View details for PubMedID 15254095

  • Anomalous brain activation during face and gaze processing in Williams syndrome NEUROLOGY Mobbs, D., Garrett, A. S., Menon, V., Rose, F. E., Bellugi, U., Reiss, A. L. 2004; 62 (11): 2070-2076

    Abstract

    To investigate the discrete neural systems that underlie relatively preserved face processing skills in Williams syndrome (WS).The authors compared face and eye-gaze direction processing abilities in 11 clinically and genetically diagnosed WS subjects with 11 healthy age- and sex-matched controls, using functional MRI (fMRI).Compared to controls, WS subjects showed a strong trend toward being less accurate in determining the direction of gaze and had significantly longer response latencies. Significant increases in activation were observed in the right fusiform gyrus (FuG) and several frontal and temporal regions for the WS group. By comparison, controls showed activation in the bilateral FuG, occipital, and temporal lobes. Between-group analysis showed WS subjects to have more extensive activation in the right inferior, superior, and medial frontal gyri, anterior cingulate, and several subcortical regions encompassing the anterior thalamus and caudate. Conversely, controls had greater activation in the primary and secondary visual cortices.The observed patterns of activation in WS subjects suggest a preservation of neural functioning within frontal and temporal regions, presumably resulting from task difficulty or compensatory mechanisms. Persons with WS may possess impairments in visual cortical regions, possibly disrupting global-coherence and visuospatial aspects of face and gaze processing.

    View details for Web of Science ID 000221890400030

    View details for PubMedID 15184616

  • An experiment of nature: Brain anatomy parallels cognition and behavior in Williams syndrome JOURNAL OF NEUROSCIENCE Reiss, A. L., Eckert, M. A., Rose, F. E., Karchemskiy, A., Kesler, S., Chang, M., Reynolds, M. F., Kwon, H., Galaburda, A. 2004; 24 (21): 5009-5015

    Abstract

    Williams syndrome (WS) is a neurogenetic-neurodevelopmental disorder characterized by a highly variable and enigmatic profile of cognitive and behavioral features. Relative to overall intellect, affected individuals demonstrate disproportionately severe visual-spatial deficits and enhanced emotionality and face processing. In this study, high-resolution magnetic resonance imaging data were collected from 43 individuals with WS and 40 age- and gender-matched healthy controls. Given the distinct cognitive-behavioral dissociations associated with this disorder, we hypothesized that neuroanatomical integrity in WS would be diminished most in regions comprising the visual-spatial system and most "preserved" or even augmented in regions involved in emotion and face processing. Both volumetric analysis and voxel-based morphometry were used to provide convergent approaches for detecting the hypothesized WS neuroanatomical profile. After adjusting for overall brain volume, participants with WS showed reduced thalamic and occipital lobe gray matter volumes and reduced gray matter density in subcortical and cortical regions comprising the human visual-spatial system compared with controls. The WS group also showed disproportionate increases in volume and gray matter density in several areas known to participate in emotion and face processing, including the amygdala, orbital and medial prefrontal cortices, anterior cingulate, insular cortex, and superior temporal gyrus. These findings point to specific neuroanatomical correlates for the unique topography of cognitive and behavioral features associated with this disorder.

    View details for DOI 10.1523/JNEUROSCI.5272-03.2004

    View details for Web of Science ID 000221654400013

    View details for PubMedID 15163693

  • Cognitive correlates of white matter growth and stress hormones in female squirrel monkey adults JOURNAL OF NEUROSCIENCE Lyons, D. M., Yang, C., Eliez, S., Reiss, A. L., Schatzberg, A. F. 2004; 24 (14): 3655-3662

    Abstract

    Neurobiological studies of stress and cognitive aging seldom consider white matter despite indications that complex brain processes depend on networks and white matter interconnections. Frontal and temporal lobe white matter volumes increase throughout midlife adulthood in humans, and this aspect of aging is thought to enhance distributed brain functions. Here, we examine spatial learning and memory, neuroendocrine responses to psychological stress, and regional volumes of gray and white matter determined by magnetic resonance imaging in 31 female squirrel monkeys between the ages of 5 and 17 years. This period of lifespan development corresponds to the years 18-60 in humans. Older adults responded to stress with greater increases in plasma levels of adrenocorticotropic hormone and modest reductions in glucocorticoid feedback sensitivity relative to young adults. Learning and memory did not differ with age during the initial cognitive test sessions, but older adults more often failed to inhibit the initial learned response after subsequent spatial reversals. Impaired cognitive response inhibition correlated with the expansion of white matter volume statistically controlling for age, stress hormones, gray matter, and CSF volumes. These results indicate that instead of enhancing cognitive control during midlife adulthood, white matter volume expansion contributes to aspects of cognitive decline. Cellular and molecular research combined with brain imaging is needed to determine the basis of white matter growth in adults, elucidate its functions during lifespan development, and provide potential new targets for therapies aimed at maintaining in humans cognitive vitality with aging.

    View details for DOI 10.1523/JNEUROSCI.0324-04.2004

    View details for Web of Science ID 000220715400022

    View details for PubMedID 15071114

  • Emotional attribution in high-functioning individuals with autistic spectrum disorder: A functional imaging study JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Piggot, J., Kwon, H., Mobbs, D., Blasey, C., Lotspeich, L., Menon, V., Bookheimer, S., Reiss, A. L. 2004; 43 (4): 473-480

    Abstract

    To determine whether expertise in the attribution of emotion from basic facial expressions in high-functioning individuals with autistic spectrum disorder (ASD) is supported by the amygdala, fusiform, and prefrontal regions of interest (ROI) and is comparable to that of typically developing individuals.Functional magnetic resonance imaging scans were acquired from 14 males with ASD and 10 matched adolescent controls while performing emotion match (EM) (perceptual), emotion label (EL) (linguistic), and control tasks. Accuracy, response time, and average activation were measured for each ROI.There was no significant difference in accuracy, response time, or ROI activation between groups performing the EL task. The ASD group was as accurate as the control group performing the EM task but had a significantly longer response time and lower average fusiform activation.Expertise in the attribution of emotion from basic facial expressions was task-dependent in the high-functioning ASD group. The hypothesis that the high-functioning ASD group would be less expert and would have reduced fusiform activation was supported in the perceptual task but not the linguistic task. The reduced fusiform activation in the perceptual task was not explained by reduced expertise; it is therefore concluded that reduced fusiform activation is associated with the diagnosis of ASD.

    View details for DOI 10.1097/01.chi.0000111363.94169.37

    View details for Web of Science ID 000220384300014

    View details for PubMedID 15187808

  • Default-mode network activity distinguishes Alzheimer's disease from healthy aging: Evidence from functional MRI PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Greicius, M. D., Srivastava, G., Reiss, A. L., Menon, V. 2004; 101 (13): 4637-4642

    Abstract

    Recent functional imaging studies have revealed coactivation in a distributed network of cortical regions that characterizes the resting state, or default mode, of the human brain. Among the brain regions implicated in this network, several, including the posterior cingulate cortex and inferior parietal lobes, have also shown decreased metabolism early in the course of Alzheimer's disease (AD). We reasoned that default-mode network activity might therefore be abnormal in AD. To test this hypothesis, we used independent component analysis to isolate the network in a group of 13 subjects with mild AD and in a group of 13 age-matched elderly controls as they performed a simple sensory-motor processing task. Three important findings are reported. Prominent coactivation of the hippocampus, detected in all groups, suggests that the default-mode network is closely involved with episodic memory processing. The AD group showed decreased resting-state activity in the posterior cingulate and hippocampus, suggesting that disrupted connectivity between these two regions accounts for the posterior cingulate hypometabolism commonly detected in positron emission tomography studies of early AD. Finally, a goodness-of-fit analysis applied at the individual subject level suggests that activity in the default-mode network may ultimately prove a sensitive and specific biomarker for incipient AD.

    View details for DOI 10.1073/pnas.0308627101

    View details for Web of Science ID 000220648700056

    View details for PubMedID 15070770

  • Frontostriatal deficits in fragile X syndrome: Relation to FMR1 gene expression PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Menon, V., Leroux, J., White, C. D., Reiss, A. L. 2004; 101 (10): 3615-3620

    Abstract

    Fragile X syndrome (fraX) is the most common known cause of inherited developmental disability. fraX is associated with a CGG expansion in the FMR1 gene on the long arm of the X chromosome. Behavioral deficits, including problems with impulse control and distractibility, are common in fraX. We used functional brain imaging with a Go/NoGo task to examine the neural substrates of response inhibition in females with fraX (ages 10-22) and age- and gender-matched typically developing subjects. Although subjects with fraX had significantly lower IQ scores, as a group their performance on the Go/NoGo task was equivalent to that of the typically developing group. However, females with fraX showed abnormal activation patterns in several cortical and subcortical regions, with significantly reduced activation in the supplementary motor area, anterior cingulate and midcingulate cortex, basal ganglia, and hippocampus. An important finding of our study is that neural responses in the right ventrolateral prefrontal cortex (PFC) and the left and right striatum were correlated with the level of FMR1 gene expression. Our findings support the hypothesis that frontostriatal regions typically associated with response inhibition are dysfunctional in females with fraX. In addition to task-related activation deficits, reduced levels of "deactivation" were observed in the ventromedial PFC, and, furthermore, these reductions were correlated with the level of FMR1 gene expression. The ventromedial PFC is a key node in a "default mode" network that monitors mental and physiological states; we suggest that self-monitoring processes may be aberrant in fraX.

    View details for DOI 10.1073/pnas.0304544101

    View details for Web of Science ID 000220163800053

    View details for PubMedID 14993603

  • Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism AMERICAN JOURNAL OF PSYCHIATRY Kates, W. R., Burnette, C. P., Eliez, S., Strunge, L. A., Kaplan, D., Landa, R., Reiss, A. L., Pearlson, G. D. 2004; 161 (3): 539-546

    Abstract

    The broader autism phenotype includes relatives of individuals with autism who display social and language deficits that are qualitatively similar to those of autism but less severe. In previous studies of monozygotic twins discordant for autism, more than 75% of the twins without autism displayed the broader phenotype. Differences in neuroanatomy between discordant monozygotic twins might be associated with the narrow and broader behavioral phenotypes. The authors examined the relationship of twin pair differences in clinical phenotype to differences in neuroanatomic phenotype.The subjects were 16 monozygotic twin pairs between the ages of 5 and 14 years and 16 matched singleton comparison subjects. Seven twin pairs were clinically concordant and nine twin pairs were clinically discordant for strictly defined autism. After magnetic resonance imaging, a semiautomated procedure was applied to images in which the brain tissue was subdivided into neurofunctional regions and segmented into gray, white, and ventricular compartments.Both the concordant and discordant twin pairs exhibited concordance in cerebral gray and white matter volumes. However, only the clinically concordant pairs exhibited concordance in cerebellar gray and white matter volumes. Within the discordant twin pairs, both the twins with autism and their co-twins exhibited frontal, temporal, and occipital white matter volumes that were lower than those of the comparison subjects.These findings support the role and the limits of genetic liability in autism. Continuing to clarify the neuroanatomic pathways in autistic spectrum disorders could illuminate the etiology of autism and, ultimately, contribute to treatments.

    View details for Web of Science ID 000221276000021

    View details for PubMedID 14992981

  • 22q11 deletion syndrome in childhood onset schizophrenia: an update MOLECULAR PSYCHIATRY Sporn, A., Addington, A., Reiss, A. L., Dean, M., Gogtay, N., Potocnik, U., Greenstein, D., Hallmayer, J., Gochman, P., Lenane, M., Baker, N., Tossell, J., Rapoport, J. L. 2004; 9 (3): 225-226

    View details for DOI 10.1038/sj.mp.4001477

    View details for Web of Science ID 000220129200001

    View details for PubMedID 14699434

  • Here's looking at you, kid - Neural systems underlying face and gaze processing in fragile X syndrome ARCHIVES OF GENERAL PSYCHIATRY Garrett, A. S., Menon, V., MacKenzie, K., Reiss, A. L. 2004; 61 (3): 281-288

    Abstract

    Children with fragile X syndrome (fraX) are at risk for manifesting abnormalities in social function that overlap with features of autism and social anxiety disorder. In this study, we analyzed brain activation in response to face and gaze stimuli to better understand neural functioning associated with social perception in fraX.Eleven female subjects with fraX, aged 10 to 22 years, were compared with age-matched female control subjects. Photographs of forward-facing and angled faces, each having direct and averted gaze (4 types of stimuli), were presented in an event-related design during functional magnetic resonance imaging. Subjects were instructed to determine the direction of gaze for each photograph. Activation in brain regions known to respond to face and gaze stimuli, the fusiform gyrus (FG) and superior temporal sulcus (STS), were compared between groups to isolate neural abnormalities in the perception of directed social stimuli.The fraX subjects had decreased accuracy in determining the direction of gaze compared with controls. Region of interest analysis of the FG revealed a significant interaction between diagnostic group and face orientation. Specifically, control subjects had greater FG activation to forward than to angled faces, whereas fraX subjects had no difference in FG activation to forward and angled faces. Controls showed greater left STS activation to all stimuli compared with fraX subjects.Our results suggest that gaze aversion in fraX subjects is related to decreased specialization of the FG in the perception of face orientation. Decreased STS activation in fraX suggests aberrant processing of gaze. These data suggest that gaze aversion in fraX may be related to dysfunction of neural systems underlying both face and gaze processing.

    View details for Web of Science ID 000220064800009

    View details for PubMedID 14993116

  • Investigation of neuroanatomical differences between autism and Asperger syndrome ARCHIVES OF GENERAL PSYCHIATRY Lotspeich, L., Kwon, H., Schumann, C. M., Fryer, S. L., Goodlin-Jones, B. L., Buonocore, M. H., Lammers, C. R., AMARAL, D. G., Reiss, A. L. 2004; 61 (3): 291-298

    Abstract

    Autism and Asperger syndrome (ASP) are neurobiological conditions with overlapping behavioral symptoms and of unknown etiologies. Results from previous autism neuroimaging studies have been difficult to replicate, possibly owing to site differences in subject samples, scanning procedures, and image-processing methods. We sought (1) to determine whether low-functioning autism (LFA; IQ<70), high-functioning autism (HFA; IQ>or=70), and ASP constitute distinct biological entities as evidenced by neuroanatomical measures, and (2) to assess for intersite differences.Case-control study examining coronally oriented 124-section spoiled gradient echo images acquired on 3 magnetic resonance imaging (MRI) systems, and processed by BrainImage 5.X. Participants were recruited and underwent scanning at 2 academic medicine departments. Participants included 4 age-matched groups of volunteer boys aged 7.8 to 17.9 years (13 patients with LFA, 18 with HFA, 21 with ASP, and 21 control subjects), and 3 volunteer adults for neuroimaging reliability. Main outcome measures included volumetric measures of total, white, and gray matter for cerebral and cerebellar tissues.Intersite differences were seen for subject age, IQ, and cerebellum measures. Cerebral gray matter volume was enlarged in both HFA and LFA compared with controls (P =.009 and P =.04, respectively). Cerebral gray matter volume in ASP was intermediate between that of HFA and controls, but nonsignificant. Exploratory analyses revealed a negative correlation between cerebral gray matter volume and performance IQ within HFA but not ASP. A positive correlation between cerebral white matter volume and performance IQ was observed within ASP but not HFA.Lack of replication between previous autism MRI studies could be due to intersite differences in MRI systems and subjects' age and IQ. Cerebral gray tissue findings suggest that ASP is on the mild end of the autism spectrum. However, exploratory assessments of brain-IQ relationships reveal differences between HFA and ASP, indicating that these conditions may be neurodevelopmentally different when patterns of multiple measures are examined. Further investigations of brain-behavior relationships are indicated to confirm these findings.

    View details for Web of Science ID 000220064800010

    View details for PubMedID 14993117

  • White matter structure in autism: Preliminary evidence from diffusion tensor imaging BIOLOGICAL PSYCHIATRY Barnea-Goraly, N., Kwon, H., Menon, V., Eliez, S., Lotspeich, L., Reiss, A. L. 2004; 55 (3): 323-326

    Abstract

    Individuals with autism have severe difficulties in social communication and relationships. Prior studies have suggested that abnormal connections between brain regions important for social cognition may contribute to the social deficits seen in autism.In this study, we used diffusion tensor imaging to investigate white matter structure in seven male children and adolescents with autism and nine age-, gender-, and IQ-matched control subjects.Reduced fractional anisotropy (FA) values were observed in white matter adjacent to the ventromedial prefrontal cortices and in the anterior cingulate gyri as well as in the temporoparietal junctions. Additional clusters of reduced FA values were seen adjacent to the superior temporal sulcus bilaterally, in the temporal lobes approaching the amygdala bilaterally, in occipitotemporal tracts, and in the corpus callosum.Disruption of white matter tracts between regions implicated in social functioning may contribute to impaired social cognition in autism.

    View details for DOI 10.1016/j.biopsych.2003.10.022

    View details for Web of Science ID 000188434000019

    View details for PubMedID 14744477

  • Functional neuroanatomy of spatial orientation processing in Turner syndrome CEREBRAL CORTEX Kesler, S. R., Haberecht, M. F., Menon, V., Warsofsky, I. S., Dyer-Friedman, J., Neely, E. K., Reiss, A. L. 2004; 14 (2): 174-180

    Abstract

    Turner syndrome (TS), a neurogenetic disorder characterized by the absence of one X chromosome in a phenotypic female, is frequently associated with visuospatial impairments. We investigated the neural mechanisms underlying deficits in spatial orientation processing in TS. Thirteen subjects with TS and 13 age-matched typically developing controls underwent neuropsychological assessments and were scanned using functional MRI while they performed easy and difficult versions of a judgment of line orientation (JLO) task. Controls and subjects with TS activated parietal-occipital regions involved in spatial orientation during the JLO task. However, activation was significantly less in the TS group. Control subjects responded to increased task difficulty by recruiting executive frontal areas whereas subjects with TS did not activate alternate brain regions to meet increased task demands. Subjects with TS demonstrate activation deficits in parietal-occipital and frontal areas during the JLO task. Activation, and possibly deactivation, deficits in these areas may be responsible for the visuospatial deficits observed in females with TS.

    View details for DOI 10.1093/cercor/bhg116

    View details for Web of Science ID 000187975800006

    View details for PubMedID 14704214

  • The neuroanatomy and neuroendocrinotogy of fragile X syndrome MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Hessl, D., Rivera, S. M., Reiss, A. L. 2004; 10 (1): 17-24

    Abstract

    Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene-brain-behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical features that are unique to this syndrome. In this article, we summarize studies focused on the neuroanatomy and neuroendocrinology of FXS. A review of structural imaging studies of individuals with the full mutation shows that several brain regions are enlarged, including the hippocampus, amygdala, caudate nucleus, and thalamus, even after controlling for overall brain volume. These regions mediate several cognitive and behavioral functions known to be aberrant in FXS such as memory and learning, information and sensory processing, and social and emotional behavior. Two regions, the cerebellar vermis, important for a variety of cognitive tasks and regulation of motor behavior, and the superior temporal gyrus, involved in processing complex auditory stimuli, are reported to be reduced in size relative to controls. Functional imaging, typically limited to females, has emphasized that individuals with FXS do not adequately recruit brain regions that are normally utilized by unaffected individuals to carry out various cognitive tasks, such as arithmetic processing or visual memory tasks. Finally, we review a number of neuroendocrine studies implicating hypothalamic dysfunction in FXS, including abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis. These studies may help to explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. In the future, innovative longitudinal studies to investigate development of neurobiologic and behavioral features over time, and ultimately empirical testing of pharmacological, behavioral, and even molecular genetic interventions using MRI are likely to yield significant positive changes in the lives of persons with FXS, as well as increase our understanding of the development of psychiatric and learning problems in the general population.

    View details for DOI 10.1002/mrdd.20004

    View details for Web of Science ID 000221595900004

    View details for PubMedID 14994284

  • Amygdala and hippocampal volumes in Turner syndrome: a high-resolution MRI study of X-monosomy NEUROPSYCHOLOGIA Kesler, S. R., Garrett, A., Bender, B., Yankowitz, J., Zeng, S. M., Reiss, A. L. 2004; 42 (14): 1971-1978

    Abstract

    Turner syndrome (TS) results from partial or complete X-monosomy and is characterized by deficits in visuospatial functioning as well as social cognition and memory. Neuroimaging studies have demonstrated volumetric differences in the parietal region of females with TS compared to controls. The present study examined amygdala and hippocampus morphology in an attempt to further understand the neural correlates of psychosocial and memory functioning in TS. Thirty females with TS age 7.6-33.3 years (mean = 14.7 +/- 6.4) and 29 age-matched controls (mean age = 14.8 +/- 5.9; range = 6.4-32.7) were scanned using high resolution MRI. Volumetric analyses of the MRI scans included whole brain segmentation and manual delineation of the amygdala and hippocampus. Compared to controls, participants with TS demonstrated significantly larger left amygdala gray matter volumes, irrespective of total cerebral tissue and age. Participants with TS also showed disproportionately reduced right hippocampal volumes, involving both gray and white matter. Amygdala and hippocampal volumes appear to be impacted by X-monosomy. Aberrant morphology in these regions may be related to the social cognition and memory deficits often experienced by individuals with TS. Further investigations of changes in medial temporal morphology associated with TS are warranted.

    View details for DOI 10.1016/j.neuropsychologia.2004.04.021

    View details for Web of Science ID 000224330500012

    View details for PubMedID 15381027

  • Humor modulates the mesolimbic reward centers NEURON Mobbs, D., Greicius, M. D., Abdel-Azim, E., Menon, V., Reiss, A. L. 2003; 40 (5): 1041-1048

    Abstract

    Humor plays an essential role in many facets of human life including psychological, social, and somatic functioning. Recently, neuroimaging has been applied to this critical human attribute, shedding light on the affective, cognitive, and motor networks involved in humor processing. To date, however, researchers have failed to demonstrate the subcortical correlates of the most fundamental feature of humor-reward. In an effort to elucidate the neurobiological substrate that subserves the reward components of humor, we undertook a high-field (3 Tesla) event-related functional MRI study. Here we demonstrate that humor modulates activity in several cortical regions, and we present new evidence that humor engages a network of subcortical regions including the nucleus accumbens, a key component of the mesolimbic dopaminergic reward system. Further, the degree of humor intensity was positively correlated with BOLD signal intensity in these regions. Together, these findings offer new insight into the neural basis of salutary aspects of humor.

    View details for Web of Science ID 000187042200020

    View details for PubMedID 14659102

  • Interactive specification of regions of interest on brain surfaces NEUROIMAGE Shiffman, S., Ng, Y. R., Brosnan, T. J., Eliez, S., Links, J. M., Kelkar, U. V., Reiss, A. L. 2003; 20 (3): 1811-1816

    Abstract

    We describe Surface Editor-a tool for interactive specification of regions of interest (ROIs) on brain surfaces. The tool allows users to define subsurfaces by tracing around areas within a triangle-mesh brain surface. The input to the program is a triangle-mesh representation of a brain volume and a set of user-defined input points on the mesh. The program connects each pair of successive input points with a polyline that results from the intersection of the mesh with a plane that is approximately normal to the mesh. The polyline comprises coplanar line segments. The boundary of an ROI is a connected set of polylines that intersects triangle edges to form a continuous path. To validate Surface Editor we demonstrated that the program could be used to interactively delineate gyri on brain surfaces, and we showed that paths that the program generated were comparable to paths that a user generated and to shortest paths.

    View details for DOI 10.1016/j.neuroimage.2003.06.001

    View details for Web of Science ID 000186723800034

    View details for PubMedID 14642490

  • The behavioral neurogenetics of fragile X syndrome: Analyzing gene-brain-behavior relationships in child developmental psychopathologies DEVELOPMENT AND PSYCHOPATHOLOGY Reiss, A. L., Dant, C. C. 2003; 15 (4): 927-968

    Abstract

    Analyzing gene-brain-behavior linkages in childhood neurodevelopmental disorders, a research approach called "behavioral neurogenetics," has provided new insights into understanding how both genetic and environmental factors contribute to complex variations in typical and atypical human development. Research into etiologically more homogeneous disorders, such as fragile X syndrome, in particular, allows the use of more precise metrics of genetic risk so that we can more fully understand the complex pathophysiology of childhood onset neurodevelopmental disorders. In this paper, we review our laboratory's behavioral neurogenetics research by examining gene-brain-behavior relationships in fragile X syndrome, a single-gene disorder that has become a well-characterized model for studying neurodevelopmental dysfunction in childhood. Specifically, we examine genetic influences, trajectories of cognition and behavior, variation in brain structure and function, and biological and environmental factors that influence developmental and cognitive outcomes of children with fragile X. The converging approaches across these multilevel scientific domains indicate that fragile X, which arises from disruption of a single gene leading to the loss of a specific protein, is associated with a cascade of aberrations in neurodevelopment, resulting in a central nervous system that is suboptimal with respect to structure and function. In turn, structural and functional brain alterations lead to early disruption in emotion, cognition, and behavior in the child with fragile X. The combination of molecular genetics, neuroimaging, and behavioral research have advanced our understanding of the linkages between genetic variables, neurobiological measures, IQ, and behavior. Our research and that of others demonstrates that neurobehavior and neurocognition, genetics, and neuroanatomy are all different views of the same intriguing biological puzzle, a puzzle that today is rapidly emerging into a more complete picture of the intricate linkages among gene, brain, and behavior in developing children. Understanding the complex multilevel scientific perspective involved in fragile X will also contribute to our understanding of normal development by highlighting developmental events throughout the life span, thereby helping us to delineate the boundaries of pathology.

    View details for DOI 10.1017/S0954579403000464

    View details for Web of Science ID 000187321100006

    View details for PubMedID 14984133

  • Towards effective and rewarding data sharing NEUROINFORMATICS Gardner, D., Toga, A. W., Ascoli, G. A., Beatty, J. T., Brinkley, J. F., Dale, A. M., Fox, P. T., Gardner, E. P., George, J. S., Goddard, N., Harris, K. M., Herskovits, E. H., Hines, M. L., Jacobs, G. A., Jacobs, R. E., Jones, E. G., Kennedy, D. N., Kimberg, D. Y., Mazziotta, J. C., Miller, P. L., Mori, S., MOUNTAIN, D. C., Reiss, A. L., Rosen, G. D., Rottenberg, D. A., Shepherd, G. M., Smalheiser, N. R., Smith, K. P., Strachan, T., Van Essen, D. C., Williams, R. W., Wong, S. T. 2003; 1 (3): 289-295

    View details for Web of Science ID 000186095000007

    View details for PubMedID 15046250

  • Investigation of white matter structure in velocardiofacial syndrome: A diffusion tensor imaging study AMERICAN JOURNAL OF PSYCHIATRY Barnea-Goraly, N., Menon, V., Krasnow, B., Ko, A., Reiss, A., Eliez, S. 2003; 160 (10): 1863-1869

    Abstract

    Velocardiofacial syndrome, caused by a deletion on chromosome 22q11.2, is often accompanied by cognitive, behavioral, and psychiatric impairments. Specifically, velocardiofacial syndrome has been proposed as a disease model for a genetically mediated subtype of schizophrenia. Velocardiofacial syndrome is also known to affect brain structure. The most prominent structural findings in velocardiofacial syndrome are reduced white matter volumes. However, the structure of white matter and extent of specific regional involvement in this syndrome have never been investigated. The current study used diffusion tensor imaging to investigate white matter structure in children and young adults with velocardiofacial syndrome.Nineteen participants with velocardiofacial syndrome and 19 age- and gender-matched comparison subjects underwent diffusion-weighted magnetic resonance imaging scans. Whole brain voxel-by-voxel analyses were conducted to investigate white matter fractional anisotropy differences between the groups.Relative to the comparison group, the velocardiofacial syndrome group had reduced white matter anisotropy in the frontal, parietal, and temporal regions as well as in tracts connecting the frontal and temporal lobes.This study demonstrates that alterations of white matter tract structure occur in velocardiofacial syndrome. Reduced white matter anisotropy was observed in individuals with velocardiofacial syndrome in areas previously implicated in the neurocognitive phenotype of velocardiofacial syndrome. The finding of aberrant parietal white matter tracts as well as aberrant frontotemporal connectivity in velocardiofacial syndrome and in previous schizophrenia studies may be associated with increased vulnerability for development of psychotic symptoms.

    View details for Web of Science ID 000185880300024

    View details for PubMedID 14514502

  • Effects of X-monosomy and X-linked imprinting on superior temporal gyrus morphology in Turner syndrome BIOLOGICAL PSYCHIATRY Kesler, S. R., Blasey, C. M., Brown, W. E., Yankowitz, J., Zeng, S. M., Bender, B. G., Reiss, A. L. 2003; 54 (6): 636-646

    Abstract

    Turner syndrome (TS) results from complete or partial monosomy X. The cognitive phenotype of TS involves preservation of verbal skills with visuospatial functioning deficits. The superior temporal gyrus (STG), which is involved in language capacities, has not been investigated in TS.The STG was measured in 30 female subjects (mean age = 14.73 +/- 6.41; range = 7.56-33.30) with TS and 30 age-matched control subjects (mean age = 14.63 +/- 5.90; range = 6.35-32.65) using volumetric magnetic resonance imaging analyses.-Right STG, including both gray and white matter volumes, was significantly larger in TS compared with control subjects. Overall left STG volume was not significantly different between groups, although left white matter volume was increased in the TS subjects. The TS subgroup with a maternally derived X chromosome (Xm) demonstrated more aberrant STG volumes compared with subjects with a paternally (Xp) derived X and control subjects. The difference in STG volumes between Xm and control subjects involved both white and gray matter. The Xm subjects differed from Xp subjects only in terms of gray matter.These findings suggest that X-monosomy and X-linked imprinting negatively affect STG development, possibly by disrupting neural pruning mechanisms.

    View details for DOI 10.1016/S0006-3223(03)00289-0

    View details for Web of Science ID 000185264700007

    View details for PubMedID 13129659

  • Functional brain imaging of olfactory processing in monkeys NEUROIMAGE Boyett-Anderson, J. M., Lyons, D. M., Reiss, A. L., Schatzberg, A. F., Menon, V. 2003; 20 (1): 257-264

    Abstract

    As a step toward bridging the gap between human and animal studies of olfactory brain systems, we report results from an fMRI study of olfaction in squirrel monkeys. High-resolution fMRI images at 3 T with 1.25 x 1.25 x 1.2 mm(3) voxels were obtained covering the whole brain using an 8-cm-diameter birdcage coil and a gradient-echo spiral pulse sequence. Data were acquired from six sedated adult males using a standard block design. All fMRI data were spatially normalized to a common template and analyzed at the individual and group levels with statistical parametric and nonparametric methods. Robust odorant-induced activations were detected in several brain regions previously implicated in conscious human olfactory processing, including the orbitofrontal cortex, cerebellum, and piriform cortex. Consistent with human data, no stimulus intensity effects were observed in any of these regions. Average signal changes in these regions exceeded 0.6%, more than three times the expected signal change based on human fMRI studies of olfaction adjusting for differences in voxel size. These results demonstrate the feasibility of studying olfaction in sedated monkeys with imaging techniques commonly used at 3 T in humans and help promote direct comparisons between humans and nonhuman primates. Our findings, for example, provide novel support for the hypothesis that the cerebellum is involved in sensory acquisition. More broadly, this study suggests that olfactory processing in sedated monkeys and nonsedated humans shares similar neural substrates both within and beyond the primary olfactory system.

    View details for DOI 10.1016/S1053-8119(03)00288-X

    View details for Web of Science ID 000185746400022

    View details for PubMedID 14527586

  • Effect of head orientation on gaze processing in fusiform gyrus and superior temporal sulcus NEUROIMAGE Pageler, N. M., Menon, V., Merin, N. M., Eliez, S., Brown, W. E., Reiss, A. L. 2003; 20 (1): 318-329

    Abstract

    We used functional MRI with an event-related design to dissociate the brain activation in the fusiform gyrus (FG) and posterior superior temporal sulcus (STS) for multiple face and gaze orientations. The event-related design allowed for concurrent behavioral analysis, which revealed a significant effect of both head and gaze orientation on the speed of gaze processing, with the face and gaze forward condition showing the fastest reaction times. In conjunction with this behavioral finding, the FG responded with the greatest activation to face and gaze forward, perhaps reflecting the unambiguous social salience of congruent face and gaze directed toward the viewer. Random effects analysis showed greater activation in both the FG and posterior STS when the subjects viewed a direct face compared to an angled face, regardless of gaze direction. Additionally, the FG showed greater activation for forward gaze compared to angled gaze, but only when the face was forward. Together, these findings suggest that head orientation has a significant effect on gaze processing and these effects are manifest not only in the STS, but also the FG.

    View details for DOI 10.1016/S1053-8119(03)00229-5

    View details for Web of Science ID 000185746400028

    View details for PubMedID 14527592

  • Factors associated with parenting stress in mothers of children with fragile X syndrome JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Johnston, C., Hessl, D., Blasey, C., Eliez, S., Erba, H., Dyer-Friedman, J., Glaser, B., Reiss, A. L. 2003; 24 (4): 267-275

    Abstract

    Whereas previous research has demonstrated elevated levels of parenting stress in parents of children with general developmental disability, there has been little investigation of stress in parents of children specifically affected by the common neurogenetic disorder fragile X syndrome (FraX). This study elucidates stress profiles in mothers of children with FraX and delineates the contribution of child characteristics, home environment, and maternal psychological functioning to specific dimensions of parental stress. Data on child, home, and family characteristics were collected from 75 families with a child affected by FraX. These characteristics were entered into multiple regression analyses with a domain or subscale of the Parenting Stress Index as the dependent variable in each analysis. The results demonstrated that aspects of child behavior, family cohesion, household income, and maternal psychopathology differentially correlate with specific dimensions of parenting stress. Determining the relative contribution of factors associated with stress will assist in the development of interventions to improve parental well-being in mothers of children with FraX.

    View details for Web of Science ID 000184777800007

    View details for PubMedID 12915799

  • Amygdalar activation associated with happy facial expressions in adolescents: A 3-T functional MRI study JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Yang, T. T., Menon, V., Reid, A. J., Gotlib, I. H., Reiss, A. L. 2003; 42 (8): 979-985

    Abstract

    To study the possible role of the amygdala in the recognition of happy and sad facial expressions in adolescents aged 13 to 17 years.Twelve healthy adolescents (6 females and 6 males) underwent noninvasive 3-Tesla functional magnetic resonance imaging while viewing pictures of happy, sad, and neutral facial expressions.Happy faces produced significant bilateral amygdalar activation when compared with neutral faces (p <.05, corrected). Sad faces relative to neutral did not produce significant amygdalar activation.These results extend the role of the amygdala in adolescents to include the recognition of happy facial expressions. They demonstrate the feasibility of using happy facial expressions to noninvasively study amygdalar function in adolescents and establish a baseline against which the amygdalar response to emotional stimuli in several psychiatric conditions may be compared.

    View details for DOI 10.1097/01.CHI.0000046886.27264.BA

    View details for Web of Science ID 000184302700016

    View details for PubMedID 12874501

  • Decreased N-acetylaspartate in children with familial bipolar disorder BIOLOGICAL PSYCHIATRY Chang, K., Adleman, N., Dienes, K., Barnea-Goraly, N., Reiss, A., Ketter, T. 2003; 53 (11): 1059-1065

    Abstract

    Relatively low levels of brain N-acetylaspartate, as measured by magnetic resonance spectroscopy, may indicate decreased neuronal density or viability. Dorsolateral prefrontal levels of N-acetylaspartate have been reported to be decreased in adults with bipolar disorder. We used proton magnetic resonance spectroscopy to investigate dorsolateral prefrontal N-acetylaspartate levels in children with familial bipolar disorder.Subjects were 15 children and adolescents with bipolar disorder, who each had at least one parent with bipolar disorder, and 11 healthy controls. Mean age was 12.6 years for subjects and controls. Subjects were allowed to continue current medications. Proton magnetic resonance spectroscopy at 3-Tesla was used to study 8 cm(3) voxels placed in left and right dorsolateral prefrontal cortex.Bipolar subjects had lower N-acetylaspartate/Creatine ratios only in the right dorsolateral prefrontal cortex (p <.02). No differences in myoinositol or choline levels were found.Children and adolescents with bipolar disorder may have decreased dorsolateral prefrontal N-acetylaspartate, similar to adults with BD, indicating a common neuropathophysiology. Longitudinal studies of at-risk children before the onset and during the early course of bipolar disorder are needed to determine the role of prefrontal N-acetylaspartate as a possible risk marker and/or indication of early bipolar illness progression.

    View details for DOI 10.1016/S0006-3223(02)01744-4

    View details for Web of Science ID 000183339900016

    View details for PubMedID 12788251

  • Corpus callosum and posterior fossa development in monozygotic females: a morphometric MRI study of Turner syndrome DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Fryer, S. L., Kwon, H., Eliez, S., Reiss, A. L. 2003; 45 (5): 320-324

    Abstract

    Previous neuroimaging research in Turner syndrome (TS) has indicated parietal lobe anomalies, while anomalies in other brain loci have been less well-substantiated. This study focused on potential cerebellar abnormalities and possible disruptions of interhemispheric (parietal) callosal connections in individuals with TS. Twenty-seven female children and adolescents with TS (mean age 13 years, SD 4 years 2 months) and 27 age-matched female control individuals (mean age 13 years 2 months, SD 4 years 1 month) underwent MRI. Age range of all participants was 7 to 20 years. Morphometric analyses of midline brain structures were conducted using standardized, reliable methods. When compared with control participants, females with TS showed reduced areas of the genu of the corpus callosum, the pons, and vermis lobules VI-VII, and an increased area of the fourth ventricle. No group difference in intracranial area measurements was observed. The reduced area of the genu in TS may reflect compromised connectivity between inferior parietal regions. Further, cerebellar vermis hypoplasia associated with TS agrees with literature that suggests the posterior fossa as a region prone to structural alterations in the face of early developmental insult.

    View details for DOI 10.1017/S0012162203000604

    View details for Web of Science ID 000182624300007

    View details for PubMedID 12729146

  • Comparison of fMRI activation at 3 and 1.5 T during perceptual, cognitive, and affective processing NEUROIMAGE Krasnow, B., Tamm, L., Greicius, M. D., Yang, T. T., Glover, G. H., Reiss, A. L., Menon, V. 2003; 18 (4): 813-826

    Abstract

    Previous studies comparing fMRI data acquired at 1.5 T and higher field strengths have focused on examining signal increases in the visual and motor cortices. No information is, however, available on the relative gain, or the comparability of data, obtained at higher field strengths for other brain regions such as the prefrontal and other association cortices. In the present study, we investigated fMRI activation at 1.5 and 3 T during visual perception, visuospatial working memory, and affect-processing tasks. A 23% increase in striate and extrastriate activation volume was observed at 3 T compared with that for 1.5 T during the visual perception task. During the working memory task significant increases in activation volume were observed in frontal and parietal association cortices as well as subcortical structures, including the caudate, globus pallidus, putamen, and thalamus. Increases in working memory-related activation volume of 82, 73, 83, and 36% were observed in the left frontal, right frontal, left parietal, and right parietal lobes, respectively, for 3 T compared with 1.5 T. These increases were characterized by increased activation at 3 T in several prefrontal and parietal cortex regions that showed activation at 1.5 T. More importantly, at 3 T, activation was detected in several regions, such as the ventral aspects of the inferior frontal gyrus, orbitofrontal gyrus, and lingual gyrus, which did not show significant activation at 1.5 T. No difference in height or extent of activation was detected between the two scanners in the amygdala during affect processing. Signal dropout in the amygdala from susceptibility artifact was greater at 3 T, with a 12% dropout at 3 T compared with a 9% dropout at 1.5 T. The spatial smoothness of T2* images was greater at 3 T by less than 1 mm, suggesting that the greater extent of activation at 3 T beyond these spatial scales was not due primarily to increased intrinsic spatial correlations at 3 T. Rather, the increase in percentage of voxels activated reflects increased sensitivity for detection of brain activation at higher field strength. In summary, our findings suggest that functional imaging of prefrontal and other association cortices can benefit significantly from higher magnetic field strength.

    View details for DOI 10.1016/S1053-8119(03)00002-8

    View details for Web of Science ID 000182606000001

    View details for PubMedID 12725758

  • White matter tract alterations in fragile X syndrome: Preliminary evidence from diffusion tensor imaging AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Barnea-Goraly, N., Eliez, S., Hedeus, M., Menon, V., White, C. D., Moseley, M., Reiss, A. L. 2003; 118B (1): 81-88

    Abstract

    Fragile X syndrome, the most common form of hereditary mental retardation, causes disruption in the development of dendrites and synapses, the targets for axonal growth in the central nervous system. This disruption could potentially affect the development, wiring, and targeting of axons. The current study utilized diffusion tensor imaging (DTI) to investigate whether white matter tract integrity and connectivity are altered in fragile X syndrome. Ten females with a diagnosis of fragile X syndrome and ten, age matched, female control subjects underwent diffusion weighted MRI scans. A whole brain analysis of fractional anisotropy (FA) values was performed using statistical parametric mapping (SPM). A follow-up, regions-of-interest analysis also was conducted. Relative to controls, females with fragile X exhibited lower FA values in white matter in fronto-striatal pathways, as well as in parietal sensory-motor tracts. This preliminary study suggests that regionally specific alterations of white matter integrity occur in females with fragile X. Aberrant white matter connectivity in these regions is consistent with the profile of cognitive and behavioral features of fragile X syndrome, and potentially provide additional insight into the detrimental effects of suboptimal levels of FMRP in the developing brain.

    View details for DOI 10.1002/ajmg.b.10035

    View details for Web of Science ID 000182401800017

    View details for PubMedID 12627472

  • A prospective test of the association between hyperarousal and emotional numbing in youth with a history of traumatic stress JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY Weems, C. F., Saltzman, K. M., Reiss, A. L., Carrion, V. G. 2003; 32 (1): 166-171

    Abstract

    Investigated the hypothesis that emotional numbing may develop as a result of hyperarousal using a prospective design. Forty-two children between the ages of 7 and 14 with a history of trauma and posttraumatic stress disorder (PTSD) symptoms were assessed with the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA; Nader et al., 1996) and were reassessed 1 year later. Results indicated that hyperarousal symptoms were concurrently positively correlated with emotional numbing at both time points. Moreover, Time 1 hyperarousal symptoms were associated with emotional numbing at Time 2 and predicted Time 2 emotional numbing even when controlling for each of the other symptom clusters of PTSD at Time 1 as well as other concurrent (i.e., Time 2) PTSD symptoms. Results are discussed in terms of the implications of the findings for enhancing the understanding of PTSD symptoms in youth.

    View details for Web of Science ID 000180579800015

    View details for PubMedID 12573941

  • Biological and environmental contributions to adaptive behavior in fragile X syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Glaser, B., Hessl, D., Dyer-Friedman, J., Johnston, C., Wisbeck, J., Taylor, A., Reiss, A. 2003; 117A (1): 21-29

    Abstract

    Fragile X syndrome is the most common cause of inherited developmental disability. The purpose of the present study is to understand how both biological and environmental influences affect the development of adaptive behavior in children with fragile X. In-home assessments were conducted on 120 children (80 boys and 40 girls) with the fragile X full mutation and their unaffected siblings (58 boys and 62 girls). Hierarchical multiple regression analyses were utilized. Independent variables included biological or demographic variables specific to the child (age, gender, full-scale IQ, and FMRP percentage), as well as factors specific to his/her environment (household income, home environment, maternal psychopathology, and effectiveness of educational/therapeutic services). Results of these analyses showed that for both boys with fragile X and the control sibling group, adaptive behavior was predicted by IQ, age, gender, and home environment. For girls with fragile X, adaptive behavior was most strongly associated with IQ. Adaptive behavior was not significantly associated with FMRP in boys or girls with fragile X. By examining the relative influences of biological and environmental factors on adaptive behavior in children with fragile X, we begin to lay the foundation for the development of more specific treatment studies in children with this disorder.

    View details for DOI 10.1002/ajmg.a.10549

    View details for Web of Science ID 000182400900005

    View details for PubMedID 12548736

  • [Williams syndrome. A summary of cognitive, electrophysiological, anatomofunctional, microanatomical and genetic findings]. Revista de neurologia Galaburda, A. M., HOLINGER, D., Mills, D., Reiss, A., Korenberg, J. R., Bellugi, U. 2003; 36: S132-7

    Abstract

    Williams syndrome (WS) is the result of a hemideletion of about 17 genes in the q11.22-23 region of chromosome 7. Patients with WS show unique phenotypic features that include elfin face, heart malformations, calcium metabolism problems and learning disorders. The latter consist of mental retardation that is characterised by serious difficulties with processing visuospatial tasks, a striking ability to easily recognise faces, a relatively developed linguistic capacity and sensitiveness to sound, a strong need to establish affective ties with other people and a fondness for music. Anatomical studies show a decrease in the postero-dorsal parts of both hemispheres of the brain, malformation in the central dorsal region and an expansion of the superior temporal gyrus, of the amygdala and of the frontal lobe. These macroscopic anomalies are accompanied by microscopic anomalies, which consist of changes in the number and size of the neurons. Studies on evoked potentials show acoustic hyperexcitability and abnormal waves related to language and to faces. Genetic studies in our laboratories show that the exact size of the deletion can vary, which means partial cases also exist and have partial phenotypes. Combining behavioural, electrophysiological, anatomical and genetic reports suggests a problem with the posterior dorsal region of the brain, possibly resulting from mistakes in establishing the dorsoventral and caudorostral genetico-molecular gradients, which specify the cortical regions during development.

    View details for PubMedID 12599114

  • Abnormal prefrontal cortex function during response inhibition in Turner syndrome: Functional magnetic resonance imaging evidence BIOLOGICAL PSYCHIATRY Tamm, L., Menon, V., Reiss, A. L. 2003; 53 (2): 107-111

    Abstract

    Turner syndrome (TuS) arises from the partial or complete absence of one X chromosome. Although neuropsychological studies report impaired attentional function and response inhibition in TuS, the neural correlates of these cognitive problems are unknown.Eleven female subjects with TuS and 11 individually matched normal control subjects were imaged using functional magnetic resonance imaging while performing a Go/NoGo task.Groups did not differ on accuracy or reaction time; however, the TuS group activated more in the bilateral superior and middle frontal gyri than control subjects. Control subjects did not activate more than the TuS group in any region.These findings suggest that female subjects with TuS compensate for executive dysfunction via recruitment of additional prefrontal cortex regions involved in inhibition, attention, and working memory, functions necessary for successful performance of Go/NoGo tasks. Elucidating brain function in TuS will advance our understanding of the influence of X-chromosome genes on neurodevelopment and brain function and contribute to planning future intervention strategies.

    View details for DOI 10.1016/S0006-3223(02)01488-9

    View details for Web of Science ID 000180518900001

    View details for PubMedID 12547465

  • Functional connectivity in the resting brain: A network analysis of the default mode hypothesis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Greicius, M. D., Krasnow, B., Reiss, A. L., Menon, V. 2003; 100 (1): 253-258

    Abstract

    Functional imaging studies have shown that certain brain regions, including posterior cingulate cortex (PCC) and ventral anterior cingulate cortex (vACC), consistently show greater activity during resting states than during cognitive tasks. This finding led to the hypothesis that these regions constitute a network supporting a default mode of brain function. In this study, we investigate three questions pertaining to this hypothesis: Does such a resting-state network exist in the human brain? Is it modulated during simple sensory processing? How is it modulated during cognitive processing? To address these questions, we defined PCC and vACC regions that showed decreased activity during a cognitive (working memory) task, then examined their functional connectivity during rest. PCC was strongly coupled with vACC and several other brain regions implicated in the default mode network. Next, we examined the functional connectivity of PCC and vACC during a visual processing task and show that the resultant connectivity maps are virtually identical to those obtained during rest. Last, we defined three lateral prefrontal regions showing increased activity during the cognitive task and examined their resting-state connectivity. We report significant inverse correlations among all three lateral prefrontal regions and PCC, suggesting a mechanism for attenuation of default mode network activity during cognitive processing. This study constitutes, to our knowledge, the first resting-state connectivity analysis of the default mode and provides the most compelling evidence to date for the existence of a cohesive default mode network. Our findings also provide insight into how this network is modulated by task demands and what functions it might subserve.

    View details for DOI 10.1073/pnas.0135058100

    View details for Web of Science ID 000180307100046

    View details for PubMedID 12506194

  • Neural correlates of auditory perception in Williams syndrome: An fMRI study NEUROIMAGE Levitin, D. J., Menon, V., Schmitt, J. E., Eliez, S., White, C. D., Glover, G. H., Kadis, J., Korenberg, J. R., Bellugi, U., Reiss, A. L. 2003; 18 (1): 74-82

    Abstract

    Williams syndrome (WS), a neurogenetic developmental disorder, is characterized by a rare fractionation of higher cortical functioning: selective preservation of certain complex faculties (language, music, face processing, and sociability) in contrast to marked and severe deficits in nearly every other cognitive domain (reasoning, spatial ability, motor coordination, arithmetic, problem solving). WS people are also known to suffer from hyperacusis and to experience heightened emotional reactions to music and certain classes of noise. We used functional magnetic resonance imaging to examine the neural basis of auditory processing of music and noise in WS patients and age-matched controls and found strikingly different patterns of neural organization between the groups. Those regions supporting music and noise processing in normal subjects were found not to be consistently activated in the WS participants (e.g., superior temporal and middle temporal gyri). Instead, the WS participants showed significantly reduced activation in the temporal lobes coupled with significantly greater activation in the right amygdala. In addition, WS participants (but not controls) showed a widely distributed network of activation in cortical and subcortical structures, including the brain stem, during music processing. Taken together with previous ERP and cytoarchitectonic studies, this first published report of WS using fMRI provides additional evidence of a different neurofunctional organization in WS people than normal people, which may help to explain their atypical reactions to sound. These results constitute an important first step in drawing out the links between genes, brain, cognition, and behavior in Williams syndrome.

    View details for DOI 10.1006/nimg.2002.1297

    View details for Web of Science ID 000180015200007

    View details for PubMedID 12507445

  • Regional analysis of hippocampal activation during memory encoding and retrieval: fMRI study HIPPOCAMPUS Greicius, M. D., Krasnow, B., Boyett-Anderson, J. M., Eliez, S., Schatzberg, A. F., Reiss, A. L., Menon, V. 2003; 13 (1): 164-174

    Abstract

    Investigators have recently begun to examine the differential role of subregions of the hippocampus in episodic memory. Two distinct models have gained prominence in the field. One model, outlined by Moser and Moser (Hippocampus 1998;8:608-619), based mainly on animal studies, has proposed that episodic memory is subserved by the posterior two-thirds of the hippocampus alone. A second model, derived by Lepage et al. (Hippocampus 1998;8:313-322) from their review of 52 PET studies, has suggested that the anterior hippocampus is activated by memory encoding while the posterior hippocampus is activated by memory retrieval. Functional magnetic resonance imaging (fMRI) studies have tended to show limited activation in the anteriormost regions of the hippocampus, providing support for the Moser and Moser model. A potential confounding factor in these fMRI studies, however, is that susceptibility artifact may differentially reduce signal in the anterior versus the posterior hippocampus. In the present study, we examined activation differences between hippocampal subregions during encoding and retrieval of words and interpreted our findings within the context of these two models. We also examined the extent to which susceptibility artifact affects the analysis and interpretation of hippocampal activation by demonstrating its differential effect on the anterior versus the posterior hippocampus. Both voxel-by-voxel and region-of-interest analyses were conducted, allowing us to quantify differences between the anterior and posterior aspects of the hippocampus. We detected significant hippocampal activation in both the encoding and retrieval conditions. Our data do not provide evidence for regional anatomic differences in activation between encoding and retrieval. The data do suggest that, even after accounting for susceptibility artifact, both encoding and retrieval of verbal stimuli activate the middle and posterior hippocampus more strongly than the anterior hippocampus. Finally, this study is the first to quantify the effects of susceptibility-induced signal loss on hippocampal activation and suggests that this artifact has significantly biased the interpretation of earlier fMRI studies.

    View details for DOI 10.1002/hipo.10064

    View details for Web of Science ID 000181005800014

    View details for PubMedID 12625466

  • Brain development in Turner syndrome: a magnetic resonance imaging study PSYCHIATRY RESEARCH-NEUROIMAGING Brown, W. E., Kesler, S. R., Eliez, S., Warsofsky, I. S., Haberecht, M., Patwardhan, A., Ross, J. L., Neely, E. K., Zeng, S. M., Yankowitz, J., Reiss, A. L. 2002; 116 (3): 187-196

    Abstract

    Turner syndrome (TS) results from the absence of an X chromosome in females. This genetic condition is associated with specific cognitive deficits and variations in brain volumes. The goal of this study was to use high-resolution magnetic resonance imaging (MRI) to determine morphological variations in TS and to investigate the effects of parental origin of the X chromosome on brain development in TS. MRI brain scans were acquired from 26 girls with TS and 26 age- and gender-matched controls. Seventeen of the TS subjects had a maternally inherited X chromosome (Xm), and nine of the subjects had a paternally inherited X chromosome (Xp). Rater-blind morphometric analyses were conducted to compare tissue volume differences between girls with TS and controls. Three-way analyses were used to compare subgroups and controls. Subjects with TS demonstrated bilateral decreases in parietal gray and occipital white matter accompanied by increased cerebellar gray matter. Subjects with Xm showed decreased occipital white matter and increased cerebellar gray matter compared to controls. No differences were found in comparisons between subjects with Xp and controls or between subjects with Xm and Xp. Results suggest that X monosomy affects posterior cerebral and cerebellar anatomy in TS. While differences between comparisons of Xm and Xp to controls might suggest an imprinting effect, no significant differences were found when the two subgroups were directly compared to each other. Further investigation into the possible role of genomic imprinting is therefore warranted.

    View details for Web of Science ID 000180535800005

    View details for PubMedID 12477602

  • Incidental findings on pediatric MR images of the brain AMERICAN JOURNAL OF NEURORADIOLOGY Kim, B. S., Illes, J., Kaplan, R. T., Reiss, A., Scott, W. 2002; 23 (10): 1674-1677

    Abstract

    Previous studies have addressed the prevalence of incidental findings in symptomatic and healthy adult populations. Our study aims to elucidate the prevalence of incidental findings in a healthy pediatric population.We retrospectively reviewed 225 conventional brain MR imaging studies obtained during structural and functional brain imaging research in a cohort of neurologically healthy children (100 boys [44%] and 125 girls [56%]) ranging in age from younger than 1 month to 18 years. All MR images were reviewed, and two board-certified neuroradiologists categorized the findings by consensus.Incidental abnormalities were detected in 47 subjects (21%), while 79% of the images were normal. Of the 47 abnormalities detected, 17 (36%) required routine clinical referral; a single lesion (2%) required urgent referral. The occurrence of these findings in the male cohort was twice that of the female cohort; however, the percentage of subjects requiring either routine or urgent referral did not differ by sex (male subjects, 34%; female subjects, 39%).Although the frequency of clinically important incidental abnormalities was not high in the sample of children studied, the presence and variety of findings in any pediatric group is particularly important for both the welfare of the subject and for research in which knowledge of the subject's neurologic status is vital to the interpretation of the results. Despite the limitations of the study in terms of the age and ethnic distribution, this work highlights the need for the routine involvement of trained radiologists in these studies to ensure that such incidental findings are detected and that appropriate follow-up is provided.

    View details for Web of Science ID 000179199000017

    View details for PubMedID 12427622

  • Amygdalar activation associated with positive and negative facial expressions NEUROREPORT Yang, T. T., Menon, V., Eliez, S., Blasey, C., White, C. D., Reid, A. J., Gotlib, I. H., Reiss, A. L. 2002; 13 (14): 1737-1741

    Abstract

    Most theories of amygdalar function have underscored its role in fear. One broader theory suggests that neuronal activation of the amygdala in response to fear-related stimuli represents only a portion of its more widespread role in modulating an organism's vigilance level. To further explore this theory, the amygdalar response to happy, sad, angry, fearful, and neutral faces in 17 subjects was characterized using 3 T fMRI. Utilizing a random effects model and hypothesis-driven analytic strategy, it was observed that each of the four emotional faces was associated with reliable bilateral activation of the amygdala compared with neutral. These findings suggest a broader role for the amygdala in modulating the vigilance level during the perception of several negative and positive facial emotions.

    View details for Web of Science ID 000179156600009

    View details for PubMedID 12395114

  • Cortisol and behavior in fragile X syndrome PSYCHONEUROENDOCRINOLOGY Hessl, D., Glaser, B., Dyer-Friedman, J., Blasey, C., Hastie, T., Gunnar, M., Reiss, A. L. 2002; 27 (7): 855-872

    Abstract

    The purpose of this study was to determine if children with fragile X syndrome, who typically demonstrate a neurobehavioral phenotype that includes social anxiety, withdrawal, and hyper-arousal, have increased levels of cortisol, a hormone associated with stress. The relevance of adrenocortical activity to the fragile X phenotype also was examined.One hundred and nine children with the fragile X full mutation (70 males and 39 females) and their unaffected siblings (51 males and 58 females) completed an in-home evaluation including a cognitive assessment and a structured social challenge task. Multiple samples of salivary cortisol were collected throughout the evaluation day and on two typical non-school days. Measures of the fragile X mental retardation (FMR1) gene, child intelligence, the quality of the home environment, parental psychopathology, and the effectiveness of educational and therapeutic services also were collected. Linear mixed-effects analyses were used to examine differences in cortisol associated with the fragile X diagnosis and gender (fixed effects) and to estimate individual subject and familial variation (random effects) in cortisol hormone levels. Hierarchical multiple regression analyses were conducted to determine whether adrenocortical activity is associated with behavior problems after controlling for significant genetic and environmental factors.Results showed that children with fragile X, especially males, had higher levels of salivary cortisol on typical days and during the evaluation. Highly significant family effects on salivary cortisol were detected, consistent with previous work documenting genetic and environmental influences on adrenocortical activity. Increased cortisol was significantly associated with behavior problems in boys and girls with fragile X but not in their unaffected siblings.These results provide evidence that the function of the hypothalamic-pituitary-adrenal axis may have an independent association with behavioral problems in children with fragile X syndrome.

    View details for Web of Science ID 000178462800008

    View details for PubMedID 12183220

  • Neural basis of protracted developmental changes in visuo-spatial working memory PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kwon, H., Reiss, A. L., Menon, V. 2002; 99 (20): 13336-13341

    Abstract

    Developmental studies have shown that visuo-spatial working memory (VSWM) performance improves throughout childhood and adolescence into young adulthood. The neural basis of this protracted development is poorly understood. In this study, we used functional MRI (fMRI) to examine VSWM function in children, adolescents, and young adults, ages 7-22. Subjects performed a 2-back VSWM experiment that required dynamic storage and manipulation of spatial information. Accuracy and response latency on the VSWM task improved gradually, extending into young adulthood. Age-related increases in brain activation were observed in focal regions of the left and right dorsolateral prefrontal cortex, left ventrolateral prefrontal cortex (including Broca's area), left premotor cortex, and left and right posterior parietal cortex. Multiple regression analysis was used to examine the relative contributions of age, accuracy, and response latency on activation. Our analysis showed that age was the most significant predictor of activation in these brain regions. These findings provide strong evidence for a process of protracted functional maturation of bilateral fronto-parietal neural networks involved in VSWM development. At least two neural systems involved in VSWM mature together: (i) a right hemisphere visuo-spatial attentional system, and (ii) a left hemisphere phonological storage and rehearsal system. These observations suggest that visually and verbally mediated mnemonic processes, and their neural representations, develop concurrently during childhood and adolescence and into young adulthood.

    View details for DOI 10.1073/pnas.162486399

    View details for Web of Science ID 000178391700150

    View details for PubMedID 12244209

  • Maturation of brain function associated with response inhibition JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Tamm, L., Menon, V., Reiss, A. L. 2002; 41 (10): 1231-1238

    Abstract

    To investigate the developmental trajectory of response inhibition and, more specifically, whether there is a dissociation of function in the prefrontal cortex over the course of development of executive function and associated response inhibition abilities.Nineteen typically developing subjects, ranging in age from 8 to 20, performed a Go/NoGo task while behavioral and functional magnetic resonance imaging (fMRI) data were collected.All subjects performed the task with few errors of omission and commission. No relationship between accuracy and age emerged, but the ability to inhibit responses significantly improved with age. Analyses of fMRI data revealed a positive correlation between activation and age in the left inferior frontal gyrus/insula/orbitofrontal gyrus, and a negative correlation between activation and age in the left middle/superior frontal gyri.These data provide the first evidence of dissociable processes occurring in the prefrontal cortex during development of executive functions associated with response inhibition: (1) Younger subjects activate more extensively than older subjects in discrete regions of the prefrontal cortex, presumably due to increased demands and inefficient recruitment of brain regions subserving executive functions including working memory. (2) Older subjects show increasingly focal activation in specific regions thought to play a more critical role in response inhibition.

    View details for DOI 10.1097/00004583-200210000-00013

    View details for Web of Science ID 000178203700013

    View details for PubMedID 12364845

  • Workgroup reports: NIMH strategic plan for mood disorders research - Future of genetics of mood disorders research BIOLOGICAL PSYCHIATRY Merikangas, K. R., Chakravarti, A., Moldin, S. O., Araj, H., Blangero, J., Burmeister, M., Crabbe, J. C., DePaulo, J. R., Foulks, E., Freimer, N. B., Koretz, D. S., Lichtenstein, W., Mignot, E., Reiss, A. L., Risch, N. J., Takahashi, J. S. 2002; 52 (6): 457-477

    Abstract

    This report summarizes the deliberations of a panel with representation from diverse disciplines of relevance to the genetics of mood disorders. The major charge to the panel was to develop a strategic plan to employ the tools of genetics to advance the understanding, treatment, and outcomes for mood disorders. A comprehensive review of the evidence for the role of genetic factors in the etiology of mood disorders was conducted, and the chief impediments for progress in gene identification were identified. The National Institute of Mental Health (NIMH) portfolios in the Genetics Research Branch and the Division of Mental Disorders, Behavioral Sciences, AIDS, and all genetics training activities were reviewed. Despite some promising leads, there are still no confirmed linkage findings for mood disorders. Impediments to gene finding include the lack of phenotypic validity, variation in ascertainment sources and methodology across studies, and genetic complexity. With respect to linkage, the committee recommended that a large-scale, integrated effort be undertaken to examine existing data from linkage and association studies of bipolar disorders using identical phenotypes and statistical methods across studies to determine whether the suggestive linkage findings at some loci can be confirmed. Confirmation would justify more intensive approaches to gene finding. The committee recommended that the NIMH support continued efforts to identify the most heritable subtypes and endophenotypes of major depression using the tools of genetic epidemiology, neuroscience, and behavioral science. The field of genetic epidemiology was identified as an important future direction because population-based, epidemiologic studies of families and unrelated affected individuals assume increasing importance for common chronic diseases. To prepare for shifts to more complex genetic models, the committee recommended that the NIMH develop new interdisciplinary training strategies to prepare for the next generation of genetics research.

    View details for Web of Science ID 000178297000002

  • Functional brain activation during arithmetic processing in females with fragile X Syndrome is related to FMRI protein expression HUMAN BRAIN MAPPING Rivera, S. M., Menon, V., White, C. D., Glaser, B., Reiss, A. L. 2002; 16 (4): 206-218

    Abstract

    Arithmetic processing deficits in persons with fragile X Syndrome (fraX), the most common heritable cause of mental retardation, are well known. In this study, we characterize the neural underpinnings of these performance deficits using functional MRI. Given that a single gene defect (FMR1) is known to be responsible for this disorder, we also assess whether brain activation in arithmetic processing areas is related to amount of FMR1 protein expression (FMRP). Subjects included 16 females with fraX, and 16 female age-matched controls. Subjects viewed arithmetic equations with two (1 + 3 = 4) or three (2 + 3 - 1 = 5) operands, and were asked to judge whether the results were correct or not. Subjects with fraX showed significant impairment in behavioral performance on the 3-operand but not the 2-operand arithmetic equations. Significant brain activation was observed bilaterally in the prefrontal and parietal cortices for unaffected subjects, and bilateral prefrontal and left angular gyrus for subjects with fraX, for both trial types. Subjects with fraX exhibited less overall activation than did unaffected subjects in both types of trials; and, unlike the unaffected group, did not show increased extent of activation in association with greater task difficulty. During the 3-operand trials, activation in bilateral prefrontal and motor/premotor, and left supramarginal and angular gyri were positively correlated with FMRP, suggesting that decreased FMR1 protein expression underlies deficits in math performance in persons with fraX. More broadly, this investigation demonstrates a unique bridging of cognitive and molecular neuroscience and represents a useful approach for the study of brain development and function.

    View details for DOI 10.1002/hbm.10048

    View details for Web of Science ID 000177176900002

    View details for PubMedID 12112763

  • Increased basal ganglia volumes in velo-cardio-facial syndrome (deletion 22q11.2) BIOLOGICAL PSYCHIATRY Eliez, S., Barnea-Goraly, N., Schmitt, J. E., Liu, Y., Reiss, A. L. 2002; 52 (1): 68-70

    Abstract

    This study evaluated differences in caudate volumes in subjects with velo-cardio-facial syndrome due to a 22q11.2 (22qDS) deletion. Because psychosis is observed in 30% of adult subjects with 22qDS, this neurogenetic disorder could represent a putative model for a genetically mediated subtype of schizophrenia.Caudate volumes were measured on high-resolution magnetic resonance images in 30 children and adolescents with 22qDS and 30 gender- and age-matched normal comparison subjects.Caudate head volumes were increased in the 22qDS group independent of neuroleptic medications. Subjects with 22qDS also displayed an abnormal pattern of asymmetry in the anterior caudate, with left side greater than right.Alterations in the basal ganglia circuitry have been implicated in learning, cognitive, and behavioral problems in children and therefore could be involved in the expression of the neurobehavioral phenotype expressed by subjects with 22qDS. Abnormal caudate volume is a neurodevelopmental feature shared with schizophrenia, further establishing 22qDS as a potential neurodevelopmental model for this disorder.

    View details for Web of Science ID 000176340700009

    View details for PubMedID 12079732

  • Prefrontal cortex involvement in processing incorrect arithmetic equations: Evidence from event-related fMRI HUMAN BRAIN MAPPING Menon, V., MacKenzie, K., Rivera, S. M., Reiss, A. L. 2002; 16 (2): 119-130

    Abstract

    The main aim of this study was to investigate the differential processing of correct and incorrect equations to gain further insight into the neural processes involved in arithmetic reasoning. Electrophysiological studies in humans have demonstrated that processing incorrect arithmetic equations (e.g., 2 + 2 = 5) elicits a prominent event-related potential (ERP) compared to processing correct equations (e.g., 2 + 2 = 4). In the present study, we investigated the neural substrates of this process using event-related functional magnetic resonance imaging (fMRI). Subjects were presented with arithmetic equations and asked to indicate whether the solution displayed was correct or incorrect. We found greater activation to incorrect, compared to correct equations, in the left dorsolateral prefrontal cortex (DLPFC, BA 46) and the left ventrolateral prefrontal cortex (VLPFC, BA 47). Our results provide the first brain imaging evidence for differential processing of incorrect vs. correct equations. The prefrontal cortex activation observed in processing incorrect equations overlaps with brain areas known to be involved in working memory and interference processing. The DLPFC region differentially activated by incorrect equations was also involved in overall arithmetic processing, whereas the VLPFC was activated only during the differential processing of incorrect equations. Differential response to correct and incorrect arithmetic equations was not observed in parietal cortex regions such as the angular gyrus and intra-parietal sulcus, which are known to play a specific role in performing arithmetic computations. The pattern of brain response observed is consistent with the hypothesis that processing incorrect equations involves detection of an incorrect answer and resolution of the interference between the internally computed and externally presented incorrect answer. More specifically, greater activation during processing of incorrect equations appears to reflect additional operations involved in maintaining the results in working memory, while subjects attempt to resolve the conflict and select a response. These findings allow us to further delineate and dissociate the contributions of prefrontal and parietal cortices to arithmetic reasoning.

    View details for DOI 10.1002/hbm.10035

    View details for Web of Science ID 000175972400006

    View details for PubMedID 11954061

  • Language skills in children with velocardiofacial syndrome (deletion 22q11.2) JOURNAL OF PEDIATRICS Glaser, B., Mumme, D. L., Blasey, C., Morris, M. A., Dahoun, S. P., Antonarakis, S. E., Reiss, A. L., Eliez, S. 2002; 140 (6): 753-758

    Abstract

    To further define the language profile of children with velocardiofacial syndrome (VCFS) and explore the influence of parental origin of the deletion on language.Children and adolescents with VCFS (n = 27) were group-matched for sex, age, and IQ with 27 children and adolescents with idiopathic developmental delay. Fifty-four typically developing control subjects were also included in the analyses investigating word association abilities.Children with VCFS had significantly lower receptive than expressive language skills, a unique finding when compared with IQ-matched control subjects. However, no significant differences in word association were detected. Children with a deletion of paternal origin score significantly higher on receptive language when compared with children with a deletion of maternal origin.The Clinical Evaluation of Language Fundamentals-III results suggest that children with VCFS show more severe deficits in receptive than expressive language abilities. Language skills of children with VCFS could be influenced by parental origin of the deletion and thus related to neuroanatomic alterations at the deletion site.

    View details for DOI 10.1067/mpd.2002.124774

    View details for Web of Science ID 000176520300021

    View details for PubMedID 12072882

  • Family environment and cognitive abilities in girls with fragile-X syndrome JOURNAL OF INTELLECTUAL DISABILITY RESEARCH Kuo, A. Y., Reiss, A. L., Freund, L. S., Huffman, L. C. 2002; 46: 328-339

    Abstract

    There remains some variance in cognitive ability that is unexplained in children with fragile-X syndrome (FXS). Studies in typically developing children suggest that family environment might be one contributor to this unexplained variance. However, the effect of family environment in relation to cognition in atypical children with FXS has been relatively unexplored to date.The present authors examined the putative genetic and environmental factors associated with cognition in a group of age-matched children consisting of 26 females with FXS and 31 typically developing children. All subjects were administered the Wechsler Intelligence Scale for Children-Revised; and the subjects' parents were administered the Wechsler Adult Intelligence Scale-Revised, and completed the Hollingshead Index of Social Status and the Moos & Moos Family Environment Scale.Using a multiple regression analytic strategy, the present authors found that family environment contributed significantly to cognitive abilities in typically developing girls, but did not have a unique contribution to cognitive abilities in girls with FXS. There was a suggestion that, for girls with FXS, socio-economic status, a measure of sociocultural environment, was correlated with IQ.The present study provides a basis for future research on the environmental contributions to cognitive abilities, particularly work related to verbal cognition.

    View details for Web of Science ID 000175531500005

    View details for PubMedID 12000584

  • A developmental fMRI study of the stroop color-word task NEUROIMAGE Adleman, N. E., Menon, V., Blasey, C. M., White, C. D., Warsofsky, I. S., Glover, G. H., Reiss, A. L. 2002; 16 (1): 61-75

    Abstract

    We used fMRI to investigate developmental changes in brain activation during a Stroop color-word interference task. A positive correlation was observed between age and Stroop-related activation (n = 30) in the left lateral prefrontal cortex, the left anterior cingulate, and the left parietal and parieto-occipital cortices. No regions showed a negative correlation between activation and age. We further investigated age-related differences by stratifying the sample into three age groups: children (ages 7-11), adolescents (ages 12-16), and young adults (ages 18-22). Young adult subjects (n = 11) displayed significant activation in the inferior and middle frontal gyri bilaterally, the left anterior cingulate, and bilateral inferior and superior parietal lobules. Between-group comparisons revealed that young adults had significantly greater activation than adolescent subjects (n = 11) in the left middle frontal gyrus and that young adults showed significantly greater activation than children (n = 8) in the anterior cingulate and left parietal and parieto-occipital regions, as well as in the left middle frontal gyrus. Compared to children, both adult and adolescent subjects exhibited significantly greater activation in the parietal cortex. Adult and adolescent groups, however, did not differ in activation for this region. Together, these data suggest that Stroop task-related functional development of the parietal lobe occurs by adolescence. In contrast, prefrontal cortex function contributing to the Stroop interference task continues to develop into adulthood. This neuromaturational process may depend on increased ability to recruit focal neural resources with age. Findings from this study, the first developmental fMRI investigation of the Stroop interference task, provide a template with which normal development and neurodevelopmental disorders of prefrontal cortex function can be assessed.

    View details for DOI 10.1006/nimg.2001.1046

    View details for Web of Science ID 000176624700007

    View details for PubMedID 11969318

  • Increased gyrification in Williams syndrome: evidence using 3D MRI methods DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Schmitt, J. E., Watts, K., Eliez, S., Galaburda, A. M., Reiss, A. L. 2002; 44 (5): 292-295

    Abstract

    Understanding patterns of gyrification in neurogenetic disorders helps to uncover the neurodevelopmental etiology underlying behavioral phenotypes. This is particularly true in Williams syndrome (WS), a condition caused by de novo deletion of approximately 1 to 2 Mb in the 7q11.23 region. Individuals with WS characteristically possess an unusual dissociation between deficits in visual-spatial ability and relative preservations in language, music, and social drive. A preliminary postmortem study reported anomalous gyri and sulci in individuals with WS. The present study examined gyrification patterns in 17 participants with WS (10 females, 7 males; mean age 28 years 11 months, SD 8 years 6 months) and 17 age- and sex-matched typically developing control participants (mean age 29 years 1 month, SD 8 years 1 month) using new automated techniques in MRI. Significantly increased cortical gyrification was found globally with abnormalities being more marked in the right parietal (p=0.0227), right occipital (p=0.0249), and left frontal (p=0.0086) regions. These results suggest that one or more genes in the 7q11.23 region are involved during the critical period when cortical folding occurs, and may be related to the hypothesized dorsal/ventral dissociation in this condition.

    View details for Web of Science ID 000175692600002

    View details for PubMedID 12033713

  • Diurnal salivary cortisol in pediatric posttraumatic stress disorder BIOLOGICAL PSYCHIATRY Carrion, V. G., Weems, C. F., Ray, R. D., Glaser, B., Hessl, D., Reiss, A. L. 2002; 51 (7): 575-582

    Abstract

    The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). Additional information on basal cortisol levels in children exposed to trauma and experiencing PTSD symptoms may contribute to the understanding of the role of this axis in PTSD.Fifty-one children (30 boys and 21 girls, mean age 10.7 years) with a history of exposure to trauma and PTSD symptoms were compared with 31 age- and gender-matched healthy control subjects. Salivary cortisol was obtained from participants during home measurements and was collected four times a day (prebreakfast, prelunch, predinner, and prebed) for up to 3 consecutive days.The clinical group demonstrated significantly elevated cortisol levels when compared with the control group. In addition, exploratory analyses revealed that girls with PTSD symptoms had significantly elevated cortisol levels when compared with boys with PTSD symptoms.The physiologic response of children with history of trauma and with PTSD symptoms may be characterized by heightened adrenal activity.

    View details for Web of Science ID 000174959100006

    View details for PubMedID 11950459

  • Relating semantic and episodic memory systems COGNITIVE BRAIN RESEARCH Menon, V., Boyett-Anderson, J. M., Schatzberg, A. F., Reiss, A. L. 2002; 13 (2): 261-265

    Abstract

    Episodic and semantic memory are two forms of declarative memory which appear to function in distinct yet interdependent ways. Here we provide direct evidence for a functional relationship between these two memory systems by showing that left lateral temporal lobe regions involved in semantic memory play an important role in accurate episodic memory retrieval.

    View details for Web of Science ID 000174786000014

    View details for PubMedID 11958970

  • Genetic and environmental influences on the cognitive outcomes of children with fragile X syndrome JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Dyer-Friedman, J., Glaser, B., Hessl, D., Johnston, C., Huffman, L. C., Taylor, A., Wisbeck, J., Reiss, A. L. 2002; 41 (3): 237-244

    Abstract

    To measure the genetic and environmental factors influencing the cognitive outcomes in children with fragile X, a common genetic disorder causing cognitive impairments.In-home evaluations were conducted on 120 children (80 boys and 40 girls) with the fragile X full mutation and their unaffected siblings.Multiple regression analyses show that the cognitive outcomes for girls with fragile X are most strongly predicted by the mean IQ of their parents, with a small proportion of the variance accounted for by the quality of their home environment. FMR1 protein (FMRP) was associated with girls' levels of distractibility. Mean parental IQ was associated only with boys' Performance IQs, while FMRP was associated with boys' Full Scale IQs. The quality of boys' home environments accounted for more of the variance in their cognitive outcomes than it did for affected girls.Both biological/genetic factors and environmental factors are significant predictors of IQ in children with fragile X syndrome; however, the influence of specific factors differs between girls and boys. These findings lay the foundation for further investigation into biological and environmental interventions.

    View details for Web of Science ID 000174118400002

    View details for PubMedID 11886017

  • fMRI study of cognitive interference processing in females with fragile X syndrome JOURNAL OF COGNITIVE NEUROSCIENCE Tamm, L., Menon, V., Johnston, C. K., Hessl, D. R., Reiss, A. L. 2002; 14 (2): 160-171

    Abstract

    Females with fragile X syndrome, the most common form of inherited developmental and learning problems, are known to be impaired in executive function. The current study is the first to investigate the performance of females with fragile X on a cognitive interference task utilizing functional magnetic resonance imaging (fMRI). Fourteen females with fragile X and 14 age-matched healthy controls were imaged while they performed a counting Stroop interference task. Compared to controls, females with fragile X appeared to have longer reaction times during the interference condition of the task, and adopted a strategy trading speed for accuracy. Females with fragile X also had a significantly different pattern of activation than controls. Whereas controls showed significant activation in the inferior/middle frontal gyrus and inferior/superior parietal lobe, females with fragile X showed more extensive activation in the anterior region of the prefrontal cortex, and failed to show expected activation in the inferior/superior parietal lobe. Further, between-group analyses revealed that females with fragile X had reduced activation in the left orbitofrontal gyrus, thought to be involved in modulating goal-directed behavior. Females with fragile X also demonstrated a markedly different pattern of deactivation from controls. These findings suggest that deficits in cognitive interference processing during the counting Stroop task observed in females with fragile X may arise from inability to appropriately recruit and modulate lateral prefrontal and parietal resources.

    View details for Web of Science ID 000173652000003

    View details for PubMedID 11970783

  • Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: Usefulness as phenotypic indicators of schizophrenia risk BIOLOGICAL PSYCHIATRY Feinstein, C., Eliez, S., Blasey, C., Reiss, A. L. 2002; 51 (4): 312-318

    Abstract

    Velocardiofacial syndrome (VCFS), a genetic deletion condition with numerous cognitive sequelae, is associated with a high rate of psychiatric disorders in childhood. More recently, VCFS has been identified as a high-risk factor for developing adult onset schizophrenia. However, it has never been demonstrated that the childhood psychiatric disorders found in children with VCFS differ from those found in children with a similar degree of cognitive impairment. Identification of a specific behavioral (psychiatric) phenotype in childhood VCFS offers the potential for elucidating the symptomatic precursors of adult onset schizophrenia.Twenty-eight children with VCFS and 29 age- and cognitively matched control subjects received a standardized assessment of childhood psychiatric disorders and behaviors measured by the Child Behavior Checklist (CBCL). Findings from the two groups were compared.The rates and types of psychiatric disorder and behavior problems in VCFS and cognitively matched control subjects were very high, but showed no significant differences.Psychopathology in children with VCFS may not differ from that found in cognitively matched control subjects. Another explanation is that subtle phenotypic differences in behavior found in VCFS can not be observed using standard symptom inventories. The high rate of psychopathology in children with VCFS is not a useful phenotypic indicator of high risk for adult onset schizophrenia.

    View details for Web of Science ID 000174281200006

    View details for PubMedID 11958782

  • Toward an empirical definition of pediatric PTSD: The phenomenology of PTSD symptoms in youth JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Carrion, V. G., Weems, C. F., Ray, R., Reiss, A. L. 2002; 41 (2): 166-173

    Abstract

    To examine the frequency and intensity of posttraumatic stress disorder (PTSD) symptoms and their relation to clinical impairment, to examine the requirement of meeting all DSM-IV symptom cluster criteria (i.e., criteria B, C, D), and to examine the aggregation of PTSD symptom clusters across developmental stages.Fifty-nine children between the ages of 7 and 14 years with a history of trauma and PTSD symptoms were assessed with the Clinician-Administered PTSD Scale for Children and Adolescents.Data support the utility of distinguishing between the frequency and the intensity of symptoms in the investigation of the phenomenology of pediatric PTSD. Children fulfilling requirements for two symptom clusters did not differ significantly from children meeting all three cluster criteria with regard to impairment and distress. Reexperience (cluster B) showed increased aggregation with avoidance and numbing (cluster C) and hyperarousal (cluster D) in the later stages of puberty.Frequency and intensity of symptoms may both contribute to the phenomenology of pediatric PTSD. Children with subthreshold criteria for PTSD demonstrate substantial functional impairment and distress.

    View details for Web of Science ID 000173451400010

    View details for PubMedID 11837406

  • Reduced size of the amygdala in individuals with 47,XXY and 47,XXX Karyotypes AMERICAN JOURNAL OF MEDICAL GENETICS Patwardhan, A. J., Brown, W. E., Bender, B. G., Linden, M. G., Eliz, S., Reiss, A. L. 2002; 114 (1): 93-98

    Abstract

    The excess of 47,XXX and 47,XXY karyotypes found in cytogenetic screening studies of individuals with schizophrenia has given support for an increased risk of psychiatric illness among men and women with sex chromosomal aneuploidy (SCA). Mesial temporal lobe structures, including the amygdala and hippocampus, are thought to be associated with abnormalities of mood and behavior in humans and in the neurobiology of schizophrenia. This study focuses on variations in volumes of mesial temporal lobe structures in men and women with SCA. Utilizing an unselected birth cohort of subjects with SCA and high-resolution magnetic resonance imaging (MRI), we investigated the neuroanatomical consequences of a supernumerary X chromosome on the morphology of the amygdala and hippocampus. Regional and total brain volumes were measured in 10 subjects with 47,XXY, 10 subjects with 47,XXX, and 20 euploid controls. Amygdala volumes were significantly reduced in men with 47,XXY, compared to control men, while the decrease in women with 47,XXX was not as pronounced. Hippocampus volumes were preserved in both groups, compared to same-gender controls. Longitudinal studies of SCA individuals have shown an increased incidence of mild psychopathology and behavioral dysfunction in men with 47,XXY and more overt psychiatric illness in women with 47,XXX, compared to control populations. The alteration in amygdala volumes in individuals with a supernumerary X chromosome may provide a neuroanatomic basis for these findings.

    View details for Web of Science ID 000173133600015

    View details for PubMedID 11840512

  • Attenuation of frontal asymmetry in pediatric posttraumatic stress disorder BIOLOGICAL PSYCHIATRY Carrion, V. G., Weems, C. F., Eliez, S., Patwardhan, A., BROWN, W., Ray, R. D., Reiss, A. L. 2001; 50 (12): 943-951

    Abstract

    Volumetric imaging research has shown abnormal brain morphology in adults with posttraumatic stress disorder (PTSD) when compared with matched control subjects. In this article, we present brain imaging findings from a study of children with PTSD symptoms.Twenty-four children between the ages of 7 and 14 with a history of trauma and PTSD symptoms were assessed with the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA). The sample underwent magnetic resonance imaging in a 1.5 T scanner. Brain images were analyzed by raters blind to diagnostic status using well-standardized methods, and images were compared with age- and gender-matched healthy control subjects.The clinical group demonstrated attenuation of frontal lobe asymmetry and smaller total brain and cerebral volumes when compared with the control group. There were no statistically significant differences in hippocampal volume between clinical and control subjects.Frontal lobe abnormalities may occur as a result of PTSD in children or, alternatively, be a risk factor for the development of the syndrome in this age group. The implications of the findings and their consistency with previous research are discussed.

    View details for Web of Science ID 000172841300003

    View details for PubMedID 11750890

  • No widespread psychological effect of the fragile X premutation in childhood: Evidence from a preliminary controlled study JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Myers, G. F., Mazzocco, M. M., Maddalena, A., Reiss, A. L. 2001; 22 (6): 353-359

    Abstract

    This study was designed to examine the effect of the fragile X premutation (pM) on cognitive function and behavior. Participants included 14 children (7 males, 7 females) with the fragile X pM and 14 children without the fragile X pM (and without the fragile X full mutation [fM]), each of whom was matched by age and gender with one of the participants from the pM group. The children ranged in age from 3 years, 1 month, to 17 years, 11 months. Participants were individually administered measures of intellectual functioning, academic achievement, and visual motor integration. Parent rating scales of problem behaviors were completed. Group differences were examined using nonparametric statistics. No statistically significant differences were found between the premutation and nonpremutation groups. The results from this study are consistent with the hypothesis that the premutation does not, in general, have an effect on a child's development. However, this does not preclude cases where specific factors may lead to a specific phenotype.

    View details for Web of Science ID 000172745700001

    View details for PubMedID 11773799

  • The influence of environmental and genetic factors on behavior problems and autistic symptoms in boys and girls with fragile X syndrome PEDIATRICS Hessl, D., Dyer-Friedman, J., Glaser, B., Wisbeck, J., Barajas, R. G., Taylor, A., Reiss, A. L. 2001; 108 (5)

    Abstract

    Fragile X syndrome, caused by mutations in a single gene of the X chromosome (FMR1), is associated with neurobehavioral characteristics including social deficits with peers, social withdrawal, gaze aversion, inattention, hyperactivity, anxiety, depression, and autistic behavior. However, there is considerable variability in the behavioral and psychiatric problems among children with this condition. The purpose of this study was to measure genetic and environmental factors influencing behavior problems and autistic symptoms in children with fragile X syndrome.We conducted an in-home evaluation of 120 children (80 boys and 40 girls) with the fragile X full mutation and their unaffected siblings, including measurements of the FMR1 protein (FMRP), quality of the home environment, maternal and paternal psychopathology, effectiveness of educational and therapeutic services, and child behavior problems.Results of multiple regression analyses showed that for boys with fragile X, effectiveness of educational and therapeutic services and parental psychological problems predicted internalizing and externalizing types of problems, while the quality of the home environment predicted autistic behavior. For girls with fragile X, the results emphasized significant effects of FMRP on behavior, in particular social withdrawal and anxious/depressed behavior.These findings are among the first to link FMRP expression to behavior. They also emphasize the significance of home- and school-based environmental variables in the neurobehavioral phenotype and help to lay the foundation for studies designed to identify specific interventions for reducing problem behavior in children with fragile X syndrome.

    View details for Web of Science ID 000171925200011

    View details for PubMedID 11694672

  • Dorsal forebrain anomaly in Williams syndrome ARCHIVES OF NEUROLOGY Galaburda, A. M., Schmitt, J. E., Atlas, S. W., Eliez, S., Bellugi, U., Reiss, A. L. 2001; 58 (11): 1865-1869

    Abstract

    Williams syndrome (WMS) is a rare neurogenetic condition with a behavioral phenotype that suggests a dorsal and/or ventral developmental dissociation, with deficits in dorsal but not the ventral hemispheric visual stream. A shortened extent of the dorsal central sulcus has been observed in autopsy specimens.To compare gross anatomical features between the dorsal and ventral portions of the cerebral hemispheres by examining the dorsal extent of the central sulcus in brain magnetic resonance images from a sample of subjects with WMS and age- and sex-matched control subjects.Twenty-one subjects having clinically and genetically diagnosed WMS (mean +/- SD age, 28.9 +/- 7.9 years) were compared with 21 age- and sex-matched typically developing controls (mean +/- SD age, 28.8 +/- 7.9 years).High-resolution structural magnetic resonance images were acquired. The extent of the central sulcus was qualitatively assessed via surface projections of the cerebral cortex.The dorsal central sulcus is less likely to reach the interhemispheric fissure in subjects with WMS than in controls for both left (P< .001, chi(2) = 15.79) and right (P< .001, chi(2) = 12.95) hemispheres. No differences between the groups were found in the ventral extent of the central sulcus.Anomalies in the dorsal region in patients with WMS are indicative of early neurodevelopmental problems affecting the development of the dorsal forebrain and are most likely related to the deficits in visuospatial ability and behavioral timing often observed in this condition.

    View details for Web of Science ID 000172055300021

    View details for PubMedID 11708996

  • Neurobehavioral phenotype in carriers of the fragile X premutation AMERICAN JOURNAL OF MEDICAL GENETICS Johnston, C., Eliez, S., Dyer-Friedman, J., Hessl, D., Glaser, B., Blasey, C., Taylor, A., Reiss, A. 2001; 103 (4): 314-319

    Abstract

    There have been contradictory findings in the fragile X (fraX) literature about possible neurocognitive and psychological symptoms due to the fraX premutation (pM). The purpose of the present study was to investigate the relationship between CGG repeat length and neurobehavioral functioning in carriers of the fraX pM. Eighty-five female carriers of the pM with allele sizes ranging from 59-166 were administered a comprehensive IQ test (WAIS-III) and completed a questionnaire designed to measure psychopathology (Symptom Checklist (SCL)-90-R). No relationship between allele size and cognition was identified. A significant negative relationship between allele size and age was found, as well as a positive relationship between allele size and depression. Follow-up analyses separating small and large allele sizes (below and above 100 CGG repeats) indicated that individuals with larger allele sizes scored significantly higher on the Interpersonal Sensitivity and Depression subscales of the SCL-90-R. Despite the limitation of few individuals with high CGG repeat lengths, our findings suggest that females with larger premutated alleles (> or = 100 repeats) display some clinical manifestations of fraX syndrome.

    View details for Web of Science ID 000171752600009

    View details for PubMedID 11746012

  • Neuroanatomy of Down's syndrome: A high-resolution MRI study AMERICAN JOURNAL OF PSYCHIATRY Pinter, J. D., Eliez, S., Schmitt, J. E., Capone, G. T., Reiss, A. L. 2001; 158 (10): 1659-1665

    Abstract

    Down's syndrome, the most common genetic cause of mental retardation, results in characteristic physical and neuropsychological findings, including mental retardation and deficits in language and memory. This study was undertaken to confirm previously reported abnormalities of regional brain volumes in Down's syndrome by using high-resolution magnetic resonance imaging (MRI), determine whether these volumetric abnormalities are present from childhood, and consider the relationship between neuroanatomic abnormalities and the cognitive profile of Down's syndrome.Sixteen children and young adults with Down's syndrome (age range=5-23 years) were matched for age and gender with 15 normal comparison subjects. High-resolution MRI scans were quantitatively analyzed for measures of overall and regional brain volumes and by tissue composition.Consistent with prior imaging studies, subjects with Down's syndrome had smaller overall brain volumes, with disproportionately smaller cerebellar volumes and relatively larger subcortical gray matter volumes. Also noted was relative preservation of parietal lobe gray and temporal lobe white matter in subjects with Down's syndrome versus comparison subjects. No abnormalities in pattern of brain asymmetry were noted in Down's syndrome subjects.The results largely confirm findings of previous studies with respect to overall patterns of brain volumes in Down's syndrome and also provide new evidence for abnormal volumes of specific regional tissue components. The presence of these abnormalities from an early age suggests that fetal or early postnatal developmental differences may underlie the observed pattern of neuroanatomic abnormalities and contribute to the specific cognitive and developmental deficits seen in individuals with Down's syndrome.

    View details for Web of Science ID 000171374500020

    View details for PubMedID 11578999

  • Functional neuroanatomy of visuo-spatial working memory in Turner syndrome HUMAN BRAIN MAPPING Haberecht, M. F., Menon, V., Warsofsky, I. S., White, C. D., Dyer-Friedman, J., Glover, G. H., Neely, E. K., Reiss, A. L. 2001; 14 (2): 96-107

    Abstract

    Turner syndrome (TS), a genetic disorder characterized by the absence of an X chromosome in females, has been associated with cognitive and visuo-spatial processing impairments. We utilized functional MRI (fMRI) to investigate the neural substrates that underlie observed deficits in executive functioning and visuo-spatial processing. Eleven females with TS and 14 typically developing females (ages 7-20) underwent fMRI scanning while performing 1-back and 2-back versions of a standard visuo-spatial working memory (WM) task. On both tasks, TS subjects performed worse than control subjects. Compared with controls, TS subjects showed increased activation in the left and right supramarginal gyrus (SMG) during the 1-back task and decreased activation in these regions during the 2-back task. In addition, decreased activation in the left and right dorsolateral prefrontal cortex (DLPFC) and caudate nucleus was observed during the 2-back task in TS subjects. Activation differences localized to the SMG, in the inferior parietal lobe, may reflect deficits in visuo-spatial encoding and WM storage mechanisms in TS. In addition, deficits in the DLPFC and caudate may be related to deficits in executive function during WM performance. Together these findings point to deficits in frontal-striatal and frontal-parietal circuits subserving multiple WM functions in TS.

    View details for Web of Science ID 000171325100003

    View details for PubMedID 11500993

  • BrainImageJ: a Java-based framework for interoperability in neuroscience, with specific application to neuroimaging. Journal of the American Medical Informatics Association Ng, Y. R., Shiffman, S., Brosnan, T. J., Links, J. M., Beach, L. S., Judge, N. S., Xu, Y., Kelkar, U. V., Reiss, A. L. 2001; 8 (5): 431-442

    Abstract

    The Human Brain Project consortium continues to struggle with effective sharing of tools. To facilitate reuse of its tools, the Stanford Psychiatry Neuroimaging Laboratory (SPNL) has developed BrainImageJ, a new software framework in Java. The framework consists of two components-a set of four programming interfaces and an application front end. The four interfaces define extension pathways for new data models, file loaders and savers, algorithms, and visualization tools. Any Java class that implements one of these interfaces qualifies as a BrainImageJ plug-in-a self-contained tool. After automatically detecting and incorporating new plug-ins, the application front end transparently generates graphical user interfaces that provide access to plug-in functionality. New plug-ins interoperate with existing ones immediately through the front end. BrainImageJ is used at the Stanford Psychiatry Neuroimaging Laboratory to develop image-analysis algorithms and three-dimensional visualization tools. It is the goal of our development group that, once the framework is placed in the public domain, it will serve as an interlaboratory platform for designing, distributing, and using interoperable tools.

    View details for PubMedID 11522764

  • Brain anatomy, gender and IQ in children and adolescents with fragile X syndrome BRAIN Eliez, S., Blasey, C. M., Freund, L. S., Hastie, T., Reiss, A. L. 2001; 124: 1610-1618

    Abstract

    This study utilized MRI data to describe neuroanatomical morphology in children and adolescents with fragile X syndrome, the most common inherited cause of developmental disability. The syndrome provides a model for understanding how specific genetic factors can influence both neuroanatomy and cognitive capacity. Thirty-seven children and adolescents with fragile X syndrome received an MRI scan and cognitive testing. Scanning procedures and analytical strategies were identical to those reported in an earlier study of 85 typically developing children, permitting a comparison with a previously published template of normal brain development. Regression analyses indicated that there was a normative age-related decrease in grey matter and an increase in white matter. However, caudate and ventricular CSF volumes were significantly enlarged, and caudate volumes decreased with age. Rates of reduction of cortical grey matter were different for males and females. IQ scores were not significantly correlated with volumes of cortical and subcortical grey matter, and these relationships were statistically different from the correlational patterns observed in typically developing children. Children with fragile X syndrome exhibited several typical neurodevelopmental patterns. Aberrations in volumes of subcortical nuclei, gender differences in rates of cortical grey matter reduction and an absence of correlation between grey matter and cognitive performance provided indices of the deleterious effects of the fragile X mutation on the brain's structural organization.

    View details for Web of Science ID 000170453400013

    View details for PubMedID 11459752

  • Enlarged cerebellar vermis in Williams syndrome JOURNAL OF PSYCHIATRIC RESEARCH Schmitt, J. E., Eliez, S., Warsofsky, I. S., Bellugi, U., Reiss, A. L. 2001; 35 (4): 225-229

    Abstract

    Williams syndrome (WMS) is a rare genetic disorder characterized by relative preservations of language ability and facial processing despite deficits in overall intelligence, problem solving, and visuospatial processing. Subjects with WMS also display hypersocial behavior and excessive linguistic affect during conversations and when giving narratives. Neuroimaging studies have shown global reductions in the brain volumes of subjects with WMS compared with normal controls, but with preservations in cerebellar volume. This study examines the neuroanatomic structure of the cerebellar vermis in 20 subjects with WMS and 20 age- and gender-matched controls via high-resolution magnetic resonance imaging. The vermis was divided into lobules I-V, VI-VII, and VIII-X. Lobules VI-VII and VIII-X were both relatively enlarged in the WMS group, and after adjusting for the smaller size of the WMS brain, the posterior vermis was significantly larger in WMS (Mann-Whitney z-value=4.27; P<0.001). Given that reductions in posterior vermis size have been implicated in flattened affect and autistic features, increased vermis size in subjects with WMS may be related to the hypersociality and heightened affective expression characteristic of individuals with this genetic condition.

    View details for Web of Science ID 000171268700003

    View details for PubMedID 11578640

  • Functional neuroanatomy of visuospatial working memory in fragile X syndrome: Relation to behavioral and molecular measures AMERICAN JOURNAL OF PSYCHIATRY Kwon, H., Menon, V., Eliez, S., Warsofsky, I. S., White, C. D., Dyer-Friedman, J., Taylor, A. K., Glover, G. H., Reiss, A. L. 2001; 158 (7): 1040-1051

    Abstract

    Fragile X syndrome is a neurogenetic disorder that is the most common known heritable cause of neurodevelopmental disability. This study examined the neural substrates of working memory in female subjects with fragile X syndrome. Possible correlations among behavioral measures, brain activation, and the FMR1 gene product (FMRP expression), as well as between IQ and behavioral measures, were investigated.Functional magnetic resonance imaging was used to examine visuospatial working memory in 10 female subjects with fragile X syndrome and 15 typically developing female subjects (ages 10-23 years). Subjects performed standard 1-back and 2-back visuospatial working memory tasks. Brain activation was examined in four regions of the cortex known to play a critical role in visuospatial working memory. Correlations between behavioral, neuroimaging, and molecular measures were examined.Relative to the comparison group, subjects with fragile X syndrome performed significantly worse on the 2-back task but not on the 1-back task. In a region-of-interest analysis focused on the inferior frontal gyrus, middle frontal gyrus, superior parietal lobule, and supramarginal gyrus, comparison subjects showed significantly increased brain activation between the 1-back and 2-back tasks, but subjects with fragile X syndrome showed no change in activation between the two tasks. Significant correlations were found in comparison subjects between activation in the frontal and parietal regions and the rate of correct responses on the 2-back task, but not on the 1-back task. In subjects with fragile X syndrome, significant correlations were found during the 2-back task between FMRP expression and activation in the right inferior and bilateral middle frontal gyri and the bilateral supramarginal gyri.Subjects with fragile X syndrome are unable to modulate activation in the prefrontal and parietal cortex in response to an increasing working memory load, and these deficits are related to a lower level of FMRP expression in fragile X syndrome subjects than in normal comparison subjects. The observed correlations between biological markers and brain activation provide new evidence for links between gene expression and cognition.

    View details for Web of Science ID 000169773000009

    View details for PubMedID 11431225

  • Effects of image orientation on the comparability of pediatric brain volumes using three-dimensional MR data JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Patwardhan, A. J., Eliez, S., Warsofsky, I. S., Glover, G. H., White, C. D., Giedd, J. N., Peterson, B. S., Rojas, D. C., Reiss, A. L. 2001; 25 (3): 452-457

    Abstract

    The purpose of this study was to examine the comparability of morphometric measurements made on pediatric data sets collected at five scanner locations, each using variations on a 3D spoiled gradient-recalled echo (SPGR) pulse sequence.Archived MR data from 60 typically developing children were collected and separated into seven groups based on the pulse sequence used. A highly automated image-processing procedure was used to segment the brain data into white tissue, gray tissue, and CSF compartments and into various neuroanatomic regions of interest.Volumetric comparisons between groups revealed differences in areas of the temporal and occipital lobes. These differences were observed when comparing data sets with different image orientations and appeared to be due to partial volume averaging (PVA) and susceptibility-induced geometric distortions.Our results indicate that slice selection and image resolution should be controlled in volumetric studies using aggregated data from multiple centers to minimize the effects of PVA and susceptibility-induced geometric distortions.

    View details for Web of Science ID 000168573200020

    View details for PubMedID 11351198

  • Amygdala and hippocampal volumes in children with Down syndrome: A high-resolution MRI study NEUROLOGY Pinter, J. D., Brown, W. E., Eliez, S., Schmitt, J. E., Capone, G. T., Reiss, A. L. 2001; 56 (7): 972-974

    Abstract

    The objective of this study was to use high-resolution MRI techniques to determine whether children with Down syndrome exhibit decreases in hippocampal and amygdala volumes similar to those demonstrated in recent studies of adults with this condition. When corrected for overall brain volumes, amygdala volumes did not differ between groups but hippocampal volumes were significantly smaller in the Down syndrome group. These findings suggest that the hippocampal volume reduction seen in adults with Down syndrome may be primarily due to early developmental differences rather than neurodegenerative changes.

    View details for Web of Science ID 000167961500026

    View details for PubMedID 11294940

  • Preliminary evidence of widespread morphological variations of the brain in dyslexia NEUROLOGY Brown, W. E., Eliez, S., Menon, V., Rumsey, J. M., White, C. D., Reiss, A. L. 2001; 56 (6): 781-783

    Abstract

    The MR images of 16 men with dyslexia and 14 control subjects were compared using a voxel-based analysis. Evidence of decreases in gray matter in dyslexic subjects, most notably in the left temporal lobe and bilaterally in the temporoparietooccipital juncture, but also in the frontal lobe, caudate, thalamus, and cerebellum, was found. Widely distributed morphologic differences affecting several brain regions may contribute to the deficits associated with dyslexia.

    View details for Web of Science ID 000167697100018

    View details for PubMedID 11274316

  • A quantitative MRI study of posterior fossa development in velocardiofacial syndrome BIOLOGICAL PSYCHIATRY Eliez, S., Schmitt, J. E., White, C. D., Wellis, V. G., Reiss, A. L. 2001; 49 (6): 540-546

    Abstract

    Velocardiofacial syndrome (VCFS) has been identified as a risk factor for developing schizophrenia. Qualitative neuroimaging studies indicated that VCFS was frequently associated with abnormal development of structures in the posterior fossa of the brain. The objective of this investigation was to identify the specific structures affected in the posterior fossa and investigate the association of these neuroanatomic variations with behaviors potentially related to later-onset psychiatric disorders.Twenty-four children and adolescents with VCFS individually matched for age and gender with 24 control subjects received magnetic resonance imaging scans. Analysis of covariance models were used to investigate regional brain differences. Association between brain areas and behaviors measured on the Child Behavior Checklist (CBCL) were assessed using simple regression models.Children with VCFS had significantly smaller size of vermal lobules VI--VII and the pons after adjusting for overall brain size. There were no significant associations between scores on the CBCL and measures of neuroanatomic variation within the VCFS group.Structural alterations of the posterior fossa in VCFS are specifically limited to cerebellar vermis lobules VI--VII and pons. Previous literature has suggested that the vermis is involved in social cognition, and alteration of lobules VI--VII could therefore partially explain the neurobehavioral profile associated with VCFS.

    View details for Web of Science ID 000167516400007

    View details for PubMedID 11257239

  • Velocardiofacial syndrome: Are structural changes in the temporal and mesial temporal regions related to schizophrenia? AMERICAN JOURNAL OF PSYCHIATRY Eliez, S., Blasey, C. M., Schmitt, E. J., White, C. D., Hu, D., Reiss, A. L. 2001; 158 (3): 447-453

    Abstract

    Velocardiofacial syndrome results from a microdeletion on chromosome 22 (22q11.2). Clinical studies indicate that more than 30% of children with the syndrome will develop schizophrenia. The authors sought to determine whether neuroanatomical features in velocardiofacial syndrome are similar to those reported in the literature on schizophrenia by measuring the volumes of the temporal lobe, superior temporal gyrus, and mesial temporal structures in children and adolescents with velocardiofacial syndrome.Twenty-three children and adolescents with velocardiofacial syndrome and 23 comparison subjects, individually matched for age and gender, received brain magnetic resonance imaging (MRI) scans. Analysis of covariance models were used to compare regional brain volumes. Correlations between residualized brain volumes and age were standardized and compared with the Fisher r-to-z transformation.Children with velocardiofacial syndrome had significantly smaller average temporal lobe, superior temporal gyrus, and hippocampal volumes than normal comparison children, although these differences were commensurate with a lower overall brain size in the affected children. In a cross-sectional analysis, children with velocardiofacial syndrome exhibited aberrant volumetric reductions with age that were localized to the temporal lobe and left hippocampal regions.Abnormal temporal lobe and hippocampal development in velocardiofacial syndrome is potentially concordant with MRI findings in the schizophrenia literature. Temporal lobe and mesial temporal structures may represent a shared substrate for the effects of the 22q11.2 deletion and for the complex etiological pathways that lead to schizophrenia. Longitudinal research may help determine which children with velocardiofacial syndrome are at risk for serious psychiatric illness in adulthood.

    View details for Web of Science ID 000167323000017

    View details for PubMedID 11229987

  • Corpus callosum morphology of Williams syndrome: relation to genetics and behavior DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Schmitt, J. E., Eliez, S., Warsofsky, I. S., Bellugi, U., Reiss, A. L. 2001; 43 (3): 155-159

    Abstract

    As the largest interhemispheric commissure in the brain, the corpus callosum is of particular interest in disorders that may preferentially affect white matter development such as Williams syndrome (WS). Individuals with WS possess a remarkable array of neurobehavioral peaks and valleys, including deficits in visuospatial ability, mathematics, and attention, but with relative preservation of language and affect. Our study measured the corpus callosum and its primary subdivisions using high-resolution MRI in 20 individuals with WS (13 females and seven males; mean age 28.5, SD 8.3 years; range 19 to 44 years) and 20 age- and sex-matched control participants (mean age 28.5, SD 8.2 years; range 19 to 48 years). Total midsagittal corpus callosum area was reduced (F=4.5, p=0.04, df=36) in the WS population. The area of the splenium (F=12.4, p=0.001, df=36) and isthmus (F=9.4, p=0.004, df=36) were disproportionately reduced in WS beyond the absolute reduction of the entire corpus callosum. These reductions are in concordance with other neuroanatomical findings of decreased parietooccipital volumes as well as the observed visuospatial problems associated with WS.

    View details for Web of Science ID 000167705000003

    View details for PubMedID 11263684

  • Error-related brain activation during a Go/NoGo response inhibition task HUMAN BRAIN MAPPING Menon, V., Adleman, N. E., White, C. D., Glover, G. H., Reiss, A. L. 2001; 12 (3): 131-143

    Abstract

    Inhibitory control and performance monitoring are critical executive functions of the human brain. Lesion and imaging studies have shown that the inferior frontal cortex plays an important role in inhibition of inappropriate response. In contrast, specific brain areas involved in error processing and their relation to those implicated in inhibitory control processes are unknown. In this study, we used a random effects model to investigate error-related brain activity associated with failure to inhibit response during a Go/NoGo task. Error-related brain activation was observed in the rostral aspect of the right anterior cingulate (BA 24/32) and adjoining medial prefrontal cortex, the left and right insular cortex and adjoining frontal operculum (BA 47) and left precuneus/posterior cingulate (BA 7/31/29). Brain activation related to response inhibition and competition was observed bilaterally in the dorsolateral prefrontal cortex (BA 9/46), pars triangularis region of the inferior frontal cortex (BA 45/47), premotor cortex (BA 6), inferior parietal lobule (BA 39), lingual gyrus and the caudate, as well as in the right dorsal anterior cingulate cortex (BA 24). These findings provide evidence for a distributed error processing system in the human brain that overlaps partially, but not completely, with brain regions involved in response inhibition and competition. In particular, the rostal anterior cingulate and posterior cingulate/precuneus as well as the left and right anterior insular cortex were activated only during error processing, but not during response competition, inhibition, selection, or execution. Our results also suggest that the brain regions involved in the error processing system overlap with brain areas implicated in the formulation and execution of articulatory plans.

    View details for Web of Science ID 000167259000001

    View details for PubMedID 11170305

  • Analysis of cerebral shape in Williams syndrome ARCHIVES OF NEUROLOGY Schmitt, J. E., Eliez, S., Bellugi, U., Reiss, A. L. 2001; 58 (2): 283-287

    Abstract

    As a neurobehavioral disorder with a specific neurocognitive profile and a well-defined genetic etiology, Williams syndrome (WMS) provides an exceptional opportunity to examine associations among measures of behavior, neuroanatomy, and genetics. This study was designed to determine how cerebral shape differs between the brains of subjects with WMS and those of normal controls.Twenty adults with clinically and genetically diagnosed WMS (mean +/- SD age, 28.5 +/- 8.3 years) and 20 healthy, age- and sex-matched controls (mean +/- SD age, 28.5 +/- 8.2 years).High-resolution structural magnetic resonance imaging data were used for shape-based morphological analysis of the right and left cerebral hemispheres and the corpus callosum. Statistical analyses were performed to examine group differences.Both right and left cerebral hemispheres of subjects with WMS bend to a lesser degree in the sagittal plane than normal controls (P<.001). The corpus callosum also bends less in subjects with WMS (P =.05). In addition, subjects with WMS have decreased cerebral (P<.001) and corpus callosum (P<.001) midline lengths.Subjects with WMS have significantly different cerebral shape from normal controls, perhaps due to decreased parieto-occipital lobe volumes relative to frontal regions. The similar observation in the corpus callosum may be associated with a decreased size of the splenium in WMS. These findings may provide important clues to the effect of genes in the WMS-deleted region on brain development.

    View details for Web of Science ID 000166899800015

    View details for PubMedID 11176967

  • Parental origin of the deletion 22q11.2 and brain development in velocardiofacial syndrome - A preliminary study ARCHIVES OF GENERAL PSYCHIATRY Eliez, S., Antonarakis, S. E., Morris, M. A., Dahoun, S. P., Reiss, A. L. 2001; 58 (1): 64-68

    Abstract

    As children with velocardiofacial syndrome (VCFS) develop, they are at increased risk for psychopathology; one third will eventually develop schizophrenia. Because VCFS and the concomitant symptomatology result from a known genetic origin, the biological and behavioral characteristics of the syndrome provide an optimal framework for conceptualizing the associations among genes, brain development, and behavior. The purpose of this study was to investigate the effect of the parental origin of the 22q11.2 microdeletion on the brain development of children and adolescents with VCFS.Eighteen persons with VCFS and 18 normal control subjects were matched individually for age and sex. Results of DNA polymorphism analyses determined the parental origin of the deletion. Nine persons with VCFS had a deletion on the maternally derived chromosome 22; 9 persons, on the paternally derived chromosome 22. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of gray and white matter brain tissue.Total brain volume was approximately 11% smaller in the VCFS group than in controls. Comparisons between VCFS subgroups (maternal vs paternal microdeletion 22q11.2) indicated a significant 9% volumetric difference in total volume of cerebral gray matter (volume was greater in patients with paternal microdeletion) but not cerebral white matter. Significant age-related changes in gray matter were detected for subjects whose 22q11.2 deletion was on the maternal chromosome.Children and adolescents with VCFS experience major alterations in brain volumes. Significant reduction in gray matter development is attributable to presence of 22q11.2 microdeletion on the maternal chromosome.

    View details for Web of Science ID 000166349500007

    View details for PubMedID 11146759

  • Functional brain imaging study of mathematical reasoning abilities in velocardiofacial syndrome (del22q11.2) GENETICS IN MEDICINE Eliez, S., Blasey, C. M., Menon, V., White, C. D., Schmitt, J. E., Reiss, A. L. 2001; 3 (1): 49-55

    Abstract

    Children with velocardiofacial syndrome (VCFS) often have deficits in mathematical reasoning. Previous research has suggested that structural abnormalities in the parietal lobe region might underlie these deficits. The present study utilized functional magnetic resonance imaging (fMRI) to explore the relationship between brain function and mathematical performance in VCFS.Eight children with VCFS and eight comparison subjects underwent fMRI scanning and completed an arithmetic computation task.In the VCFS group, increased activation was observed in the left supramarginal gyrus (LSMG) as the task difficulty increased.Aberrant LSMG activation, possibly due to structural deficits of the left parietal lobe, may explain decrements in arithmetic performance observed in VCFS.

    View details for Web of Science ID 000167393400011

    View details for PubMedID 11339378

  • Enfants et adolescents atteints du syndrome vélo-cardio-facial. Une étude quantitative du développement cérébral à l'aide de l'imagerie par résonance magnétique nucléaire Médecine et hygiène Eliez, S., Schmitt, JE, White CD, Reiss AL 2001; 59: 414-418
  • Dissociating prefrontal and parietal cortex activation during arithmetic processing NEUROIMAGE Menon, V., Rivera, S. M., White, C. D., Glover, G. H., Reiss, A. L. 2000; 12 (4): 357-365

    Abstract

    Lesion and brain-imaging studies have implicated the prefrontal and parietal cortices in arithmetic processing, but do not exclude the possibility that these brain areas are also involved in nonarithmetic operations. In the present study, we used functional magnetic resonance imaging to explore which brain areas contribute uniquely to numeric computation. Task difficulty was manipulated in a factorial design by varying the number of operands and the rate of stimulus presentation. Both manipulations increased the number of operations to be performed in unit time. Manipulating the number of operands allowed us to investigate the specific effect of calculation, while manipulating the rate of presentation allowed us to increase task difficulty independent of calculation. We found quantitative changes in activation patterns in the prefrontal and parietal cortices as well as the recruitment of additional brain regions, including the caudate and midcerebellar cortex, with increasing task difficulty. More importantly, the main effect of arithmetic complexity was observed in the left and right angular gyrus, while the main effect of rate of stimulus presentation was observed in the left insular/orbitofrontal cortex. Our findings indicate a dissociation in prefrontal and parietal cortex function during arithmetic processing and further provide the first evidence for a specific role for the angular gyrus in arithmetic computation independent of other processing demands.

    View details for Web of Science ID 000089737000001

    View details for PubMedID 10988030

  • Analysis of a distributed neural system involved in spatial information, novelty, and memory processing HUMAN BRAIN MAPPING Menon, V., White, C. D., Eliez, S., Glover, G. H., Reiss, A. L. 2000; 11 (2): 117-129

    Abstract

    Perceiving a complex visual scene and encoding it into memory involves a hierarchical distributed network of brain regions, most notably the hippocampus (HIPP), parahippocampal gyrus (PHG), lingual gyrus (LNG), and inferior frontal gyrus (IFG). Lesion and imaging studies in humans have suggested that these regions are involved in spatial information processing as well as novelty and memory encoding; however, the relative contributions of these regions of interest (ROIs) are poorly understood. This study investigated regional dissociations in spatial information and novelty processing in the context of memory encoding using a 2 x 2 factorial design with factors Novelty (novel vs. repeated) and Stimulus (viewing scenes with rich vs. poor spatial information). Greater activation was observed in the right than left hemisphere; however, hemispheric effects did not differ across regions, novelty, or stimulus type. Significant novelty effects were observed in all four regions. A significant ROI x Stimulus interaction was observed - spatial information processing effects were largest effects in the LNG, significant in the PHG and HIPP and nonsignificant in the IFG. Novelty processing was stimulus dependent in the LNG and stimulus independent in the PHG, HIPP, and IFG. Analysis of the profile of Novelty x Stimulus interaction across ROIs provided evidence for a hierarchical independence in novelty processing characterized by increased dissociation from spatial information processing. Despite these differences in spatial information processing, memory performance for novel scenes with rich and poor spatial information was not significantly different. Memory performance was inversely correlated with right IFG activation, suggesting the involvement of this region in strategically flawed encoding effort. Stepwise regression analysis revealed that memory encoding accounted for only a small fraction of the variance (< 16%) in medial temporal lobe activation. The implications of these results for spatial information, novelty, and memory processing in each stage of the distributed network are discussed.

    View details for Web of Science ID 000089712000005

    View details for PubMedID 11061338

  • Functional brain activation during cognition is related to FMR1 gene expression BRAIN RESEARCH Menon, V., Kwon, H., Eliez, S., Taylor, A. K., Reiss, A. L. 2000; 877 (2): 367-370

    Abstract

    Fragile X syndrome, the most common known cause of inherited mental retardation, is caused by alterations of the FMR1 gene encoding the FMRP protein. We investigated the relation between FMRP protein levels and functional brain activation during a working memory task. Our study provides the first evidence for a relation between FMR1 gene expression and neural activity during higher-order cognition. More broadly, our findings provide the first demonstration of how gene-brain-behavior investigations can help to bridge the gap between molecular and systems neuroscience.

    View details for Web of Science ID 000089388500029

    View details for PubMedID 10986352

  • Annotation: MRI neuroimaging of childhood psychiatric disorders: A selective review JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Eliez, S., Reiss, A. L. 2000; 41 (6): 679-694

    Abstract

    Over the past 10 years, innovations in physics and computer science have promoted magnetic resonance imaging (MRI) as an essential tool for investigating the biological substrates of psychiatric disorders. Requiring no radiation exposure, MRI is now the preferred imaging technique for pediatric populations. However, the rapid technical advances in MRI pulse sequences, data processing, and analysis have made it increasingly complex for clinicians to compare and critically evaluate MRI research studies. This paper selectively reviews MRI research on five psychiatric conditions occurring in childhood or adolescence: ADHD, autism, childhood-onset schizophrenia, Tourette syndrome, and early-onset depression. The selection of papers reviewed was based on four criteria: the originality of the idea underlying the paper, the quality of the sample and methodologies used, the presence of controversial findings in the paper, and whether the paper was a clear illustration of specific methodological strengths or weaknesses. The two goals of this review paper are to update clinicians on morphometric brain imaging in child psychiatry and the methodological issues pertaining to image acquisition and analysis, and to promote critical reading of future MRI studies.

    View details for Web of Science ID 000089630300002

  • Cortisol and social stressors in children with fragile X: A pilot study JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Wisbeck, J. M., Huffman, L. C., Freund, L., Gunnar, M. R., Davis, E. P., Reiss, A. L. 2000; 21 (4): 278-282

    Abstract

    Evidence of neuroendocrine dysfunction, behavioral features of social anxiety and avoidance, and neuroanatomical abnormalities suggest that abnormal hypothalamic-pituitary-adrenal (HPA) function may be a component of the fragile X (fra X) syndrome. In this preliminary study, salivary cortisol levels of males (n = 8, mean age = 13.5 yr) and females (n = 7, mean age = 13.9 yr) with the fra X full mutation were studied for 3 days. Day 1 was an experimental day, during which subjects experienced a Social Stressor task midmorning. Days 2 and 3 were routine days, during which the subjects were engaged in their typical activities. Saliva samples were collected before breakfast, lunch, dinner, and bedtime. On the experimental day, the prelunch sample collection occurred 30 and 90 minutes after the Social Stressor task. Compared with children's norms, the combined group of males and females with fra X had significantly higher cortisol levels in the prelunch and the prebedtime samples for the routine days. Comparisons between the two fra X groups for the experimental day revealed similar diurnal patterns for cortisol level. However, compared with females with fra X, males with fra X had significantly higher cortisol levels at two points during the day: 30 minutes after the social stressor and at bedtime. These preliminary data suggest that individuals with fra X have abnormal HPA function. Understanding the relations among HPA dysfunction, abnormalities in brain structure and/or function, and maladaptive behavior and cognition in fra X could inform the design of early interventions using pharmacological or environmental measures designed to normalize neuroendocrine function.

    View details for Web of Science ID 000088913700004

    View details for PubMedID 10972251

  • Morphological alteration of temporal lobe gray matter in dyslexia: An MRI study JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Eliez, S., Rumsey, J. M., Giedd, J. N., Schmitt, J. E., Patwardhan, A. J., Reiss, A. L. 2000; 41 (5): 637-644

    Abstract

    Functional imaging studies of developmental dyslexia have reported reduced task-related neural activity in the temporal and inferior parietal cortices. To examine the possible contribution of subtle anatomic deviations to these reductions, volumes were measured for the major lobes of the brain, the subcortical nuclei, cerebellum, and lateral ventricles on magnetic resonance imaging (MRI) scans from 16 right-handed dyslexic men, ages 18 to 40, and 14 matched controls, most of whom had previously undergone PET imaging. A specific decrease in tissue volume was localized to the temporal lobes and was particularly prominent on the left (p < .01). An analysis of tissue composition revealed that this reduction was primarily attributable to decreased gray matter within the left temporal lobe (p < .002). Further segmentation of the temporal lobe showed that this reduction was not confined to the superior temporal gyrus, the primary location of primary auditory cortex. Reductions of temporal lobe gray matter may reflect a regional decrease in neuronal number or neuropil, which in turn may result in reading impairment.

    View details for Web of Science ID 000088318300010

    View details for PubMedID 10946755

  • Brain morphology in Klinefelter syndrome - Extra X chromosome and testosterone supplementation NEUROLOGY Patwardhan, A. J., Eliez, S., Bender, B., Linden, M. G., Reiss, A. L. 2000; 54 (12): 2218-2223

    Abstract

    This study focuses on variation in brain morphology associated with supernumerary X chromosome and Klinefelter syndrome (KS). Using an unselected birth cohort of KS subjects and high-resolution MRI, the authors investigated the neuroanatomic consequences of the 47,XXY karyotype in the presence and absence of exogenous testosterone supplementation.Regional brain volumes were measured in 10 subjects with KS and 10 age-matched control men. Five of the KS subjects had received testosterone supplementation since puberty (KS+T) and five had not (KS-T).KS subjects showed significant (p < 0.01) reduction in left temporal lobe gray matter volumes compared with normal control subjects. Differences in left temporal gray volumes were also significant between the KS+T and KS-T groups (p < 0.01). Verbal fluency scores were significantly different between the KS+T and KS-T groups as well.Supernumerary X chromosome material in men is associated with a reduction in left temporal lobe gray matter, a finding that is consistent with the verbal and language deficits associated with KS. Also, relative preservation of gray matter in the left temporal region is associated with exposure to exogenous androgen during development. A history of testosterone supplementation also appears to be associated with increased verbal fluency scores in KS patients.

    View details for Web of Science ID 000087804600007

    View details for PubMedID 10881243

  • Functional optimization of arithmetic processing in perfect performers COGNITIVE BRAIN RESEARCH Menon, V., Rivera, S. M., White, C. D., Eliez, S., Glover, G. H., Reiss, A. L. 2000; 9 (3): 343-345

    Abstract

    Lesion and imaging studies to date have not clarified which sub-regions of the parietal lobe are specialized for arithmetic processing, and which perform supporting functions. We used functional magnetic resonance imaging to investigate parietal lobe function during arithmetic processing. Functional optimization was examined by analyzing regional differences in brain activation between perfect (100% accuracy) and imperfect performers. Perfect performers had significantly less activation only in the left angular gyrus, a finding that may be associated with skill mastery and long-term practice effects. The present results provide the first direct evidence of localized functional optimization for arithmetic processing in the human brain.

    View details for Web of Science ID 000087193400013

    View details for PubMedID 10808145

  • Children and adolescents with velocardiofacial syndrome: A volumetric MRI study AMERICAN JOURNAL OF PSYCHIATRY Eliez, S., Schmitt, J. E., White, C. D., Reiss, A. L. 2000; 157 (3): 409-415

    Abstract

    Velocardiofacial syndrome is a common genetic condition often accompanied by mild cognitive impairment. Children and adolescents with velocardiofacial syndrome also are at greater risk for developing serious neuropsychiatric disorders in adulthood, particularly schizophrenia-like disorders. The purpose of this preliminary study was to 1) elucidate through brain imaging the neurobiological basis of cognitive and neuropsychiatric problems in velocardiofacial syndrome, and 2) consider the association between variations in neuroanatomy in velocardiofacial syndrome subjects and the associated neurobehavioral phenotype.Fifteen children and adolescents with velocardiofacial syndrome were matched by age and gender with 15 comparison subjects. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of specified brain tissues and regions. Rater-blind morphometric analyses were conducted to examine tissue volumes of the four lobes and the cerebellum.Total brain volume was approximately 11% smaller in the children with velocardiofacial syndrome. Gray matter volume was reduced to a lesser extent (7.5%) than white matter volume (16.3%). Multivariate analyses of variance indicated a distinct pattern of regional morphological variation among the children with velocardiofacial syndrome. Specifically, frontal lobe tissue tended to be enlarged relative to the overall reduction in brain volume. Normal symmetry of parietal lobe tissue observed in the comparison group was not evident in the velocardiofacial syndrome group. This loss of symmetry was attributable to a significant reduction of gray matter in the left parietal lobe.Aberrant brain morphology is associated with velocardiofacial syndrome. These changes are potentially related to the language and learning deficits associated with the syndrome and may provide clues about neurodevelopmental pathways associated with schizophrenia.

    View details for Web of Science ID 000085731200014

    View details for PubMedID 10698817

  • Generics of childhood disorders: XI. Fragile X syndrome JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Eliez, S., Reiss, A. L. 2000; 39 (2): 264-266

    View details for Web of Science ID 000085031900028

    View details for PubMedID 10673840

  • Survey of the fragile X syndrome CGG repeat and the short-tendem-repeat and single-nucleotide-polymorphism haplotypes in an African American population AMERICAN JOURNAL OF HUMAN GENETICS Crawford, D. C., Schwartz, C. E., Meadows, K. L., Newman, J. L., Taft, L. F., Gunter, C., Brown, W. T., Carpenter, N. J., Howard-Peebles, P. N., Monaghan, K. G., Nolin, S. L., Reiss, A. L., Feldman, G. L., Rohlfs, E. M., WARREN, S. T., Sherman, S. L. 2000; 66 (2): 480-493

    Abstract

    Previous studies have shown that specific short-tandem-repeat (STR) and single-nucleotide-polymorphism (SNP)-based haplotypes within and among unaffected and fragile X white populations are found to be associated with specific CGG-repeat patterns. It has been hypothesized that these associations result from different mutational mechanisms, possibly influenced by the CGG structure and/or cis-acting factors. Alternatively, haplotype associations may result from the long mutational history of increasing instability. To understand the basis of the mutational process, we examined the CGG-repeat size, three flanking STR markers (DXS548-FRAXAC1-FRAXAC2), and one SNP (ATL1) spanning 150 kb around the CGG repeat in unaffected (n=637) and fragile X (n=63) African American populations and compared them with unaffected (n=721) and fragile X (n=102) white populations. Several important differences were found between the two ethnic groups. First, in contrast to that seen in the white population, no associations were observed among the African American intermediate or "predisposed" alleles (41-60 repeats). Second, two previously undescribed haplotypes accounted for the majority of the African American fragile X population. Third, a putative "protective" haplotype was not found among African Americans, whereas it was found among whites. Fourth, in contrast to that seen in whites, the SNP ATL1 was in linkage equilibrium among African Americans, and it did not add new information to the STR haplotypes. These data indicate that the STR- and SNP-based haplotype associations identified in whites probably reflect the mutational history of the expansion, rather than a mutational mechanism or pathway.

    View details for Web of Science ID 000088373100015

    View details for PubMedID 10677308

  • Neuroanatomy of Williams syndrome: A high-resolution MRI study JOURNAL OF COGNITIVE NEUROSCIENCE Reiss, A. L., Eliez, S., Schmitt, J. E., Straus, E., Lai, Z., Jones, W., Bellugi, U. 2000; 12: 65-73

    Abstract

    Williams syndrome (WMS), a genetic condition resulting from a contiguous deletion on the long arm of chromosome 7, is associated with a relatively consistent profile of neurocognitive and neurobehavioral features. The distinctiveness and regularity of the profile of learning and behavioral characteristics in this genetic condition suggests that underlying neurobiological correlates may be identifiable. In this initial study, we report findings derived from a high-resolution neuroimaging study of 14 young adult subjects with WMS and an individually matched normal control group. Compared to controls, subjects with WMS were noted to have decreased overall brain and cerebral volumes, relative preservation of cerebellar and superior temporal gyrus (STG) volumes, and disproportionate volume reduction of the brainstem. Analyses also suggested that the pattern of cerebral lobe proportions in WMS may be altered compared to normal controls with a greater ratio of frontal to posterior (parietal+occipital) tissue. Assessment of tissue composition indicated that, relative to controls, individuals with WMS have relative preservation of cerebral gray matter volume and disproportionate reduction in cerebral white matter volume. However, within the cerebral gray matter tissue compartment, the right occipital lobe was noted to have excess volume loss. Combined with our growing knowledge of the function of genes in the commonly deleted region for WMS, more detailed information regarding the structure and function of the WMS brain will provide a unique opportunity for elucidating meaningful correlations amongst genetic, neurobiological, and neurobehavioral factors in humans.

    View details for Web of Science ID 000087725700005

    View details for PubMedID 10953234

  • Brain imaging in neurogenetic conditions: Realizing the potential of behavioral neurogenetics research MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Reiss, A. L., Eliez, S., Schmitt, J. E., Patwardhan, A., Haberecht, M. 2000; 6 (3): 186-197

    Abstract

    Behavioral neurogenetics research is a new method of scientific inquiry that focuses on investigation of neurodevelopmental dysfunction associated with specific genetic conditions. This research method provides a powerful tool for scientific inquiry into human gene-brain-behavior linkages that complements more traditional research approaches. In particular, the use of specific genetic conditions as models of common behavioral and cognitive disorders occurring in the general population can reveal insights into neurodevelopmental pathways that might otherwise be obscured or diluted when investigating more heterogeneous, behaviorally defined subject groups. In this paper, we review five genetic conditions that commonly give rise to identifiable neurodevelopmental and neuropsychiatric disability in children: fragile X syndrome, velo-cardio-facial syndrome, Williams syndrome, Turner syndrome, and Klinefelter syndrome. While emphasis is placed on describing the brain morphology associated with these conditions as revealed by neuroimaging studies, we also include information pertaining to molecular genetic, postmortem, and neurobehavioral investigations to illustrate how behavioral neurogenetics research can contribute to an improved understanding of brain disorders in childhood.

    View details for Web of Science ID 000089075600006

    View details for PubMedID 10982496

  • Automated Talairach atlas-based parcellation and measurement of cerebral lobes in children PSYCHIATRY RESEARCH-NEUROIMAGING Kates, W. R., Warsofsky, I. S., Patwardhan, A., Abrams, M. T., Liu, A. M., Naidu, S., Kaufmann, W. E., Reiss, A. L. 1999; 91 (1): 11-30

    Abstract

    This study applied a Talairach-based automated parcellation method, originally proposed for adults, to the measurement of lobar brain regions in pediatric study groups. Manual measures of lobar brain regions in a sample of 15 healthy boys, girls and adults were used initially to revise the original Talairach-based grid to increase its applicability to pediatric brains. The applicability of the revised Talairach grid was then tested on an independent sample of five girls with Rett syndrome. As Tables 3 and 4 in the text demonstrate, sensitivity, specificity and positive predictive values either remained unchanged or increased as a result of revising the sectors to fit the brains of children. High levels of sensitivity and specificity were achieved for all revised Talairach-based calculations in relation to the manual measures. Both positive predictive values and intraclass correlations between volumetric measures produced by the revised automated and manual methods varied with the relative size of the brain region. Values were relatively low for smaller structures such as the brainstem and subcortical region, and high for lobar regions. These results suggest that the automated Talairach atlas-based parcellation method can produce sensitive and specific volumetric measures of lobar brain regions in both normal children and children with brain disorders. Accordingly, the method holds much promise for facilitating quantitative pediatric neuroimaging research.

    View details for Web of Science ID 000082458000002

    View details for PubMedID 10496689

  • Molecular and cellular genetics of fragile X syndrome AMERICAN JOURNAL OF MEDICAL GENETICS Kaufmann, W. E., Reiss, A. L. 1999; 88 (1): 11-24

    View details for Web of Science ID 000078397400003

    View details for PubMedID 10050961

  • Normal Variation in Size of the FMR2next term Gene Is Not Associated With Variation In Intellectual Performance Intelligence Mazzocco, M., Reiss, AL 1999; 27 (2): 175-182
  • FMR1 gene expression in olfactory neuroblasts from two males with fragile X syndrome AMERICAN JOURNAL OF MEDICAL GENETICS Abrams, M. T., Kaufmann, W. E., Rousseau, F., Oostra, B. A., Wolozin, B., Taylor, C. V., Lishaa, N., Morel, M. L., Hoogeveen, A., Reiss, A. L. 1999; 82 (1): 25-30

    Abstract

    The fragile X mental retardation 1 gene (FMR1) mutation is strongly correlated with specific and marked neurobehavioral and neuroanatomical abnormalities. The protein product, FMRP, is highly expressed in neurons of the normal mammalian brain, and absent or in low levels in leukocytes from individuals with fragile X (FraX)-associated mental impairment. Inferences which arise from these findings are that FMRP has a critical role in the development and functioning of the brain, and that leukocyte-derived molecular assessments provide a good indicator of FMR1 expression in that organ. This latter conclusion appears true in most cases even though the typical FMR1 mutation is an unstable triplet repeat expansion which demonstrates somatic heterogeneity within and across tissues. Blood to brain correspondence in FraX patients has only rarely been confirmed by the direct study of human brain specimens and, to our knowledge, it has never been studied in living individuals with the FMR1 mutation. In this report, we describe the FMR1 patterns in olfactory neuroblasts (ON) from two living brothers with expansion mutations in their leukocytes who are mentally retarded and autistic. ON were chosen for study because they are accessible neurons closely linked to the brain. In both subjects, the ON genotype was highly, but not perfectly, consistent with that observed in leukocytes. Protein phenotypes across tissues were completely consistent showing the absence of FMRP-immunoreactivity (-ir). These results augment the limited amount of direct evidence which indicates that FMR1 mutation patterns in leukocytes are a good, albeit potentially fallible, reflection of such patterns in the brain. This report further demonstrates the feasibility of using ON samples to evaluate the FMR1 mutation in humans in vivo.

    View details for Web of Science ID 000078009200005

    View details for PubMedID 9916838

  • Children's Participation in Genetic Prevalence Research: Influences on Enrollment and Reports of Parent Satisfaction Journal of Applied Social Psychology Mazzocco, M., Myers GF, Harum K, Reiss AL 1999; 29 (11): 2308-2327
  • Social functioning among girls with fragile X or Turner syndrome and their sisters JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS MAZZOCCO, M. M., Baumgardner, T., Freund, L. S., Reiss, A. L. 1998; 28 (6): 509-517

    Abstract

    Social behaviors among two genetically homogeneous groups--girls with fragile X (fraX) or Turner syndrome (TS)--were examined to address the role of family environment versus biological determinants of social dysfunction in girls with these disorders. Using a sibling pair design, girls with fraX or TS were compared with their own sisters on measures of IQ and social functioning. The 8 girls with fraX and the 9 girls with TS had lower FSIQ scores and higher ratings of social and attention problems relative to their own sisters. Girls with fraX also had higher ratings of withdrawn behaviors, relative to their own sisters. The unaffected sisters were not rated as demonstrating any difficulties in these areas, relative to controls. Correlations between problem ratings and FSIQ were not statistically significant. Although these preliminary findings do not indicate a lack of familial impact on social development in girls with either disorder, the results provide preliminary evidence that social dysfunction reported for girls with fraX or TS cannot be attributed solely, nor primarily, to global aspects of the family environment.

    View details for Web of Science ID 000078364400006

    View details for PubMedID 9932237

  • Autism: The point of view from fragile X studies JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Feinstein, C., Reiss, A. L. 1998; 28 (5): 393-405

    Abstract

    The relationship between the fragile X syndrome (FXS) and autism is reviewed. Shortly after the FXS was first described, it was noted that certain behaviors commonly found in afflicted individuals resemble certain features of autism. Research concerning a possible relationship between these conditions is summarized. The outcome of this research indicates that FXS is not a common cause of autism, although the number of individuals with FXS who meet diagnostic criteria for autism is higher than can be accounted for by chance. The major focus of this paper highlights that FXS is a well-defined neurogenetic disease that includes a cognitive behavioral phenotype, and has both a known biological cause and an increasing well-delineated pathogenesis. Autism is a behaviorally defined syndrome whose syndromic boundaries and biological causes are not known. These profound differences complicate comparisons and causal discussions. However, the behavioral neurogenetic information available about FXS suggests certain pathways for future research directed at elucidating the syndrome of autism.

    View details for Web of Science ID 000076763600004

    View details for PubMedID 9813775

  • Evaluation of cerebellar size in attention-deficit hyperactivity disorder JOURNAL OF CHILD NEUROLOGY Mostofsky, S. H., Reiss, A. L., Lockhart, P., Denckla, M. B. 1998; 13 (9): 434-439

    Abstract

    Evidence from animal and human research suggests that the cerebellum may play a role in cognition. This includes domains of executive function that are normally attributed to the prefrontal cortex and are typically deficient in individuals with attention-deficit hyperactivity disorder (ADHD). To investigate cerebellar structure in ADHD, magnetic resonance imaging morphometry was used to measure the area of the cerebellar vermis in 12 males with ADHD and 23 male controls matched for age and Wechsler Full-Scale IQ. Analyses were conducted to evaluate group differences, as well as differences between matched pairs of subjects with ADHD and those without ADHD. All measurements were corrected for overall brain size. Both analyses revealed that the size of the posterior vermis was significantly decreased in males with ADHD (P < .05 in both analyses), and that within the posterior vermis, the inferior posterior lobe (lobules VIII-X) was involved in this reduction (P < .05 for group analysis, P < .005 for matched pair analysis), while the superior posterior lobe (lobules VI/VII) was not involved in the reduction. The finding of abnormal inferior posterior vermal size suggests that dysfunction within this region of the cerebellum may underlie clinical deficits seen in individuals with ADHD.

    View details for Web of Science ID 000075512900004

    View details for PubMedID 9733289

  • Neuroanatomical and neurocognitive differences in a pair of monozygous twins discordant for strictly defined autism ANNALS OF NEUROLOGY Kates, W. R., Mostofsky, S. H., Zimmerman, A. W., MAZZOCCO, M. M., Landa, R., Warsofsky, I. S., Kaufmann, W. E., Reiss, A. L. 1998; 43 (6): 782-791

    Abstract

    In this study, we investigated the neuroanatomical similarities and differences between a pair of monozygotic, 7.5-year-old twin boys discordant for strictly defined autism, to identify neuroanatomical pathways that are impaired in individuals with autism. Although the unaffected twin did not fulfill the traditional diagnostic criteria for autism, he displayed constrictions in social interaction and play that were consistent with the broader phenotype for autism that has been described in nonautistic co-twins. Magnetic resonance imaging scans were obtained for each brother and compared with the scans of 5 age- and sex-matched unaffected peers. Quantitative analysis of brain anatomy revealed that the affected twin had markedly smaller caudate, amygdaloid, and hippocampal volumes, and smaller cerebellar vermis lobules VI and VII, in comparison with his brother. Both twins evidenced disproportionately reduced volumes of the superior temporal gyrus and the frontal lobe relative to the comparison sample. The results suggest the dysfunction of two separate but overlapping neuroanatomical pathways, ie, one subcortical network differentiating the twins from each other that may underlie the traditional neurobehavioral phenotype for strictly defined autism, and a second cortical network differentiating the twins from the comparison sample that may lead to the broader phenotype for autism.

    View details for Web of Science ID 000074023800012

    View details for PubMedID 9629848

  • Edge complexity and partial volume effects JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Links, J. M., Beach, L. S., Subramaniam, B., Rubin, M. A., Hennessey, J. G., Reiss, A. L. 1998; 22 (3): 450-458

    Abstract

    The accuracy of MR brain image segmentation is limited by so-called partial volume effects. We hypothesized that "edge complexity" (i.e., tissue class interface border complexity) significantly influences the magnitude of such effects.To investigate partial volume effects and provide a vehicle for validation of segmentation algorithm accuracy in brain MRI. We developed a computer simulation, the "gigabrain." The simulation is based on interpolated (supersampled) data from actual MR studies. The voxels are assigned to one of five compartments (gray matter, white matter, CSF, fat, or "background"), the compartment interfaces are "jittered" to add high frequency "signal" or "edge complexity," and the voxels are populated with appropriate values determined from human data, low pass filtered (based on the MR scanner's point spread function), and subsampled back to the sampling and voxel size of the original MR data set.In comparison studies with actual phantoms and human MR data, our simulation approach was able to produce images whose appearance and quantitative values were comparable with the actual data, but only when edge complexity was added to the original MR data.Edge complexity is a significant source of partial volume effects. MR simulations must include edge complexity to adequately test segmentation algorithms.

    View details for Web of Science ID 000073590700019

    View details for PubMedID 9606389

  • The prevalence of the FMR1 and FMR2 mutations among preschool children with language delay JOURNAL OF PEDIATRICS MAZZOCCO, M. M., Myers, G. F., Hamner, J. L., Panoscha, R., Shapiro, B. K., Reiss, A. L. 1998; 132 (5): 795-801

    Abstract

    We examined the prevalence of the fragile X mental retardation (FMR1) full mutation and fragile X E mutation (FMR2) among preschoolers evaluated for language delay. A total of 534 preschoolers recruited from a Developmental Pediatric or Speech and Language Disorders clinic were tested with Southern blot and polymerase chain reaction DNA analyses; 3 were found to have the FMR1 full mutation. None of the 534 children tested positive for the FMR2 full mutation; however, 3 children had unusually small FMR2 alleles suggestive of FMR2 deletions. Screening for fragile X among language-delayed preschoolers is warranted, particularly when there is a family history of mental retardation, but regardless of sex or the presence of behavioral or physical features associated with the fragile X phenotype. The potential benefit of screening for FMR2 alterations is an unexpected implication of the study and is worthy of continued exploration.

    View details for Web of Science ID 000073610400012

    View details for PubMedID 9602188

  • Reliability and validity of an algorithm for fuzzy tissue segmentation of MRI JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Reiss, A. L., Hennessey, J. G., Rubin, M., Beach, L., Abrams, M. T., Warsofsky, I. S., Liu, A. M., Links, J. M. 1998; 22 (3): 471-479

    Abstract

    A new multistep, volumetric-based tissue segmentation algorithm that results in fuzzy (or probabilistic) voxel description is described. This algorithm is designed to accurately segment gray matter, white matter, and CSF and can be applied to both single channel high resolution and multispectral (multiecho) MR images.The reliability and validity of this method are evaluated by assessing (a) the stability of the algorithm across time, rater, and pulse sequence; (b) the accuracy of the method when applied to both real and synthetic image datasets; and (c) differences in specific tissue volumes between individuals with a specific genetic condition (fragile X syndrome) and normal control subjects.The algorithm was found to have high reliability, accuracy, and validity. The finding of increased caudate gray matter volume associated with the fragile X syndrome is replicated in this sample.Since this segmentation approach incorporates "fuzzy" or probabilistic methods, it has the potential to more accurately address partial volume effects, anatomical variation within "pure" tissue compartments, and more subtle changes in tissue volumes as a result of disease and treatment. The method is a component of software that is available in the public domain and has been implemented on an inexpensive personal computer thus offering an attractive and promising method for determining the status and progression of both normal development and pathology of the CNS.

    View details for Web of Science ID 000073590700021

    View details for PubMedID 9606391

  • Decreased cerebellar posterior vermis size in fragile X syndrome - Correlation with neurocognitive performance NEUROLOGY Mostofsky, S. H., MAZZOCCO, M. M., Aakalu, G., Warsofsky, I. S., Denckla, M. B., Reiss, A. L. 1998; 50 (1): 121-130

    Abstract

    We examined whether posterior vermis size is smaller in individuals with fragile X syndrome (fra X) than in control subjects and whether this decreased size is associated with cognitive performance. Cognitive and behavioral dysfunctions have been identified in fra X; however, underlying neuropathogenic mechanisms remain unclear. MRI was used to investigate the posterior fossa in 32 males with fra X, 28 males with other causes of cognitive disability (CD), and 38 males with normal development (ND) as well as and in 37 females with fra X and 53 female control subjects. Among females with fra X, neurocognitive correlates of posterior vermis size were examined. Posterior vermis size (cross-sectional area) in males with fra X was significantly smaller compared with CD and ND groups, particularly when corrected for intracranial area. Posterior vermis size corrected for intracranial area was significantly smaller in females with fra X compared with control subjects. Compared with males with fra X and non-fra X control subjects, posterior vermis size in females with fra X was intermediate. After statistically removing the effect of mean parental IQ, posterior vermis size predicted a significant proportion of the variance (10 to 23%) of performance on full-scale, verbal, and performance IQ; block design; categories achieved on the Wisconsin Card Sorting Test; and the Rey inventory score. The size of the posterior vermis is significantly decreased in fra X, more so in males than in females. In females with fra X, posterior vermis size predicts performance on selected cognitive measures.

    View details for Web of Science ID 000071486900024

    View details for PubMedID 9443468

  • Effective Procedures for Conducting Genetic Prevalence Studies With Children Journal of Applied Social Psychology Mazzocco, M., Sonna NL, Shapiro BK, Pinit A, Reiss AL 1998; 28 (1): 23-40
  • Effective procedures for conducting genetic prevalence studies with children JOURNAL OF APPLIED SOCIAL PSYCHOLOGY Mazzocco, M. M., Sonna, N. L., Shapiro, B. K., Pinit, A., Reiss, A. L. 1998; 28 (1): 23-40
  • The FMR1 and FMR2 mutations are not common etiologies of academic difficulty among school-age children JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Mazzocco, M. M., Sonna, N. L., Teisl, J. T., Pinit, A., Shapiro, B. K., Shah, N., Reiss, A. L. 1997; 18 (6): 392-398

    Abstract

    The prevalence of the fragile X mental retardation (FMR) 1 and FMR2 full mutations (fM) was examined among 1014 school-age children with academic difficulties but without mental retardation. Both Southern blot and polymerase chain reaction analyses for FMR1 and FMR2 were performed on samples obtained from these children. No fM genes were found, and one FMR1 premutation was identified. The distribution of allele sizes for both genes was comparable to those reported for other clinical and normal population samples. These results suggest that neither the FMR1 nor the FMR2 mutation is a common etiology of academic failure among school-age children without mental retardation and that the prevalence of the FMR1 premutation is no more frequent in children with academic failure than it is in the general population.

    View details for Web of Science ID 000071027400004

    View details for PubMedID 9431501

  • Application of an automated parcellation method to the analysis of pediatric brain volumes PSYCHIATRY RESEARCH-NEUROIMAGING Kaplan, D. M., Liu, A. M., Abrams, M. T., Warsofsky, I. S., Kates, W. R., White, C. D., Kaufmann, W. E., Reiss, A. L. 1997; 76 (1): 15-27

    Abstract

    New techniques in quantitative imaging are needed to accelerate understanding of brain development and function in children. In this study we evaluate the reliability and validity of an automated parcellation method for the measurement of large and small brain regions in normal and developmentally disabled children. We utilized an adaptation of the Talairach atlas to semi-automatically quantify brain volumes from 10 children with fragile X syndrome, 10 age- and gender-matched controls and 10 adult controls comparing them to 'gold standard' manually delineated regions. Excellent sensitivity, specificity, intra-class correlation and positive predictive value were achieved for large structures although results were less satisfactory for smaller structures, illustrating the limits of resolution of the method. Statistically significant differences in regional brain volumes were shown between males and females, children and adults, and individuals with fragile X and matched controls. This study demonstrates an automated method which rapidly and accurately quantifies large neuroanatomical structures, but not smaller structures. This method is sufficiently accurate to demonstrate some known anatomical differences in individuals with fragile X; the results suggest that this method could be applied to the assessment of brain volume in other neurodevelopmental disabilities.

    View details for Web of Science ID 000071897300002

    View details for PubMedID 9498306

  • Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome PSYCHIATRY RESEARCH-NEUROIMAGING Kates, W. R., Abrams, M. T., Kaufmann, W. E., Breiter, S. N., Reiss, A. L. 1997; 75 (1): 31-48

    Abstract

    Evidence from numerous structural magnetic resonance imaging (MRI) studies has converged to implicate mesial temporal lobe structures in the pathophysiology of several developmental and psychiatric disorders. Efforts to integrate the results of these studies are challenged, however, by the lack of consistency, detail and precision in published protocols for the manual measurement of the amygdala and hippocampus. In this study, we describe a highly detailed, standardized protocol for measuring the amygdala and the hippocampus. Within the context of this protocol, we tested the inter- and intra-rater reliability of two frequently cited methods for normalizing the anatomical position of the amygdala and hippocampus prior to measurement. One method consisted of creating a coronal data set in which images are rotated in a plane perpendicular to the long axis of the hippocampus. The second method consisted of creating a coronal data set in which images are rotated in a plane perpendicular to the axis connecting the anterior and posterior commissures. Inter- and intra-rater reliability coefficients (using the intraclass correlation) ranged from 0.80 to 0.98, indicating that both methods for positional normalization are highly reliable. In addition, we tested the validity of each method by comparing the temporal lobe anatomy of children with fragile X syndrome to a group of unaffected children matched by age and gender. We found that hippocampal volumes in children with fragile X were significantly increased when either rotational method was used. These results replicated previous findings, suggesting that either method can be validly applied to neuronanatomic studies of pediatric populations.

    View details for Web of Science ID A1997XT98400004

    View details for PubMedID 9287372

  • A Tourette-like syndrome following cardiopulmonary bypass and hypothermia: MRI volumetric measurements MOVEMENT DISORDERS Singer, H. S., DELACRUZ, P. S., Abrams, M. T., BEAN, S. C., Reiss, A. L. 1997; 12 (4): 588-592

    Abstract

    We present the case of an adolescent boy who developed a variety of simple and complex motor and vocal tics (Tourette-like syndrome), along with inattentiveness and obsessive-compulsive behaviors after cardiac surgery with cardiopulmonary bypass and profound hypothermia. A single photon emission computed tomography study 2 months after surgery showed reduced uptake in the left hemisphere and 2 years later a perfusion defect in the basal ganglia. Serial magnetic resonance imaging (MRI) studies were normal. Volumetric MRI studies were obtained 4 years after surgery and compared with published values for normal individuals and children with Tourette syndrome (TS), including subsets matched for age, sex, and handedness. Measurement of basal ganglia structures showed a right-dominant asymmetry of the caudate and putamen, in part similar to findings previously reported in patients with TS. Other volumetric abnormalities included a > 2-SD reduction of cortical gray matter, a small decrease of total cerebral volume, and increase in cerebral white matter. Although a variety of neurological problems may occur after cardiopulmonary bypass, to our knowledge this case represents the first report of a chronic tic disorder following cardiac surgery with cardiopulmonary bypass and hypothermia.

    View details for Web of Science ID A1997XM20000016

    View details for PubMedID 9251079

  • Cognitive, behavioral, and neuroanatomical assessment of two unrelated male children expressing FRAXE AMERICAN JOURNAL OF MEDICAL GENETICS MAZZOCCO, M. M., Knight, S. J., Abrams, M. T., Doheny, K. F., Baumgardner, T. L., Freund, L. S., Davies, K. E., Reiss, A. L. 1997; 74 (1): 73-81

    Abstract

    Standardized cognitive, behavioral, and neuroanatomical data are presented on 2 unrelated boys with the FRAXE (FMR2) GCC expansion mutation. In the context of normal IQ, both boys had a history of developmental delay, including significant problems with communication, attention, and overactivity. Additionally, one child was diagnosed with autistic disorder. Data from these 2 cases are compared to analogous information from previous reports about individuals with the FRAXE or FRAXA (FMR1) mutation. These comparisons support the idea that FRAXE is associated with nonspecific developmental delay and possibly high-functioning autism.

    View details for Web of Science ID A1997WG27300016

    View details for PubMedID 9034011

  • Neuroanatomy in Rett syndrome: Cerebral cortex and posterior fossa NEUROLOGY Subramaniam, B., Naidu, S., Reiss, A. L. 1997; 48 (2): 399-407

    Abstract

    Rett syndrome (RS), a neurodevelopmental disorder of unknown etiology occurring almost exclusively in females, is characterized by autistic-like behavior, motor dysfunction, loss of language skills, dementia, and microcephaly. This study is a follow-up and extension of a previously reported neuroimaging study of patients with RS. We replicated previously reported findings with a larger patient population, and the volumetric MRI analysis was extended to include an analysis of neuroanatomy of the posterior fossa. Twenty girls with RS were compared with individually age- and gender-matched normal controls. Patients with RS showed global reduction in gray- and white-matter volumes. The prefrontal, posterior-frontal, and anterior-temporal regions showed the largest bilateral decrease in gray-matter volume, whereas white-matter volume was uniformly reduced throughout the brain. We found confirmation for the preferential reduction in caudate nucleus volume. However, we observed no preferential reduction in midbrain volume despite a preferential reduction in the midsagittal area of this region. We also present an individual case comparison between monozygotic twins discordant for RS.

    View details for Web of Science ID A1997WH53500020

    View details for PubMedID 9040729

  • The name assigned to the document by the author. This field may also contain sub-titles, series names, and report numbers. Neurogenetic and Neurodevelopmental Pathways to Learning Disabilities. Learning Disabilities Mazzocco, M., Denckla MB, Singer H, Scanlon DM, Vellutino FR, Reiss AL 1997; 8 (1): 31-43
  • Normal variation in size of the FMR1 gene is not associated with variation in intellectual performance Intelligence Mazzocco, M., Reiss, AL 1997; 24 (2): 355-366
  • Brain development, gender and IQ in children - A volumetric imaging study BRAIN Reiss, A. L., Abrams, M. T., Singer, H. S., Ross, J. L., Denckla, M. B. 1996; 119: 1763-1774

    Abstract

    Normal brain development during childhood is a complex and dynamic process for which detailed scientific information is lacking. MRI techniques, combined with methods for advanced image analysis, offer the potential to begin to construct a quantitative map of normal paediatric brain development in vivo. In this study we utilize volumetric analysis of high resolution brain images obtained from MRI to describe cerebral development and morphology in 85 normal children and adolescents ranging in age from 5 to 17 years. The results show that total cerebral volume is 10% larger in boys compared with girls. However, both boys and girls show little change in total cerebral volume after the age of 5 years. Increased cortical grey matter is the primary contributor to larger brain volume in boys, thus supporting the hypothesis that gender associated differences in brain size are related to differences in cortical neuronal density. Prominent, age-related changes in grey matter, white matter and CSF volumes are evident during childhood and appear to reflect ongoing maturation and remodelling of the CNS. Both boys and girls show a similar pattern of cerebral asymmetry; a rightward prominence of cortical and subcortical grey matter and a leftward prominence of CSF is observed. IQ is positively correlated with total cerebral volume in children, in particular, with the volume of cortical grey matter in the prefrontal region of the brain. Subcortical grey matter also contributes to the variance in IQ, although to a lesser extent than cortical grey volume. Quantitative knowledge of the developing human brain will play an increasingly greater role in improving sensitivity and specificity in the interpretation of brain abnormalities in patients within the clinical environment, as well as in groups of children with suspected brain dysfunction in the research setting.

    View details for Web of Science ID A1996VX51400030

    View details for PubMedID 8931596

  • Bupropion hydrochloride in attention deficit disorder with hyperactivity JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Conners, C. K., Casat, C. D., GUALTIERI, C. T., Weller, E., Reader, M., Reiss, A., Weller, R. A., Khayrallah, M., Ascher, J. 1996; 35 (10): 1314-1321

    Abstract

    This is a multisite, double-blind, placebo-controlled trial to determine the safety and efficacy of bupropion in the treatment of children with attention deficit disorder with hyperactivity (ADDH).In a four-center, double-blind comparison of bupropion (n = 72) and placebo (n = 37), children aged 6 to 12 years meeting DSM-III criteria for ADDH were randomized to receive bupropion 3 to 6 mg/kg per day or placebo, administered twice daily, at 7 A.M. and 7 P.M. Measures of efficacy included the Conners Parent and Teacher Questionnaires (93-item, 39-item, and 10 item), Clinical Global Impressions Scales of Severity and Improvement, the Sternberg Short-Term Memory Task, and the Continuous Performance Test. Screen and posttreatment physical examinations, electrocardiograms, electroencephalograms, and clinical laboratory evaluations were performed. Height, weight, and vital signs were measured and adverse experiences were assessed weekly.A significant treatment effect, apparent as early as day 3, was present for both conduct problems and hyperactivity on the Conners 10-item and 39-item teacher's checklist, and at day 28 for conduct problems and restless-impulsive behavior on the 93-item parent questionnaire. Findings were of smaller magnitude for parent ratings than teacher ratings. Significant treatment effects were present on both the Continuous Performance Test and memory retrieval test. Effect sizes of bupropion/placebo differences for teacher and parent ratings in this study were somewhat smaller than for standard stimulant drugs used to treat ADDH. Bupropion appeared to be well tolerated in most children. Dermatological reactions were twice as frequent in the drug group as the placebo group, with four reactions involving rash and urticaria that were serious enough to require discontinuation of medication.Bupropion may be a useful addition to available treatments for ADDH. Comparative trials with such standard drugs as methylphenidate are warranted to determine the relative clinical merits of bupropion.

    View details for Web of Science ID A1996VK05500018

    View details for PubMedID 8885585

  • Corpus callosum morphology in children with Tourette syndrome and attention deficit hyperactivity disorder NEUROLOGY Baumgardner, T. L., Singer, H. S., Denckla, M. B., Rubin, M. A., Abrams, M. T., COLLI, M. J., Reiss, A. L. 1996; 47 (2): 477-482

    Abstract

    The aim of this study was to investigate the morphology of the corpus callosum (CC) in Tourette syndrome (TS) and attention deficit hyperactivity disorder (ADHD) to determine whether these conditions affect distinct regional differences. Seventy-seven children and adolescents, aged 6 to 16 years, comprised the four research groups--16 patients with TS, 21 patients with TS plus ADHD, 13 patients with ADHD, and 27 unaffected control subjects. A semiautomated, computer-assisted procedure was used to measure the total area, five subregions, centerline length, perimeter, and bending angle of the CC. MRI data were analyzed using several statistical methods, primarily two-tailed analysis of variance to test the effects of TS and ADHD status, while controlling for the influence of age, gender, and total intracranial area (an estimate of brain size). TS was associated with significant increases in the area of four of five subdivisions, the total area, and the perimeter of the CC. ADHD was associated with a significant decrease in the area of the rostral body. There were no interactions between TS and ADHD factors. These findings suggest that the area of the CC is larger in children with TS, and that this difference is independent of age, handedness, intracranial area, and the diagnosis of ADHD. Our findings support hypotheses that the neurobiologic mechanisms in TS and ADHD involve frontal/subcortical circuits.

    View details for Web of Science ID A1996VC63400027

    View details for PubMedID 8757024

  • Differential response of psychotic and obsessive symptoms to risperidone in an adolescent JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY DrydenEdwards, R. C., Reiss, A. L. 1996; 6 (2): 139-145

    Abstract

    A 13-year-old boy with psychotic, depressive, and obsessive-compulsive symptoms initially presented with auditory and visual hallucinations and a lifetime of excessive worries about contamination. Family history was significant for schizophrenia and compulsive behavior. When treated with clomipramine 100 mg daily (plasma level 85 ng/mL), obsessive-compulsive symptoms but not the hallucinations improved significantly, and racing thoughts and grandiosity developed later. Haloperidol 0.5 mg daily reduced the psychotic symptoms but was poorly tolerated, and then trifluoperazine 3 mg daily was ineffective, so clomipramine was discontinued (without worsening of OCD symptoms). Trifluoperazine in combination with lithium 1500 mg daily (0.9 meq/L), and then with the addition of carbamazepine 250 mg daily (3.7 micrograms/mL), was only partially helpful. Dose reductions in any medication led to increased psychotic symptoms within days. Trifluoperazine was then replaced by risperidone 3 mg twice daily. Within 2 weeks of starting risperidone, psychotic symptoms ceased but the patient experienced an incapacitating exacerbation of obsessive-compulsive symptoms, experiencing the most severe symptoms in his illness. Sertraline 50 mg reduced the OCD symptoms only briefly. After 5 months on risperidone, risperidone and sertraline were discontinued, and the obsessive-compulsive symptoms significantly decreased within 2 weeks. These clinical observations suggest that even when risperidone has a therapeutic antipsychotic effect, it may exacerbate obsessive-compulsive symptoms in predisposed adolescents.

    View details for Web of Science ID A1996VD56200005

    View details for PubMedID 9231306

  • Trajectories and profiles of adaptive behavior in males with fragile X syndrome: Multicenter studies JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Dykens, E., Ort, S., Cohen, I., Finucane, B., Spiridigliozzi, G., Lachiewicz, A., Reiss, A., Freund, L., Hagerman, R., OCONNOR, R. 1996; 26 (3): 287-301

    Abstract

    We conducted two multicenter studies on adaptive trajectories and profiles in males with fragile X syndrome. Study 1 longitudinally assessed 29 males ages 1-20 years using age-equivalent scores from the Vineland Adaptive Behavior Scales. Fragile X boys ages 1-10 years showed significant gains in adaptive skills from first to second testing; males ages 11-20 years were stable in their adaptive development. Study 2 cross-sectionally examined 132 males ages 1-20 years. Significant age-related gains were found in boys ages 1-10, particularly in preschool children. Subjects ages 11-20 showed increased variability and nonsignificant relations between age and adaptive skills. Preliminary findings from 26 young adults with fragile X syndrome ages 21-40 years showed stable age-equivalent adaptive scores during these years. Relative strengths in daily living skills and weaknesses in communication were only evident among older subjects. Significant relations were found between adaptive behavior standard scores and IQ; these two scores also showed age-related declines that likely parallel one another. Findings are related to adaptive features in other genetic syndromes, and to directions for future adaptive behavior research.

    View details for Web of Science ID A1996UP76200002

    View details for PubMedID 8792261

  • Neuropsychological status of children with Tourette's syndrome with and without attention deficit hyperactivity disorder NEUROLOGY Schuerholz, L. J., Baumgardner, T. L., Singer, H. S., Reiss, A. L., Denckla, M. B. 1996; 46 (4): 958-965

    Abstract

    To determine the frequency of learning disabilities (LD) and describe the neuropsychological profile of children with Tourette's syndrome (TS) with and without attention deficit hyperactivity disorder (ADHD), we analyzed psychosocial, psychoeducational, and neuropsychological data from 65 children between the ages of 6 and 14 years selected from a larger study of LD. Three groups were formed: TS only, TS+ADHD, and TS +/- ADHD. The third group was composed of children whose ADHD status was not as strongly confirmed by the three different instruments used for ADHD diagnosis. From other (non-TS) research projects in the Center, a comparison group of 27 unaffected siblings who had no diagnosis of ADHD was formed. All children were unmedicated at the time of assessment and had the full set of data available for analysis. LDs were present in 23% of the total TS sample, but LD was not present in the TS-only group. All TS groups had scores at or below 1 SD from the mean on measures of choice reaction time, but the TS-only group was significantly poorer on a measure of executive function (letter word fluency). We discuss the implication of the finding in the TS-only group in terms of a slowing of linguistic productivity.

    View details for Web of Science ID A1996UG63500014

    View details for PubMedID 8780072

  • Basal ganglia volumes in children with attention-deficit hyperactivity disorder JOURNAL OF CHILD NEUROLOGY Aylward, E. H., Reiss, A. L., READER, M. J., Singer, H. S., Brown, J. E., Denckla, M. B. 1996; 11 (2): 112-115

    Abstract

    Previous research has demonstrated volume reduction of the left globus pallidus in children with the codiagnoses of Tourette syndrome and attention-deficit hyperactivity disorder (ADHD), in comparison with children who have Tourette syndrome alone and with normal controls. The purpose of this study was to determine whether children with ADHD alone also had volume reduction of the globus pallidus or other basal ganglia structures. Subjects were 10 boys with ADHD, 16 boys with Tourette syndrome and ADHD, and 11 normal control boys. Groups were matched for age. Boys with ADHD were individually matched for age, handedness, and IQ to 10 of the 16 boys with Tourette syndrome and ADHD. Volumes of caudate, putamen, and globus pallidus were measured and corrected for brain volume. The boys with ADHD had significantly smaller left globus pallidus volume and total globus pallidus volume (corrected for brain volume) than the normal controls. The Tourette syndrome plus ADHD group did not differ from the ADHD group on any of the measures. We conclude that small globus pallidus volume, particularly on the left side, is associated with ADHD.

    View details for Web of Science ID A1996UB13300008

    View details for PubMedID 8881987

  • Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1 AMERICAN JOURNAL OF MEDICAL GENETICS Denckla, M. B., Hofman, K., MAZZOCCO, M. M., Melhem, E., Reiss, A. L., Bryan, R. N., Harris, E. L., Lee, J., Cox, C. S., Schuerholz, L. J. 1996; 67 (1): 98-102

    Abstract

    To address the controversy regarding the relationship between cognitive impairment (lowering of IQ) and magnetic resonance imaging (MRI) characteristics (T2-weighted hyperintensities or unidentified bright objects [UBOs]) in children with neurofibromatosis-1 (NF-1), we used a pairwise NF-1/ sibling design; we set out to predict the lowering of IQ in each child with NF-1 as a discrepancy from the IQ of an unaffected sibling (D-SIQ). Our multiple regression model included the age of the child with NF-1, familial or sporadic nature of the NF-1, number of locations in the child's brain occupied by T2-weighted hyperintensities (UBOs), and the volumetric percentage of brain tissue occupied by T2-weighted hyperintensities (UBOs). Only the number of locations occupied by UBOs accounted for IQ lowering (D-SIQ) in children with NF-1 (42% of the variance in D-SIQ). This is the first report to confirm that a continuum of lowered IQs in NF-1-affected children exists in relation to the distribution of UBOs (range 0-7), not just presence (vs. absence) of any UBOs.

    View details for Web of Science ID A1996TY40300018

    View details for PubMedID 8678124

  • CONTRIBUTION OF THE FMR1 GENE MUTATION TO HUMAN INTELLECTUAL DYSFUNCTION NATURE GENETICS Reiss, A. L., Freund, L. S., Baumgardner, T. L., Abrams, M. T., Denckla, M. B. 1995; 11 (3): 331-334

    Abstract

    The degree to which genetic factors influence human intelligence remains a matter of some controversy. However, there is little doubt that single gene mutations can significantly alter brain development and function. For example, mutations affecting the FMR1 gene cause the fragile X syndrome, the most prevalent known inherited cause of intellectual dysfunction. The most common mutation occurring in the FMR1 locus involves expansion of a trinucleotide (CGG)n repeat sequence within the promoter region of the gene. Between 6 and 54 repeats are typically observed in individuals from the general population. When > or = 200 CGG repeats are present, the expanded repeat sequence and an adjacent CpG island are usually hypermethylated, Aa phenomenon associated with transcriptional silencing of the gene and commonly referred to as the FMR1 full mutation. The intermediate range of repeats (approximately 50 to 200 CGGs), referred to as the premutation, is characterized by the absence of hypermethylation within the promoter region and normal phenotype. Some individuals have a combination of methylated and unmethylated alleles of differing size and are referred to as having mosaic status. Most males with the FMR1 full mutation function in the mentally retarded range of intelligence; in contrast, females with the FMR1 full mutation show a broader range of intelligence, from mental retardation to normal IQ.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1995TC63900025

    View details for PubMedID 7581460

  • NEURODEVELOPMENTAL EFFECTS OF X-MONOSOMY - A VOLUMETRIC IMAGING STUDY ANNALS OF NEUROLOGY Reiss, A. L., MAZZOCCO, M. M., Greenlaw, R., Freund, L. S., Ross, J. L. 1995; 38 (5): 731-738

    Abstract

    Thirty girls with Turner syndrome (TuS) were compared with 30 individually age-matched controls on volumetric brain measures derived from magnetic resonance imaging and on measures of psychological functioning. As expected, girls with TuS performed more poorly on visual-spatial and intellectual measures relative to controls, and were rated by their parents as having more significant problems in attention and social behaviors. Although no group differences in overall cerebral or subcortical volumes were observed, the regional distribution of gray and white matter differed across groups in both right and left parietal regions. Differences in total tissue volume ratios were seen for both right and left parietal areas, but differences in individual gray and white matter ratios were seen exclusively in the right parietal regions. In general, girls with TuS had a smaller proportion of tissue (gray and white) within the right and left parietal regions, and a larger proportion of tissue within the right inferior parietal-occipital region relative to girls in the control group. These data suggest a potentially important role for X chromosome genes and/or sex steroids in the development and specialization of brain structure and function.

    View details for Web of Science ID A1995TE95500006

    View details for PubMedID 7486864

  • SPECIFICATION OF THE NEUROBEHAVIORAL PHENOTYPE IN MALES WITH FRAGILE-X SYNDROME PEDIATRICS Baumgardner, T. L., Reiss, A. L., Freund, L. S., Abrams, M. T. 1995; 95 (5): 744-752

    Abstract

    A controlled clinical study was designed to identify the neurobehavioral profile that is specific to males with fragile X syndrome.Thirty-one males with fragile X syndrome and 30 age and IQ-matched male controls were evaluated with instruments that assess multiple domains of adaptive functioning and problem behaviors. The Vineland Adaptive Behavior Scales and the Aberrant Behavior Checklist were selected for their dimensional scaling of behavioral ratings.Parent and Teacher versions of the Aberrant Behavior Checklist demonstrated a profile of behaviors specific to males with fragile X syndrome characterized by significantly higher levels of hyperactivity, stereotypic movements, and unusual speech. The Vineland Adaptive Behavior Scales revealed no fragile X-specific profile of adaptive skills development.The distinct pattern of aberrant behavior observed among males with fragile X emphasizes the importance of drawing subtype distinctions within the classification of individuals with mental retardation on the basis of underlying etiology. For clinical research, specifying the fragile X phenotype is a vital part in the effort to elucidate the neurodevelopmental pathways of normal behavior and psychopathology. Understanding the fragile X symptom pattern is essential for designing symptom-specific treatment interventions, as well as for research into the efficacy of interventions strategies.

    View details for Web of Science ID A1995QW47900023

    View details for PubMedID 7724315

  • NEURODEVELOPMENTAL EFFECTS OF THE FMR-1 FULL MUTATION IN HUMANS NATURE MEDICINE Reiss, A. L., Abrams, M. T., Greenlaw, R., Freund, L., Denckla, M. B. 1995; 1 (2): 159-167

    Abstract

    Brain dysfunction is the most important sequelae of the fragile X (FMR-1) mutation, the most common heritable cause of developmental disability. Using magnetic resonance imaging (MRI) and quantitative morphometry, we have compared the neuroanatomy of 51 individuals with an FMR-1 mutation with matched controls and showed that subjects with an FMR-1 mutation have increased volume of the caudate nucleus and, in males, the lateral ventricle. Both caudate and lateral ventricular volumes are correlated with IQ. Caudate volume is also correlated with the methylation status of the FMR-1 gene. Neuroanatomical differences between two monozygotic twins with an FMR-1 mutation who are discordant for mental retardation are localized to the cerebellum, lateral ventricles and subcortical nuclei. These findings suggest that the FMR-1 mutation causing the fragile X syndrome leads to observable changes in neuroanatomy that may be relevant to the neurodevelopmental disability and behavioural problems observed in affected individuals.

    View details for Web of Science ID A1995QX55800028

    View details for PubMedID 7585014

  • The neurobiology of fragile X syndrome Mental Retardation and Developmental Disabilities Research Reviews Abrams MT, Reiss AL 1995; 1: 269-275
  • Neuropsychological and Psychosocial Effects of the FMR-1 Full Mutation: Case Report of Monozygotic Twins Discordant for the Fragile X Syndrome Neuropsychology Mazzocco, M., Freund LS, Baumgardner TL, Forman F, Reiss AL 1995; 9 (4)
  • AN ANALYSIS OF 2 DISCREPANCY-BASED MODELS AND A PROCESSING-DEFICIT APPROACH IN IDENTIFYING LEARNING-DISABILITIES JOURNAL OF LEARNING DISABILITIES Schuerholz, L. J., Harris, E. L., Baumgardner, T. L., Reiss, A. L., Freund, L. S., Church, R. P., Mohr, J., Denckla, M. B. 1995; 28 (1): 18-29

    Abstract

    The incidence of learning disabilities (LD) in a research center sample of 107 boys and 103 girls between 6 and 12 years of age was calculated using Wechsler IQ and Woodcock-Johnson cluster scores in a regression model (REG) and a reliability model (REL). The REL method identified LD three times more often than the REG method, and all those identified by REG were also identified by REL. When stratified by IQ, REG and REL identified similar percentages in the lowest IQ group; however, REG identified at a lower rate as IQ increased. All 87 children identified with reading disabilities (both REL-RD and REG-RD) were weak to a similar extent on phonemic awareness. Comorbid elevated attention ratings were found in 62% of children with RD; 26% had elevated attention ratings but no linguistic processing deficits, and 21% had at least one linguistic processing deficit but no attentionally suspect rating.

    View details for Web of Science ID A1995PY84100003

    View details for PubMedID 7844483

  • Preliminary report on cognitive and adaptive behaviors of preschool-aged males with fragile X Developmental Brain Dysfunction Freund LS, Peebles CD, Aylward E, Reiss AL 1995; 8: 242-251
  • MAGNETIC-RESONANCE-IMAGING MEASUREMENT OF POSTERIOR-FOSSA STRUCTURES IN SCHIZOPHRENIA AMERICAN JOURNAL OF PSYCHIATRY Aylward, E. H., Reiss, A., Barta, P. E., Tien, A., Han, W., Lee, J., Pearlson, G. D. 1994; 151 (10): 1448-1452

    Abstract

    Previous research has yielded conflicting results regarding the hypothesis that structural abnormalities of the cerebellar vermis and other posterior fossa structures are associated with schizophrenia. The purpose of this study was to apply techniques of measuring posterior fossa structures from magnetic resonance imaging scans that have proven reliable in identifying structural abnormalities in other patient populations.Midsagittal areas of cerebellar vermis and its subsections (anterior vermis, lobules VI-VII, and lobules VIII-X), brainstem (pons, medulla, and midbrain), and fourth ventricle, as well as intracranial area and cortical area, were measured. Subjects included 36 schizophrenic patients and 51 normal comparison subjects. Groups were matched on age, sex, race, and family socioeconomic status.No significant group differences were detected for any posterior fossa structure. When corrected for intracranial area, fourth ventricle area was significantly larger in patients than in the comparison group. Fourth ventricle area was not, however, correlated with any measures of symptom severity.The size of posterior fossa structures is not abnormal in schizophrenia.

    View details for Web of Science ID A1994PJ93700008

    View details for PubMedID 8092338

  • LENGTH OF UNINTERRUPTED CGG REPEATS DETERMINES INSTABILITY IN THE FMR1 GENE NATURE GENETICS Eichler, E. E., Holden, J. J., Popovich, B. W., Reiss, A. L., Snow, K., Thibodeau, S. N., Richards, C. S., Ward, P. A., Nelson, D. L. 1994; 8 (1): 88-94

    Abstract

    Analysis of 84 human X chromosomes for the presence of interrupting AGG trinucleotides within the CGG repeat tract of the FMR1 gene revealed that most alleles possess two interspersed AGGs and that the longest tract of uninterrupted CGG repeats is usually found at the 3' end. Variation in the length of the repeat appears polar. Alleles containing between 34 and 55 repeats, with documented unstable transmissions, were shown to have lost one or both AGG interruptions. These comparisons define an instability threshold of 34-38 uninterrupted CGG repeats. Analysis of premutation alleles in Fragile X syndrome carriers reveals that 70% of these alleles contain a single AGG interruption. These data suggest that the loss of an AGG is an important mutational event in the generation of unstable alleles predisposed to the Fragile X syndrome.

    View details for Web of Science ID A1994PE15700021

    View details for PubMedID 7987398

  • NEUROANATOMY OF FRAGILE-X SYNDROME - THE TEMPORAL-LOBE NEUROLOGY Reiss, A. L., Lee, J., Freund, L. 1994; 44 (7): 1317-1324

    Abstract

    Fragile X syndrome, an X-linked genetic disorder caused by a mutation in the FMR-1 gene, is associated with a particular profile of abnormalities of behavior, learning, language, and memory, suggesting temporal lobe dysfunction. We undertook a quantitative neuroimaging study investigating the neuroanatomy of the temporal lobe in individuals with the fragile X mutation. The temporal lobe neuroanatomy of 15 young fragile X subjects was quantified and compared with that of 26 age- and IQ-matched control subjects. Analyses showed the right and left hippocampal volumes to be significantly larger in the fragile X group compared with the control group. Subjects with the fragile X mutation showed an age-related increase in volume of the hippocampus an age-related decrease in volume of the superior temporal gyrus. Along with the findings of previous imaging studies of fragile X subjects, the results of the present investigation are consistent with studies showing a nonrandom distribution of expression of the FMR-1 gene in the developing brain, with increased expression in the cerebellum, hippocampus, and specific cortical regions. The results also suggest involvement of temporal lobe regions in the behavioral and cognitive abnormalities associated with fragile X syndrome.

    View details for Web of Science ID A1994NX63200025

    View details for PubMedID 8035938

  • FOLIC-ACID IN NEURODEVELOPMENT AND CHILD-PSYCHIATRY PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Greenblatt, J. M., Huffman, L. C., Reiss, A. L. 1994; 18 (4): 647-660

    Abstract

    1. Folic acid deficiency has been associated with diverse neuropsychiatric symptoms. 2. This paper discusses the impact of folate on brain development, maturation and function and reviews the role of folate in psychiatric disorders, particularly childhood disorders. 3. A brief case report examines the use of folate in the treatment of attentional problems in a child with fragile X syndrome.

    View details for Web of Science ID A1994NX41900002

    View details for PubMedID 7938557

  • A BEHAVIORAL NEUROGENETICS APPROACH TO DEVELOPMENTAL-DISABILITIES - GENE-BRAIN-BEHAVIOR ASSOCIATIONS CURRENT OPINION IN NEUROLOGY Baumgardner, T. L., Green, K. E., Reiss, A. L. 1994; 7 (2): 172-178

    Abstract

    This review provides a discussion of behavioral neurogenetics' contribution to understanding neurodevelopmental pathways in learning and developmental disabilities. A brief overview is given of several common neurogenetic disorders with various genetic etiologies including Down syndrome, Turner syndrome, Prader-Willi syndrome, Angelman syndrome, and Tourette's syndrome. Special emphasis is placed on fragile X syndrome as representative of a newly-discovered class of genetic conditions characterized by an unstable trinucleotide repeat. A spectrum of cognitive, behavioral, and social-emotional phenotypic features associated with fragile X syndrome is examined. Also included are findings from recent neuroimaging research and a discussion of the need for the classification of symptoms on the basis of underlying genetic/medical conditions.

    View details for Web of Science ID A1994ND72400013

    View details for PubMedID 8019664

  • FREQUENCY AND STABILITY OF THE FRAGILE-X PREMUTATION HUMAN MOLECULAR GENETICS Reiss, A. L., Kazazian, H. H., KREBS, C. M., MCAUGHAN, A., Boehm, C. D., Abrams, M. T., Nelson, D. L. 1994; 3 (3): 393-398

    Abstract

    Although considered the most common heritable cause of neurodevelopmental disability, precise prevalence figures for the FMR1 mutation in the general population are lacking. Since no fragile X premutation alleles have yet been observed to originate from FMR1 alleles within the normal size range, there is also little information available about the origin of the fragile X premutation and mechanisms leading to instability of the FMR1 trinucleotide repeat region. In this study, 977 genetically unrelated individuals from families unselected for mental retardation or fragile X were analyzed with Southern blot analysis for the presence of FMR1 mutations. A subgroup of subjects with evidence of a large CGG repeat number, and any available relatives, were further studied with PCR to investigate the stability of the trinucleotide repeat segment of FMR1. One subject had a 75 repeat length which was unstable (increased in size) when passed to subsequent generations. This includes one male descendent who had a premutation/full mutation mosaic pattern. Two other alleles with > or = 46 repeats from different subjects were also found to be unstable and increased in size in subsequent generations. Considering all three unstable alleles to be indicative of an evolving or actual premutation, the estimated frequency of the fragile X premutation is one in 510 X chromosomes. However, since 11 other alleles with > or = 46 repeats were found to be stable through at least one meiotic transmission, repeat length appears to be an important but not sufficient condition leading to instability of the FMR1 gene.

    View details for Web of Science ID A1994NA58300001

    View details for PubMedID 8012350

  • MRI measurement of posterior fossa structures in schizophrenia American Journal of Psychiatry Aylward E, Reiss AL, Barta PE, Tien A, Han W, Lee J, Pearlson GD 1994; 151: 1448-1452
  • Genetic disorders and advances Current Opinion in Psychiatry Mazzocco, M., Reiss, AL 1994; 7 (5): 392-396
  • NEUROANATOMY OF RETT-SYNDROME - A VOLUMETRIC IMAGING STUDY ANNALS OF NEUROLOGY Reiss, A. L., Faruque, F., Naidu, S., Abrams, M., Beaty, T., Bryan, R. N., Moser, H. 1993; 34 (2): 227-234

    Abstract

    Rett syndrome is a pediatric neurological disorder of unknown etiology defined by the presence of severe neurodevelopment decline, acquired microcephaly, dementia, abnormalities of movement, autistic behavior, and seizures in young female children. In this study, the neuroanatomy of 11 females with Rett syndrome and 15 age- and gender-matched control subjects was investigated in vivo with quantitative neuroimaging techniques. Compared to control subjects, the patients with Rett syndrome were found to have significantly reduced cerebral volume; evidence of greater loss of gray matter in comparison to white matter; regional variation in cortical gray matter, with the frontal regions showing the largest decrease; and reduced volume of the caudate nucleus and midbrain, even when taking into account general reduction in the size of the brain. In addition, there was no evidence of an ongoing degenerative process in this sample of girls with Rett syndrome. The consistency of these data with results from neuropathological investigations points to the need for continued quantitative neuroimaging studies of children with this condition. In particular, research employing serial longitudinal scans of very young children manifesting early signs of the clinical syndrome holds promise for helping to elucidate the neuropathological pathways leading to the debilitating clinical manifestations of Rett syndrome.

    View details for Web of Science ID A1993LR02400018

    View details for PubMedID 8338347

  • DNA METHYLATION OF THE FRAGILE-X LOCUS IN SOMATIC AND GERM-CELLS DURING FETAL DEVELOPMENT - RELEVANCE TO THE FRAGILE-X SYNDROME AND X-INACTIVATION SOMATIC CELL AND MOLECULAR GENETICS Luo, S. Y., Robinson, J. C., Reiss, A. L., Migeon, B. R. 1993; 19 (4): 393-404

    Abstract

    To obtain insights into mechanisms responsible for methylation of CpG islands on the inactive X chromosome of normal females, we examined methylation of the fragile X (FraX) locus in a variety of tissues from normal fetuses and adults, and from males with the FraX syndrome. We identified 20 CCGG sites (MspI-HpaII sites M1-M20) within a 12-kb BglII fragment that includes the CpG island. Sites M3-M18, within the 1.2-kb CpG island are unmethylated on the active X in normal males and females at all ages and in all tissues studied. In contrast, these sites are at least partially methylated on the inactive X chromosome in a variety of tissues from normal females by six weeks from conception. The exceptional tissues are chorionic villi and gonads, which are significantly undermethylated. In addition, fetal germ cells are unmethylated at site M3, which is methylated on the inactive X in other tissues; thus, the methylation imprint of the inactive X has been erased. Methylation of the locus on the fragile X chromosome is similar to that of the normal inactive X but is more extensive and less heterogeneous. This suggests that the expansion of the island and the greater number of CpGs that result from amplification of the CGG repeat enhance the methylatibility of the island. Additional studies show that the chromatin of the CpG island is nuclease hypersensitive on the active X but insensitive on both inactive and FraX.

    View details for Web of Science ID A1993LZ82100008

    View details for PubMedID 8211380

  • THE EFFECTS OF X-MONOSOMY ON BRAIN-DEVELOPMENT - MONOZYGOTIC TWINS DISCORDANT FOR TURNERS-SYNDROME ANNALS OF NEUROLOGY Reiss, A. L., Freund, L., Plotnick, L., Baumgardner, T., Green, K., SOZER, A. C., Reader, M., BOEHM, C., Denckla, M. B. 1993; 34 (1): 95-107

    Abstract

    Monosomy for the X chromosome is the most frequent cause of Turner's syndrome, a common clinical syndrome associated with particular physical and neurobehavioral features. The results from comprehensive assessment of prepubertal monozygotic female twins discordant for X monosomy are presented. Zygosity was established with DNA Fingerprinting and no evidence of chromosomal mosaicism was seen in either child. Physical features in the affected twin were relatively mild with respect to the full spectrum of physical malformations and disabilities associated with Turner's syndrome. The neurobehavioral phenotypes of the twins were compared. Although both sisters scored in the superior range of intelligence, the affected twin's Performance IQ was 18 points less than her sister, whereas Verbal IQ showed only a 3-point difference between the sisters. Other relative differences were noted within the executive, visuospatial, and visuomotor domains of function. Behavioral evaluation indicated greater problems with attention, hyperactivity, and anxiety in the affected twin. Quantitative analysis of brain anatomy revealed evidence of both general and regional effects of X monosomy on neurodevelopment. Cerebrospinal fluid volume was increased by 25% in the affected twin compared with her sister with a corresponding decrease in gray matter volume. The right frontal, right parietal-occipital, and left parietal-perisylvian regions showed the greatest discrepancy between the sisters with respect to increased cerebrospinal fluid and decreased gray matter volumes in twin with X monosomy. Differences in the posterior fossa were also noted with a 50% relative increase in the volumes of the fourth ventricle and cisterna magna and a 10 to 15% relative reduction in size of the cerebellar vermis, pons, and medulla in the affected twin. The association between the neurobehavioral and neuroanatomical findings in the affected twin is discussed. The unique nature of the naturally occurring genetic phenomenon seen in this twin pair provides an opportunity to more fully elucidate the neurobehavioral phenotype associated with X monosomy and Turner's syndrome.

    View details for Web of Science ID A1993LK40400015

    View details for PubMedID 8517687

  • DUAL DIAGNOSES - PSYCHIATRIC-DISORDERS IN DEVELOPMENTAL-DISABILITIES PEDIATRIC CLINICS OF NORTH AMERICA Lovell, R. W., Reiss, A. L. 1993; 40 (3): 579-592

    Abstract

    A high prevalence of psychiatric illness exists in persons with mental retardation. Among children with mild to moderate retardation, psychiatric illnesses resemble those seen in the general population. Major affective disorders, ADHD, and conduct disorder are common and respond to the same interventions used in children without mental retardation. Persons with severe to profound retardation are more likely to engage in stereotypies and self-injurious behaviors. In addition, certain specific syndromes associated with mental retardation present with particular neurocognitive, behavioral, and psychiatric profiles. Common examples are fetal alcohol syndrome, Down syndrome, fragile X syndrome, and Rett syndrome. Specific challenges exist for pediatricians who diagnose and treat patients with mental retardation and psychiatric illness. The child's impaired ability to communicate his or her thoughts and feelings with words makes clinical history taking difficult. The clinician must frequently rely on the observation of family members and teachers. An understanding of developmental profiles and interpersonal, peer, and family dynamics is important. Specific behaviors must be targeted and realistic objectives set in treatment planning, which may include psychotherapy, medication, behavior management techniques, and rehabilitation therapy.

    View details for Web of Science ID A1993LD17300010

    View details for PubMedID 7684122

  • NEUROBEHAVIORAL EFFECTS OF THE FRAGILE-X PREMUTATION IN ADULT WOMEN - A CONTROLLED-STUDY AMERICAN JOURNAL OF HUMAN GENETICS Reiss, A. L., Freund, L., Abrams, M. T., BOEHM, C., Kazazian, H. 1993; 52 (5): 884-894

    Abstract

    Although previous studies have suggested that the fragile X premutation (fra [X] pM) does not cause deleterious effects, methodological constraints have prevented more definitive conclusions from being reached. In this report, we describe the neuropsychiatric and cognitive-neuropsychological status of 34 adult women with the fra (X) pM, as compared with a well-matched control group of 41 mothers of fra (X)-negative children with developmental disability. The results indicate that there are no meaningful differences between adult women with the fra (X) pM and control subjects with respect to cognitive abilities or profile, neuropsychological function, psychiatric diagnoses or symptoms, and self-rated personality profile. No measure for either group showed evidence of functioning outside the normal range except for a high lifetime prevalence of major depression in both groups. Additional exploratory analyses within the fra (X) group showed no significant effect of either the size of the fra (X) insert or X chromosome inactivation pattern in leukocytes, on any measure of neurobehavioral function. These findings provide additional information to professionals providing genetic counseling to, and assessment of, fra (X) families.

    View details for Web of Science ID A1993LB88900005

    View details for PubMedID 8488838

  • VOLUMETRIC MRI CHANGES IN BASAL GANGLIA OF CHILDREN WITH TOURETTES-SYNDROME NEUROLOGY Singer, H. S., Reiss, A. L., Brown, J. E., Aylward, E. H., Shih, B., Chee, E., Harris, E. L., READER, M. J., Chase, G. A., Bryan, R. N., Denckla, M. B. 1993; 43 (5): 950-956

    Abstract

    To define the site of pathology in Tourette's syndrome (TS), we performed a volumetric MRI study of basal ganglia structures and lateral ventricles on 37 children with this disorder and 18 controls. There were no statistically significant differences in the size of the right or left caudate, putamen, globus pallidus, or ventricles in these populations. In contrast, there were significant differences for measures of symmetry in the putamen and the lenticular region. Virtually all controls (17 right- and one left-handed) had a left-sided predominance of the putamen, whereas in 13 of 37 TS subjects, a right predominance exceeded that of any control. Statistical comparisons among TS patients, with (n = 18) or without (n = 19) attention-deficit hyperactivity disorder (ADHD), and controls showed significant differences for the volume of the left globus pallidus and for lenticular asymmetry. Post hoc evaluations showed that in the TS + ADHD group, the volume of the left globus pallidus was significantly smaller than the volume of the right and that lenticular asymmetry was due to a greater right-sided predominance in the TS+ADHD group. This study lends further support to proposals that claim the basal ganglia is involved in the pathogenesis of TS and also suggests that the comorbid problem of ADHD is related to regional changes that differ from those primarily associated with tics.

    View details for Web of Science ID A1993LC36300020

    View details for PubMedID 8492951

  • PSYCHIATRIC-DISORDERS ASSOCIATED WITH FRAGILE-X IN THE YOUNG FEMALE PEDIATRICS Freund, L. S., Reiss, A. L., Abrams, M. T. 1993; 91 (2): 321-329

    Abstract

    Seventeen females with the fragile X mutation and 17 non-fragile X females group-matched on age (range 4 to 27 years), IQ (range 34 to 126), and socioeconomic status were compared on Diagnostic and Statistical Manual of Mental Disorders (3rd ed, revised) criteria for selected psychiatric disorders. Additional comparisons were made on level of social development and parent and teacher ratings of maladaptive behaviors. Correlations of genetic testing data with psychiatric and behavioral variables were investigated. Consistent with hypotheses, females with the fragile X mutation showed a greater frequency of avoidant disorder and mood disorders compared with control subjects. Females with the fragile X mutation also showed greater frequency of stereotypy/habit disorder when compared with control subjects. Contrary to predictions, females with the fragile X mutation did not show higher frequencies of attention deficit hyperactivity disorder or undifferentiated attention deficit. They showed greater deficits in their interpersonal socialization skills and were rated by their parents and teachers as significantly more withdrawn and depressed when compared with control subjects. The size of the DNA insertion associated with the genetic abnormality was correlated with IQ, severity of attention problems, and anxiety/withdrawal symptoms. Evidence from this study points to an association between a specific genetic syndrome and characteristic developmental and psychiatric difficulties. Implications for the clinician are discussed.

    View details for Web of Science ID A1993KK57800008

    View details for PubMedID 8380924

  • BIPOLAR SPECTRUM DISORDER AND FRAGILE-X SYNDROME - A FAMILY STUDY BIOLOGICAL PSYCHIATRY JEFFRIES, F. M., Reiss, A. L., Brown, W. T., Meyers, D. A., GLICKSMAN, A. C., Bandyopadhyay, S. 1993; 33 (3): 213-216

    View details for Web of Science ID A1993KR26300012

    View details for PubMedID 8448271

  • NEUROCOGNITIVE FUNCTION AND BRAIN IMAGING IN TURNER SYNDROME - PRELIMINARY-RESULTS HORMONE RESEARCH Ross, J. L., Reiss, A. L., Freund, L., Roeltgen, D., Cutler, G. B. 1993; 39: 65-69

    Abstract

    Girls with Turner syndrome were investigated in order to determine the anatomical differences in their brains compared with those of normal age-matched female controls, and to relate these differences to deficits in neurocognitive function with a view to understanding the abnormal brain development in Turner syndrome. During the 2-year study period, it is planned to evaluate 50 girls with Turner syndrome and 50 age-matched controls. A wide range of authentic neurocognitive tests will be applied to establish the neurocognitive profile, and brain anatomy will be studied by magnetic resonance imaging (MRI). Ten patients with Turner syndrome have been evaluated by neurocognitive testing to date, and 8 girls with Turner syndrome and 13 controls have had MRI scans performed. There is preliminary evidence of both specific and generalized processes affecting brain development and cognitive function in Turner syndrome. The evidence of a role for sex hormones in socio-behavioural and cognitive abilities in Turner syndrome is discussed.

    View details for Web of Science ID A1993LN15200016

    View details for PubMedID 8359792

  • BRIEF SCREENING QUESTIONNAIRE FOR DETERMINING AFFECTED STATE IN FRAGILE-X SYNDROME - A CONSENSUS RECOMMENDATION AMERICAN JOURNAL OF MEDICAL GENETICS Reiss, A. L., Cianchetti, C., Cohen, I. L., DeVries, B., Hagerman, R., Hinton, V., Froster, U., Lachiewicz, A., Mazzocco, M., Sobesky, W., Sudhalter, V. 1992; 43 (1-2): 61-64

    Abstract

    New molecular research has provided strong evidence for different forms of the fragile X mutation. These findings suggest the need to develop a more standardized and sensitive method for determining neurobehavioral effects of the fragile X gene(s), particularly for molecular studies of patients who do not have obvious mental retardation. This report describes a brief screening questionnaire designed to increase the detection of neurobehavioral dysfunction in individuals from fragile X families who are included in new molecular studies. Improved detection of the affected state in fragile X syndrome will allow more valid clinical data to be correlated with the important molecular information currently being collected.

    View details for Web of Science ID A1992HT25900008

    View details for PubMedID 1605236

  • BEHAVIORAL-PHENOTYPE OF FRAGILE-X SYNDROME - DSM-III-R AUTISTIC BEHAVIOR IN MALE-CHILDREN AMERICAN JOURNAL OF MEDICAL GENETICS Reiss, A. L., Freund, L. 1992; 43 (1-2): 35-46

    Abstract

    Comparison of 34 fragile X [(fra(X)] male children (age 3-18 years) with 32 IQ- and age-matched, non-fra(X) male control children was conducted using specific DSM-III-R criteria for autism. Statistical analyses supported predictions that fra(X) males show increased dysfunction in peer social play, nonverbal communication (e.g., gaze aversion, gesturing), verbal communication (e.g., rate, volume, word/phrase perseveration), and repetitive motor behaviors (e.g., handflapping, rocking). There was a trend for fra(X) children to show abnormal responsivity to sensory stimuli as well such as oversensitivity to sound and increased mouthing or smelling of objects. The investigation supports the contention that fra(X) males manifest a specific subset of behaviors from the autistic spectrum. Implications for treatment are discussed.

    View details for Web of Science ID A1992HT25900005

    View details for PubMedID 1605210

  • THE MESIAL-TEMPORAL LOBE AND AUTISM - CASE-REPORT AND REVIEW DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY Hoon, A. H., Reiss, A. L. 1992; 34 (3): 252-259

    Abstract

    Human and non-human primate research has shown that pathological processes affecting the temporal lobe, particularly the amygdala and hippocampus, are related to the development of the autistic syndrome. This case report describes a young male child with left temporal oligodendroglioma, who demonstrated a constellation of autistic behaviors meeting DSM-III-R criteria for pervasive developmental disorder. Abnormalities in social interaction, affective expression and communication were particularly evident. Some of the symptoms improved after tumor resection, while other signs of qualitative abnormalities in development emerged or persisted. This case adds evidence to the hypothesis that damage to mesial-temporal structures at an early developmental period may lead to the autistic syndrome.

    View details for Web of Science ID A1992HE19600009

    View details for PubMedID 1559605

  • CHROMOSOMAL DISORDERS - BACKGROUND AND NEURORADIOLOGY AMERICAN JOURNAL OF NEURORADIOLOGY Kumar, A. J., Naidich, T. P., Stetten, G., Reiss, A. L., Wang, H., Thomas, G. H., Hurko, O. 1992; 13 (2): 577-593

    View details for Web of Science ID A1992HH84800012

    View details for PubMedID 1533086

  • CLINICAL, BIOCHEMICAL, AND NEUROPSYCHIATRIC EVALUATION OF A PATIENT WITH A CONTIGUOUS GENE SYNDROME DUE TO A MICRODELETION XP11.3 INCLUDING THE NORRIE DISEASE LOCUS AND MONOAMINE-OXIDASE (MAOA AND MAOB) GENES AMERICAN JOURNAL OF MEDICAL GENETICS Collins, F. A., Murphy, D. L., Reiss, A. L., Sims, K. B., Lewis, J. G., Freund, L., Karoum, F., Zhu, D. P., Maumenee, I. H., Antonarakis, S. E. 1992; 42 (1): 127-134

    Abstract

    Norrie disease is a rare X-linked recessive disorder characterized by blindness from infancy. The gene for Norrie disease has been localized to Xp11.3. More recently, the genes for monoamine oxidase (MAOA, MAOB) have been mapped to the same region. This study evaluates the clinical, biochemical, and neuropsychiatric data in an affected male and 2 obligate heterozygote females from a single family with a submicroscopic deletion involving Norrie disease and MAO genes. The propositus was a profoundly retarded, blind male; he also had neurologic abnormalities including myoclonus and stereotopy-habit disorder. Both obligate carrier females had a normal IQ. The propositus' mother met diagnostic criteria for "chronic hypomania and schizotypal features." The propositus' MAO activity was undetectable and the female heterozygotes had reduced levels comparable to patients receiving MAO inhibiting antidepressants. MAO substrate and metabolite abnormalities were found in the propositus' plasma and CSF. This study indicates that subtle biochemical and possibly neuropsychiatric abnormalities may be detected in some heterozygotes with the microdeletion in Xp11.3 due to loss of the gene product for the MAO genes; this deletion can also explain some of the complex phenotype of this contiguous gene syndrome in the propositus.

    View details for Web of Science ID A1992GW60700025

    View details for PubMedID 1308352

  • The psychological effects associated with fragile x syndrome Current Opinion in Pediatrics Baumgardner T, Green K, Reiss AL 1992; 4 (4): 609-615
  • CHROMOSOME FRAGILITY AND PSYCHOPATHOLOGY IN OBLIGATE FEMALE CARRIERS OF THE FRAGILE X-CHROMOSOME ARCHIVES OF GENERAL PSYCHIATRY Freund, L. S., Reiss, A. L., Hagerman, R., Vinogradov, S. 1992; 49 (1): 54-60

    Abstract

    The relationship between fragility (the percentage of cells exhibiting the fragile X chromosome abnormality) and psychopathological conditions was investigated in a sample of 40 obligate female carriers of the fragile X chromosome. Subjects were categorized by those with positive fragility greater than 0% (n = 19) and those with 0% fragility (n = 21). Compared with women with 0% fragility, it was expected that women with positive fragility would have a higher likelihood of manifesting a spectrum of social and psychological disability previously shown to be associated with fragile X syndrome in women. It was also expected that within the group with positive fragility, degree of fragility would be related to severity of symptoms. Results partially supported the hypotheses: women with fragility over 0% were more likely to be assigned a diagnosis of schizotypal features, were rated higher on symptoms associated with the schizophrenia spectrum, and scored lower on IQ, level of healthiest functioning, education, and socioeconomic status than women with 0% fragility. Subsequent comparisons with a control group indicated that the group with 0% fragility and normal controls did not differ on these variables. Within the group with positive fragility, increasing fragility was related to greater severity of symptoms and lower IQ, education, socioeconomic status, and levels of adaptive functioning, as predicted. Contrary to expectations, positive fragility was not associated with proportion of affective disorder diagnoses or ratings on affective disorder symptoms. The results of the study provide evidence that degree of fragility is a potentially important predictor of psychopathology among women with normal IQ who are carriers of the fragile X chromosome abnormality.

    View details for Web of Science ID A1992GY80000006

    View details for PubMedID 1728251

  • 49,XXXXY SYNDROME - BEHAVIORAL AND DEVELOPMENTAL PROFILES JOURNAL OF MEDICAL GENETICS LOMELINO, C. A., Reiss, A. L. 1991; 28 (9): 609-612

    Abstract

    Behavioural, psychological, and cognitive profiles of three cases, including a 5 year old male with a 49,XXXXY karyotype and a (3;15) translocation, a 9 year old male with a 49,XXXXY karyotype, and a 32 year old male with 48,XXXY/49,XXXXY mosaicism, are presented. Significant behavioural problems were seen in the two older patients. The degree of mental retardation and impairment of language abilities were shown to be more severe in the older subjects as well. These findings are discussed with respect to the effects of the X chromosome on brain development.

    View details for Web of Science ID A1991GE98800007

    View details for PubMedID 1956059

  • NEUROANATOMY IN FRAGILE-X FEMALES - THE POSTERIOR-FOSSA AMERICAN JOURNAL OF HUMAN GENETICS Reiss, A. L., Freund, L., Tseng, J. E., Joshi, P. K. 1991; 49 (2): 279-288

    Abstract

    The relative homogeneity of the neuropsychiatric phenotype in individuals with fragile (fra) X syndrome suggests that there are consistent central nervous system (CNS) abnormalities underlying the observed cognitive and behavioral abnormalities. In this study, the neuroanatomy of the posterior fossa and other selected CNS regions in 12 young fra X females were compared with those of a group of 12 age-, sex-, and IQ-matched females without evidence of the fra X syndrome. Fra X females were shown to have decreased size of the posterior cerebellar vermis and increased size of the fourth ventricle, findings that are identical to those previously reported for fra X males. When compared with fra X male and nonfra X control groups, the distribution of the posterior-vermis and fourth-ventricle variables for the fra X female group was intermediate. These results support the hypothesis that the fra X genetic abnormality leads to hypoplasia of the posterior cerebellar vermis, a neuroanatomical variation of potential importance to both developmental and neuropsychiatric syndromes.

    View details for Web of Science ID A1991GA86600004

    View details for PubMedID 1867191

  • COGNITIVE PROFILES ASSOCIATED WITH THE FRA(X) SYNDROME IN MALES AND FEMALES AMERICAN JOURNAL OF MEDICAL GENETICS Freund, L. S., Reiss, A. L. 1991; 38 (4): 542-547

    Abstract

    Twenty-three fragile X [fra(X)] males (mean IQ 50, mean age 10 years) and 11 fra(X) females (mean IQ 84, mean age 11.3 years) were administered the Stanford-Binet Intelligence Scale, 4th ed. (S-B). The cognitive profiles generated from the S-B indicated a pattern of subtest strengths and weaknesses that was similar for both groups. Consistent weaknesses in both groups were found in quantitative skills and short-term memory recall for visually presented, abstract stimuli, whereas a consistent strength was observed for short-term memory recall of visually presented, meaningful stimuli. Strengths in verbal labeling and comprehension and deficits in spatial visualization and visual-motor coordination were identified by the S-B for the male group but not for the female group. Fragility in the female group was negatively correlated with the S-B score for the short-term memory area and the combined S-B scores for the verbal reasoning and quantitative reasoning areas. The specific, S-B-identified cognitive strengths and weaknesses associated with the fra(X) condition are potentially useful indicators for investigation of specific cognitive process deficits associated with the fra(X) condition and the design of appropriate educational interventions for fra(X) children.

    View details for Web of Science ID A1991FA60200008

    View details for PubMedID 2063895

  • AUTISTIC FEATURES IN JOUBERT SYNDROME - A GENETIC DISORDER WITH AGENESIS OF THE CEREBELLAR VERMIS BIOLOGICAL PSYCHIATRY Holroyd, S., Reiss, A. L., Bryan, R. N. 1991; 29 (3): 287-294

    Abstract

    Recent reports in the literature have suggested a link between abnormalities of the cerebellar vermis and the behavioral syndrome of autism. Joubert syndrome is an autosomal recessive disorder characterized by partial or complete agenesis of the cerebellar vermis. However, there is little behavioral or psychiatric description of patients with this genetic condition. In this report, the neuropsychiatric characteristics of two children with Joubert syndrome are described in detail. One child met DSM-III-R diagnostic criteria for autistic disorder, while the other displayed autistic features. The female child displayed stereotypic behavior and impairments in social interaction and communication, had a markedly restricted repertoire of interests, and showed distress over changes in the environment. The male child demonstrated perseveration and preoccupation with sounds and textures, but had no abnormalities in social interaction. Although both children showed developmental disabilities, the degree of cognitive delay was significantly less than that described in previous reports of children with Joubert syndrome. This report adds to the growing body of evidence implicating cerebellar involvement in developmental disabilities and autistic behavior.

    View details for Web of Science ID A1991EX03700011

    View details for PubMedID 2015333

  • Area and volume measurement of posterior fossa structures in MRI Journal of Psychiatric Research Aylward E, Reiss AL 1991; 25: 159-168
  • Brain and behavior correlates of the fragile X syndrome Current Opinion in Psychiatry Freund L, Abrams M, Reiss AL 1991; 4: 667-673
  • Rating problem behaviors in mentally retarded outpatients: Use of the Aberrant Behavior Checklist Research in Developmental Disabilities Freund L, Reiss AL 1991; 12: 435-451
  • FRAGILE X SYNDROME, DSM-III-R, AND AUTISM JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Reiss, A. L., Freund, L. 1990; 29 (6): 885-891

    Abstract

    Although reports of autistic behavior in fragile X males have been published for 8 years, there is little information about specific behaviors shown by fragile X males that are suggestive of the diagnosis of autism. The new diagnostic criteria for autistic disorder contained in the DSM-III-R provided the opportunity for more closely investigating the topography of autistic behavior in 17 fragile X males and the effects of age and IQ on its occurrence. The criteria most frequently met by these subjects were related to deficits in social interaction with peers, abnormalities in verbal and nonverbal communication, stereotypic motor behavior, and unusual responses to sensory stimuli. Fragile X subjects did not frequently show abnormalities in attachment behaviors and reciprocal interaction with caregivers. There were no discernable age or IQ effects. The importance and implications of these findings are discussed and the need for greater exploration of autism "subtypes" is emphasized.

    View details for Web of Science ID A1990EJ19200007

    View details for PubMedID 2273015

  • METHYLATION STATUS OF GENES FLANKING THE FRAGILE SITE IN MALES WITH THE FRAGILE-X SYNDROME - A TEST OF THE IMPRINTING HYPOTHESIS AMERICAN JOURNAL OF HUMAN GENETICS Khalifa, M. M., Reiss, A. L., Migeon, B. R. 1990; 46 (4): 744-753

    Abstract

    Laird has suggested that the mutation responsible for the fragile X (FraX) syndrome interferes with the process of X chromosome reactivation in oocytes, thus blocking the transcription of loci at or neighboring the fragile site (Xq27.3) and producing the clinical FraX phenotype; he has also suggested that the transcriptional block might result from inappropriate DNA methylation. We have explored the latter possibility by examining the methylation status of several genes flanking the fragile site in eight FraX males from seven unrelated families. These genes (HPRT, G6PD, P3, and GdX), contain 5' clusters of CpG dinucleotides which are differentially methylated in transcriptionally active and inactive loci. Using the methylation-sensitive restriction enzyme, HpaII, we observed no differences between FraX and normal males in the methylation either of CpG islands in any of these genes or in nonclustered CpGs within the body of the HPRT gene. The same was true for the CpG cluster in intron 22 of the clotting factor VIII gene. In each gene, the island is methylated on the inactive X chromosome and not on the active one, but in no case were these islands methylated in FraX males. The four anonymous loci (DXS98, DXS304, DXS52, and DXS15) that are closely linked to the FraX locus (the closest is within 5 centimorgans) are not differentially methylated on active and inactive X, nor are they unusually methylated in FraX males. Therefore, our observations provide no evidence that DNA methylation in the vicinity of the FraX locus has a role in producing the clinical phenotype of the FraX syndrome.

    View details for Web of Science ID A1990CW54900012

    View details for PubMedID 2316521

  • FRAGILE X-SYNDROME BIOLOGICAL PSYCHIATRY Reiss, A. L., Freund, L. 1990; 27 (2): 223-240

    Abstract

    Fragile X syndrome is the most important X-linked etiology of mental retardation and developmental disability currently known. Accumulating evidence also indicates that male and female carriers of the fragile X genetic abnormality demonstrate a relatively specific pattern of psychiatric disturbance. Fragile X males frequently manifest behaviors from the autistic spectrum whereas females show dysfunction in social interaction, thought processes, and affective regulation. In this review, an overview of the fragile X syndrome is presented with a focus on the occurrence of particular neuropsychiatric characteristics in males and females. Relevant data from recent genetic and neurobiological research is also described. The ability to study individuals with a specific genetic cause of psychopathology such as fragile X syndrome makes this condition of particular interest to biological psychiatry.

    View details for Web of Science ID A1990CH93800012

    View details for PubMedID 2403814

  • Neuroanatomy of fragile X syndrome: The posterior fossa Annals of Neurology Reiss AL, Aylward E, Freund L, Bryan N, Joshi P 1990; 29: 26-32
  • The fragile X phenotype: Cognitive behavioral and neurobiological profiles Current Opinion in Psychiatry Simon VA, Abrams M, Freund L, Reiss AL 1990; 3: 581-586
  • Neuropsychiatric aspects of fragile X syndrome Brain Dysfunction Reiss AL, Freund L 1990; 3: 9-22
  • PARENTAL INHERITANCE AND PSYCHOLOGICAL DISABILITY IN FRAGILE-X FEMALES AMERICAN JOURNAL OF HUMAN GENETICS Reiss, A. L., Freund, L., Vinogradov, S., Hagerman, R., Cronister, A. 1989; 45 (5): 697-705

    Abstract

    Studies of adult female carriers of the fragile X chromosome indicate that certain psychological problems occur with a greater frequency and severity than expected. This study examines the association of parental origin of the fragile X chromosome and of fragility detected in the karyotype with measures of social, educational, and psychological functioning in a group of adult fragile X females of normal intelligence. The results show that, as a group, women who inherit the fragile X chromosome from their mother and who demonstrate positive fragility in the karyotype (MI+ group = [maternal inheritance with positive fragility]) manifest significantly more impairment of social, educational, and psychological functioning when compared with fragile X females with paternal inheritance or negative fragility or with a matched control group comprising non-fragile X women. In particular, MI+ women show lower levels of both educational achievement and socioeconomic status and a greater degree of disturbance in communication, socialization, affect, and thought processes. These clinical findings are consistent with the recently advanced hypothesis which proposes that a two-stage process leading to chromosome imprinting in a preoogonial cell causes the fragile X syndrome.

    View details for Web of Science ID A1989AZ04900006

    View details for PubMedID 2816940

  • EFFECTS OF FENFLURAMINE ON SOCIAL-BEHAVIOR IN AUTISTIC-CHILDREN JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Reiss, A. L., Egel, A. L., Feinstein, C., Goldsmith, B., BORENGASSERCARUSO, M. A. 1988; 18 (4): 617-625

    Abstract

    Deficit in social interaction is a primary component of infantile autism. However, in the majority of drug studies, social interaction has not been measured consistently over time. Therefore, we examined, in a crossover design, the effect of fenfluramine on the social interactions of seven autistic children. Social interaction was measured one to three times per week, while the children were in open placebo, placebo, or drug phases of the study. The results demonstrated that the effect of fenfluramine on social interaction was inconsistent across children, with two children possibly demonstrating a tolerance to the behavioral effects of the drug. The results are discussed with respect to genetic and pharmacologic factors.

    View details for Web of Science ID A1988R608100012

    View details for PubMedID 3215887

  • PRELIMINARY COMMUNICATION - NEUROANATOMICAL VARIATIONS OF THE POSTERIOR-FOSSA IN MEN WITH THE FRAGILE-X (MARTIN-BELL) SYNDROME AMERICAN JOURNAL OF MEDICAL GENETICS Reiss, A. L., Patel, S., Kumar, A. J., Freund, L. 1988; 31 (2): 407-414

    Abstract

    Four men with fragile X (fra (X], or Martin-Bell, syndrome were studied by magnetic resonance imaging (MRI) to determine whether detectable abnormalities of the cerebellum were present. The cerebellum was chosen because of the apparently increased tendency for fra (X) patients to demonstrate autistic behavior and accumulating evidence implicating cerebellar abnormalities in autism. Compared with a control group of four normal men, fra (X) patients had a significantly decreased area of the cerebellar vermis, particularly the posterior portion, on planimetric analysis in the midsagittal plane. The pons and fourth ventricular areas also were decreased and increased, respectively, in the fra (X) men. Neuroanatomical and animal research increasingly implicates the cerebellar vermis as an important component in functional brain systems subserving sensory and motor integration, learning, and modulation of affect, motivation, and social behavior. Thus, vermis dysfunction could account for many of the behavioral and cognitive abnormalities observed in fra (X) males, particularly those which overlap with the behavioral syndrome of autism.

    View details for Web of Science ID A1988Q621500019

    View details for PubMedID 3232704

  • CYTOGENETIC STUDIES OF MALES WITH SCHIZOPHRENIA - SCREENING FOR THE FRAGILE X-CHROMOSOME AND OTHER CHROMOSOMAL-ABNORMALITIES SCHIZOPHRENIA RESEARCH DeLisi, L. E., Reiss, A. L., White, B. J., Gershon, E. S. 1988; 1 (4): 277-281

    Abstract

    Genetic factors appear to play a role in the etiology of schizophrenia, although no specific genetic mechanism has yet been identified. As a preliminary measure in the search for the chromosomal location of a gene or genes relevant to this illness, cytogenetic screening of populations of patients might provide clues for further in depth molecular studies. Additionally, since the X chromosome has been implicated as a possible site, specific examinations aimed at identifying abnormalities in this chromosome including the presence of the fragile X site, could also be important. The following report reviews the previous literature on chromosomal aberrations in schizophrenia and presents data from a new survey of 46 unrelated male patients with schizophrenia. No chromosomal aberrations or folate-sensitive fragile sites were found in samples from these patients.

    View details for Web of Science ID A1988R262000004

    View details for PubMedID 3154515

  • PSYCHIATRIC DISABILITY IN FEMALE CARRIERS OF THE FRAGILE X-CHROMOSOME ARCHIVES OF GENERAL PSYCHIATRY Reiss, A. L., Hagerman, R. J., Vinogradov, S., Abrams, M., KING, R. J. 1988; 45 (1): 25-30

    Abstract

    Fragile X syndrome, an X-linked genetic condition, is an important genetic cause of mental retardation in males. In addition to mental retardation, hemizygous males with fragile X syndrome appear to have a greater likelihood of displaying behaviors classified under the diagnostic category of pervasive developmental disorder than would be expected on the basis of mental retardation alone. Although the majority of female heterozygotes with the fragile X genetic defect are of normal intelligence, our clinical work with this population and a recent case report have suggested that females with fragile X syndrome have an increased rate of schizophrenia spectrum and affective disorders. In this study, the relationship of the fragile X genetic defect to psychopathology in female heterozygotes is investigated by psychiatric evaluation of 35 obligate female carriers of the fragile X chromosome and a comparison group of 24 fragile X-negative controls. Female fragile X carriers were found to have a greater frequency of psychopathology associated with schizophrenia spectrum diagnoses, particularly schizotypal features. A weaker association between the fragile X genetic defect and chronic affective disorders was detected. The specificity of the neuropsychiatric phenotype occurring in particular genetic conditions such as the fragile X syndrome adds a potentially valuable tool to the study of psychopathology in the general population.

    View details for Web of Science ID A1988L573900003

    View details for PubMedID 3337608

  • Cerebellar hypoplasia and autism New England Journal of Medicine Reiss AL 1988; 319: 1152-1153
  • Inpatient Psychiatric Research Annals of Psychiatry Reiss AL, Harris J, Stahl SM 1988; 18: 97-101
  • THE EFFECTS OF PIRACETAM UPON VISUAL EVENT-RELATED POTENTIALS IN DYSLEXIC-CHILDREN PSYCHOPHYSIOLOGY Conners, C. K., Reader, M., Reiss, A., Caldwell, J., Caldwell, L., Adesman, A., Mayer, L., Berg, M., Clymer, R., Erwin, R. 1987; 24 (5): 513-521

    View details for Web of Science ID A1987J727200002

    View details for PubMedID 3685231

  • DETERMINATION OF A REFERENCE RANGE FOR WHOLE-BLOOD SEROTONIN IN A PEDIATRIC POPULATION USING HIGH-PRESSURE LIQUID-CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION CLINICAL BIOCHEMISTRY Goldsmith, B. M., Feinstein, C., Munson, S., Reiss, A., BORENGASSERCARUSO, M. A. 1986; 19 (6): 359-363

    Abstract

    Whole blood serotonin (5HT) concentrations were measured in a group of children and adolescents to determine a reference range for this population. Blood was collected after at least a 6-hour fast, mixed with ascorbic acid and EDTA, and frozen at -70 degrees C until analysis. 5HT was determined by HPLC with electrochemical detection. Matrix-matched whole blood standards and controls were used to determine 5HT concentrations, and monitor performance of the assay. 5HT concentrations in boys ranged from 0.53 to 3.13 mumol/L (mean = 1.27, SD = 0.47) while the range for girls was 0.63 to 2.46 mumol/L (mean = 1.21, SD = 0.47). There was no significant difference in 5HT concentrations between boys and girls, nor was there any significant change in 5HT concentration with age. The nonparametric central 95 percent reference range for boys and girls was determined to be 0.64-2.45 mumol/L.

    View details for Web of Science ID A1986G214800009

    View details for PubMedID 3581469

  • USE OF LORAZEPAM IN TREATMENT-RESISTANT CATATONIA JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Vinogradov, S., Reiss, A. L. 1986; 6 (5): 323-325

    View details for Web of Science ID A1986E228500019

    View details for PubMedID 3771823

  • CLONIDINE THERAPY IN WITHDRAWAL FROM HIGH-DOSE ALPRAZOLAM TREATMENT AMERICAN JOURNAL OF PSYCHIATRY Vinogradov, S., Reiss, A. L., Csernansky, J. G. 1986; 143 (9): 1188-1188

    View details for Web of Science ID A1986D780700034

    View details for PubMedID 2875667

  • Inpatient clinical research: its importance in psychiatry and psychopharmacology. Psychiatric medicine Reiss, A. L., Stahl, S. M. 1986; 4 (4): 407-416

    Abstract

    We have outlined the essential components found in an inpatient psychiatry research unit from the point of patient recruitment through discharge. In virtually every phase of a patient's hospitalization on the unit, there is the potential for significant tension between research and clinical goals. We conclude that, as Braff and associates have suggested, clinical and research interests are compatible when both receive appropriate support. We have also discussed the potential advantages of an inpatient research setting for patient care. Because of the washout period, there is greater opportunity for an extended diagnostic assessment and response to the therapeutic milieu alone. The attention and priority patients receive during the research phase can be of significant therapeutic benefit. Findings from research protocols can be used to help with diagnosis and clinical care. Working on an inpatient research unit provides residents and other trainees with special learning experiences. In particular, observational and diagnostic skills are sharpened. Techniques of non-pharmacologic behavioral management are added to the trainees' repertoire of therapeutic interventions. By nature, the research experience promotes creative thinking and problem solving. In this era of fiscal restrictions and cost accountability in medicine, potential advantages for immediate patient care and for staff training are only secondary reasons which justify the existence of inpatient research centers in psychiatry. We must also ask what specific and unique research information an inpatient research setting offers compared to less expensive outpatient research environments. The first factor to be considered is the ability to study individuals whose illness is so severe as to make outpatient management difficult or impossible. It is becoming increasingly clear that for many categories of psychiatric disorders, there is a spectrum of severity of possible behavioral manifestations seen in affected individuals. In depressive illness, for example, the spectrum of expression appears to range from dysthymic disorder to major depressive disorder with psychotic features. Individuals with more severe symptomatology tend to create the greater cost to society because of their correspondingly greater degree of dysfunctional behavior, need for repeated and extended hospitalization, requirement for social services, etc. Such individuals, therefore, need to be studied in a research setting at least as much as patients with milder manifestations of psychiatric illness. This would not be possible without the control, structure, and staffing found in an inpatient setting.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for PubMedID 3432583

  • AUTISM AND GENETIC-DISORDERS SCHIZOPHRENIA BULLETIN Reiss, A. L., Feinstein, C., Rosenbaum, K. N. 1986; 12 (4): 724-738

    Abstract

    The syndrome of autism has been documented as occurring in association with a wide variety of genetic conditions. Autistic patients with a coexistent genetic condition, however, are not behaviorally or developmentally distinct from autistic patients for whom there is no known etiology or associated organic condition. This report reviews the literature linking autistic behavior with genetic conditions. Genetic, neurodevelopmental, and neuropathological findings in three genetic conditions which frequently give rise to autism are presented in detail. On the basis of this review, two hypotheses are supported: autism is a behaviorally defined phenotype which arises from diverse causes of central nervous system (CNS) damage, and the autistic phenotype represents only one point along a continuum of psychological dysfunction resulting from CNS damage. Current theories of genetic influences on brain development are reviewed, with emphasis on the relationships among qualitative, quantitative, and temporal abnormalities of CNS maturation and behavioral dysfunction. A hypothesis of abnormal brain development resulting from dysfunctional myelination is proposed as a potential etiologic factor in autism.

    View details for Web of Science ID A1986F065000014

    View details for PubMedID 3810072

  • PSYCHIATRIC DISABILITY ASSOCIATED WITH THE FRAGILE-X CHROMOSOME AMERICAN JOURNAL OF MEDICAL GENETICS Reiss, A. L., Feinstein, C., Toomey, K. E., Goldsmith, B., Rosenbaum, K., Caruso, M. A. 1986; 23 (1-2): 393-401

    Abstract

    Fragile X (or Martin-Bell) syndrome, a common, genetic, mental retardation disorder is increasingly being recognized as a major cause of cognitive disability and psychiatric illness in boys. Here, we present a study in which relatives in 4 generations of a large family with the fra(X) chromosome were given comprehensive psychiatric evaluations in order to further describe the psychopathology associated with this condition. Three of 4 males with the fra(X) chromosome were found to have autistic behavior. An adult fra(X) male had a chronic schizoaffective disorder and mental retardation. In female relatives, a relationship was found between the fra(X) carrier status and psychopathology including schizoaffective and major affective disorders.

    View details for Web of Science ID A1986AYQ1600029

    View details for PubMedID 3953657

  • DEVELOPMENTAL MANIFESTATIONS IN A BOY WITH PREPUBERTAL BIPOLAR DISORDER JOURNAL OF CLINICAL PSYCHIATRY Reiss, A. L. 1985; 46 (10): 441-443

    Abstract

    Bipolar affective disorder is not commonly reported in prepubertal children. This may be secondary to age-related variability in patterns of symptomatology, lack of appropriate diagnostic criteria, and/or confusion with other psychiatric disorders of childhood. A case of adult-type bipolar disorder in a prepubertal child is presented, with emphasis on developmental history, genetic influences, and response to pharmacologic intervention. Studies of children affected by, or at risk for, bipolar disorder are needed to identify biologic and developmental markers of this syndrome.

    View details for Web of Science ID A1985ATW3600010

    View details for PubMedID 4044536

  • AUTISM ASSOCIATED WITH WILLIAMS SYNDROME JOURNAL OF PEDIATRICS Reiss, A. L., Feinstein, C., Rosenbaum, K. N., BORENGASSERCARUSO, M. A., Goldsmith, B. M. 1985; 106 (2): 247-249

    View details for Web of Science ID A1985ABV1300015

    View details for PubMedID 3968612

  • CARBAMAZEPINE-INDUCED MANIA IN 2 CHILDREN - CASE-REPORT JOURNAL OF CLINICAL PSYCHIATRY Reiss, A. L., ODONNELL, D. J. 1984; 45 (6): 272-274

    Abstract

    Carbamazepine-induced mania is described in two case reports of prepubertal boys, one of whom also developed manic symptoms after receiving imipramine and dextroamphetamine. The structural and chemical similarities between carbamazepine and polycyclic antidepressants are discussed and it is suggested that caution and close observation be employed when using carbamazepine to treat children who have been identified as being at risk for developing this adverse effect.

    View details for Web of Science ID A1984SU48300010

    View details for PubMedID 6725221

Conference Proceedings


  • Maximizing the sensitivity of a screening questionnaire for determining fragile X at-risk status Teisl, J. T., Reiss, A. L., MAZZOCCO, M. M. WILEY-LISS. 1999: 281-285

    Abstract

    Parents of 55 preschool and school-aged children with the FMR1 full mutation (fM) completed a brief screening questionnaire. Parents of 55 additional children, each of whom was individually matched for sex, age, and IQ to one of the 55 children with Fragile X syndrome, also completed a questionnaire. Items on the questionnaire concerned behavior, rather than physical features or family history, associated with Fragile X syndrome. Children with the fM were more likely than controls to be on prescription medication, to have poor eye contact, to be described as nervous or anxious, and to regularly engage in repetitive movements and/or repetitive speech. Moreover, children with the fM received higher total scores on the questionnaire than their matched controls. These results suggest that questions about behavior are useful in the diagnostic evaluation of Fragile X syndrome, especially in the absence of the recognizable physical features associated with this condition.

    View details for Web of Science ID 000079339300009

    View details for PubMedID 10208162

  • Genotype, molecular phenotype, and cognitive phenotype: Correlations in fragile X syndrome Kaufmann, W. E., Abrams, M. T., Chen, W. M., Reiss, A. L. WILEY-LISS. 1999: 286-295

    Abstract

    The study of the neurobehavioral consequences of mutations of FMR1, the gene responsible for fragile X syndrome (FraX), has been based largely on correlations between mutation patterns and cognitive profile. Following the characterization of FMRP, the FMR1 gene product, preliminary correlations between FMRP levels, and neurologic phenotype have been established. However, most of these investigations have focused on individuals at both ends of the genetic and cognitive spectra of FraX, subjects with normal or premutation (PM) alleles or males with the FMR1 full mutation (FM). The present study is designed to characterize FMRP expression and to correlate it with IQ, in a sample representing a wide spectrum of FMR1 mutations. For this purpose we developed a highly sensitive immunoblotting assay using peripheral leukocytes. Three distinct patterns of FMRP immunoreactivity (-ir) emerged. Individuals with normal (n = 28) and PM (n = 8) alleles as well as most females with the FM (n = 14) showed the highest levels with multiple approximately 70-80 kDa FMRP-ir bands. Males with the FM (n = 10) demonstrated only a 70 kDa FMRP-ir band, and had significantly lower levels when compared with any previous groups. Males with mosaicism and three of 14 females with FM displayed a doublet with equal amounts of the highest and lowest molecular weight FMRP-ir bands. Multiple regression models that adjust for the effect of parental IQ indicated that both activation ratio and FMRP-ir are significantly correlated to subject IQ. We conclude that FMRP-ir offers promise as an indicator of the impact of FMR1 mutations upon neurologic function. Furthermore, our unexpected finding of FMRP-ir in all males with FM suggests that most of them are not transcriptionally silent.

    View details for Web of Science ID 000079339300010

    View details for PubMedID 10208163

  • Autistic behaviors among girls with fragile X syndrome MAZZOCCO, M. M., Kates, W. R., Baumgardner, T. L., Freund, L. S., Reiss, A. L. PLENUM PUBL CORP. 1997: 415-435

    Abstract

    Reports of autistic behaviors were examined for 30 school-age girls with fragile X (fraX) and 31 age- and IQ-matched controls through a structured interview administered to each girl's parent(s). IQ scores were obtained for each participant; anxiety, neuroanatomical, and molecular-genetic data were derived for girls with fraX. Girls with fraX had significantly more autistic behaviors than controls. These behaviors were qualitatively similar to those reported for boys with fraX, but were not correlated with IQ. Anxiety in girls with fraX was positively correlated with abnormal social and communication behaviors; posterior cerebellar vermis area was negatively correlated with measures of communication and stereotypic/restricted behaviors. Severity of stereotypic/restricted behaviors was negatively correlated with the prevalence of active non-fraX chromosomes. Thus anxiety and posterior cerebellar area measures had distinct associations with subsets of autistic behaviors; these associations may have important implications for understanding the neurobiology of autism.

    View details for Web of Science ID A1997XP25800006

    View details for PubMedID 9261667

  • MOLECULAR-NEUROBEHAVIORAL ASSOCIATIONS IN FEMALES WITH THE FRAGILE-X FULL MUTATION Abrams, M. T., Reiss, A. L., Freund, L. S., Baumgardner, T. L., Chase, G. A., Denckla, M. B. WILEY-LISS. 1994: 317-327

    Abstract

    In this study, young females with the fragile X [fra(X)] full mutation (fM) were assessed using quantitative measures of mutation amplification size (Amp) as well as the ratio of active normal X chromosome to total normal X chromosome (activation ratio-AR). Neurobehavioral assessments of females with the fM were performed and included specific and general measures of cognitive and behavioral/developmental functioning. To investigate molecular-behavioral associations, Amp and AR were used as independent variables, while cognitive and behavioral scores were used as dependent variables. Significant correlations were observed between both molecular variables (Amp and AR) and measures of cognitive functioning, with AR showing the most consistent and robust correlations. As AR increased, overall IQ and specific subtest and area scores from the cognitive tests increased. Conversely, as Amp increased, the overall IQ and specific subtest and area cognitive scores decreased. No significant associations were observed between AR or Amp and measures of behavior or development. The molecular-cognitive associations were generally consistent with the cognitive profile previously described in studies comparing females with fra(X) to age-matched controls. Amp and AR were not associated with one another, nor were they associated with the same cluster of cognitive measures. Though this report does not conclusively show that AR and Amp can be used to clinically assess the risk of a female with the fM for cognitive disability, the evidence presented does suggest that these molecular variables, especially AR, reflect important underlying genetic factors contributing to the fra(X) phenotype.

    View details for Web of Science ID A1994NV28200006

    View details for PubMedID 7942994

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