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Larry J Seidman

Publications and source records attributed to Larry J Seidman.

At least 19 recordsLinked to original sources
PubMed2006

Neuroanatomic substrates of sex differences in language dysfunction in schizophrenia: a pilot study.

OBJECTIVE: This pilot study investigated whether our previous findings of disrupted normal sexual brain dimorphisms in language-associated regions in schizophrenia were linked with our previously reported sex differences in language dysfunction in schizophrenia. METHOD: Nineteen adults with schizophrenia and 15 normal comparisons were tested on phonology, semantics and grammar and underwent structural MRI. RESULTS: Among males, left hippocampal and left planum temporale (PT) abnormalities were associated with phonological, semantic and grammar deficits, accounting for 17-52% and 27-33%, respectively, of variance in diagnostic group differences. Anterior cingulate gyrus was significantly associated with semantics. Among females, right Heschl's Gyrus (HG) and left PT were significantly associated with phonology, right HG with semantics and grammar and right hippocampus with semantics. CONCLUSIONS: These preliminary findings suggest disrupted sexual brain dimorphisms in schizophrenia are associated with sex-specific language deficits, and left hippocampal abnormalities, in particular, contribute to language dysfunction among men. Abnormalities in right cortical temporal regions showed stronger associations with language dysfunction among females.

Adolescent↗
PubMed2006

The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes.

The Consortium on the Genetics of Schizophrenia (COGS) is a 7-site collaboration that examines the genetic architecture of quantitative endophenotypes in families with schizophrenia. Here we review the background and rationale for selecting neurocognitive tasks as endophenotypic measures in genetic studies. Criteria are outlined for the potential of measures as endophenotypic vulnerability markers. These include association with illness, state independence (ie, adequate test-retest stability, adequate between-site reliability, impairments in patients not due to medications, impairments observed regardless of illness state), heritability, findings of higher rates in relatives of probands than in the general population, and cosegregation within families. The COGS required that, in addition, the measures be "neurocognitive" and thus linked to neurobiology and that they be feasible in multisite studies. The COGS neurocognitive assessment includes measures of attention, verbal memory, working memory, and a computerized neurocognitive battery that also includes facial processing tasks. Here we describe data demonstrating that these neurobehavioral measures meet criteria for endophenotypic candidacy. We conclude that quantitative neurocognitive endophenotypes need further evidence for efficacy in identifying genetic effects but have the potential of providing unprecedented insight into gene-environment interaction related to dimensions of brain and behavior in health and disease.

Cognition Disorders↗
PubMed2006

Hypothalamic abnormalities in schizophrenia: sex effects and genetic vulnerability.

BACKGROUND: This is a unique hypothalamic magnetic resonance imaging (MRI) study in schizophrenia, an important region in the limbic system. We hypothesized abnormal volumetric increases, with greater severity in multiplex families (more than one ill member) compared with simplex families (one ill). We tested the hypothesis that normal hypothalamic sexual dimorphism is disrupted in schizophrenia. METHODS: Eighty-eight DSM-III-R schizophrenia cases (40 simplex and 48 multiplex), 43 first-degree nonpsychotic relatives, and 48 normal comparisons systematically were compared. A 1.5-Tesla General Electric scanner was used to acquire structural MRI scans, and contiguous 3.1-mm slices were used to segment anterior and posterior hypothalamus. General linear model for correlated data and generalized estimating equations were used to compare cases, relatives, and controls on right and left hypothalamus, controlled for age, sex, and total cerebral volume. Spearman's correlations of hypothalamic volumes with anxiety were calculated to begin to examine arousal correlates with structural abnormalities. RESULTS: Findings demonstrated significantly increased hypothalamic volume in cases and nonpsychotic relatives, particularly in regions of paraventricular and mammillary body nuclei, respectively. This increase was linear from simplex to multiplex cases, was positively correlated with anxiety, and had a greater propensity in women. CONCLUSIONS: Findings suggest important implications for understanding genetic vulnerability of schizophrenia and the high rate of endocrine abnormalities.

Adult↗
PubMed2006

The Consortium on the Genetics of Endophenotypes in Schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration.

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health-funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment. METHODS: The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database. RESULTS: As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110). DISCUSSION: Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia.

Cooperative Behavior↗
PubMed2006

MRI abnormalities of the hippocampus and cavum septi pellucidi in females with schizotypal personality disorder.

OBJECTIVE: This study examined MRI hippocampal volume and cavum septi pellucidi (CSP) in female subjects with schizotypal personality disorder (SPD) and comparison subjects. METHOD: MRI was performed on 20 SPD and 29 comparison subjects with delineation of left and right hippocampi. Number of slices containing the CSP was counted. Subjects were given a working memory task, the Delayed Alternation task and other measures of working memory including the Wechsler Memory Test-Revised and the California Verbal Learning Test. Clinical measures were derived from the SCID-II. RESULTS: SPD females evinced bilaterally smaller hippocampal volumes compared with non-psychiatric female subjects (15.1% on left, 15.7% on right). Additionally, SPD subjects showed statistically significantly more slices containing CSP, and a trend level difference when large CSP was defined as four or more slices (20% vs. 6.9%). SPD subjects demonstrated more errors, more perseverations, and a trend toward more failure to maintain set on the Delayed Alternating task, which were associated with smaller left hippocampal volumes. There was no difference between groups in logical memory, verbal learning or semantic clustering nor a significant correlation between these measures and hippocampal volumes. Clinically, in SPD subjects, right hippocampal volumes correlated negatively with odd appearance/behavior and positively with suspiciousness/paranoia, and odd speech was positively correlated with the number of slices containing a CSP in exploratory analyses. CONCLUSIONS: Female SPD subjects showed bilaterally smaller hippocampal volumes and larger CSP than comparison subjects, similar to what has been shown in schizophrenia. Moreover, these abnormalities have clinically significant associations which may help to explain some of the manifestations of the disorder.

Adolescent↗
PubMed2006

Successful multi-site measurement of antisaccade performance deficits in schizophrenia.

The antisaccade task is a promising schizophrenia endophenotype; it is stable over time and reflects neurophysiological deficits present in both schizophrenia subjects and their first-degree relatives. Meaningful genetic research requires large sample sizes that are best ascertained using multi-site study designs. To establish the criterion validity of the antisaccade task in a multi-site design, the Consortium on the Genetics of Schizophrenia (COGS) examined whether seven sites could detect previously reported antisaccade deficits in schizophrenia subjects. Investigators presented 3 blocks of 20 antisaccade stimuli to 143 schizophrenia subjects and 195 comparison subjects. Frequent collaborator communication, standardized training, and ongoing quality assurance optimized testing uniformity. Data were discarded from only 1.2% of subjects due to poor quality, reflecting the high fidelity of data collection and scoring methods. All sites detected a significant difference in the proportion of correct antisaccades between schizophrenia and comparison subjects (p<.02 at all sites); group differences in gain and latency were less robust. Regression analyses to adjust for the effects of group, site, age, gender, smoking, and parental education on the proportion of correct antisaccades revealed a significant effect of group, site, and age but no effect of gender, smoking, or parental education, and no group-by-site interactions. Intraclass correlations between proportion of correct antisaccades across the blocks of stimuli ranged from 0.87 to 0.93, demonstrating good within-session reliability at sites. These results confirm previous findings of antisaccade deficits in schizophrenia subjects and support the use of the antisaccade task as a potential schizophrenia endophenotype in multi-site genetic studies.

Adolescent↗
PubMed2006

Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder.

BACKGROUND: Although there are many structural neuroimaging studies of attention-deficit/hyperactivity disorder (ADHD) in children, there are inconsistencies across studies and no consensus regarding which brain regions show the most robust area or volumetric reductions relative to control subjects. Our goal was to statistically analyze structural imaging data via a meta-analysis to help resolve these issues. METHODS: We searched the MEDLINE and PsycINFO databases through January 2005. Studies must have been written in English, used magnetic resonance imaging, and presented the means and standard deviations of regions assessed. Data were extracted by one of the authors and verified independently by another author. RESULTS: Analyses were performed using STATA with metan, metabias, and metainf programs. A meta-analysis including all regions across all studies indicated global reductions for ADHD subjects compared with control subjects, standardized mean difference=.408, p<.001. Regions most frequently assessed and showing the largest differences included cerebellar regions, the splenium of the corpus callosum, total and right cerebral volume, and right caudate. Several frontal regions assessed in only two studies also showed large significant differences. CONCLUSIONS: This meta-analysis provides a quantitative analysis of neuroanatomical abnormalities in ADHD and information that can be used to guide future studies.

Attention Deficit Disorder with Hyperactivity↗
PubMed2006

Evidence for reduced cerebellar volumes in trichotillomania.

BACKGROUND: Limited knowledge exists regarding the neurobiology of trichotillomania (TTM). Cerebellum (CBM) volumes were explored, given its role in complex, coordinated motor sequences. METHODS: Morphometric magnetic resonance imaging (MRI) scans were obtained for 14 female subjects with DSM-IV diagnoses of TTM and 12 age-, education-, and gender-matched normal control (NC) participants. Parcellation was performed utilizing a recently developed methodology to measure subterritory volumes of the CBM. Regions were defined based on knowledge of the structural and functional subunits of the CBM. RESULTS: As predicted, significant group differences were reported for CBM raw cortical volumes (p = .008) that survived correction for total brain volume (TBV; p = .037) and head circumference (HC; p = .011). A priori and post hoc group raw volume comparisons for CBM subterritories and functional clusters revealed many significant differences. However, most differences failed to withstand correction for total CBM volumes (TCV). Smaller volumes were consistently reported for the TTM versus NC cohorts. Total Massachusetts General Hospital Hair Pulling Scale (MGHHPS) scores were significantly inversely correlated with left primary sensorimotor cluster volumes (p = .008), with smaller volumes associated with more severe TTM symptoms. CONCLUSIONS: These findings implicate the CBM in the neurobiology of TTM, with reduced subterritory volumes reported for the TTM versus NC groups.

Adolescent↗
PubMed2006

Human cerebral cortex: a system for the integration of volume- and surface-based representations.

We describe an MRI-based system for topological analysis followed by measurements of topographic features for the human cerebral cortex that takes as its starting point volumetric segmentation data. This permits interoperation between volume-based and surface-based topographic analysis and extends the functionality of many existing segmentation schemes. We demonstrate the utility of these operations in individual as well as to group analysis. The methodology integrates analyses of cortical segmentation data generated by manual and semi-automated volumetric morphometry routines (such as the program cardviews) with the procedures of the FreeSurfer program to generate a cortical ribbon of the cerebrum and perform cortical topographic measurements (including thickness, surface area and curvature) in individual subjects as well as in subject populations. This system allows the computation of topographical cortical measurements for segmentation data generated from manual and semi-automated volumetric sources other than FreeSurfer. These measurements can be regionally specific and integrated with systems of cortical parcellation that subdivides the neocortex into gyral-based parcellation units (PUs). This system of topographical analysis of the cerebral cortex is consistent with current views of cortical development and neural systems organization of the human and non-human primate brain.

Adult↗
PubMed2006

Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) has been associated with structural alterations in brain networks influencing cognitive and motor behaviors. Volumetric studies in children identify abnormalities in cortical, striatal, callosal, and cerebellar regions. In a prior volumetric study, we found that ADHD adults had significantly smaller overall cortical gray matter, prefrontal, and anterior cingulate volumes than matched controls. Thickness and surface area are additional indicators of integrity of cytoarchitecture in the cortex. To expand upon our earlier results and further refine the regions of structural abnormality, we carried out a structural magnetic resonance imaging study of cortical thickness in the same sample of adults with ADHD (n = 24) and controls (n = 18), hypothesizing that the cortical networks underlying attention and executive function (EF) would be most affected. Compared with healthy adults, adults with ADHD showed selective thinning of cerebral cortex in the networks that subserve attention and EF. In the present study, we found significant cortical thinning in ADHD in a distinct cortical network supporting attention especially in the right hemisphere involving the inferior parietal lobule, the dorsolateral prefrontal, and the anterior cingulate cortices. This is the first documentation that ADHD in adults is associated with thinner cortex in the cortical networks that modulate attention and EF.

Adolescent↗
PubMed2006

Dorsolateral prefrontal and anterior cingulate cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging.

OBJECTIVES: Gray and white matter volume deficits have been reported in a number of studies of children with attention-deficit/hyperactivity disorder (ADHD); however, there is a paucity of structural magnetic resonance imaging (MRI) studies of adults with ADHD. This structural MRI study used an a priori region of interest approach. METHODS: Twenty-four adults with DSM-IV ADHD and 18 healthy controls comparable on age, socioeconomic status, sex, handedness, education, IQ, and achievement test performance had an MRI on a 1.5T Siemens scanner. Cortical and sub-cortical gray and white matter were segmented. Image parcellation divided the neocortex into 48 gyral-based units per hemisphere. Based on a priori hypotheses we focused on prefrontal, anterior cingulate cortex (ACC) and overall gray matter volumes. General linear analyses of the volumes of brain regions, adjusting for age, sex, and total cerebral volumes, were used to compare groups. RESULTS: Relative to controls, ADHD adults had significantly smaller overall cortical gray matter, prefrontal and ACC volumes. CONCLUSIONS: Adults with ADHD have volume differences in brain regions in areas involved in attention and executive control. These data, largely consistent with studies of children, support the idea that adults with ADHD have a valid disorder with persistent biological features.

Adult↗
PubMed2006

Neuropsychological functioning in adolescents and young adults at genetic risk for schizophrenia and affective psychoses: results from the Harvard and Hillside Adolescent High Risk Studies.

Siblings and offspring of persons with schizophrenia carry elevated genetic risk for the illness and manifest attentional and memory impairments. Because less is known about other neuropsychological functions and their specificity in adolescents, we conducted a genetic high-risk (HR) study of schizophrenia (HR-SCZ) and affective psychosis (HR-AFF). Participants (ages 12-25) were from the Harvard Adolescent High-Risk and Hillside Family studies, including 73 HR-SCZ, 18 HR-AFF, and 84 community controls (CCs) recruited in metropolitan Boston and New York. Groups were compared on overall neurocognitive functioning, 6 domains, and 13 test scores, controlling for age, parental education, and correlated data within families. The HR-SCZ group was significantly impaired overall, while the HR-AFF group demonstrated a trend toward overall impairment. HR-SCZ subjects showed significantly lower Verbal Ability (d = .73) and Executive Functioning/Working Memory (d = .47) than CCs. HR-AFF subjects showed reduced Verbal Ability (d = .64) compared to CCs. Excluding 12 CCs with a parental history of depression (without psychosis) led to larger differences between HR and CC groups across domains. Moreover, HR-SCZ and CC group differences in Verbal Memory (d = .39) and Visual-Spatial (d = .34) became statistically significant. There were no significant differences between HR-SCZ and HR-AFF groups. Data support a modest neuropsychological deficit in persons at genetic HR for psychosis, with a broader range of deficits in HR-SCZ. Future work should assess the relationship of neurocognition to adaptive functioning and possible onset of psychosis in HR samples. Ascertainment criteria for controls may markedly influence results and interpretation of group differences.

Adolescent↗
PubMed2006

Altered brain activation in dorsolateral prefrontal cortex in adolescents and young adults at genetic risk for schizophrenia: an fMRI study of working memory.

OBJECTIVE: Adult first-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness, demonstrate working memory (WM) impairments, and manifest alterations in dorsolateral prefrontal cortical (DLPFC) function during WM. Because substantially less is known about these phenotypes in adolescent subjects we sought to demonstrate that young relatives of persons with schizophrenia manifest impaired WM and altered prefrontal activation. METHODS: Participants were 21 non-psychotic, unmedicated first-degree relatives of persons with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, depressed type and 24 unmedicated controls, recruited from the community and hospitals in metropolitan Boston (ages 13-28). We compared groups on an auditory WM task with interference prior to scanning and used functional magnetic resonance imaging (fMRI) to compare groups while performing visual 2-back WM and control vigilance tasks. Blood oxygen level dependent signal change was measured using two whole-brain gradient echo EPI pulse acquisitions (21 contiguous, 5mm axial slices), acquired on a Siemens 1.5T MR scanner. Data were analyzed using Statistical Parametric Mapping-99. RESULTS: The high risk subjects were significantly impaired on the auditory WM task, had significantly greater Phobic Anxiety, and marginally greater Psychoticism than controls on the Symptom Checklist-90-Revised, and showed significantly greater task-elicited activation in the right DLPFC (BA 46). Psychopathology, IQ, and in-scanner WM performance did not account for group differences in brain activation. CONCLUSIONS: Data support a physiological difference (an exaggerated fMRI response) in DLPFC in adolescents at genetic risk for schizophrenia, independent of psychosis. Future work can study the relationship of these measures to possible onset of schizophrenia.

Adolescent↗
PubMed2006

Change in neurocognition by housing type and substance abuse among formerly homeless seriously mentally ill persons.

OBJECTIVE: To test the effect of living in group housing rather than independent apartments on executive functioning, verbal memory and sustained attention among formerly homeless persons with serious mental illness and to determine whether substance abuse modifies this effect. METHOD: In metropolitan Boston, 112 persons in Department of Mental Health shelters were randomly assigned to group homes ("Evolving Consumer Households", with project facilitator, group meetings, resident decision-making) or independent apartments. All were case managed. A neuropsychological test battery was administered at baseline, at 18 months (Time 2), with an 81% follow-up rate, and at 48 months (Time 3), with a 59% follow-up rate. Hierarchical Linear Modeling was applied to executive functioning--assessed with the Wisconsin Card Sorting Test (Perseverations)-Logical Memory story recall, and an auditory Continuous Performance Test (CPT) for sustained attention. Subject characteristics were controlled. RESULTS: When moved to group homes, subjects without a lifetime substance abuse history improved on Perseverations, while those who moved to independent apartments deteriorated on Perseverations. Across the two housing conditions, subjects showed no change in Perseverations, but improved on Logical Memory story recall and the CPT. CONCLUSIONS: Type of housing placement can influence cognitive functioning; notably, socially isolating housing is associated with weakened executive functioning. Substance abuse significantly diminishes environmental effects. These are important factors to consider in housing placement and subsequent treatment.

Boston↗
PubMed2006

Neuropsychological functioning in people with ADHD across the lifespan.

ADHD is defined by behavioral characteristics similar to neuropsychological disorders of executive dysfunction. This paper is a literature review of the neurocognitive characteristics of ADHD from early childhood through adulthood. The author addresses the development of the concept of attention and executive function (EF) deficits in ADHD, clinical neuropsychological studies of pre-teenage children, teenagers and adults with ADHD, gender and the role of psychiatric co-morbidity including the relationship of learning disabilities to ADHD, heterogeneity of neuropsychological dysfunctions, experimental neuropsychological studies, the relationship of brain structure to function, psychopharmacology of ADHD, and clinical neuropsychological assessment. The group data clearly supports the hypothesis that executive dysfunctions are correlates of ADHD regardless of gender and age, and these EF deficits are exacerbated by co-morbidity with learning disabilities such as dyslexia. However, there is limited data on children under the age of 5, teenagers from age 13-18, and adults with ADHD over the age of 40. Studies of individual classification of people with ADHD compared to healthy, non-psychiatric controls do not support the use of neuropsychological tests for the clinical diagnosis of ADHD, and indicate that not all persons with ADHD have EF deficits. Some persons with ADHD may have deficits in brain reward systems that are relatively independent of EF impairments. Future research should clarify the multiple sources of ADHD impairments, continue to refine neuropsychological tools optimized for assessment, and incorporate longitudinal, developmental designs to understand ADHD across the lifespan.

Attention Deficit Disorder with Hyperactivity↗
PubMed2006

Reduction of caudate nucleus volumes in neuroleptic-naïve female subjects with schizotypal personality disorder.

BACKGROUND: The caudate nucleus might contribute to the psychopathological and cognitive deficits observed in schizotypal personality disorder (SPD), a schizophrenia spectrum disorder. Here we focused on female patients, because this group is underrepresented in studies of SPD and schizophrenia, and we might learn more about the caudate and clinical and cognitive impairments that are unique to female patients diagnosed with SPD. METHODS: Magnetic resonance imaging scans, obtained on a 1.5-T magnet with 1.5-mm contiguous slices, were used to measure the caudate in 32 neuroleptic-naïve women with SPD and in 29 female normal comparison subjects. Subjects were group-matched for age, parental socioeconomic status, and intelligence quotient. RESULTS: We found significantly reduced left and right caudate relative volume (8.3%, 7.7%) in female SPD subjects compared with normal comparison subjects. In female SPD subjects, we found significant correlations between smaller total caudate relative volume and worse performance on the Wisconsin Card Sorting test (nonperseverative errors) and on the California Verbal Learning Test (verbal memory and learning), and significant correlations between smaller total caudate relative volume and both positive and negative symptoms on the Structured Interview for Schizotypy. CONCLUSIONS: These findings demonstrate that, for female SPD subjects, smaller caudate volume is associated with poorer cognitive performance and more schizotypal symptomatology.

Adolescent↗