Longitudinal functional brain imaging study in early course schizophrenia before and after cognitive enhancement therapy.

OBJECTIVE: Schizophrenia is characterized by impaired -social and non social cognition both of which lead to functional deficits. These deficits may benefit from cognitive remediation, but the neural underpinnings of such improvements have not been clearly delineated. METHODS: We conducted a functional magnetic resonance (fMRI) study in early course schizophrenia patients randomly assigned to cognitive enhancement therapy (CET) or enriched supportive therapy (EST) and treated for two years. Imaging data over three time points including fMRI blood oxygen level dependent (BOLD) data were acquired during performance of a cognitive control paradigm, the Preparing to Overcome Prepotency (POP) task, and functional connectivity data, were analyzed. RESULTS: During the two years of treatment, CET patients showed a continual increase in BOLD activity in the right dorsolateral prefrontal cortex (DLPFC), whereas EST patients tended to show no change in prefrontal brain function throughout treatment. Increases in right DLPFC activity were modestly associated with improved neurocognition (ß = .14, p = .041), but not social cognition. Functional connectivity analyses showed reduced connectivity between the DLPFC and the anterior cingulate cortex (ACC) in CET compared to EST over the two years of treatment, which was associated with neurocognitive improvement. CONCLUSIONS: These findings suggest that CET leads to enhanced neural activity in brain regions mediating cognitive control and increased efficiency in prefrontal circuits; such changes may be related to the observed therapeutic effects of CET on neurocognitive function.

Association of variants in DRD2 and GRM3 with motor and cognitive function in first-episode psychosis.

Similar smooth pursuit eye tracking dysfunctions are present across psychotic disorders. They include pursuit initiation and maintenance deficits that implicate different functional brain systems. This candidate gene study examined psychosis-related genotypes regulating dopamine and glutamate neurotransmission in relation to these pursuit deficits. One hundred and thirty-eight untreated first-episode patients with a psychotic disorder were genotyped for four markers in DRD2 and four markers in GRM3. The magnitude of eye movement abnormality in patients was defined in relation to performance of matched healthy controls (N = 130). Eighty three patients were followed after 6 weeks of antipsychotic treatment. At baseline, patients with a -141C deletion in DRD2 rs1799732 had slower initiation eye velocity and longer pursuit latency than CC insertion carriers. Further, GRM3 rs274622_CC carriers had poorer pursuit maintenance than T-carriers. Antipsychotic treatment resulted in prolonged pursuit latency in DRD2 rs1799732_CC insertion carriers and a decline in pursuit maintenance in GRM3 rs6465084_GG carriers. The present study demonstrates for the first time that neurophysiological measures of motor and neurocognitive deficits in patients with psychotic disorders have different associations with genes regulating dopamine and glutamate systems, respectively. Alterations in striatal D2 receptor activity through the -141C Ins/Del polymorphism could contribute to pursuit initiation deficits in psychotic disorders. Alterations in GRM3 coding for the mGluR3 protein may impair pursuit maintenance by compromising higher perceptual and cognitive processes that depend on optimal glutamate signaling in corticocortical circuits. DRD2 and GRM3 genotypes also selectively modulated the severity of adverse motor and neurocognitive changes resulting from antipsychotic treatment.

HLA associations in schizophrenia: are we re-discovering the wheel?

Associations between human leukocyte antigen (HLA) polymorphisms on chromosome 6p and schizophrenia (SZ) risk have been evaluated for over five decades. Numerous case-control studies from the candidate gene era analyzed moderately sized samples and reported nominally significant associations with several loci in the HLA region (sample sizes, n = 100-400). The risk conferred by individual alleles was modest (odds ratios < 2.0). The basis for the associations could not be determined, though connections with known immune and auto-immune abnormalities in SZ were postulated. Interest in the HLA associations has re-emerged following several recent genome-wide association studies (GWAS); which utilized 10- to 100-fold larger samples and also identified associations on the short arm of chromosome 6. Unlike the earlier candidate gene studies, the associations are statistically significant following correction for multiple comparisons. Like the earlier studies; they have modest effect sizes, raising questions about their utility in risk prediction or pathogenesis research. In this review, we summarize the GWAS and reflect on possible bases for the associations. Suggestions for future research are discussed. We favor, in particular; efforts to evaluate local population sub-structure as well as further evaluation of immune-related variables in future studies.

Diagnostically distinct resting state fMRI energy distributions: A subject-specific maximum entropy modeling study.

Objective: Existing neuroimaging studies of psychotic and mood disorders have reported brain activation differences (first-order properties) and altered pairwise correlation-based functional connectivity (second-order properties). However, both approaches have certain limitations that can be overcome by integrating them in a pairwise maximum entropy model (MEM) that better represents a comprehensive picture of fMRI signal patterns and provides a system-wide summary measure called energy. This study examines the applicability of individual-level MEM for psychiatry and identifies image-derived model coefficients related to model parameters. Method: MEMs are fit to resting state fMRI data from each individual with schizophrenia/schizoaffective disorder, bipolar disorder, and major depression (n=132) and demographically matched healthy controls (n=132) from the UK Biobank to different subsets of the default mode network (DMN) regions. Results: The model satisfactorily explained observed brain energy state occurrence probabilities across all participants, and model parameters were significantly correlated with image-derived coefficients for all groups. Within clinical groups, averaged energy level distributions were higher in schizophrenia/schizoaffective disorder but lower in bipolar disorder compared to controls for both bilateral and unilateral DMN. Major depression energy distributions were higher compared to controls only in the right hemisphere DMN. Conclusions: Diagnostically distinct energy states suggest that probability distributions of temporal changes in synchronously active nodes may underlie each diagnostic entity. Subject-specific MEMs allow for factoring in the individual variations compared to traditional group-level inferences, offering an improved measure of biologically meaningful correlates of brain activity that may have potential clinical utility.

Over 30 years of STEP: The Pittsburgh experience with first-episode psychosis.

AIMS: For over 30 years, combined research and treatment settings in the US have been critical to conceptualizing care for first-episode psychosis (FEP). Here we describe an early example of such a context, the Services for the Treatment of Early Psychosis (STEP) clinic, which is affiliated with the University of Pittsburgh. METHODS: We describe STEP's historical roots and establishment in the early 1990s; STEP's research and treatment contributions, alongside its growth and ongoing leadership. RESULTS: Research-based clinics, like STEP, preceded and helped pave the way for the Recovery After an Initial Schizophrenia Episode project in the US and the ensuing Coordinated Specialty Care (CSC) approach, now widely adopted in the US. Early clinic-based research at STEP helped establish protocols for psychopharmacology, the relevance of effective early treatment, including psychosocial approaches, and highlighted disparities in treatment outcomes across race/ethnicity. Multidisciplinary collaboration and dialogue with consumers contributed to early treatment, combining psychosocial and pharmacological approaches. STEP adopted CSC and is situated within a bi-state Learning Health System. STEP has retained a relatively unique 5-year treatment model and exists within continuum of care ideally suited to studying psychotic illness and treatment outcomes. CONCLUSIONS: STEP remains the largest academic FEP clinic in Pennsylvania. Academic FEP clinics like STEP will have a critical role within Learning Health Systems nationally to model participatory approaches, sustain early intervention treatment quality and ongoing treatment developments.

Gene Expressions Preferentially Influence Cortical Thickness of Human Connectome Project Atlas Parcellated Regions in First-Episode Antipsychotic-Naïve Psychoses.

Altered gene expressions may mechanistically link genetic factors with brain morphometric alterations. Existing gene expression studies have examined selected morphometric features using low-resolution atlases in medicated schizophrenia. We examined the relationship of gene expression with cortical thickness (CT), surface area (SA), and gray matter volume (GMV) of first-episode antipsychotic-naïve psychosis patients (FEAP = 85) and 81 controls, hypothesizing that gene expressions often associated with psychosis will differentially associate with different morphometric features. We explored such associations among schizophrenia and non-schizophrenia subgroups within FEAP group compared to controls. We mapped 360 Human Connectome Project atlas-based parcellations on brain MRI on to the publicly available brain gene expression data from the Allen Brain Institute collection. Significantly correlated genes were investigated using ingenuity pathway analysis to elucidate molecular pathways. CT but not SA or GMV correlated with expression of 1137 out of 15 633 genes examined controlling for age, sex, and average CT. Among these ≈19%, ≈39%, and 8% of genes were unique to FEAP, schizophrenia, and non-schizophrenia, respectively. Variants of 10 among these 1137 correlated genes previously showed genome-wide-association with schizophrenia. Molecular pathways associated with CT were axonal guidance and sphingosine pathways (common to FEAP and controls), selected inflammation pathways (unique to FEAP), synaptic modulation (unique to schizophrenia), and telomere extension (common to NSZ and healthy controls). We demonstrate that different sets of genes and molecular pathways may preferentially influence CT in different diagnostic groups. Genes with altered expressions correlating with CT and associated pathways may be targets for pathophysiological investigations and novel treatment designs.

Multipronged investigation of morphometry and connectivity of hippocampal network in relation to risk for psychosis using ultrahigh field MRI.

Hippocampal abnormalities are associated with psychosis-risk states. Given the complexity of hippocampal anatomy, we conducted a multipronged examination of morphometry of regions connected with hippocampus, and structural covariance network (SCN) and diffusion-weighted circuitry among 27 familial high-risk (FHR) individuals who were past the highest risk for conversion to psychoses and 41 healthy controls using ultrahigh-field high-resolution 7 Tesla (7T) structural and diffusion MRI data. We obtained fractional anisotropy and diffusion streams of white matter connections and examined correspondence of diffusion streams with SCN edges. Nearly 89 % of the FHR group had an axis-I disorder including 5 with schizophrenia. Therefore, we compared the entire FHR group regardless of the diagnosis (All_FHR = 27) and FHR-without-schizophrenia (n = 22) with 41 controls in this integrative multimodal analysis. We found striking volume loss in bilateral hippocampus, particularly the head, bilateral thalamus, caudate, and prefrontal regions. All_FHR and FHR-without-SZ SCNs showed significantly lower assortativity and transitivity but higher diameter compared to controls, but FHR-without-SZ SCN differed on every graph metric compared to All_FHR suggesting disarrayed network with no hippocampal hubs. Fractional anisotropy and diffusion streams were lower in FHR suggesting white matter network impairment. White matter edges showed significantly higher correspondence with SCN edges in FHR compared to controls. These differences correlated with psychopathology and cognitive measures. Our data suggest that hippocampus may be a "neural hub" contributing to psychosis risk. Higher correspondence of white matter tracts with SCN edges suggest that shared volume loss may be more coordinated among regions within the hippocampal white matter circuitry.

Threshold Selection for Brain Connectomes.

Introduction: Structural and functional brain connectomes represent macroscale data collected through techniques such as magnetic resonance imaging (MRI). Connectomes may contain noise that contributes to false-positive edges, thereby obscuring structure-function relationships and data interpretation. Thresholding procedures can be applied to reduce network density by removing low-signal edges, but there is limited consensus on appropriate selection of thresholds. This article compares existing thresholding methods and introduces a novel alternative "objective function" thresholding method. Methods: The performance of thresholding approaches, based on percolation and objective functions, is assessed by (1) computing the normalized mutual information (NMI) of community structure between a known network and a simulated, perturbed networks to which various forms of thresholding have been applied, and by (2) comparing the density and the clustering coefficient (CC) between the baseline and thresholded networks. An application to empirical data is provided. Results: Our proposed objective function-based threshold exhibits the best performance in terms of resulting in high similarity between the underlying networks and their perturbed, thresholded counterparts, as quantified by NMI and CC analysis on the simulated functional networks. Discussion: Existing network thresholding methods yield widely different results when graph metrics are subsequently computed. Thresholding based on the objective function maintains a set of edges such that the resulting network shares the community structure and clustering features present in the original network. This outcome provides a proof of principle that objective function thresholding could offer a useful approach to reducing the network density of functional connectivity data.

Energy in functional brain states correlates with cognition in adolescent schizophrenia and healthy persons.

Adolescent-onset schizophrenia (AOS) is a relatively rare and under-studied form of schizophrenia with more severe cognitive impairments and poorer outcome compared to adult-onset schizophrenia. Several neuroimaging studies have reported alterations in regional activations that account for activity in individual regions (first-order model) and functional connectivity that reveals pairwise co-activations (second-order model) in AOS compared to controls. The pairwise maximum entropy model, also called the Ising model, can integrate both first-order and second-order terms to elucidate a comprehensive picture of neural dynamics and captures both individual and pairwise activity measures into a single quantity known as energy, which is inversely related to the probability of state occurrence. We applied the MEM framework to task functional MRI data collected on 23 AOS individuals in comparison with 53 healthy control subjects while performing the Penn Conditional Exclusion Test (PCET), which measures executive function that has been repeatedly shown to be more impaired in AOS compared to adult-onset schizophrenia. Accuracy of PCET performance was significantly reduced among AOS compared to controls as expected. Average cumulative energy achieved for a participant over the course of the fMRI negatively correlated with task performance, and the association was stronger than any first-order associations. The AOS subjects spent more time in higher energy states that represent lower probability of occurrence and were associated with impaired executive function suggesting that the neural dynamics may be less efficient compared to controls who spent more time in lower energy states occurring with higher probability and hence are more stable and efficient. The energy landscapes in both conditions featured attractors that corresponded to two distinct subnetworks, namely fronto-temporal and parieto-motor. Attractor basins were larger in the controls than in AOS; moreover, fronto-temporal basin size was significantly correlated with cognitive performance in controls but not among the AOS. The single trial trajectories for the AOS group also showed higher variability in concordance with shallow attractor basins among AOS. These findings suggest that the neural dynamics of AOS features more frequent occurrence of less probable states with narrower attractors, which lack the relation to executive function associated with attractors in control subjects suggesting a diminished capacity of AOS to generate task-effective brain states.

Brain activation patterns during visual episodic memory processing among first-degree relatives of schizophrenia subjects.

Episodic memory deficits are proposed as a potential intermediate phenotype of schizophrenia. We examined deficits in visual episodic memory and associated brain activation differences among early course schizophrenia (n=22), first-degree relatives (n=16) and healthy controls without personal or family history of psychotic disorders (n=28). Study participants underwent functional magnetic resonance imaging on a 3T scanner while performing visual episodic memory encoding and retrieval task. We examined in-scanner behavioral performance evaluating response time and accuracy of performance. Whole-brain BOLD response differences were analyzed using SPM5 correcting for multiple comparisons. There was an incremental increase in response time among the study groups (healthy controls

Age-dependent effects of schizophrenia genetic risk on cortical thickness and cortical surface area: Evaluating evidence for neurodevelopmental and neurodegenerative models of schizophrenia.

Risk for schizophrenia peaks during early adulthood, a critical period for brain development. Although several influential theoretical models have been proposed for the developmental relationship between brain pathology and clinical onset, to our knowledge, no study has directly evaluated the predictions of these models for schizophrenia developmental genetic effects on brain structure. To address this question, we introduce a framework to estimate the effects of schizophrenia genetic variation on brain structure phenotypes across the life span. Five-hundred and six participants, including 30 schizophrenia probands, 200 of their relatives (aged 12-85 years) from 32 families with at least two first-degree schizophrenia relatives, and 276 unrelated controls, underwent MRI to assess regional cortical thickness (CT) and cortical surface area (CSA). Genetic variance decomposition analyses were conducted to distinguish among schizophrenia neurogenetic effects that are most salient before schizophrenia peak age-of-risk (i.e., early neurodevelopmental effects), after peak age-of-risk (late neurodevelopmental effects), and during the later plateau of age-of-risk (neurodegenerative effects). Genetic correlations between schizophrenia and cortical traits suggested early neurodevelopmental effects for frontal and insula CSA, late neurodevelopmental effects for overall CSA and frontal, parietal, and occipital CSA, and possible neurodegenerative effects for temporal CT and parietal CSA. Importantly, these developmental neurogenetic effects were specific to schizophrenia and not found with nonpsychotic depression. Our findings highlight the potentially dynamic nature of schizophrenia genetic effects across the lifespan and emphasize the utility of integrating neuroimaging methods with developmental behavior genetic approaches to elucidate the nature and timing of risk-conferring processes in psychopathology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Age-dependent patterns of schizophrenia genetic risk affect cognition.

Cognition shares substantial genetic overlap with schizophrenia, yet it remains unclear whether such genetic effects become significant during developmental periods of elevated risk for schizophrenia, such as the peak age of onset. We introduce an investigative framework integrating epidemiological, developmental, and genetic approaches to determine whether genetic effects shared between schizophrenia and cognition are significant across periods of differing risk for schizophrenia onset, and whether these effects are shared with depression. 771 European-American participants, including 636 (ages 15-84 years) from families with at least two first-degree relatives with schizophrenia and 135 unrelated controls, were divided into three age-risk groups based on ages relative to epidemiological age of onset patterns for schizophrenia: Pre-Peak (before peak age-of-onset: 15 to 22 years), Post-Peak (after peak age-of-onset: 23-42 years), and Plateau (during plateau of age-of-onset: over 42 years). For general cognition and 11 specific cognitive traits, we estimated genetic correlations with schizophrenia and with depression within each age-risk group. Genetic effects shared between deficits in general cognition and schizophrenia were nonsignificant before peak age of onset, yet were high and significant after peak age of onset and during the plateau of onset. These age-dependent genetic effects were largely consistent across specific cognitive traits and not transdiagnostically shared with depression. Schizophrenia genetic effects appear to influence cognitive traits in an age-dependent manner, supporting late developmental and perhaps neurodegenerative models that hypothesize increased expression of schizophrenia risk genes during and after the peak age of risk. Our findings underscore the utility of cognitive traits for tracking schizophrenia genetic effects across the lifespan.

Gray matter loss in young relatives at risk for schizophrenia: relation with prodromal psychopathology.

The maturation of neocortical regions mediating social cognition during adolescence and young adulthood in relatives of schizophrenia patients may be vulnerable to heritable alterations of neurodevelopment. Prodromal psychotic symptoms, commonly emerging during this period in relatives, have been hypothesized to result from alterations in brain regions mediating social cognition. We hypothesized these regions to show longitudinal alterations and these alterations to predict prodromal symptoms in adolescent and young adult relatives of schizophrenia patients. 27 Healthy controls and 23 relatives were assessed at baseline and one-year follow-up using scale of prodromal symptoms and gray matter volumes of hypothesized regions from T1-MRI images. Regional volumes showing deficits on ANCOVA and repeated-measures ANCOVAs (controlling intra cranial volume, age and gender) were correlated with prodromal symptoms. At baseline, bilateral amygdalae, bilateral pars triangulares, left lateral orbitofrontal, right frontal pole, angular and supramarginal gyrii were smaller in relatives compared to controls. Relatives declined but controls increased or remained stable on bilateral lateral orbitofrontal, left rostral anterior cingulate, left medial prefrontal, right inferior frontal gyrus and left temporal pole volumes at follow-up relative to baseline. Smaller volumes predicted greater severity of prodromal symptoms at both cross-sectional assessments. Longitudinally, smaller baseline volumes predicted greater prodromal symptoms at follow-up; greater longitudinal decreases in volumes predicted worsening (increase) of prodromal symptoms over time. These preliminary findings suggest that abnormal longitudinal gray matter loss may occur in regions mediating social cognition and may convey risk for prodromal symptoms during adolescence and early adulthood in individuals with a familial diathesis for schizophrenia.

Abnormalities of the corpus callosum in non-psychotic high-risk offspring of schizophrenia patients.

Alterations in the structure of the corpus callosum (CC) have been observed in schizophrenia. Offspring of schizophrenia parents have 10-15 times higher risk for developing schizophrenia. We examined CC volume in offspring at genetic high-risk (HR) subjects. Since the sub-regions of the CC are topographically mapped to cortical brain regions, we hypothesized that HR subjects may show a decrement in total volume and differential volume decreases in sub-regions of the CC. The offspring of schizophrenia parents (HR; n=70; 36 males) and healthy volunteers with no family or personal history of psychotic disorders (healthy controls (HC); n=73; 37 males) matched for age, gender and education were selected for the study. Magnetic resonance images were collected using a GE 1.5 T scanner and processed using FreeSurfer image analysis software. The CC was divided into five neuroanatomically based partitions. The volume of total CC and the five sub-regions were measured blind to clinical information. With covariation for intracranial volume, HR subjects had significantly reduced total CC, more prominently observed in the anterior splenium. An age-related increase in CC volume was found in the anterior and posterior splenium of healthy controls but not in HR subjects. The volume reduction was greater in male than female HR subjects. The volume reduction in the CC may reflect a reduction in axonal fibers crossing the hemispheres and/or myelination between the left and right temporo-parietal cortices. The absence of an age-related volume increase suggests an abnormal developmental trajectory that may underlie susceptibility to schizophrenia.

Fine-mapping reveals novel alternative splicing of the dopamine transporter.

The dopamine transporter gene (SLC6A3, DAT) has been implicated in the pathogenesis of numerous psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). We previously detected association between SZ and intronic SLC6A3 variants that replicated in two independent Caucasian samples, but had no obvious function. In follow-up analyses, we sequenced the coding and intronic regions of SLC6A3 to identify complete linkage disequilibrium patterns of common variations. We genotyped 78 polymorphisms, narrowing the potentially causal region to two correlated clusters of associated SNPs localized predominantly to introns 3 and 4. Our computational analysis of these intronic regions predicted a novel cassette exon within intron 3, designated E3b, which is conserved among primates. We confirmed alternative splicing of E3b in post-mortem human substantia nigra (SN). As E3b introduces multiple in-frame stop codons, the SLC6A3 open reading frame is truncated and the spliced product may undergo nonsense mediated decay. Thus, factors that increase E3b splicing could reduce the amount of unspliced product available for translation. Observations consistent with this prediction were made using cellular assays and in post-mortem human SN. In mini-gene constructs, the extent of splicing is also influenced by at least two common haplotypes, so the alternative splicing was evaluated in relation to SZ risk. Meta-analyses across genome-wide association studies did not support the initial associations and further post-mortem studies did not suggest case-control differences in splicing. These studies do not provide a compelling link to schizophrenia. However, the impact of the alternative splicing on other neuropsychiatric disorders should be investigated. © 2010 Wiley-Liss, Inc.

Neuroimaging in Schizophrenia.

Schizophrenia is a chronic psychotic disorder with a lifetime prevalence of about 1%. Onset is typically in adolescence or early adulthood; characteristic symptoms include positive symptoms, negative symptoms, and impairments in cognition. Neuroimaging studies have shown substantive evidence of brain structural, functional, and neurochemical alterations that are more pronounced in the association cortex and subcortical regions. These abnormalities are not sufficiently specific to be of diagnostic value, but there may be a role for imaging techniques to provide predictions of outcome. Incorporating multimodal imaging datasets using machine learning approaches may offer better diagnostic and predictive value in schizophrenia.

Regionally Distinct Alterations in Membrane Phospholipid Metabolism in Schizophrenia: A Meta-analysis of Phosphorus Magnetic Resonance Spectroscopy Studies.

BACKGROUND: Existing data on altered membrane phospholipid metabolism in schizophrenia are diverse. We conducted a meta-analysis of studies of phosphorus magnetic resonance spectroscopy, a noninvasive imaging approach that can assess molecular biochemistry of cortex by measuring phosphomonoester (PME) and phosphodiester (PDE) levels, which can provide evidence of altered biochemical processes involved in neuropil membrane expansion and contraction in schizophrenia. METHODS: We analyzed PME and PDE data in the frontal and temporal lobes in subjects with schizophrenia from 24 peer-reviewed publications using the MAVIS package in R by building random- and fixed-effects models. Heterogeneity of effect sizes, effects of publication bias, and file drawer analysis were also assessed. RESULTS: Subjects with schizophrenia showed lower PME levels in the frontal regions (p = .008) and elevated PDE levels in the temporal regions (p < .001) with significant heterogeneity. We noted significant publication bias and file drawer effect for frontal PME and PDE and temporal PDE levels, but not for temporal PME levels. Fail-safe analysis estimated that a high number of negative studies were required to provide nonsignificant results. CONCLUSIONS: Despite methodological differences, these phosphorus magnetic resonance spectroscopy studies demonstrate regionally specific imbalance in membrane phospholipid metabolism related to neuropil in subjects with schizophrenia compared with control subjects reflecting neuropil contraction. Specifically, decreased PME levels in the frontal regions and elevated PDE levels in the temporal regions provide evidence of decreased synthesis and increased degradation of neuropil membrane, respectively. Notwithstanding significant heterogeneity and publication bias, a large number of negative studies are required to render the results of this meta-analysis nonsignificant. These findings warrant further postmortem and animal studies.

Neurological abnormalities among offspring of persons with schizophrenia: relation to premorbid psychopathology.

BACKGROUND: Neurological Examination Abnormalities (NEA, often called "neurological soft signs") have been observed in early schizophrenia and may be heritable. We investigated the prevalence, and neurocognitive and psychopathological correlates of NEA among offspring of schizophrenia patients who are at increased genetic risk for this illness. METHODS: Neurological examinations were conducted on high risk (HR, n=74) and healthy comparison subjects (HS, n=86), using the Heinrichs-Buchanan scale. Cognitive-perceptual (CogPer) and repetitive motor (RepMot) subscores, and total NEA scores were computed. All HR and HS were assessed using K-SADS/SCID for diagnoses. Schizotypy was measured using the Magical Ideation and the Perceptual Aberration subscales (Chapman scale), attention using Continuous Performance Test (CPT-IP) and executive functions using the Wisconsin Card Sorting Test (WCST). RESULTS: CogPer (F(1,160)=7.14, p=0.008) but not RepMot NEA scores were higher in HR subjects compared to HS after controlling for age and sex. CogPer NEA scores were higher in HR subjects with axis I psychopathology compared to those without (F(2,170)-6.41, p=0.002). HR subjects had higher schizotypy scores (composite of the magical ideation and perceptual aberration scales) (F(1,141)=23.25, p=0.000004). Schizotypy scores were negatively correlated with sustained attention and executive functions. In addition, schizotypy was positively correlated with CogPer NEA scores. CONCLUSIONS: Young relatives at increased genetic risk for schizophrenia show more frequent NEA. CogPer but not RepMot NEA scores were elevated, consistent with our prior observation of CogPer NEA being relatively specific for schizophrenia. The observed relationships between NEA, cognitive impairments, schizotypy and axis I disorders suggest that NEA may characterize a subgroup of HR offspring at an elevated risk for psychopathology.