Sparse deep neural networks on imaging genetics for schizophrenia case-control classification.

Deep learning methods hold strong promise for identifying biomarkers for clinical application. However, current approaches for psychiatric classification or prediction do not allow direct interpretation of original features. In the present study, we introduce a sparse deep neural network (DNN) approach to identify sparse and interpretable features for schizophrenia (SZ) case-control classification. An L0 -norm regularization is implemented on the input layer of the network for sparse feature selection, which can later be interpreted based on importance weights. We applied the proposed approach on a large multi-study cohort with gray matter volume (GMV) and single nucleotide polymorphism (SNP) data for SZ classification. A total of 634 individuals served as training samples, and the classification model was evaluated for generalizability on three independent datasets of different scanning protocols (N = 394, 255, and 160, respectively). We examined the classification power of pure GMV features, as well as combined GMV and SNP features. Empirical experiments demonstrated that sparse DNN slightly outperformed independent component analysis + support vector machine (ICA + SVM) framework, and more effectively fused GMV and SNP features for SZ discrimination, with an average error rate of 28.98% on external data. The importance weights suggested that the DNN model prioritized to select frontal and superior temporal gyrus for SZ classification with high sparsity, with parietal regions further included with lower sparsity, echoing previous literature. The results validate the application of the proposed approach to SZ classification, and promise extended utility on other data modalities and traits which ultimately may result in clinically useful tools.

Dentate gyrus volume deficit in schizophrenia.

BACKGROUND: Schizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined. METHODS: Hippocampal formation (HF) subregion volumes were obtained using FreeSurfer 6.0 from individuals with schizophrenia (n = 176, mean age ± s.d. = 39.0 ± 11.5, 132 males) and healthy volunteers (n = 173, mean age ± s.d. = 37.6 ± 11.3, 123 males) with similar mean age, gender, handedness, and race distributions. Relationships between the HF subregion volume with the largest between group difference, neuropsychological performance, and single-nucleotide polymorphisms were assessed. RESULTS: This study found a significant group by region interaction on hippocampal subregion volumes. Compared to healthy volunteers, individuals with schizophrenia had significantly smaller dentate gyrus (DG) (Cohen's d = -0.57), Cornu Ammonis (CA) 4, molecular layer of the hippocampus, hippocampal tail, and CA 1 volumes, when statistically controlling for intracranial volume; DG (d = -0.43) and CA 4 volumes remained significantly smaller when statistically controlling for mean hippocampal volume. DG volume showed the largest between group difference and significant positive associations with visual memory and speed of processing in the overall sample. Genome-wide association analysis with DG volume as the quantitative phenotype identified rs56055643 (ß = 10.8, p < 5 × 10-8, 95% CI 7.0-14.5) on chromosome 3 in high linkage disequilibrium with MOBP. Gene-based analyses identified associations between SLC25A38 and RPSA and DG volume. CONCLUSIONS: This study suggests that DG dysfunction is fundamentally involved in schizophrenia pathophysiology, that it may contribute to cognitive abnormalities in schizophrenia, and that underlying biological mechanisms may involve contributions from MOBP, SLC25A38, and RPSA.

Personality traits and negative consequences associated with binge drinking and marijuana use in college students.

Background: Binge drinking is common in college students, and many drink in quantities greater than the standard definition of bingeing. Combined use of additional substances, particularly marijuana, is also common. Objectives: Increased impulsivity and sensation seeking are risk factors for bingeing, and this study was designed to characterize their association with extreme compared to standard bingeing, as well as with combined bingeing and marijuana use. Negative consequences of alcohol use were also investigated. Methods: Self-report personality measures and a measure of the negative consequences of alcohol use were given to a sample of 221 college students (109 females) sorted into a control and 4 binge groups based upon their patterns of bingeing and marijuana use. Narrowly defined, non-overlapping measures of impulsivity and sensation seeking were analyzed to assess the association of these personality measures with substance-use patterns and negative consequences of bingeing. Results: Standard bingers did not differ from non-bingeing controls on either impulsivity or sensation seeking, whereas extreme bingers had significantly higher impulsivity and sensation seeking scores than controls and also significantly higher sensation seeking than standard bingers. Exploratory analyses of a broader set of personality scales showed that a disinhibition scale was also significant predictor of substance use group. A number of personality traits significantly predicted substance use patterns as well as specific negative consequences of bingeing. Conclusions: Impulsivity, sensation seeking and disinhibition are significant associates of substance use patterns and the negative consequences of use in college students.

Cortical Thickness in Adolescents with a Family History of Alcohol Use Disorder.

BACKGROUND: Individuals with a family history (FH+) of alcohol use disorder (AUD) have a higher risk for developing an AUD than those with no family history (FH-) of AUD. In addition, FH+ individuals tend to perform worse on neuropsychological measures and show heightened impulsivity, which may be due to underlying differences in brain structure such as cortical thickness. The primary aim of this study was to investigate differences in cortical thickness in FH+ compared to FH- adolescents. Secondary aims were to (i) investigate differences in executive functioning and impulsivity, and (ii) examine associations between brain structure and behavior. METHODS: Brain scans of 95 FH- and 93 FH+ subjects aged 13 to 18 were obtained using magnetic resonance imaging. FH+ subjects were required to have at least 1 biological parent with a history of an AUD. FH+ and FH- individuals had limited or no past alcohol use, thereby minimizing potential effects of alcohol. Subjects were evaluated on impulsivity and executive functioning tasks. Thicknesses of cortical lobes and subregions were analyzed using FreeSurfer. Regions showing group differences were examined for group-by-age interactions and correlations with neuropsychological and personality measures. RESULTS: FH+ adolescents had thinner cortices in frontal and parietal lobes, notably in the medial orbitofrontal, lateral orbitofrontal, and superior parietal cortices. The difference in cortical thickness between family history groups was strongest among the youngest subjects. FH+ subjects were also more impulsive and had poorer performance on a spatial memory task. CONCLUSIONS: These findings demonstrate frontal and parietal structural differences in FH+ adolescents that might underlie cognitive and behavioral characteristics associated with AUD risk.

The Function Biomedical Informatics Research Network Data Repository.

The Function Biomedical Informatics Research Network (FBIRN) developed methods and tools for conducting multi-scanner functional magnetic resonance imaging (fMRI) studies. Method and tool development were based on two major goals: 1) to assess the major sources of variation in fMRI studies conducted across scanners, including instrumentation, acquisition protocols, challenge tasks, and analysis methods, and 2) to provide a distributed network infrastructure and an associated federated database to host and query large, multi-site, fMRI and clinical data sets. In the process of achieving these goals the FBIRN test bed generated several multi-scanner brain imaging data sets to be shared with the wider scientific community via the BIRN Data Repository (BDR). The FBIRN Phase 1 data set consists of a traveling subject study of 5 healthy subjects, each scanned on 10 different 1.5 to 4 T scanners. The FBIRN Phase 2 and Phase 3 data sets consist of subjects with schizophrenia or schizoaffective disorder along with healthy comparison subjects scanned at multiple sites. In this paper, we provide concise descriptions of FBIRN's multi-scanner brain imaging data sets and details about the BIRN Data Repository instance of the Human Imaging Database (HID) used to publicly share the data.

Recreational Marijuana Use, Adolescent Cognitive Development, and Schizophrenia Susceptibility.

Background: We investigated how low marijuana (MJ) use levels, the typical use pattern in most adolescent users, affect cognitive maturation and schizophrenia risk. Methods: In two complementary adolescent samples where the majority reported minimal MJ use, we compared cognitive performances before and after MJ use initiation. The Iowa sample (40 first-degree relatives and 54 second-degree relatives of patients with schizophrenia and 117 control subjects with no schizophrenia family history) underwent a battery of standardized neuropsychological tests at 0, 18, and 36 months. Based on self-administered Timeline Followback interviews, 26.5% of adolescents had emergent MJ use (eMJ) during follow-up. The second sample (n = 3463), derived from a birth cohort, received substance use and sustained attention assessments between ages 10 and 15 years. Mixed linear models and regression analyses tested the effects of eMJ on longitudinal changes in cognitive performance. Results: In the Iowa sample, longitudinal changes in 5 of 8 cognitive domains were significantly associated with eMJ. On sustained attention, visuospatial working memory, and executive sequencing, adolescents with eMJ showed less age-expected improved performance. In addition, first-degree relatives with eMJ were less improved on processing speed and executive reasoning than first-degree relatives without eMJ. In the birth cohort, greater intraindividual variability in reaction times (indicative of poorer sustained attention) was significantly associated with more frequent MJ use and with recreational use levels. Conclusions: Nonheavy MJ use disrupts normal adolescent maturation and compounds aberrant adolescent maturation associated with familial schizophrenia risk. These findings underscore the importance of reducing adolescent MJ access in the context of increased availability to high-potency MJ.

Auditory oddball hypoactivation in schizophrenia.

Individuals with schizophrenia (SZ) show aberrant activations, assessed via functional magnetic resonance imaging (fMRI), during auditory oddball tasks. However, associations with cognitive performance and genetic contributions remain unknown. This study compares individuals with SZ to healthy volunteers (HVs) using two cross-sectional data sets from multi-center brain imaging studies. It examines brain activation to auditory oddball targets, and their associations with cognitive domain performance, schizophrenia polygenic risk scores (PRS), and genetic variation (loci). Both sample 1 (137 SZ vs. 147 HV) and sample 2 (91 SZ vs. 98 HV), showed hypoactivation in SZ in the left-frontal pole, and right frontal orbital, frontal pole, paracingulate, intracalcarine, precuneus, supramarginal and hippocampal cortices, and right thalamus. In SZ, precuneus activity was positively related to cognitive performance. Schizophrenia PRS showed a negative correlation with brain activity in the right-supramarginal cortex. GWA analyses revealed significant single-nucleotide polymorphisms associated with right-supramarginal gyrus activity. RPL36 also predicted right-supramarginal gyrus activity. In addition to replicating hypoactivation for oddball targets in SZ, this study identifies novel relationships between regional activity, cognitive performance, and genetic loci that warrant replication, emphasizing the need for continued data sharing and collaborative efforts.

Function biomedical informatics research network recommendations for prospective multicenter functional MRI studies.

This report provides practical recommendations for the design and execution of multicenter functional MRI (MC-fMRI) studies based on the collective experience of the Function Biomedical Informatics Research Network (FBIRN). The study was inspired by many requests from the fMRI community to FBIRN group members for advice on how to conduct MC-fMRI studies. The introduction briefly discusses the advantages and complexities of MC-fMRI studies. Prerequisites for MC-fMRI studies are addressed before delving into the practical aspects of carefully and efficiently setting up a MC-fMRI study. Practical multisite aspects include: (i) establishing and verifying scan parameters including scanner types and magnetic fields, (ii) establishing and monitoring of a scanner quality program, (iii) developing task paradigms and scan session documentation, (iv) establishing clinical and scanner training to ensure consistency over time, (v) developing means for uploading, storing, and monitoring of imaging and other data, (vi) the use of a traveling fMRI expert, and (vii) collectively analyzing imaging data and disseminating results. We conclude that when MC-fMRI studies are organized well with careful attention to unification of hardware, software and procedural aspects, the process can be a highly effective means for accessing a desired participant demographics while accelerating scientific discovery.

Eyeblink conditioning in healthy adults: a positron emission tomography study.

Eyeblink conditioning is a paradigm commonly used to investigate the neural mechanisms underlying motor learning. It involves the paired presentation of a tone-conditioning stimulus which precedes and co-terminates with an airpuff unconditioned stimulus. Following repeated paired presentations a conditioned eyeblink develops which precedes the airpuff. This type of learning has been intensively studied and the cerebellum is known to be essential in both humans and animals. The study presented here was designed to investigate the role of the cerebellum during eyeblink conditioning in humans using positron emission tomography (PET). The sample includes 20 subjects (10 male and 10 female) with an average age of 29.2 years. PET imaging was used to measure regional cerebral blood flow (rCBF) changes occurring during the first, second, and third blocks of conditioning. In addition, stimuli-specific rCBF to unpaired tones and airpuffs ("pseudoconditioning") was used as a baseline level that was subtracted from each block. Conditioning was performed using three, 15-trial blocks of classical eyeblink conditioning with the last five trials in each block imaged. As expected, subjects quickly acquired conditioned responses. A comparison between the conditioning tasks and the baseline task revealed that during learning there was activation of the cerebellum and recruitment of several higher cortical regions. Specifically, large peaks were noted in cerebellar lobules IV/V, the frontal lobes, and cingulate gyri.

Impact of binge drinking during college on resting state functional connectivity.

AIM: The current study examined the longitudinal effects of standard binge drinking (4+/5+ drinks for females/males in 2 hours) and extreme binge drinking (8+/10+ drinks for females/males in 2 hours) on resting-state functional connectivity. METHOD: 119 college students (61 males) were recruited in groups of distinct bingeing patterns at baseline: non-bingeing controls, standard and extreme bingers. Resting-state scans were first obtained when participants were freshmen/sophomores and again approximately two years later. Associations between longitudinal bingeing (reported during this two-year gap) and network connectivity were examined. Network connectivity was calculated by aggregating all edges affiliated with the same network (an edge is a functional connection between two brain regions). The relationship between longitudinal bingeing and connectivity edges was also studied using connectome-based predictive modeling (CPM). RESULTS: Greater standard bingeing was negatively associated with change in connectivity between Default Mode Network and Ventral Attention Network (DMN-VAN; False Discovery Rate corrected), controlling for initial binge groups, longitudinal network changes, motions, scanner, SES, sex, and age. The correlations between change in DMN-VAN connectivity and change in cognitive performance (Stroop, Digit Span, Letter Fluency, and Trail Making) were also tested, but the results were not significant. Lastly, CPM failed to identify a generalizable predictive model of longitudinal bingeing from change in connectivity edges. CONCLUSIONS: Binge drinking is associated with abnormality in networks implicated in attention and self-focused processes, which, in turn, have been implicated in rumination, craving, and relapse. More extensive alterations in functional connectivity might be observed with heavier or longer binge drinking pattern.

Sex, drugs, and cognition: effects of marijuana.

Despite the knowledge that many drugs affect men and women differently, few studies exploring the effects of marijuana use on cognition have included women. Findings from both animal and human studies suggest marijuana may have more marked effects in women. This study examined sex differences in the acute effects of marijuana on cognition in 70 (n=35 male, 35 female) occasional users of marijuana. Tasks were chosen to tap a wide variety of cognitive domains affected by sex and/or marijuana including attention, cognitive flexibility, time estimation, and visuospatial processing. As expected, acute marijuana use impaired performance on selective and divided attention, time estimation, and cognitive flexibility. While there did not appear to be sex differences in marijuana's effects on cognition, women requested to discontinue the smoking session more often than men, likely leading to an underestimation of differences. Further study of psychological differences in marijuana's effects on men and women following both acute and residual effects of marijuana is warranted.

Sex differences in the effects of marijuana on simulated driving performance.

In the United States, one in six teenagers has driven under the influence of marijuana. Driving under the influence of marijuana and alcohol is equally prevalent, despite the fact that marijuana use is less common than alcohol use. Much of the research examining the effects of marijuana on driving performance was conducted in the 1970s and led to equivocal findings. During that time, few studies included women and driving simulators were rudimentary. Further, the potency of marijuana commonly used recreationally has increased. This study examined sex differences in the acute effects of marijuana on driving performance using a realistic, validated driving simulator. Eighty-five subjects (n = 50 males, 35 females) participated in this between-subjects, double-blind, placebo controlled study. In addition to an uneventful, baseline segment of driving, participants were challenged with collision avoidance and distracted driving scenarios. Under the influence of marijuana, participants decreased their speed and failed to show expected practice effects during a distracted drive. No differences were found during the baseline driving segment or collision avoidance scenarios. No differences attributable to sex were observed. This study enhances the current literature by identifying distracted driving and the integration of prior experience as particularly problematic under the influence of marijuana.

Behavioral inhibition and reward processing in college binge drinkers with and without marijuana use.

AIM: Binge drinking is common during college, and studies have shown that many college students drink in quantities that far exceed the standard binge drinking threshold. Previous research has noted personality differences in individuals who engage in binge drinking, but few studies have examined neurobiological differences in both standard bingers (4/5 drinks in two hours for females/males; sBinge) and extreme binge drinkers (8+/10+ drinks in two hours for females/males; eBinge). METHOD: The current study of 221 college students used functional magnetic resonance imaging (fMRI) to study neural activation on a stop signal task (SST) to assess behavioral inhibition and a monetary incentive delay (MID) task to assess activation to rewards and losses. Non-bingeing controls, sBinge, and eBinge freshmen and sophomores were recruited. In addition, because binge/extreme binge drinking is often associated with marijuana (MJ) use, MJ + sBinge and MJ + eBinge groups were also included. RESULTS: All five groups showed strong activation in expected key cortical and striatal regions on both the SST and the MID. However, there were no significant differences between groups either at the whole-brain level or in specific regions of interest. Behavioral performance on the fMRI tasks also did not differ between groups. CONCLUSIONS: These results suggest that our sample of individuals who engage in binge or extreme binge drinking with or without MJ co-use do not differ in brain activity on reward and inhibitory tasks. Neural differences may be present on other cognitive tasks or may emerge later after more sustained use of alcohol, MJ, and other drugs.

Tuning in to the voices: a multisite FMRI study of auditory hallucinations.

INTRODUCTION: Auditory hallucinations or voices are experienced by 75% of people diagnosed with schizophrenia. We presumed that auditory cortex of schizophrenia patients who experience hallucinations is tonically "tuned" to internal auditory channels, at the cost of processing external sounds, both speech and nonspeech. Accordingly, we predicted that patients who hallucinate would show less auditory cortical activation to external acoustic stimuli than patients who did not. METHODS: At 9 Functional Imaging Biomedical Informatics Research Network (FBIRN) sites, whole-brain images from 106 patients and 111 healthy comparison subjects were collected while subjects performed an auditory target detection task. Data were processed with the FBIRN processing stream. A region of interest analysis extracted activation values from primary (BA41) and secondary auditory cortex (BA42), auditory association cortex (BA22), and middle temporal gyrus (BA21). Patients were sorted into hallucinators (n = 66) and nonhallucinators (n = 40) based on symptom ratings done during the previous week. RESULTS: Hallucinators had less activation to probe tones in left primary auditory cortex (BA41) than nonhallucinators. This effect was not seen on the right. DISCUSSION: Although "voices" are the anticipated sensory experience, it appears that even primary auditory cortex is "turned on" and "tuned in" to process internal acoustic information at the cost of processing external sounds. Although this study was not designed to probe cortical competition for auditory resources, we were able to take advantage of the data and find significant effects, perhaps because of the power afforded by such a large sample.

Association Between Age and Familial Risk for Alcoholism on Functional Connectivity in Adolescence.

OBJECTIVE: Youth with a family history of alcohol use disorder (family history positive [FHP]) are at increased risk for developing maladaptive substance use relative to family history negative (FHN) peers. Building on earlier studies demonstrating morphological differences and distinct patterns of neural activation in FHP, the purpose of the present study was to investigate differential intrinsic functional connectivity among brain networks indexing premorbid risk of developing alcohol use disorder (AUD). METHOD: The current study examined intrinsic functional connectivity using resting state functional magnetic resonance imaging in 191 adolescents 13 to 18 years of age with and without family history of AUD via independent component analysis, a method enabling data-driven investigation of internetwork and intranetwork connectivity among brain regions at rest. RESULTS: Analyses revealed significantly lower intranetwork connectivity in FHP compared to FHN participants between the dorsal premotor cortex and other sensorimotor network regions. Reduced intranetwork connectivity in this region was further correlated with the number of biological family members with AUD and mood disorders. Robust differences were also evident in internetwork connectivity as a function of age. However, there was no evidence for family history by age interactions. CONCLUSION: Intra- but not internetwork connectivity appears to differentiate FHP and FHN adolescents, whereas age differences within adolescence are marked by differences in internetwork connectivity.

Theory of mind and schizophrenia: a positron emission tomography study of medication-free patients.

BACKGROUND: "Theory of mind" (TOM) refers to the ability to attribute mental states (ie, beliefs and goals) to one's self and others and to recognize that behaviors are guided by these mental states. This capacity, critical for social competence, is impaired in schizophrenia. We undertook a study of TOM in a group of patients with schizophrenia and healthy controls. METHOD: We used positron emission tomography to identify the neural circuits recruited during a verbal task that required participants to attribute mental states to a character in a story of their creation. The comparison task consisted of reading aloud a neutral story, controlling for the speech component of the task. RESULTS: Patients and controls generated the same percentage of TOM utterances. However, the two groups had markedly different patterns of brain activation. Compared with controls, patients had a lower blood flow in multiple regions in the left hemisphere including the frontal and visual association cortices, posterior hippocampus, and insula. The flow was also lower in contralateral areas in the lateral cerebellum and vermis, thalamus, and posterior insula. On the other hand, the flow was higher in the patients predominantly in the right hemisphere, including multiple frontal and parietal regions, insula, visual association cortex, and pulvinar. DISCUSSION: The areas of lower flow are consistent with previous studies indicating impairment in recruiting cortical-cerebellar circuitry in schizophrenia. The areas of higher flow may reflect a need to draw on the right hemisphere to compensate for deficits in left hemisphere networks that include frontal cortex, anterior cingulate, cerebellum, and thalamus.

A positive take on schizophrenia negative symptom scales: Converting scores between the SANS, NSA and SDS.

AIMS: To provide quantitative conversions between commonly used scales for the assessment of negative symptoms in schizophrenia. METHOD: Linear regression analyses generated conversion equations between symptom scores from the Scale for the Assessment of Negative Symptoms (SANS), the Schedule for the Deficit Syndrome (SDS), the Positive and Negative Syndrome Scale (PANSS), or the Negative Symptoms Assessment (NSA) based on a cross sectional sample of 176 individuals with schizophrenia. Intraclass correlations assessed the rating conversion accuracy based on a separate sub-sample of 29 patients who took part in the initial study as well as an independent sample of 28 additional subjects with schizophrenia. RESULTS: Between-scale negative symptom ratings were moderately to highly correlated (r = 0.73-0.91). Intraclass correlations between the original negative symptom rating scores and those obtained via using the conversion equations were in the range of 0.61-0.79. CONCLUSIONS: While there is a degree of non-overlap, several negative symptoms scores reflect measures of similar constructs and may be reliably converted between some scales. The conversion equations are provided at http://www.converteasy.org and may be used for meta- and mega-analyses that examine negative symptoms.

Polygenic risk score, genome-wide association, and gene set analyses of cognitive domain deficits in schizophrenia.

This study assessed genetic contributions to six cognitive domains, identified by the MATRICS Cognitive Consensus Battery as relevant for schizophrenia, cognition-enhancing, clinical trials. Psychiatric Genomics Consortium Schizophrenia polygenic risk scores showed significant negative correlations with each cognitive domain. Genome-wide association analyses identified loci associated with attention/vigilance (rs830786 within HNF4G), verbal memory (rs67017972 near NDUFS4), and reasoning/problem solving (rs76872642 within HDAC9). Gene set analysis identified unique and shared genes across cognitive domains. These findings suggest involvement of common and unique mechanisms across cognitive domains and may contribute to the discovery of new therapeutic targets to treat cognitive deficits in schizophrenia.

Multimodal neuromarkers in schizophrenia via cognition-guided MRI fusion.

Cognitive impairment is a feature of many psychiatric diseases, including schizophrenia. Here we aim to identify multimodal biomarkers for quantifying and predicting cognitive performance in individuals with schizophrenia and healthy controls. A supervised learning strategy is used to guide three-way multimodal magnetic resonance imaging (MRI) fusion in two independent cohorts including both healthy individuals and individuals with schizophrenia using multiple cognitive domain scores. Results highlight the salience network (gray matter, GM), corpus callosum (fractional anisotropy, FA), central executive and default-mode networks (fractional amplitude of low-frequency fluctuation, fALFF) as modality-specific biomarkers of generalized cognition. FALFF features are found to be more sensitive to cognitive domain differences, while the salience network in GM and corpus callosum in FA are highly consistent and predictive of multiple cognitive domains. These modality-specific brain regions define-in three separate cohorts-promising co-varying multimodal signatures that can be used as predictors of multi-domain cognition.

Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers.

CONTEXT: Relatively little is known about genetic determinants of cognitive dysfunction in schizophrenia. Recent studies suggest that a brain-derived neurotrophic factor (BDNF) prodomain single nucleotide polymorphism resulting in a valine (Val)-to-methionine (Met) substitution is associated with impaired declarative memory in healthy volunteers and patients with schizophrenia. These studies indicate that the BDNF(Met) variant may mediate hippocampal cognitive functions by modulating intracellular trafficking and activity-dependent BDNF release. To our knowledge, the way in which this functional single nucleotide polymorphism affects other neurocognitive measures has not been examined. Its role in determining cognitive deficits in schizophrenia has also not been systematically studied. OBJECTIVES: To characterize the neurocognitive and brain morphometric phenotypic correlates of the BDNF Val66Met polymorphism and to test the specificity of the BDNF(Met) variant on cognitive dysfunction in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: A comprehensive battery of standardized neuropsychological tests was administered to 144 healthy volunteers and 293 patients with schizophrenia spectrum disorder at a tertiary care university hospital. Approximately two thirds of the sample also underwent high-resolution magnetic resonance imaging brain scans. MAIN OUTCOME MEASURES: Genotype effects (in Met allele carriers vs Val homozygotes) on 5 cognitive domain z scores and magnetic resonance imaging gray matter brain volume measures (Talairach atlas-based cerebral lobes and optimized voxel-based morphometry) were examined using general linear models. RESULTS: On verbal memory, there was a significant genotype effect but no genotype x diagnosis effects. In both patients with schizophrenia and healthy volunteers, Met allele carriers had poorer verbal memory performance than their Val-homozygous counterparts. On visuospatial abilities, there were significant genotype and genotype x diagnosis effects. Met allele-associated visuospatial impairment was specific to patients with schizophrenia but not healthy volunteers. There were significant genotype effects on gray matter volumes within brain regions known to subserve these 2 cognitive domains, with Met allele carriers having smaller temporal and occipital lobar gray matter volumes. Optimized voxel-based morphometry further suggests that parietal heteromodal cortical gray matter deficits may underlie visuospatial impairment in patients with schizophrenia carrying the Met allele. CONCLUSIONS: We replicated the association between the BDNF(Met) variant and poor medial temporal lobe-related memory performance. The consonance of our cognitive and brain morphology findings further suggests that the BDNF(Met) variant may have a specific role in conferring visuospatial dysfunction in schizophrenia.