Childhood trauma moderates schizotypy-related brain morphology: analyses of 1182 healthy individuals from the ENIGMA schizotypy working group.

BACKGROUND: Schizotypy represents an index of psychosis-proneness in the general population, often associated with childhood trauma exposure. Both schizotypy and childhood trauma are linked to structural brain alterations, and it is possible that trauma exposure moderates the extent of brain morphological differences associated with schizotypy. METHODS: We addressed this question using data from a total of 1182 healthy adults (age range: 18-65 years old, 647 females/535 males), pooled from nine sites worldwide, contributing to the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Schizotypy working group. All participants completed both the Schizotypal Personality Questionnaire Brief version (SPQ-B), and the Childhood Trauma Questionnaire (CTQ), and underwent a 3D T1-weighted brain MRI scan from which regional indices of subcortical gray matter volume and cortical thickness were determined. RESULTS: A series of multiple linear regressions revealed that differences in cortical thickness in four regions-of-interest were significantly associated with interactions between schizotypy and trauma; subsequent moderation analyses indicated that increasing levels of schizotypy were associated with thicker left caudal anterior cingulate gyrus, right middle temporal gyrus and insula, and thinner left caudal middle frontal gyrus, in people exposed to higher (but not low or average) levels of childhood trauma. This was found in the context of morphological changes directly associated with increasing levels of schizotypy or increasing levels of childhood trauma exposure. CONCLUSIONS: These results suggest that alterations in brain regions critical for higher cognitive and integrative processes that are associated with schizotypy may be enhanced in individuals exposed to high levels of trauma.

Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Parasympathetic arousal-related cortical activity is associated with attention during cognitive task performance.

Parasympathetic arousal is associated with states of heightened attention and well-being. Arousal may affect widespread cortical and subcortical systems across the brain, however, little is known about its influence on cognitive task processing and performance. In the current study, healthy adult participants (n â€‹= â€‹20) underwent multi-band echo-planar imaging (TR â€‹= â€‹0.72 â€‹s) with simultaneous pulse oximetry recordings during performance of the Multi Source Interference Task (MSIT), the Oddball Task (OBT), and during rest. Processing speed on both tasks was robustly related to heart rate (HR). Participants with slower HR responded faster on both the MSIT (33% variance explained) and the OBT (25% variance explained). Within all participants, trial-to-trial fluctuations in processing speed were robustly related to the heartbeat-stimulus interval, a metric that is dependent both on the concurrent HR and the stimulus timing with respect to the heartbeat. Models examining the cardiac-BOLD response revealed that a distributed set of regions showed arousal-related activity that was distinct for different task conditions. Across these cortical regions, activity increased with slower HR. Arousal-related activity was distinct from task-evoked activity and it was robust to the inclusion of additional physiological nuisance regressors into the models. For the MSIT, such arousal-related activity occurred across visual and dorsal attention network regions. For the OBT, this activity occurred within fronto-parietal regions. For rest, arousal-related activity also occurred, but was confined to visual regions. The pulvinar nucleus of the thalamus showed arousal-related activity during all three task conditions. Widespread cortical activity, associated with increased parasympathetic arousal, may be propagated by thalamic circuits and contributes to improved attention. This activity is distinct from task-evoked activity, but affects cognitive performance and therefore should be incorporated into neurobiological models of cognition and clinical disorders.

Frequency specific resting state functional abnormalities in psychosis.

Resting state functional magnetic resonance imaging studies of psychosis have focused primarily on the amplitude of low-frequency fluctuations in the blood oxygen level dependent (BOLD) signal ranging from .01 to 0.1 Hz. Few studies, however, have investigated the amplitude of frequency fluctuations within discrete frequency bands and higher than 0.1 Hz in patients with psychosis at different illness stages. We investigated BOLD signal within three frequency ranges including slow-4 (.027-.073 Hz), slow-3 (.074-0.198 Hz) and slow-2 (0.199-0.25 Hz) in 89 patients with either first-episode or chronic psychosis and 119 healthy volunteers. We investigated the amplitude of frequency fluctuations within three frequency bands using 47 regions-of-interest placed within 14 known resting state networks derived using group independent component analysis. There were significant group x frequency interactions for the visual and motor cortex networks, with the largest significant group differences (patients < healthy volunteers) evident in slow-4 and slow-3, respectively. Also, healthy volunteers had an overall higher amplitude of frequency fluctuations compared to patients across the three frequency ranges in the visual cortex, dorsal attention and motor cortex networks with the opposite effect (patients > healthy volunteers) evident within the salience and frontal gyrus networks. Subsequent analyses indicated that these effects were evident in both first-episode and chronic patients. Our study provides new data regarding the importance of BOLD signal fluctuations within different frequency bands in the neurobiology of psychosis.

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.

Brain white matter development is associated with a human-specific haplotype increasing the synthesis of long chain fatty acids.

The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with ω-3 and ω-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9-86 years of age (n = 207). Diffusion tensor imaging was performed to measure fractional anisotropy (FA), a putative measure of myelination, of the cerebral WM tracts. FADS haplotype status was determined with a single nucleotide polymorphism (rs174583) that tags this haplotype. Overall, normal age-related WM differences were observed, including higher FA values in early adulthood compared with childhood, followed by lower FA values across older age ranges. However, individuals homozygous for the minor allele (associated with lower LC-PUFA concentrations) did not display these normal age-related WM differences (significant age × genotype interactions, p(corrected) < 0.05). These findings suggest that LC-PUFAs are involved in human brain WM development from childhood into adulthood. This haplotype and LC-PUFAs may play a role in myelin-related disorders of neurodevelopmental origin.

The accumbofrontal tract: Diffusion tensor imaging characterization and developmental change from childhood to adulthood.

The presence of an anatomical connection between the orbitofrontal cortex and ventral striatum, forming a so-called reward network, is well established across species. This connection has important implications for reward processing and is relevant to a number of neuropsychiatric disorders. Moreover, white matter (WM) is known to continue to mature across adolescence and into early adulthood, and developmental change in the reward network is an important component of models of decision making and risk taking. Despite the importance of this connection, the underlying WM has only recently been characterized in humans histologically, and not yet in-vivo using brain imaging. Here, we implemented diffusion tensor imaging (DTI) in a large cross-sectional sample of 295 healthy individuals ages 8-68 to further characterize the WM of this connection and its development from childhood into adulthood. We demonstrate that the accumbofrontal tract, connecting the orbitofrontal cortex and nucleus accumbens, can be identified using standard DTI sequences. Using Poisson modeling, we show that the accumbofrontal tract undergoes significant change across the lifespan, with males showing a higher and earlier peak compared to females. Moreover, the change occurs in a pattern consistent with developmental models of decision-making. These findings support the hypothesis that developmental differences in WM integrity may be a contributing factor to the observed risk taking that occurs in adolescence. The accumbofrontal tract is not yet included in standard WM atlases, but may be important for inclusion in studies investigating fronto-striatal networks, as well as in investigations of substance abuse and decision making.

Age and sex effects on corpus callosum morphology across the lifespan.

The corpus callosum (CC) is the largest interhemispheric white matter tract in the human brain, and is characterized by pronounced differences in morphology among individuals. There are limited data, however, regarding typical development, sex differences, and the neuropsychological correlates of individual differences within CC subregions. Magnetic resonance (MR) imaging exams were collected in a large cohort (N = 305) of healthy individuals (ages 8-68). We used a highly reliable program to automatically identify the midsagittal plane and obtain CC subregion measures according to approaches described by Witelson [1989]: Brain 112:799-835 and Hampel et al. [1998]: Arch Neurol 55:193-198 and a measure of whole CC shape (i.e., circularity). CC measurement parameters, including area, perimeter, length, circularity, and CC subregion area values were generally characterized by inverted U-shaped curves across the observed age range. Peak values for CC subregions were observed between ages 32 and 45, and descriptive linear correlations were consistent with sharper area changes in development. We also observed differing age-associated changes across the lifespan between males and females in the CC subregion corresponding to the genu (Witelson's subregion 2), as well as CC circularity. Mediation analysis using path modeling indicated that genu area mediated the relationship between age and processing speed for females, and the relationship between age and visual learning and executive functioning for males. Taken together, our findings implicate sex differences in CC morphology across the lifespan that are localized to the genu, which appear to mediate neuropsychological functions.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment.

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.

Decoding Early Psychoses: Unraveling Stable Microstructural Features Associated with Psychopathology Across Independent Cohorts.

Background: Early Psychosis patients (EP, within 3 years after psychosis onset) show significant variability, making outcome predictions challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, limiting the development of early interventions. Methods: A data-driven approach, Partial Least Squares (PLS) correlation, was used across two independent datasets to examine multivariate relationships between white matter (WM) properties and symptomatology, to identify stable and generalizable signatures in EP. The primary cohort included EP patients from the Human Connectome Project-Early Psychosis (n=124). The replication cohort included EP patients from the Feinstein Institute for Medical Research (n=78). Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders. Results: In both cohorts, a significant latent component (LC) corresponded to a symptom profile combining negative symptoms, primarily diminished expression, with specific somatic symptoms. Both LCs captured comprehensive features of WM disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the PLS model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use. Conclusions: This data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural WM alterations in EP, across diagnoses and datasets, showing a strong covariance of these alterations with a unique profile of negative and somatic symptoms. This finding suggests the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings.

Decoding Early Psychoses: Unraveling Stable Microstructural Features Associated With Psychopathology Across Independent Cohorts.

BACKGROUND: Patients with early psychosis (EP) (within 3 years after psychosis onset) show significant variability, which makes predicting outcomes challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, which limits the development of early interventions. METHODS: A data-driven approach, partial least squares correlation, was used across 2 independent datasets to examine multivariate relationships between white matter properties and symptomatology and to identify stable and generalizable signatures in EP. The primary cohort included patients with EP from the Human Connectome Project for Early Psychosis (n = 124). The replication cohort included patients with EP from the Feinstein Institute for Medical Research (n = 78) as part of the MEND (Multimodal Evaluation of Neural Disorders) Project. Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders. RESULTS: In both cohorts, a significant latent component corresponded to a symptom profile that combined negative symptoms, primarily diminished expression, with specific somatic symptoms. Both latent components captured comprehensive features of white matter disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the partial least squares model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use. CONCLUSIONS: This data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural white matter alterations in EP across diagnoses and datasets, showing strong covariance of these alterations with a unique profile of negative and somatic symptoms. These findings suggest the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings.

Contributions of Parasympathetic Arousal-Related Activity to Cognitive Performance in Patients With First-Episode Psychosis and Control Subjects.

BACKGROUND: Cognitive impairment is integral to the pathophysiology of psychosis. Recent findings implicate autonomic arousal-related activity in both momentary fluctuations and individual differences in cognitive performance. Although altered autonomic arousal is common in patients with first-episode psychosis (FEP), its contribution to cognitive performance is unknown. METHODS: A total of 24 patients with FEP (46% male, age = 24.31 [SD 4.27] years) and 24 control subjects (42% male, age = 27.06 [3.44] years) performed the Multi-Source Interference Task in-scanner with simultaneous pulse oximetry. First-level models included the cardiac-blood oxygen level-dependent regressor, in addition to task (congruent, interference, and error) and nuisance (motion and CompCor physiology) regressors. The cardiac-blood oxygen level-dependent regressor reflected parasympathetic arousal-related activity and was created by convolving the interbeat interval at each heartbeat with the hemodynamic response function. Group models examined the effect of group or cognitive performance (reaction times × error rate) on arousal-related and task activity, while controlling for sex, age, and framewise displacement. RESULTS: Parasympathetic arousal-related activity was robust in both groups but localized to different regions for patients with FEP and healthy control subjects. Within both groups, arousal-related activity was significantly associated with cognitive performance across occipital and temporal cortical regions. Greater arousal-related activity in the bilateral prefrontal cortex (Brodmann area 9) was related to better performance in healthy control subjects but not patients with FEP. CONCLUSIONS: Autonomic arousal circuits contribute to cognitive performance and the pathophysiology of FEP. Arousal-related functional activity is a novel indicator of cognitive ability and should be incorporated into neurobiological models of cognition in psychosis.

Multivariate Associations Among White Matter, Neurocognition, and Social Cognition Across Individuals With Schizophrenia Spectrum Disorders and Healthy Controls.

BACKGROUND AND HYPOTHESIS: Neurocognitive and social cognitive abilities are important contributors to functional outcomes in schizophrenia spectrum disorders (SSDs). An unanswered question of considerable interest is whether neurocognitive and social cognitive deficits arise from overlapping or distinct white matter impairment(s). STUDY DESIGN: We sought to fill this gap, by harnessing a large sample of individuals from the multi-center Social Processes Initiative in the Neurobiology of the Schizophrenia(s) (SPINS) dataset, unique in its collection of advanced diffusion imaging and an extensive battery of cognitive assessments. We applied canonical correlation analysis to estimates of white matter microstructure, and cognitive performance, across people with and without an SSD. STUDY RESULTS: Our results established that white matter circuitry is dimensionally and strongly related to both neurocognition and social cognition, and that microstructure of the uncinate fasciculus and the rostral body of the corpus callosum may assume a "privileged role" subserving both. Further, we found that participant-wise estimates of white matter microstructure, weighted by cognitive performance, were largely consistent with participants' categorical diagnosis, and predictive of (cross-sectional) functional outcomes. CONCLUSIONS: The demonstrated strength of the relationship between white matter circuitry and neurocognition and social cognition underscores the potential for using relationships among these variables to identify biomarkers of functioning, with potential prognostic and therapeutic implications.

Metabolic disturbances, hemoglobin A1c, and social cognition impairment in Schizophrenia spectrum disorders.

Social cognitive impairments are core features of schizophrenia spectrum disorders (SSD) and are associated with greater functional impairment and decreased quality of life. Metabolic disturbances have been related to greater impairment in general neurocognition, but their relationship to social cognition has not been previously reported. In this study, metabolic measures and social cognition were assessed in 245 participants with SSD and 165 healthy comparison subjects (HC), excluding those with hemoglobin A1c (HbA1c) > 6.5%. Tasks assessed emotion processing, theory of mind, and social perception. Functional connectivity within and between social cognitive networks was measured during a naturalistic social task. Among SSD, a significant inverse relationship was found between social cognition and cumulative metabolic burden (ß = -0.38, p < 0.001) and HbA1c (ß = -0.37, p < 0.001). The relationship between social cognition and HbA1c was robust across domains and measures of social cognition and after accounting for age, sex, race, non-social neurocognition, hospitalization, and treatment with different antipsychotic medications. Negative connectivity between affect sharing and motor resonance networks was a partial mediator of this relationship across SSD and HC groups (ß = -0.05, p = 0.008). There was a group x HbA1c effect indicating that SSD participants were more adversely affected by increasing HbA1c. Thus, we provide the first report of a robust relationship in SSD between social cognition and abnormal glucose metabolism. If replicated and found to be causal, insulin sensitivity and blood glucose may present as promising targets for improving social cognition, functional outcomes, and quality of life in SSD.

Emotional modulation of response inhibition in stable patients with bipolar I disorder: a comparison with healthy and schizophrenia subjects.

OBJECTIVES: Bipolar disorder (BD) has been associated with impairment in affective processing during depressive and manic states; however, there are limited data as to whether this population exhibits such difficulty during stable periods. We examined the pattern of affective processing in stable BD patients and compared their profile to that of healthy controls (HC) and patients diagnosed with schizophrenia (SZ). METHODS: A total of 336 subjects were administered an Affective Go/No-go test to evaluate target detection of negatively valenced, positively valenced, and neutral stimuli. Accuracy and response bias served as dependent variables in a series of multivariate analyses of covariance to test for group differences. RESULTS: The BD group relative to the HC group exhibited response biases toward negatively valenced information (p<0.01). Deficits were also evident in discrimination of and accurate responses to positively valenced information in the BD group versus the HC group (p<0.05). In contrast to the controls, the SZ group performed poorly on all task components and was less accurate across all conditions regardless of affective valence (p<0.01). Patients with SZ evidenced reverse biases for positive information, as they were less likely to respond to positive words (p<0.05) despite comparable response bias on neutral and negative conditions. CONCLUSIONS: Affective processing impairment evident in BD is a feature of the disorder that is present even during stable periods. Prior studies comparing BD with SZ have highlighted clear quantitative but inconsistent qualitative differences in cognitive functioning. Our data suggest that a response bias toward negative stimuli may be a critical and relatively specific feature of BD.

Overlapping Neurobiological Substrates for Early-Life Stress and Resilience to Psychosis.

Early-life stress, such as childhood maltreatment, is a well-known etiological factor in psychopathology, including psychosis. Exposure to early-life stress disrupts the neurodevelopment of widespread brain systems, including key components of the hypothalamic-pituitary-adrenal axis stress response, such as the amygdala, hippocampus, and medial prefrontal cortex, as well as key components of the brain's reward system, such as the nucleus accumbens and orbitofrontal cortex. These disruptions have a considerable impact on the function of emotion and reward circuitry, which play a central role in the emergence and severity of psychosis. While this overlap may provide insight into the pathophysiology of psychosis, it also provides unique opportunities to elucidate neurobiological substrates that may promote resilience to psychosis. In this review, we discuss the hypothalamic-pituitary-adrenal axis stress response, discuss the disruption in the neurodevelopment of emotion and reward processing associated with early stress exposures, and examine how this circuitry may contribute to resilience to psychotic disorders.

Social Cognitive Networks and Social Cognitive Performance Across Individuals With Schizophrenia Spectrum Disorders and Healthy Control Participants.

BACKGROUND: Schizophrenia spectrum disorders (SSDs) feature social cognitive deficits, although their neural basis remains unclear. Social cognitive performance may relate to neural circuit activation patterns more than to diagnosis, which would have important prognostic and therapeutic implications. The current study aimed to determine how functional connectivity within and between social cognitive networks relates to social cognitive performance across individuals with SSDs and healthy control participants. METHODS: Participants with SSDs (n = 164) and healthy control participants (n = 117) completed the Empathic Accuracy task during functional magnetic resonance imaging as well as lower-level (e.g., emotion recognition) and higher-level (e.g., theory of mind) social cognitive measures outside the scanner. Functional connectivity during the Empathic Accuracy task was analyzed using background connectivity and graph theory. Data-driven social cognitive networks were identified across participants. Regression analyses were used to examine network connectivity-performance relationships across individuals. Positive and negative within- and between-network connectivity strengths were also compared in poor versus good social cognitive performers and in SSD versus control groups. RESULTS: Three social cognitive networks were identified: motor resonance, affect sharing, and mentalizing. Regression and group-based analyses demonstrated reduced between-network negative connectivity, or segregation, and greater within- and between-network positive connectivity in worse social cognitive performers. There were no significant effects of diagnostic group on within- or between-network connectivity. CONCLUSIONS: These findings suggest that the neural circuitry of social cognitive performance may exist dimensionally. Across participants, better social cognitive performance was associated with greater segregation between social cognitive networks, whereas poor versus good performers may compensate via hyperconnectivity within and between social cognitive networks.

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.