Introduction:Total and social cognition deficits independently predict functioning in psychosis, but targeting these in clinical trials are unsuccessful in improving function. The admixture of schizophrenia and affective psychoses cases could be a roadblock if these differ in cellular pathology. Method:We examined cognitive functioning (MATRICS) and hippocampal cellular pathologies based on metabolite biomarker concentrations ( 1 H-MRSI), using categorical and transdiagnostic classifications in 80 participants: 22 non-psychotic affective disorder (NP-aff), 25 healthy controls (HC), and 33 with psychosis (Psy), including 20 schizophrenia and 13 affective psychoses (aff-P) cases. Results:NP-aff and HC had similar total cognition (46.64±12.01 vs 41.10±17.88), both superior to Psy (28.34±12.34; p's<0.01). Mean metabolite concentrations were similar across all groups but showed significant within-group associations to cognitive tests. For HC, total cognition, working memory and reasoning deficits were associated with reduced neuronal integrity (-.414, -.422, -.433, p's<.05), although no biomarker predicted total cognition in the clinical groups. For NP-aff, elevated myelin/membrane concentrations accompanied cognitive deficits; significantly so for visual learning deficits (.446, p<.05), which were also associated with decreased glia (-.503, p<.05). Opposite NP-aff, reduced myelin/membrane concentrations predicted cognitive deficits in Psy (-.514, p<.05). Separating schizophrenia from aff-P on social cognition showed reduced glutamate/excitation in schizophrenia (-.673, p<.05) but higher myelin/membrane turnover and neuronal integrity concentrations in aff-P (.575, .581, p's<.05). Conclusions:Schizophrenia and affective psychosis significantly differed for biomarkers of cellular pathology related to social cognition. Distinctly different underpinnings for cognition were also identified for other groups, aligning with DSM-5 and ICD disorder based categories. These findings include support for heterogeneous, but not transdiagnostic, conceptualizations of cognition and psychosis.

Cortical brain morphology in early-onset psychosis (EOP; age of onset < 19 years) is poorly understood, partly due to recruitment constraints linked to its low incidence. We pooled T1-weighted magnetic resonance imaging (MRI) data from 387 adolescents with EOP (mean age=16.1±1.5; 49.6% female) and 338 healthy controls (CTR; mean age=15.8±1.9, 54.4% female) from nine research sites worldwide. Using harmonized processing protocols with FreeSurfer, we extracted cortical brain metrics from 34 bilateral regions. Univariate regression analysis revealed widespread lower bilateral cortical thickness (left/right hemisphere: d=-0.36/-0.31), surface area (left/right: d=-0.42/-0.41), cortical volume (left/right: d=-0.58/-0.56), and Local Gyrification Index (LGI; left/right: d=-0.39/-0.52) in EOP relative to CTR. Subgroup analyses showed broader and more pronounced case-control differences in early-onset schizophrenia for area, volume, and LGI. We found no associations with antipsychotic medication use, illness duration, age of onset, or positive symptoms. Negative symptoms were related to smaller left lingual volumes (partial r=-0.21; p FDR =0.014) and antidepressant users had smaller area (d=-0.43; p FDR =0.034) and volume (d=-0.50; p FDR =0.003) of the right rostral anterior cingulate compared to non-users. Cortical alterations in EOP showed a similar pattern to those observed in prior studies on adults with schizophrenia (SCZ; r=0.62) and bipolar disorders (BD; r=0.61). However, surface area alterations were overall 1.5 times greater for EOP than adult SCZ and 4.6 times greater than adult BD. In the largest study of its kind, we observed an extensive pattern of cortical alterations in adolescents with psychotic disorders, highlighting the potential impact of aberrant neurodevelopment on cortical morphology in this clinical group.

Background:Differences in age of psychosis onset (AOO) in schizophrenia (SCZ) are associated with different illness trajectories. Determining whether AOO differences can be explained by genome-wide or pathway-partitioned polygenic risk for SCZ (SCZ-PRS) may elucidate mechanisms underlying clinical variability. This study examined relationships between AOO, genome-wide SCZ-PRS, and pathway-partitioned SCZ-PRS in a harmonized, multi-ancestry North American dataset (SCZ-NA) and in UK Biobank (SCZ-UKBB). Methods:For each cohort, we computed one genome-wide SCZ-PRS and 18 mutually-exclusive pathway-based PRS derived from previous published and validated neurodevelopmental gene-sets. We evaluated 13 SNP-to-gene mapping strategies, including comparing non-coding SNP-to-gene mappings informed by functional annotations versus distance-based windows. SCZ case-control prediction and AOO associations were tested using logistic and linear mixed models, respectively, controlling for sex, ancestry principal components, and genetic relatedness. Results:Genome-wide SCZ-PRS robustly predicted SCZ case-control status in both cohorts but not AOO. In contrast, pathway-based analyses identified AOO associations for a fetal angiogenesis and a postnatal synaptic signaling and plasticity gene-set across both cohorts ( p < .05), alongside nominal cohort-specific associations in other gene-sets. Associations depended on SNP-to-gene mapping definitions; experimentally informed strategies, particularly those incorporating brain expression Quantitative Trait Locus (eQTL) annotations performed best. Conclusion:Findings suggest that neurovascular and postnatal synaptic signaling and refinement mechanisms contribute to AOO variation in SCZ, and that pathway-informed PRS, especially with brain-specific non-coding SNP-to-gene mappings, can help identify mechanisms contributing to variability in AOO. Replication in larger, prospectively phenotyped cohorts with harmonized AOO definitions will further clarify genetic mechanisms underlying clinical variability in SCZ.

Both autism spectrum disorder (ASD) and psychosis are associated with challenges in social cognition. The triple-network model posits that dysfunction within and between the default mode network (DMN), central executive network (CEN), and salience network (SN) contributes to these deficits. However, the relationship between triple-network connectivity and social cognition has not been systematically compared across these groups during adolescence. We examined whole-brain functional connectivity of the triple-network in a sample of youth with ASD (N = 24), youth with early-onset psychosis (EOP; N = 25), and age-matched typically developing (TD) controls (N = 26, overall mean age = 16.39 ± 2.36, % female = 41%). Additionally, we examined relationships between connectivity patterns of the triple-network and behavioral measures of social cognition and emotion recognition in each group. ASD youth showed mixed over- and under-connectivity in the DMN, CEN overconnectivity, and SN underconnectivity, while EOP youth showed DMN and CEN overconnectivity, with relatively intact SN connectivity, compared to TD controls. Compared to EOP, ASD participants had reduced SN connectivity and mixed disruptions in DMN connectivity. Across groups, connectivity patterns were linked to social behaviors: in EOP, DMN overconnectivity was associated with poorer social cognition; in ASD, SN underconnectivity was associated with poorer social cognition. These findings highlight both shared and distinct patterns of triple-network dysconnectivity in ASD and EOP, supporting transdiagnostic models of social cognitive dysfunction, and reinforcing adolescence as a key developmental window for network-based brain changes.

INTRODUCTION:Discrimination is a risk factor for psychotic symptoms among minoritised individuals. Social support has been shown to be a broad protective factor for stressors like discrimination and for psychosis outcomes. However, it is unclear whether social support equally benefits all groups. METHODS:In this study, 134 young adults identifying as Asian American, Latine, or non-Hispanic White reported on recent experiences of discrimination, perceived social support, and subclinical psychotic and depressive symptoms. RESULTS:Distinct moderation effects of social support on the association between discrimination and psychosis and depression were found in the NHW and Asian American groups. Above average social support mitigated the effects of discrimination in the NHW group. For Asian American young adults, social support was not sufficient to mitigate the effects of discrimination on psychosis or depression outcomes. CONCLUSIONS:Prevention of psychotic disorders among Asian and Asian American groups may require targeting distinct coping strategies to address disparities in illness outcomes.

The corpus callosum is the largest white matter tract in the brain, connecting the left and right cerebral hemispheres. Callosal agenesis is a condition where this tract fails to form during neurodevelopment. Despite this, individuals with callosal agenesis can present as cognitively and behaviorally asymptomatic, retaining some alternate form of interhemispheric communication. Afferent and efferent pathways linking the cortex to the contralateral cerebellum, such as the corticopontocerebellar tract (CPCT) and dentatorubrothalamic tract (DRTT), could serve as compensatory routes in individuals with callosal agenesis, and thus display adaptive changes in white matter structure. To investigate this possibility, we examined a 9-year-old boy with complete callosal agenesis, who performed in line with his peers on IQ and social communication measures, and compared his cerebellar and association tractography to 12 age-matched controls. Diffusion tensor imaging (DTI) metrics were calculated for a whole-brain seed, the cerebellar peduncles, the pontine decussations, the arcuate fasciculus, and the uncinate fasciculus. Whole-brain metrics showed typical fractional anisotropy (FA) but increased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in the callosal agenesis child compared with controls. This pattern was also observed in the right superior cerebellar peduncle. Dorsal pontine fibers exhibited low FA and high RD values in callosal agenesis. The left uncinate and right arcuate fasciculi exhibited a similar pattern of low FA and high RD compared with controls. Overall, this case study characterizes microstructural differences in cerebellar and association tracts in a child with complete callosal agenesis and intact cognitive abilities.

ABSTRACT Introduction Discrimination is a risk factor for psychotic symptoms among minoritised individuals. Social support has been shown to be a broad protective factor for stressors like discrimination and for psychosis outcomes. However, it is unclear whether social support equally benefits all groups. Methods In this study, 134 young adults identifying as Asian American, Latine, or non‐Hispanic White reported on recent experiences of discrimination, perceived social support, and subclinical psychotic and depressive symptoms. Results Distinct moderation effects of social support on the association between discrimination and psychosis and depression were found in the NHW and Asian American groups. Above average social support mitigated the effects of discrimination in the NHW group. For Asian American young adults, social support was not sufficient to mitigate the effects of discrimination on psychosis or depression outcomes. Conclusions Prevention of psychotic disorders among Asian and Asian American groups may require targeting distinct coping strategies to address disparities in illness outcomes.

Importance:As the percentage of young people in the US identifying as transgender and gender-diverse increases, more youths face identity-linked social and structural stigma and discrimination. Little is known about the impact of stigma on psychotic-like experiences in gender-diverse youths. Objective:To assess the association of being bullied and state policies with psychotic-like experiences among gender-diverse youths. Design, Setting, and Participants:In this prospective cohort study, cross-sectional and longitudinal analyses were conducted between 2023 and 2025 using data collected between January 1, 2017, and December 31, 2022, across 17 states. The Adolescent Brain Cognitive Development (ABCD) Study is a US population-based, longitudinal study that follows and deeply phenotypes youths from the age of 9 to 18 years. Cross-sectional analyses included data from 8463 participants collected between January 1, 2019, and December 31, 2022. Longitudinal analyses included 4200 participants with data collected across 5 waves between January 1, 2017, and December 31, 2022. Statistical analysis was performed from January 1, 2023, to December 31, 2025. Exposures:Self-reported frequency of being bullied and data on annual state policies related to gender identity. Main Outcomes and Measures:Self-reported PLEs and associated distress, measured by the Prodromal Questionnaire-Brief Child Version. Results:The study sample included 8463 youths (mean [SD] age, 12.9 [0.6] years; 4490 [53.1%] assigned male at birth). Based on a dimensional measure of gender, 531 youths (6.3%) were identified as most gender diverse (ie, least congruent with birth-assigned sex) and 6867 (81.1%) as least gender diverse (ie, most congruent with birth-assigned sex). Rates of being bullied and PLEs were significantly elevated in the most vs least gender-diverse group, with bullying partially mediating the difference in PLEs (indirect association = 0.15, P < .001; direct association = 0.63, P < .001). Moreover, the persistence of unsupportive legislation across 4 years was associated with significantly greater increases in PLEs over time in gender-diverse youth (interaction β = 0.31; 95% CI, 0.21-0.42; P < .001). Conclusions and Relevance:In this cohort study, being bullied and unsupportive legislation were associated with greater and increasing rates of PLEs in gender-diverse youths. This study's findings suggest that mental health in gender-diverse youths could benefit from supportive environments and policies that reduce bullying and avoid perpetuating stigma.

INTRODUCTION:The NIMH Research Domain Criteria (RDoC) posits similar cellular pathologies for particular symptom domains across diagnostic categories. Conversely, knowledge that these differ could advance treatment discovery, especially for affective and non-affective psychoses, as studies usually intermix them. METHODS:We tested this by comparing metabolite biomarker concentrations for cellular pathologies from whole hippocampal proton magnetic spectroscopic imaging (1H MRSI) with symptoms from the original and five factor PANSS, and the Hamilton Depression and Young Mania Scales. Participants were 26 healthy controls; 22 non-psychotic affective cases (NP-aff); and 33 with psychosis (including 20 schizophrenia (Scz) and 13 affective psychosis (aff-P) cases). RESULTS:PANSS activation factor was related to reductions in all cellular component biomarkers in Scz, including glia, membrane turnover, neural integrity, glutaminergic neurotransmission, and energy metabolism (p's<.05), but only to energy metabolism in NP-aff (p=.03). Biomarkers for mood symptoms also varied across categories, suggesting gliosis for mania and depression in HC (p's≤.025), but increased membrane turnover for mania in aff-P (p=.015), and decreased neural integrity and energy metabolism for depression in Scz (p's<.05). In contrast, negative symptoms and autistic preoccupation were related to reduced glia in both NP-aff and aff-P (p's<.05). Autistic preoccupation in Scz was related to both reduced glia and membrane turnover (p's<.05). Only Scz showed a significant finding for positive symptoms, specifically reduced membrane turnover (p=.018). DISCUSSION:These results suggest both distinct and similar cellular pathologies for symptoms across diagnoses, including affective and non-affective psychoses. The differences support categorizing disorders and stratifying different psychoses in research rather than transdiagnostic approaches.

Extended duration of under-treated psychosis (DUP) is among the strongest predictors of poor outcome, yet diagnostic heterogeneity impedes treatment matching, with approximately 50% of patients failing to respond to first-line antipsychotics. Negative symptoms and cognitive impairment are particularly refractory, lacking effective pharmacological treatments. Identifying neurotransmitter systems associated with specific symptom dimensions could accelerate targeted therapeutic development and reduce DUP. We applied Partial Least Squares correlation (PLSc) to derive whole-brain resting-state functional connectivity (RSFC) and anatomical (cortical thickness and subcortical volume) signatures associated with five psychopathology dimensions (positive symptoms, negative symptoms, general psychopathology, mania, and cognition) in a transdiagnostic sample from the Human Connectome Project-Early Psychosis (HCP-EP; n=124). We tested associations with potential confounds including antipsychotic medication dosage and substance use. Signatures were spatially correlated with 21 Positron Emission Tomography (PET)-derived receptor and transporter maps across 9 neurotransmitter systems using the neuromaps toolbox. Significant RSFC signatures emerged for positive symptoms, negative symptoms, general psychopathology, and cognition, but not mania. The negative symptom RSFC signature correlated with norepinephrine transporter (NET; ρ=.40, q=.030) and vesicular acetylcholine transporter (VAChT; ρ=.38, q=.048) distributions. The cognition signature similarly correlated with VAChT (ρ=.48, q=.025). Anatomical signatures were associated with positive symptoms, general psychopathology, and cognition, but were more susceptible to confounding by medication and substance use. No significant receptor associations were detected for anatomical signatures. These findings implicate cholinergic and noradrenergic systems as molecular targets for negative symptoms and cognitive impairment, supporting prioritization of these systems in pharmacotherapy development in early psychosis.

Adolescence is a period of marked cognitive development, especially for inhibitory control-the ability to inhibit prepotent responses in accordance with one's goals. Neural specialization is speculated to undergird adolescent cognition, where neural activity within a region becomes spatially focalized and less variable while handling multiple cognitive functions. However, quantifying this kind of focalization is difficult with univariate neuroimaging methods. The present study quantifies neural focalization underlying inhibitory control using Gini coefficients, an adapted multivariate method that measures neural focalization. We replicated non-linear, age-related behavioral stabilization of inhibitory control around mid-adolescence in a sample of 49 adolescents aged 9-22 years (mean =15.3 years, SD = 3.7 years; 49% female). Neural specialization was estimated from task-related neural activity within and between pre-specified regions of dorsal anterior cingulate (dACC), dorsolateral prefrontal cortex (DLPFC), insula, and inferior parietal lobule (IPL). After accounting for age, individuals with greater specialization (more focalization) in subregions of DLPFC demonstrated better behavioral performance. Gini coefficients within dACC and IPL were consistently and positively correlated with task performance, but not age. These results suggest neural focalization is an important neurodevelopmental feature that facilitates successful inhibitory control during adolescence over and above chronological age.

OBJECTIVE:Schizophrenia is a neurodevelopmental disorder involving clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for schizophrenia spectrum disorders (SSDs). However, it is unclear how known risk CNVs and broader genome-wide CNVs influence clinical variability. Furthermore, whether biological annotation of CNV scores can improve power for patient stratification is unknown. This study therefore investigated the relationships between severe SSD-related phenotypes and varied CNV metrics, including CNV burden affecting genes involved in different aspects of neurodevelopment. METHODS:This study of 617 individuals with SSDs examined associations of two severe phenotypes-childhood-onset psychosis and borderline intellectual functioning (IQ)-with 1) known risk CNVs, 2) genome-wide deletion burden scores, and 3) novel scores capturing deletion burden in 18 previously validated and mutually exclusive gene sets, representing distinct aspects of neurodevelopment. Associations with borderline IQ were assessed for replicability in 233 relatives of SSD patients, 581 control subjects, and 9,930 youths from the Adolescent Brain Cognitive Development (ABCD) Study. RESULTS:Known SSD-risk CNVs (odds ratio=7.07, 95% CI=1.60, 31.32) and neurodevelopmental disorder (NDD)-risk CNVs (odds ratio=4.56, 95% CI=1.48, 14.10) were associated with borderline IQ in SSDs. Furthermore, beyond effects of known NDD-risk CNVs, deletion of genes involved in regulating gene expression during fetal brain development was associated with borderline IQ across SSD cases and noncases (odds ratio=2.57, 95% CI=1.44, 4.60) and in the ABCD cohort (odds ratio=1.33, 95% CI=1.00, 1.76). Exploratory structural MRI-based analyses showed associations between fetal gene regulatory gene deletions and altered gray matter volume (b=0.09, 95% CI=0.004, 0.17) and cortical thickness (b=0.14, 95% CI=0.05, 0.24) across SSD cases and noncases. CONCLUSIONS:The study results confirm contributions of known risk CNVs to severe phenotypes in SSDs, implicate disrupted fetal brain development in poor cognition, and demonstrate the utility of a neurodevelopmental framework for identifying mechanisms underlying severe SSD-relevant phenotypes.

Background:Early psychosis (EP) is characterized by neurobiological changes, including alterations in resting-state functional connectivity (RSFC). We now understand that symptoms and neural changes may overlap across EP diagnostic categories. However, the relationship between RSFC patterns and transdiagnostic symptom dimensions remains poorly understood. Methods:We employed Partial Least Squares correlation to examine multivariate relationships between whole-brain RSFC and clinical symptoms in 124 EP patients (aged 16-35 years) diagnosed with schizophrenia, schizoaffective disorder, or a psychotic mood disorder. RSFC was computed among 216 cortical and subcortical regions. Clinical assessment included 41 symptom measures spanning positive, negative, general psychopathology, and manic dimensions. Results:Analysis revealed one significant latent component (p<0.001) capturing 41.6% of the RSFC-symptom covariance. This component was characterized by increased between-network connectivity, particularly involving sensory-motor, default mode, and subcortical regions including the amygdala and thalamus. The associated symptom profile included cognitive rigidity and arousal dysregulation (stereotyped thinking, anxiety, and somatic concerns), rather than traditional positive or negative symptoms. This brain-behavior relationship was consistent across diagnoses and independent of medication and substance use. The clinical relevance was validated through significant correlations with standardized measures of hostility (r=0.23), negative affect (r=0.25), and perceived stress (r=0.22). Conclusions:Our findings reveal a distinct transdiagnostic phenotype in EP characterized by cognitive inflexibility and arousal dysregulation that is associated with altered integration between sensory, default mode, and subcortical networks. This work suggests that specific patterns of network-level functional connectivity may relate to symptom dimensions that cut across conventional diagnostic boundaries, potentially informing more targeted therapeutic approaches.

Objective:Schizophrenia is a neurodevelopmental disorder involving clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for schizophrenia spectrum disorders (SSD). However, how known risk CNVs and broader genome-wide CNVs influence clinical variability is unclear. Furthermore, whether biological annotation of CNV scores can improve power for patient stratification is unknown. Methods:This study examined associations between severe phenotypes in 617 SSD individuals, namely, child-onset psychosis or borderline intellectual functioning (IQ), and: 1) known risk CNVs; 2) genome-wide deletion burden scores; and 3) novel scores capturing deletion burden in 18 previously validated and mutually exclusive gene-sets, representing distinct aspects of neurodevelopment. Associations with borderline IQ were assessed for replicability in 233 SSD-relatives and 581 controls, and 9,930 youth from the Adolescent Brain Cognitive Development (ABCD) Study. Results:Known SSD- (odds ratios (OR)=7.07, 95%CI[1.60,31.32]) and neurodevelopmental disorder (NDD)-risk CNVs (OR=4.56, 95%CI[1.48,14.10]) were associated with borderline IQ in SSD. Furthermore, beyond effects of known NDD-risk CNVs, deletion of genes involved in regulating gene expression during fetal brain development was associated with borderline IQ across SSD cases and non-cases (OR=2.57, 95%CI[1.44,4.60]), and in the ABCD cohort (OR=1.33, 95%CI[1.00,1.76]). Exploratory structural MRI-based analyses showed associations between fetal gene regulatory gene deletions and altered gray matter volume ( b =0.09, 95%CI[0.004,0.17]) and cortical thickness ( b =0.14, 95%CI[0.05,0.24]) across SSD cases and non-cases. Conclusions:Results confirm contributions of known risk CNVs to severe phenotypes in SSD, implicate disrupted fetal brain development in poor cognition, and demonstrate the utility of a neurodevelopmental framework for identifying mechanisms underlying severe SSD-relevant phenotypes.

BACKGROUND:Adolescence and early adulthood are associated with increased risk-taking, with a growing understanding that risk-taking may be adaptive during this developmental period. In psychosis, failure to appropriately engage in optimal risk-taking due to altered reward processing may contribute to poor social and role functioning. We investigated differences in optimal risk-taking in early psychosis (EP), as well as the relationship between optimal risk-taking and the negative symptom of avolition. METHODS:Fifty-six EP participants and 52 healthy controls (HC) completed a modified version of the Balloon Analog Risk Task (BART). In the BART, individuals inflated a virtual balloon to gain points; if the balloon exploded, no points were gained. We manipulated degree of risk, such that trials were low-risk (high probability of reward, low probability of punishment) or high-risk (low probability of reward, high probability of punishment). We investigated differences between EP and HC in (1) risk-propensity on low- and high-risk trials, (2) total adverse outcomes, and (3) behavior changes following punishment. RESULTS:There were no significant differences between EP and HC on any BART metrics; however, in EP, the negative symptom of avolition was associated with reduced risk-propensity on low-risk trials and reduced risk-taking immediately following punishment on low-risk trials. In the high-risk condition, avolition was not associated with risk-propensity, number of adverse outcomes, or behavior following punishment. CONCLUSIONS:These results suggest that risk-taking and response to punishment in high-risk situations may be preserved in psychosis, and that in lower-risk situations that allow for greater variability, behavior may be moderated by negative symptom severity.

Experimental cognitive tests are designed to measure particular cognitive domains, although evidence supporting test validity is often limited. The Consortium for Neuropsychiatric Phenomics test battery administered 23 experimental and traditional neuropsychological tests to a large sample of community volunteers (n = 1,059) and patients with psychiatric diagnoses (n = 137), providing a unique opportunity to examine convergent validity with factor analysis. Traditional tests included subtests from the Wechsler and Delis-Kaplan batteries, while experimental tests included the Attention Networks Test, Balloon Analogue Risk Task, Delay Discounting Task, Remember-Know, Reversal Learning Task, Scene Recognition, Spatial and Verbal Capacity and Manipulation Tasks, Stop-Signal Task, and Task Switching. Several experimental cognitive measures were insufficiently related to other tests and were excluded from factor analyses. In the remaining 18 tests, exploratory factor analysis and subsequent multigroup confirmatory factor analysis supported a three-factor structure broadly corresponding to domains of verbal/working memory, inhibitory control, and memory. In sum, several experimental measures of inhibitory control had weak relationships with all other tests, while the convergent validity of most tests of working memory and memory was supported.

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.

One of the greatest barriers to clarifying the core biological processes that underlie schizophrenia (SCZ) and improving patient outcomes is the clinical and genetic heterogeneity of the disorder. For example, while psychosis onset is most common in early adulthood, some patients experience psychotic symptoms as early as childhood. Similarly, while cognitive functioning is impaired on average among SCZ patients compared to controls, there is considerable variability between patients. Determining whether severe phenotypes such as borderline intellectual functioning or child-onset psychosis can be explained by distinct genetic profiles, such as burden of known neuropsychiatric copy number variants (CNVs) or rare deletions affecting genes involved in early brain development is an important question with implications for personalized medicine. CNVs were called in a cohort of 618 patients with SCZ spectrum disorders, as well as 231 relatives of SCZ patients, and 586 unaffected controls. Logistic regression tested for differences in rates of neuropsychiatric CNVs among cases versus non-cases, and for associations between borderline intellectual functioning and child-onset psychosis and burden of known neuropsychiatric-associated CNVs or rare deletions affecting genes involved in distinct neurodevelopmental processes for SCZ spectrum patients. Neurodevelopmental gene-sets were defined previously via weighted gene co-expression network analysis of transcriptomic data from 1,061 brain samples from the developing human brain (Forsyth et al., 2020). Rates of SCZ-associated and broader neurodevelopmental disorder (NDD)-associated CNVs were significantly elevated in cases (up to 2.4%) compared to non-cases (up to 0.9%). SCZ- and NDD-associated CNVs were found at non-significantly higher rates in child-onset (up to 8.3%) compared to later-onset psychosis (up to 2.1%) and were associated with significantly higher likelihood of borderline intellectual functioning across SCZ spectrum patients (odds ratio up to 7.0). There were no associations between rare deletions affecting genes in any neurodevelopmental gene-set and child-onset psychosis; however, deletion of genes in a fetal gene regulatory gene-set and a glia maturation gene-set were associated with increased likelihood of borderline intellectual functioning. The association between deletion of fetal gene regulatory genes and borderline intellectual functioning remained nominally significant after excluding patients with known neuropsychiatric CNVs, and was also replicated among controls and relatives of patients with SCZ spectrum disorders. Results suggest that poor cognitive functioning in SCZ is associated with presence of known neuropsychiatric CNVs, and additionally with deletion of genes involved in regulating gene expression during early brain development. Associations between neurodevelopmental gene-sets and severe phenotypes in schizophrenia may offer opportunities to prioritize pathogenic genes outside known risk loci.