Neurobiology of Stress

Cortisol, our stress hormone, exerts widespread influence on neural activity. However, its influence on the aperiodic component of the electroencephalography power spectrum remains to be investigated. Given individual differences in the capacity to cope with stress and adversity, it also remains unclear whether trait resilience moderates this relationship. Hence, the present study examined whether individual differences in trait resilience moderates the association between resting cortisol and aperiodic activity. Participants (N=145) completed various self-report questionnaires (e.g., trait resilience). Electroencephalography was recorded over a 20-minute baseline period, followed by salivary cortisol collection. The results revealed a significant moderating effect of trait resilience in the occipital scalp region. Specifically, higher cortisol concentration was associated with flatter 1/f slopes amongst individuals with low trait resilience, whereas this association was reversed amongst those with high trait resilience. Overall, our findings highlight the role of individual differences in trait resilience in shaping hypothalamic-pituitary-adrenal axis-related neural dynamics.

Objective: Polygenic risk scores (PRS) for posttraumatic stress disorder (PTSD) often account for a low amount of variance. Ancestry-related differences in PRS scale and variance limit cross-group comparisons. This methodological challenge further complicates gene-by-environment (GxE) analyses, given that socioenvironmental exposures are inequitably distributed across ethnoracial groups. We constructed an ancestry-calibrated polygenic risk score (AC-PRS) for PTSD in the largest longitudinal study of trauma survivors to date and investigated GxE interactions. Method: Recent trauma survivors (N=1,801) provided a blood specimen for genotyping. Six PTSD trajectories were previously identified from PTSD Checklist for DSM-5 (PCL-5) scores at 2-weeks, 8-weeks, 3-months, and 6-months post-trauma. Greenspace (normalized difference vegetation index [NDVI) and socioeconomic disadvantage (area deprivation index [ADI]) were derived from residential addresses. Logistic regressions examined interactions between newly developed AC-PRS and neighborhood factors on trajectories after adjusting for sociodemographic and trauma-related covariates. Secondary linear models considered GxE interactions on 6-month PCL-5 scores. Results: AC-PRS performed well across ethnoracial groups, explaining significant variability in PTSD trajectories (R2=.053). ADI moderated the association between AC-PRS and the likelihood of assignment in a high nonremitting trajectory of PTSD symptoms and severity of symptoms at 6-months (ps < .05). There were no NDVI x AC-PRS interactions in any models. Conclusions: AC-PRS captures genetic risk for PTSD in admixed trauma survivors, demonstrating good discrimination between nonremitting and resilient courses of PTSD. However, neighborhood disadvantage may modify utility of PRS for PTSD, warranting careful consideration when applying these scores across contexts.

Traumatic brain injury (TBI) is one of the leading causes of emergency room visits in children under 10. Children are potentially more vulnerable to the adverse effects of TBI, given that their brains are still developing at the time of injury. Indeed, early life TBI has been linked to cognitive, social, and mood-related impairments later in life. The neuroimmune system has been implicated in adult TBI mechanisms and plays numerous key roles in brain development, making it an interesting candidate for linking pediatric TBI and prolonged behavioral alterations. Here we establish a rat model of mild pediatric TBI to investigate the relationship between early life TBI, acute responses of neuroimmune cells, and chronic behavioral dysregulation. At postnatal day 15, which is roughly equivalent to toddler age, male and female rat pups received a TBI via lateral fluid percussion injury. At 3 days post injury, TBI increased microglia and astrocyte coverage locally in the Perilesional Cortex but not in more distant corticolimbic regions. However, the hippocampus and prefrontal cortex did exhibit increased expression of the phagocytic marker CD68 in microglia, suggesting widespread glial activation even in the absence of gross coverage change. TBI also impacted mast cells, early-response innate immune cells, increasing their number and degranulation in multiple regions. In the juvenile and early adult periods, TBI impaired cognitive function, reduced sociability, and increased avoidance, with no change in anxiety-like behavior. Later in adulthood, TBI continued to impact cognitive behavior, increasing risky decision-making and impairing optimization months after injury. Together, these results suggest that pediatric TBI causes lasting cognitive and social dysregulation, possibly via acute neuroimmune alterations following injury at a critical period of brain development.

Background: Post-traumatic stress disorder (PTSD) remains highly prevalent affecting ~23% of World Trade Center (WTC) responders more than two decades after 9/11. While MRI studies have identified neural differences associated with PTSD, these findings have not translated into improved treatment. We introduce a novel multimodal MRI approach, DAta-driven Network Connectivity Estimate (DANCE), integrating structural and functional magnetic resonance imaging (MRI) to better capture PTSD mechanisms and inform biomarkers. Methods: In 96 WTC responders , including 45 with current WTC-related PTSD and 51 without PTSD. We applied graph theory to resting-state functional MRI to identify functional hubs via eigenvector centrality and identified divergence between groups using partial least squares discriminant analysis (PLS-DA). From diffusion MRI, we reconstructed five anatomical tracts (i.e., streamlines) in the temporal lobes. Using DANCE, we quantified the differential distribution of streamlines of the reconstructed tracts connecting the functional hubs. We then tested whether WTC exposure duration moderated associations between PTSD and DANCE indices. Results: Responders with PTSD showed altered centrality in nine functional hubs (AUC=0.75 (0.651-0.847)) including bilateral anterior inferior temporal gyrus, right superior parietal lobule, right anterior parahippocampal gyrus, right anterior/posterior superior temporal gyrus (STG), right caudate nucleus, left amygdala and brainstem. Connectivity differences emerged in four tracts: hippocampus, parahippocampus, inferior and superior temporal gyri (STG). DANCE differed in the inferior fronto-occipital fasciculus (IFOF), medial (IFLmed) and lateral (IFLlat) components of the inferior longitudinal fasciculus and in the middle longitudinal fascicle (MdLF). WTC exposure duration significantly moderated the association between PTSD and DANCE values in the IFLmed, right posterior STG (p= 0.035). Conclusion: Our novel DANCE approach revealed converging functional and anatomical connectivity alterations uniquely associated with PTSD in WTC responders and offers compelling evidence for distinct neurobiological signatures of the disorder. These findings significantly advance our understanding of PTSD pathophysiology and highlight potential biomarkers for diagnosis and targeted intervention.

Background: Childhood adversity (CA) has been identified as one of the most robust risk factors for psychotic disorders; several treatable mediating mechanisms have been proposed. Aims: To conduct a systematic review and meta-analysis examining mediating pathways linking CA and psychosis. Method: This PRISMA-compliant systematic review (PROSPERO: CRD42024542972). consisted of a search conducted in January 2026 on Ovid (PsycINFO, Medline, and Embase) using search terms related to psychosis, CA, and mediation analyses. Evidence was appraised by calculating the percentage of the total effect mediated in each study, grouping mediators into meaningful groups. When possible, meta-analyses using two-stage meta-analytic structural equation modelling (METASEM) were conducted. Results: 117 studies were included (54 in clinical samples, 59 in non-clinical samples, and four studies in both clinical and non-clinical samples). 107 studies examined psychological mediators and 12 examined biological. The median percentages of total effect mediated across all analyses per mediator family were: 49% for dissociation (k = 24), 45% for psychosocial stressors (k = 6), 37.9% for negative schemas (k = 23), 35.2% for post-traumatic symptoms (k = 10), 31.5% for depressive symptoms (k = 14), 27.8% for anxiety (k = 11), 27.1% for attachment styles (k = 12), and 8.7% for mentalization domains (k = 5). Meta-analyses confirmed a robust mediating effect of dissociation (k = 7; N = 2143; indirect effect (I.E) =0.42 [0.17, 0.66] on psychosis; 50.49%), on delusions (k =7; N = 1053; I.E = 0.36, [0.27, 0.46]; 46.44%]) and on hallucinations (k =10; N = 5705; I.E = 0.28 [0.20, 0.36]; 57.59%). Robust mediation via depression (k =5; N= 5028; indirect effect= 0.33 [0.31, 0.35]; 31.05%) and negative schemas of the association between trauma and psychosis broadly defined (k = 7; N=10791; I.E= 0.26 [0.17, 0.35]; 26.36%) was also observed. High heterogeneity was observed across all meta-analyses. Fewer studies examined biological mediators, preventing quantitative synthesis. Conclusions: Childhood adversity impacts psychosis through psychosocial mediators, particularly dissociation. Further work is required to on the potential role of biological mechanisms and its interplay with psychological mechanisms.

Non-suicidal self-injury (NSSI) is common among adolescents with emotional disorders, yet biological indicators of current NSSI status remain limited. We developed a genome-aware multi-omics modeling framework in 107 adolescents with emotional disorders, including 53 without NSSI and 54 with current NSSI. The model integrated metabolomic, inflammatory, clinical blood and genome-derived features, with polygenic risk score and rare variant burden used as genetic-context variables. The fusion model achieved the strongest classification performance (mean AUC = 0.811) and outperformed single-omics alternatives, indicating that NSSI status was better represented by distributed multi-omics patterns than by a single biomarker layer. Repeated modeling prioritized 42 stable features, many of which were not significant in conventional univariate testing. Group-specific network reconstruction further revealed peripheral reorganization, including convergence of non-NSSI modules into an NSSI-associated module that linked inflammatory recruitment with weaker immune-communication, repair and support-related signals. Exploratory MRI, gut-related and stress-endocrine analyses provided additional biological anchors, while a compact sentinel marker panel translated the full model into clinically readable profiles. These findings support a distributed, genome-aware peripheral state associated with current NSSI and provide a framework for future validation of multi-omics state markers in adolescent emotional disorders.

Air pollution exposure has been associated with increased risk of developing mental health problems. It is possible that individuals at high genetic risk for psychopathology may be more vulnerable to these effects; however, this question remains to be investigated. We leveraged longitudinal data from n=10,620 participants from the Adolescent Brain Cognitive Development Study to first investigate sex-stratified associations of particulate matter (PM2.) exposure and genetic risk with mental health trajectories across 9-16 years including internalizing symptoms and psychotic like experiences (PLEs). Additionally, we tested whether genetic risk for schizophrenia (PRS-SCZ) and major depressive disorder (PRS-MDD) exacerbate the association with PM2. exposure and change in symptoms over time. PM2. exposure was associated with lower decreases in PLEs over time in females (p-FDR=0.005), with no effects on internalising symptom trajectories in either sex. Genetic influences were sex-specific, with higher PRS-SCZ and PRS-MDD linked to greater increases in internalising symptoms in females (p-FDR=0.009; p-FDR=0.022) and higher PRS-MDD associated with greater decreases in PLEs in males (p-FDR=0.001). In females we also observed an interaction between PM2. and PRS-MDD on PLEs trajectories (p-FDR=0.048) such that those with high genetic risk and high PM2.5 exposure demonstrated increases in PLEs over time. Our results suggest that PM2. exposure and polygenic risk for depression jointly shape mental health during adolescence. This underscores the potential of interventions aimed at lowering air pollution during sensitive periods of neurodevelopment in improving adolescent mental health.

Background Brain abnormalities related to childhood adversity (CA) have been reported across clinical presentations in psychotic disorder (PD) and bipolar disorder (BD). This systematic review and meta-analysis examined gray matter volume (GMV) alterations linked to CA in PD and BD. Methods A PRISMA-compliant systematic review was conducted (PROSPERO ID: CRD42022351133). The EMBASE, MEDLINE, and PsycINFO databases were searched from inception to June 2024 for studies investigating CA and structural brain imaging in PD and BD. Study quality was assessed with the Newcastle Ottawa Scale (NOS). Data were extracted and synthesized accounting for sex differences and CA subtypes with brain findings categorized by the presence and direction of associations. Meta-analyses were performed for hippocampal and amygdala volumes. Results In the systematic review (k = 29), 3,056 participants with PD and BD (mean age = 36.6; SD =16.1; 47% female), published between 2011 and 2023, were included. Study quality was fair, with high heterogeneity. Most studies reported significant negative associations between CA and GMV, especially in prefrontal regions, while findings for the hippocampus and amygdala were largely null or inconsistent. Meta-analyses of a study subset identified no significant association between CA and hemisphere-specific and combined volumes of the hippocampus (k = 5; p [&ge;] 8805; 0.66) or amygdala (k = 4; p [&ge;] 8805; 0.87). Conclusion CA was not consistently associated with hippocampal or amygdala volume alterations in PD and BD. More consistent evidence emerged for reduced GMV in prefrontal regions, suggesting that neurobiological impact of CA may be more robustly captured at the cortical level.

Sensory processing differences are a core feature of autism, affecting 60-95% of individuals, yet the associated neural mechanisms remain unclear. An excitation-inhibition (E/I) imbalance in brain circuits has been proposed, but in vivo evidence linking genetic variation in E/I pathways, regional neurochemistry, neural circuit function, and sensory behaviour has been lacking. Here we performed a multimodal investigation in 206 individuals (130 autistic), integrating gene-set polygenic scores for excitatory glutamatergic and inhibitory gamma-aminobutyric acid (GABA)-ergic pathways, magnetic resonance spectroscopy (MRS) measures of regional GABA and Glx (glutamate + glutamine) levels, vibrotactile psychophysical measures of tactile perception, and questionnaire measures of behavioural sensory reactivity. We found that glutamatergic polygenic scores predicted thalamic glutamate levels in neurotypical but not autistic individuals, suggesting altered genotype-neurochemistry coupling in autism. Thalamic Glx:GABA levels associated with tactile perception in both groups, but with opposing directions of effect, indicating that autistic and neurotypical individuals achieve similar perceptual outcomes with potentially differing thalamocortical circuit mechanisms. Within autistic individuals, tactile perceptual differences further related to behavioural sensory reactivity. Together, these findings suggest that autistic sensory processing potentially relies on distinct circuit mechanisms linking genetic variation, neurochemistry and perception. This work thus has important implications for how sensory differences are conceptualised, studied, and interpreted, and ultimately for how interventions and support are developed.

Insulin signalling contributes to neurodevelopment and brain function, and insulin resistance (IR)-related traits are associated with cognitive performance. However, the genetic architecture shared across specific cognitive domains and IR-related phenotypes remains insufficiently defined. We analysed large-scale genome-wide association study summary statistics for 11 IR-related traits (N=53,334-933,970) and 10 cognitive measures (N=28,156-436,853) to quantify global and local genetic correlations, fine-map shared association signals, and annotate implicated genes and drug-gene interactions. Pairwise global and local genetic correlations were estimated, and shared high-confidence variants were prioritised using the multivariate Sum of Single Effects model. Positional and expression quantitative trait locus mapping was performed, and implicated genes were examined through functional annotation, tissue enrichment, and drug-gene interaction analyses. Low-to-moderate genetic correlations were observed between six IR-related traits and seven cognitive measures (|rg|=0.08-0.34), with predominantly opposite directions, except for correlations involving visual declarative short-term memory. Local genetic correlations showed mixed effect directions across most trait pairs, and multivariate fine-mapping prioritised 696 shared likely causal variants with high posterior support. Gene annotation indicated enrichment in several pathways, including immune-related, signal transduction, neurogenesis, neurotransmitter metabolism, receptor regulation, and lipid and cholesterol metabolism regulation. Implicated genes were expressed across various brain regions and showed prior associations with neuropsychiatric and cardiometabolic conditions. Several drug-gene interactions were identified, involving immunomodulatory and anti-inflammatory compounds. These findings indicate widespread heterogeneous genetic overlap between IR-related traits, particularly body mass index and waist-to-hip ratio, and cognitive measures of general intelligence, processing speed, and short-term visual declarative memory. The findings prioritise apolipoprotein-related lipid transport and inflammatory and oxidative stress pathways as candidate mechanisms linking cognitive, cardiometabolic, and neuropsychiatric phenotypes.

Stress-related psychiatric disorders and inflammatory bowel diseases share high co-morbidity and contribute to the symptom severity of one another. In mice, ten days of Chronic Social Defeat Stress (CSDS) is sufficient to reduce gut microbiome diversity and the relative abundance of Firmicutes, which are hallmarks of inflammatory bowel diseases. However, mechanisms by which stress causes gut microbiome dysbiosis are largely unknown. Here, we demonstrate that pharmacologically inhibiting {beta}-adrenergic receptors (ARs), which are activated by (nor)adrenaline during stress, mitigates gut dysbiosis otherwise caused by CSDS. Compared to vehicle-treated mice following CSDS, propranolol-treated mice displayed a modest increase in sociability, increased alpha diversity, and increased abundance of anaerobic commensal Clostridia. Abundance of short-chain fatty acid-producing anaerobic Firmicutes abundance correlated with sociability following CSDS across all treatments. Pharmacologically blocking -ARs during stress increased subsequent sociability, but had little effect on gut microbiome composition. Together, our findings support the hypothesis that {beta}-AR activation contributes to stress-induced changes of the gut microbiome. One Sentence SummaryPharmacologically inhibiting beta-adrenergic receptors during chronic stress mitigates reductions in anaerobic, short-chain fatty acid-producing bacteria in the gut.

Background: Depression is clinically heterogeneous, and immune-metabolic disturbances may not map uniformly onto categorical diagnosis or symptom severity. In populations exposed to substantial structural adversity, it remains unclear whether inflammatory and metabolic biomarker differences reflect adversity exposure itself or cluster around specific depressive phenotypes. Methods: Data were drawn from the Sao Paulo Megacity Mental Health Survey, a population-based study in which 5,037 household residents underwent structured psychiatric interviews. Among 770 participants assessed as having clinically significant symptoms (SCID-I), individuals with chronic physical illnesses, hs-CRP >20 mg/L, or missing data were excluded, yielding an analytic sample of 653. Latent class analysis of 16 DSM-IV depressive symptoms was used to identify symptom-derived phenotypes. Multinomial logistic regression tested associations between latent classes and immune-metabolic biomarkers, including hs-CRP, lipid fractions, fasting glucose, and triglycerides, adjusting for age, sex, education, smoking, and BMI. Results: A four-class solution identified asymptomatic (44.56%), mild-moderate (19.14%), atypical-like (16.69%), and melancholic-like (19.60%) classes. The two highseverity classes diverged by neurovegetative features: atypical-like depression was characterised by weight gain, hypersomnia, and psychomotor retardation, whereas melancholic-like depression was characterised by weight loss, insomnia, and psychomotor agitation. hs-CRP was highest in the atypical-like class and lowest in the melancholic-like class despite similar symptom severity. After BMI adjustment, elevated hs-CRP in the atypical-like class attenuated, whereas lower hs-CRP in the melancholic-like class persisted. Other metabolic markers did not robustly differentiate classes after adjustment. Conclusions: Immune-metabolic differences in depression do not simply follow symptom severity. In this Sao Paulo cohort, higher and lower hs-CRP profiles clustered around distinct latent depressive phenotypes, supporting biologically heterogeneous depressive presentations within a socially exposed urban population.

Insulin resistance, an often-untreated precursor of type 2 diabetes mellitus (T2DM), is implicated in cognitive decline in adults, yet its impact on the developing brain in youth with obesity remains poorly understood. We investigate whether insulin resistance moderates the relation between hippocampal volume and unhealthy food-seeking in overweight and depressed youth ages 9-17 who completed an oral glucose tolerance test and a cognitive task assessing unhealthy food-seeking motivation at baseline, 6-, and 24-months follow-up, and structural MRI at baseline and 6-months follow-up. Insulin sensitivity moderated this relation: smaller baseline hippocampal subfield volumes predicted increased unhealthy food-seeking over 24 months (ps<0.05). Categorical grouping revealed subfield CA2/3 and 4 volumes predicted this relation among insulin-resistant (ps<0.05), but not insulin-sensitive (ps>0.10), youth, suggesting that threshold criteria for insulin resistance are physiologically meaningful. These findings identify a neuro-metabolic risk phenotype that precedes T2DM and may accelerate unhealthy food-seeking severity in youth with obesity.

The increased vulnerability to mental health problems in adolescence is frequently reported but poorly understood, hampered by a rigid diagnostic system which fails to capture intertwining symptoms and only loosely aligns with biological axes of variability. Here, we reconceptualised the mental health symptoms of young adolescents in the ABCD cohort (N=11862) as a latent topology of overlapping symptom dimensions, using an unsupervised machine learning algorithm to establish how transdiagnostic dimensions co-occur and overlap within individuals. Combining this with a novel classification approach, we delineated zones within this landscape, within which specific profiles of symptoms were robustly represented. These data-driven profiles were leveraged to establish associated resting-state functional connectivity and genetic characteristics. In doing so we recaptured the commonly reported p-factor axis as well as further symptom-subtype dimensions. Gene ontology analysis revealed that shared neurobiological and cellular mechanisms embedded in both the genome and transcriptome may confer risk for psychopathology.

IntroductionBipolar disorder (BD) is characterized by recurring episodes of mania and depression. Despite extensive research, the pathophysiology underlying these mood swings remains elusive. Emerging evidence indicates a potential role for neuroinflammation and microglial activation in the pathophysiology of BD. MethodsWe employed a reverse-translational approach to generate directly induced microglia-like (iMG) cells from peripheral blood monocytes of a single patient with BD, repeatedly sampled across depressive, manic, and subsequent depressive phases. RNA sequencing was performed on iMG cells at each time point to identify differentially expressed genes related to mood state transitions. ResultsA thorough analysis of longitudinal gene expression data has led to the identification of three functional gene categories: "state-dependent genes", "depression-to-mania transition genes (named: firing genes)", and "mania-to-depression transition genes (named: extinguishing genes)". A total of 168 firing, 59 extinguishing, and 77 state-dependent genes were identified. Notably, functional annotation revealed that, compared to the extinction gene set, the firing gene set was enriched in immune and inflammatory response pathways, particularly early-response cytokines such as IL1B and TNF. ConclusionsBased on these findings, we propose that inflammatory immunomodulation by microglia contributes to mood switching in BD, especially in the process of depression-to-mania transition. The classification of genes by their relationship to state transitions offers a novel framework for understanding the molecular mechanisms underlying this complex disorder and may identify potential therapeutic targets to stabilize mood. Further validation with larger cohorts is warranted.

Prenatal alcohol exposure (PAE) is a major cause of neurodevelopmental disorders, yet most children are diagnosed late or misdiagnosed. Neuroplacentology suggest that placental factors released into maternal and/or umbilical cord blood contribute to fetal brain development. Consistently, a preclinical inter-organ transcriptomic database revealed that PAE disrupts the expression ratio of angiogenic and inflammatory factors suggesting an angio-inflammatory response. This study aimed i) to assay, by multiplex immunoassay, angiogenic and inflammatory factors in maternal and umbilical cord blood from alcohol-consuming women and ii) to perform a maternofetal analysis according to neonatal sex. Afterwards, dysregulated factors from mothers who gave birth to females or males were submitted to STRING and ShinyGO analyses. Results showed that PAE differently altered the distribution profiles of dysregulated angiogenic and inflammatory factors in maternal and umbilical cord blood. Moreover, sex-specific differences were observed, with 36% of dysregulated proteins specific to males, 48% to females, and 16% common to both. STRING analysis revealed robust functional protein-protein interactions linking together inflammatory and angiogenic clusters while the ShinyGO analysis identified enriched pathways related to vascular shear stress. These findings provide the first maternofetal analysis of combined angiogenic and inflammatory factors from alcohol-consuming mothers.

Abstract Background: Medical students carry a disproportionate burden of mental health problems, but large multicentre studies from low- and middle-income countries remain scarce, and most evidence relies on single-institution samples and odds-ratio-based analyses that overstate associations for common outcomes. We provide a comprehensive epidemiological overview of mental health among medical students across an entire Brazilian state, quantifying the burden, its co-occurrence, and its socioeconomic and academic determinants. Methods: Cross-sectional online survey of 1,560 medical students covering all 20 medical schools in operation in Rio Grande do Sul, Brazil (August-December 2023). Validated instruments assessed depressive and anxiety symptoms (PHQ-4), suicidal ideation (PHQ-9 item 9), non-suicidal self-injury, burnout (ESB-eu), quality of life (EUROHIS-QOL-8), spirituality (SSRS), substance use (ASSIST), prescription stimulant misuse, and mistreatment during training. Associations were estimated as adjusted prevalence ratios (aPR) using modified Poisson regression with robust variance, with linear trend tests, prespecified interactions, sensitivity analyses and E-values. Results: Anxiety symptoms affected 64.5% (95% CI 62.1-66.9), depressive symptoms 45.5% (43.1-48.0), burnout 49.1% (46.7-51.6), recent suicidal ideation 20.6% (18.7-22.7), lifetime self-injury 13.1% (11.6- -4.9) and stimulant misuse 7.9%; 57.4% screened positive for >=2 outcomes. Quality of life declined monotonically with cumulative burden. Low family income showed inverse gradients across five outcomes (e.g., depression: PR 0.93 per income level, p = 0.002). Four factors were independently associated with nearly all outcomes: short sleep (<6 h; aPR up to 2.73), minority sexual orientation (aPR up to 2.02), family psychiatric history, and mistreatment during training (reported by 55.6%; aPR up to 1.49). Stimulant misuse tripled from the basic cycle to clerkship (aPR 2.30, 95% CI 1.36-3.88). There was no evidence of multiplicative interaction, indicating that the risk factors acted independently on the outcomes. Estimates were robust across sensitivity analyses. Conclusions: One in two medical students in this state-wide sample screened positive for at least two mental health problems. Socioeconomic vulnerability, sleep deprivation, mistreatment and minority status operate as independent and largely modifiable determinants - actionable targets for medical schools and policymakers.

Background: Emotion dysregulation is a core feature of bipolar disorder (BD), yet its behavioral expression during depressive episodes, and potential differences between its types, BD-I and BD-II, remain unclear. This study used automated facial-expression analysis during naturalistic affective film viewing to examine subtype-specific and context-dependent emotional responding in bipolar depression. Methods: The sample included 135 participants: 69 healthy controls and 66 patients with BD (BD-I, 23; BD-II, 43). Participants viewed nine emotionally evocative film clips spanning negative, positive, neutral, and socially threatening contexts, while their facial expressions were continuously recorded and quantified using computer vision-based facial-expression analysis. Results: Patients with BD-I showed a distinct, context-dependent facial-expression profile, characterized by greater negative responses across multiple contexts than other groups. Specifically, they showed increased sadness during sad, reward, and amusing clips, and elevated anger during sad and neutral clips. In socially threatening contexts, BD-I participants showed a multivalent pattern of elevated anger, fear, and joy, suggesting poorly coordinated or context-incongruent affective expression. In contrast, BD-II participants did not differ significantly from healthy controls on any emotion, despite depressive symptom severity comparable to BD-I participants. Conclusions: These findings suggest that facial-expression patterns in bipolar depression differ across subtypes. BD-I may be characterized by heightened negative reactivity and altered context-appropriate modulation of emotional expression, whereas BD-II may not show comparable alterations in overt facial output. Automated facial-expression analysis during naturalistic stimulation may provide a useful behavioral marker for characterizing subtype-specific affective disturbance in bipolar depression and related psychopathology.

Cognitive flexibility is an executive function that allows individuals to adjust behaviour in response to changing environmental demands. We assessed volitional switching under uncertainty, without rule-based learning, in the Change Your Mind task. Nineteen patients with obsessive-compulsive disorder (OCD), 19 patients with attention-deficit hyperactivity disorder (ADHD) and matched control participants (20 per group) completed the task whilst undergoing a functional MRI scan. The task was a two-alternative forced choice paradigm where each stimulus was presented twice successively, with spurious feedback following the first presentation. This allowed participants the opportunity to repeat or change their response. Participants with ADHD changed their response more frequently than controls following a previously correct response, associated with reduced accuracy on the second trial. This was accompanied with smaller differences between change and repeat trials in the superior frontal gyrus, paracingulate gyrus and frontal pole compared to controls. Participants with OCD did not differ from healthy controls in their performance but exhibited greater activity on both change and repeat trials in the pre- and postcentral gyri than controls. These results point to distinct neurobehavioural differences in patients with ADHD and OCD underlying what is often termed more broadly inflexible behaviour.

Background: Opioid use disorder (OUD) is heritable, yet most genome-wide association studies (GWAS) have focused on European populations, leaving the genetic architecture of OUD in non-European populations underexplored. Methods: We conducted GWAS of OUD across three ancestries using electronic health records and genomic data from 52,357 All of Us Research Program participants (8,912 cases; 43,445 matched opioid-exposed controls; 48.5% female). Participants were stratified into European (EUR), African (AFR), and Admixed American (AMR) ancestry groups for logistic regression GWAS, with independent replication in the Million Veteran Program. We then applied the deep-learning model AlphaGenome to predict the tissue-specific transcriptomic and splicing consequences of top risk variants across 13 reward-pathway brain regions. Results: We identified and replicated a novel DDX6 risk locus, alongside established OPRM1 and FURIN signals. AlphaGenome predicted the DDX6 regulatory allele downregulates the stress-resistance gene FOXR1 in the nucleus accumbens, while the protective OPRM1 variant (rs1799971) upregulates OPRM1 expression across reward networks. Other signals of interest included IL6R and SHISA9 (EUR); GHR (AFR); and ASTN2 (AMR). Conclusions: This study identifies DDX6 as a novel OUD risk locus, replicates associations with OPRM1 and FURIN, and highlights biologically plausible ancestry-specific signals in AFR and AMR populations. We also replicated top variants in an independent population. Finally, integrating GWAS with deep-learning annotations provides specific, localized biological hypotheses to guide future experimental validation and targeted therapeutics.