Biological Psychiatry Global Open Science

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.

Prenatal and early postnatal life is a period of rapid brain growth, making the developing brain particularly susceptible to external influences. Adapting the biopsychosocial model of mental health and illness, this review provides a systematic overview of how biological, psychological, and social exposures from conception to age three critically converge to shape brain development and neurodevelopmental outcomes. Following a pre-registered protocol and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, 55 studies were included, primarily published in the past 15 years. Earlier studies focused predominantly on biological exposures, while more recent work has increasingly examined psychological exposures and, more rarely, social exposures. While each exposure exhibited its own pattern of brain alterations and neurodevelopmental changes, an overarching pattern emerged across the different components of the biopsychosocial model. Adverse biological exposures were consistently associated with delayed brain maturation as reflected by brain imaging measures. Adverse psychosocial exposures showed a more complex pattern of associations with both delayed and accelerated brain maturation. Crucially, adverse exposures, whether associated with delayed or accelerated brain maturation, were consistently associated with poorer neurodevelopmental outcomes, underscoring the necessity of considering both brain and behavior when estimating the impact of early exposures. We conclude that research into early-life exposures on brain maturation and neurodevelopmental outcomes is on the rise, but there is a great need for further investigation, in particular of psychological and social exposures. The interactions between exposures, the brain, and outcomes are highly complex, requiring assessment of both brain development and behavior together, ideally in within-subject longitudinal designs in future studies.

Background: Sleep disruption is prevalent in people with neurodevelopmental disorders such as autism but is not clear whether it occurs as an endophenotype or secondary to other behaviours. The ABCD Study is a population-based longitudinal study that monitors the health, demography and lifestyle of over 11,000 children in the US. In this study we leverage these data to investigate whether traits consistent with autism (social responsiveness) are associated with sleep disruption independent of lifestyle and other behavioural measures. Methods: Autistic traits were assessed using the Social Responsiveness Scale at age 11, and sleep disruption and behavioural outcomes were assessed at ages 11 and 13 years using the Sleep Disturbance Scale, and the Child Behaviour Check List, respectively. Demographic, health and lifestyle-related variables were assessed by caregiver questionnaires. Regression models were applied to investigate associations between autistic traits and sleep outcomes. Results: There was a significant cross-sectional association between sleep disturbance and SRS at age 11 years old that was independent of sex, ethnicity, socioeconomic position, physical activity, sedentary behaviour and anxiety/depression ({beta} = 0.12, 95% CI (0.07, 0.17); p < 0.001), that persisted at age 13, and that was modulated by chronotype, with evening types showing a stronger association. Discussion: Social responsiveness assessed in early adolescence (age 11) were associated with sleep disruption independent of multiple confounding factors and were prospectively associated with sleep disruption at age 13 years. These findings contribute to the evidence that disruption of sleep and circadian timing may have a primary role in the neurobiological mechanisms that mediate autistic traits.

Background. Psychosis spectrum symptoms (PSS) are prevalent in youth and are associated with increased risk for psychotic disorder, suicidality, and functional impairment. Computationally, PSS may stem from altered predictive coding of basic sensory surprises and environmental volatility. Formalized as hierarchical precision-weighted prediction errors (pwPEs), this altered processing is a proposed mechanistic substrate of aberrant perceptual inference across disorders, including psychosis-risk populations. While the auditory mismatch negativity (MMN) provides an electrophysiological index of pwPEs, it remains unknown if distinct hierarchical pwPE components distinguish youth who endorse PSS. Methods. A sample of 131 participants (PSS-=66, PSS+=65; ages 11-24) from the ongoing Toronto Adolescent and Youth (TAY-CAMH) Cohort study were stratified by PSS status using the PRIME Screen-Revised and were assessed for their psychosocial functioning. 64-channel EEG was recorded during an auditory oddball paradigm with stable and volatile phases. A hierarchical Bayesian model applied to the stimulus stream generated trajectories of low-level sensory and high-level volatility-related pwPEs. Alongside standard phase-averaged event-related potentials (ERPs), Bayesian trajectories derived model-based ERPs. Results. Replicating prior findings in non-clinical controls, stable-phase MMN significantly exceeds volatile-phase MMN and lower psychosocial functioning was associated with reduced volatile-phase MMN amplitude. Age significantly modulated oddball MMN and unweighted prediction errors ({delta}1, {delta}2). Group differences between PSS+ and PSS- were statistically significant for volatility-level pwPE ({epsilon}3), peaking at ~180 ms Peri-Stimulus Time (pFWE-peak =.024). Conclusions. Independent of age-related developmental effects, volatility-level pwPE learning ({epsilon}3) constitutes a more sensitive EEG marker associated with PSS status in help-seeking youth than low-level sensory pwPE.

Introduction: Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a debilitating condition characterised by severe fatigue and post-exertional malaise (PEM). Reported neuropsychophysiological abnormalities suggest ME/CFS is multifactorial, but current knowledge remains fragmented. This study protocol outlines a multimodal investigation designed to (1) compare neuropsychophysiological mechanisms between ME/CFS patients and healthy participants, (2) test an integrative model of ME/CFS, (3) identify neuropsychophysiological subgroups within the patient population, and (4) identify predictors of symptom response during rehabilitation. Methods and analysis: This study will enroll 115 ME/CFS patients and 55 healthy participants. Groups will be comparable in age, sex, and education level, with a larger patient sample enabling subgroup and longitudinal analyses. A cross-sectional assessment at baseline will be carried out in both groups. Patients will then be evaluated longitudinally throughout a standardized cognitive-behavioral therapy rehabilitation program delivered as routine care. Baseline measures include systemic inflammation and general health biomarkers, measures of autonomic and central nervous system function, neuroinflammation (magnetic resonance spectroscopy, [18F]DPA714 PET in a subsample), serum short-chain fatty acid levels, gut microbiota composition and function, and neuroendocrine and self-reported responses to psychosocial stress. Fatigue severity (physical and cognitive) and PEM will be assessed through validated questionnaires, ecological momentary assessment, and laboratory tasks. These will be re-evaluated during therapy, and all non-neuroimaging measures will be repeated after the rehabilitation program. Statistical analyses will comprise multivariate analysis of variance, general linear models, classification algorithms, structural equation models, least absolute shrinkage selection operator principal component regression (LASSO-PCR), cluster analysis and latent class growth analysis (LCGA).

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.

Exposure to chronic environmental challenges triggers divergent behavioral trajectories across individuals. At the core, these different trajectories can be classified as individuals actively adapting to the challenges ("responders") and those displaying a rigid, non-responsive phenotype ("non-responders"). The brain system-wide network configurations that dictate why individuals diverge along these differential coping strategies, which can also lead to disease vulnerability or resilience, remain poorly understood. Here, we paired machine-learning-based deep behavioral phenotyping with multi-modal whole-brain imaging, integrating longitudinal Manganese-Enhanced MRI (MEMRI) and post-challenge cFOS mapping, to chart the functional landscape of individual stress trajectories in mice subjected to chronic social defeat stress. High-dimensional behavioral phenotyping revealed that active stress adaptation is a complex trajectory marked by latent, pre-stress kinetic signatures in vigilance-like and locomotive behaviors. At the neural level, longitudinal MEMRI captured distinct, consolidated activity reconfigurations across canonical valence and stress-regulatory circuits that segregated responders from non-responders. Complementary whole-brain cellular cFOS network analysis after an additional acute challenge revealed that non-responders exhibited marked hyper-modularity and network fragmentation, whereas responders feature a tightly integrated functional module co-clustering the periaqueductal gray, ventral tegmental area, basolateral amygdala (BLA), and dorsal raphe (DR). Notably, functional network connectivity along the DR-BLA axis was completely lost in non-responsive animals. Finally, pathway-specific chemogenetic inhibition of BLA-projecting DR neurons during a social challenge significantly attenuated social avoidance and reversed anxiety-like behavioral deficits, effectively shifting active behavioral adaptation toward a non-responsive phenotype. Together, these findings demonstrate that individual stress-coping strategies are driven by coordinated, system-wide reconfigurations of activity and plasticity, identifying the DR-BLA circuit as a critical gatekeeper of adaptive stress responses. Graphical AbstractGlobal neural functional alterations defining responding vs non-responding populations following chronic stress are understudied, yet crucial. Deep phenotyping followed by mapping brain-wide activity and plasticity changes identified these underlying divergent functional networks. Acute manipulation of a dorsal raphe - basolateral amygdala pathway ameliorated adaptive stress responses, highlighting the significance of this network-based approach. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/740522v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1850a04org.highwire.dtl.DTLVardef@1549284org.highwire.dtl.DTLVardef@15f3ebforg.highwire.dtl.DTLVardef@107ca9_HPS_FORMAT_FIGEXP M_FIG C_FIG

IntroductionAnhedonia is a transdiagnostic psychiatric symptom linked to increased functional connectivity between the prefrontal cortex and striatum. Here, we examined how dimensions of early adversity contribute to this profile of connectivity. MethodsIn a European community sample of young adults (IMAGEN), we examined cross-sectional (n=613) and longitudinal (n=332) associations of adversity dimensions with resting-state fMRI-derived connectivity. We selected 10 ROIs from anhedonia literature, defined in the functional images as 4mm-radius spheres. We then used network-based regression models to identify clusters of ROI-ROI connections associated with threat and deprivation scores, using interaction terms to examine sex and age-specific associations. We also examined associations between adversity and anhedonia, operationalized using factor analysis of six items from self-report surveys. ResultsAt age 18-22, we identified sex-specific associations between deprivation and connectivity for a cluster of 9 ROI-ROI connections (p-FWE=0.038), primarily involving the nucleus accumbens. Specifically, we observed positive associations between deprivation and connectivity in males, and negative associations in females. In the longitudinal analysis, negative deprivation associations in females attenuated with age for a cluster of 14 connections (p-FWE=0.009). A cluster of 17 connections also had initial positive associations with threat in females that attenuated with age (p-FWE=0.008). No such longitudinal changes were observed in males. Higher deprivation was linked to increased later anhedonia in males but not females (p=0.026). ConclusionCompared to females, young adult males may be more vulnerable to developing anhedonia after experiencing deprivation in childhood. Dimensions of early adversity are linked to distinct pathways of frontostriatal development.

Autism is a heterogeneous neurodevelopmental condition, often accompanied by challenges in language and cognitive development. Although atypical functional connectivity (FC) has been reported in autism, the timing of when it first emerges and its relevance for later behavior remain poorly understood. In this study, we examined developmental trajectories of alpha-band FC and network organization across the first three years of life. We computed global alpha-band measures, including peak alpha connectivity frequency (PACF), mean FC, clustering coefficient, and modularity, to characterize nonlinear developmental trajectories from longitudinal EEGs collected from 238 children (3-to-36-month-olds) with (Autism; n=58) and without (LL-noAutism; n=180) autism. Network-based statistics (NBS-Predict) identified subnetworks contributing to group differences at each age. Exploratory graph analyses (EGA) examined associations among FC, network measures, and language outcomes. We observed that PACF increased linearly with age in both groups. Global alpha-band connectivity measures showed a similar developmental pattern, with mean global FC, clustering coefficient, and modularity all increasing rapidly during the first year in both groups. Thereafter, these measures declined in the Autism group but continued to gradually increase in the LL-noAutism group. Compared to LL-noAutism, NBS-Predict identified both hyper- and hypo-connectivity subnetworks in Autism at 3 months, followed by a hypo-connectivity subnetwork at 24 and 36 months. EGA indicated that early hyperconnectivity predicted later hypoconnectivity and was associated with subsequent network organization and language outcomes. These findings indicate that altered alpha-band connectivity trajectories are detectable in infancy in children later diagnosed with autism and may contribute to later differences in developmental outcomes.

Background: Rett syndrome (RTT), a rare neurodevelopmental disorder caused primarily by pathogenic variants in the MECP2 gene, is characterized by severe cognitive, motor, and autonomic impairments. Atypical sensory processing, including co-occurring hypo- and hyper-responsivity, is a core yet poorly understood feature. While evoked potentials (EPs) show delayed and attenuated sensory responses in RTT, the underlying mechanisms of these impairments remain unclear. Inter-trial phase coherence (ITPC), which quantifies trial-by-trial neural response consistency, offers a promising functional biomarker of variability in sensory processing. Methods: We characterized caregiver-reported sensory responsivity in 32 individuals with RTT (all female) and 28 typically developing controls (26 female, 2 male). EPs were then recorded during passive visual and auditory stimulation and ITPC was computed to assess whether variability in the timing of neural responses could account for reduced EP amplitudes and atypical sensory responsivity. Results: Hypo- and hyper-responsivity to sensory stimuli were both significantly elevated in RTT and were positively correlated, co-occurring within individuals. ITPC was significantly reduced in RTT across visual and auditory modalities and was associated with reduced EP amplitudes. Notably, reduced ITPC in visual-evoked potentials was further associated with elevated visual responsivity and greater behavioral symptom severity. Conclusions: Increased variability in neural response timing may contribute to both reduced EPs and atypical sensory responsivity in RTT, supporting ITPC as a functional biomarker. Decreased temporal precision of neural activity may explain the co-occurrence of hypo- and hyper-responsivity and provide a unifying framework for sensory dysfunction across neurodevelopmental disorders.

Background: Autism spectrum disorder is a prevalent neurodevelopmental condition featuring marked social difficulties. Oxytocin supplementation shows promising therapeutic efficacy in alleviating autism-like traits in rodent models, but clinical effects in humans remain inconsistent. The rodent-derived social salience network (SSN) comprises several oxytocin-modulated brain regions implicated in social behavior, but its conservation has not been established in humans. Here we assess, for the first time, functional connectivity (FC) within a homologous human SSN in autistic men to examine its relationship with behavioral traits and modulation by oxytocin. Methods: The human SSN atlas was collated from open-access cortical and subcortical parcellations, and used to retrospectively analyze a resting-state fMRI dataset of adult men with autism from a previously published, randomized, placebo-controlled oxytocin trial. SSN-wide and sub-network ROI-to-ROI FC correlations with social trait expression and salivary oxytocin concentrations were performed at baseline and post-administration. Treatment specific outcomes on FC were calculated using ANCOVA. Results: We observed SSN sub-network FC correlations with social and repetitive behavioral scores and identified strong oxytocin sensitivity of nucleus accumbens-somatosensory and paraventricular nucleus-somatosensory circuits at baseline. Following nasal spray administration, a strengthening of amygdala-somatosensory circuit was detected as the largest oxytocin-induced FC shift. Notably, baseline connectivity within this circuit strongly predicted treatment response, with individuals having lower baseline FC showing greater post-treatment FC. Conclusions: These findings provide first evidence for clinical relevance of the SSN in humans with autism and highlight circuits that may represent promising biomarkers for predicting oxytocin responsiveness.

ImportanceCallous Unemotional (CU) traits are associated with significant clinical and neurophysiological heterogeneity that may affect treatment effectiveness. ObjectiveTo uncover neuroanatomical subtypes of CU traits using weakly-supervised machine learning and assess whether emerging subtypes differ on relevant clinical, temperamental, and environmental constructs. Design, Setting, and ParticipantsImaging data was from the longitudinal Adolescent, Brain, Cognitive Development (ABCD) Study. Participants were 9-10 years old at baseline (M=9.925, 69.9% male) and included 222 children with CU traits and 234 typically developing controls matched on age, sex and income. Main Outcomes and MeasuresThe weakly-supervised heterogeneity through discriminative analysis (HYDRA) model was trained on grey matter (GM) volumes from 84 regions of interest (ROIs) and tested for reproducibility using cross-validation and permutation testing. Derived subtypes were compared cross-sectionally and prospectively on relevant clinical, temperamental, and environmental measures and subsequent GM volume at 2-year follow up. ResultsHYDRA revealed an optimal 2-subtype solution within children with CU traits. Subtypes showed comparable levels of aggression that were significantly higher than typically developing controls. At the same time, subtype 1 had larger GM volume, fewer internalizing symptoms, and less adversity exposure, while subtype 2 was characterized by smaller GM volume, more internalizing symptoms, and more adversity exposure. Conclusions and RelevanceThis study provides evidence of neuroanatomically distinct subtypes of CU traits characterized by different clinical and etiological profiles, with implications for diagnosis and treatment.

Background: Suicide attempts (SA) are elevated in individuals with autism spectrum disorder (ASD), but population-level data characterizing how SA prevalence varies across demographic and clinical subgroups - at the scale and granularity needed to inform evidence-based risk stratification - have been largely unavailable. This study examines SA prevalence across sex, age group, psychiatric comorbidity type, and substance use disorder subtype in the largest real-world ASD cohort to date. Methods: We conducted a retrospective cross-sectional analysis using Epic Cosmos electronic health record data from 2,311,171 individuals with ASD identified by International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes, spanning 2016-2025. SA prevalence was calculated with Wilson score 95% confidence intervals. Modified Poisson regression with robust variance estimation was used to estimate adjusted prevalence ratios (aPRs) for sex, age group, and psychiatric comorbidity. Unadjusted prevalence ratios (uPRs) were calculated separately for individual comorbidity types and substance use disorder subtypes. Results: Overall SA prevalence was 1.7% (38,160 individuals). Females showed higher SA prevalence than males (2.9% vs. 1.2%; aPR 1.61, 95% CI 1.35-1.92). SA prevalence peaked in the 15-24 age group overall (aPR 5.14, 95% CI 3.62-7.29), with sex-stratified analyses revealing that females peaked earlier (15-24 years; aPR 4.33, 95% CI 4.23-4.43) than males (25-34 years; aPR 6.08, 95% CI 5.05-7.31) - a sex-specific divergence in the timing of peak SA prevalence not previously documented in ASD. Having at least one psychiatric comorbidity was associated with a 30-fold higher SA prevalence (aPR 30.56, 95% CI 26.03-35.89), with the effect stronger in females (aPR 36.54, 95% CI 31.04-43.01) than males (aPR 27.77, 95% CI 22.65-34.06). Among comorbidity subtypes, substance-related disorders showed the highest crude SA prevalence (16.9%; uPR 134.20, 95% CI 67.68-266.10). Subtype-level characterization revealed SA prevalence ranging from 19.7% to 24.3% across all five substance use disorder subtypes examined, with stimulant use disorder showing the highest unadjusted prevalence ratio of any subtype (uPR 196.11, 95% CI 100.63-382.20). Conclusion: SA prevalence in ASD is markedly elevated relative to the general population and varies meaningfully by sex, age, and comorbidity profile in clinically important ways. Females carry a disproportionate SA burden relative to males, with peak vulnerability arriving earlier in adolescence; males peak later in young adulthood and remain at elevated risk into midlife. Psychiatric comorbidity - particularly substance use disorders - is associated with the largest relative elevations in SA prevalence. These population-level estimates are directly applicable to EHR-based risk stratification models and can inform the development of ASD-specific clinical decision support tools that concentrate surveillance and intervention on those at demonstrably elevated risk, rather than applying uniform approaches across a heterogeneous population.

Background: Sleep problems are common in autism, emerge early in life and reduce quality of life, yet the mechanistic link between autism and poor sleep remains unclear. Human and rodent data indicate that difficulty falling asleep is a core feature of autistic insomnia, pointing to impaired responses to sleepiness as the underlying cause. We previously showed that adult mice carrying a mutation in the high-confidence autism gene Shank3 (Shank3{Delta}C) recapitulate this insomnia phenotype and struggle to respond to sleepiness after acute sleep deprivation. Here, we used Shank3{Delta}C mice to examine the molecular basis of sleepiness and how this autism-associated mutation alters it to inform understanding of sleep problems in autistic individuals. Methods: This study used RNA-sequencing and bioinformatics to identify molecular targets underlying the effect of the Shank3{Delta}C mutation on the molecular basis of sleepiness across development in male mice. We first compared cortical genome-wide gene expression following acute sleep deprivation and recovery sleep in adult wild-type (WT) and mutant mice. We then used polysomnography and RNA-sequencing to assess the response to increased sleepiness in WT and mutant mice at postnatal days 24 and 30. Results: The neurotypical response to acute sleep deprivation shifted from upregulating neuronal growth and development pathways at P24/P30 to upregulating DNA damage repair and neuronal activity-dependent transcription in adulthood. The Shank3{Delta}C mutation largely blocked recruitment of these pathways at P24 and in adulthood while paradoxically increasing the magnitude of the mutant response at P30. In addition, mutants consistently upregulated oxidative stress pathways linked to neurodegeneration and protein synthesis regardless of age, whereas WT animals downregulated these functions. Limitations: This study examined gene expression only in male mice, used a single autism rodent model, and averaged signals across mixed cortical cell types. Future work should include females, additional autism models, and single-cell approaches in additional brain regions to further characterize the cellular effects of sleep deprivation and autism-associated mutations. Conclusions: The Shank3{Delta}C mutation impairs the molecular accumulation of and response to sleepiness, both by elevating oxidative stress responses and by blocking the age-typical upregulation of pathways that differ between juveniles and adults.

Neuropsychiatric polygenic indices (NPGIs) are used as genetic predictors of poor mental health. However, NPGIs are also associated with environmental factors which could affect mental health in adulthood, including the rearing environment. Hence, their "genetic" effects are both direct and environmentally mediated. There is a need to identify alternative genetic predictors without environmental signal. Endophenotype-based polygenic indices (EPGIs) trained on brain structure and function are under-studied alternatives which, due to their relative biological proximity, may exhibit associations with mental health outcomes which are less environmentally mediated than those of NPGIs. Using four representative UK samples (Understanding Society; UKHLS, NCDS, BCS70 and MCS) we employ sex-stratified path models to estimate the direct and environmentally mediated effects of eleven NPGIs and 30 EPGIs on adult mental health, focussing on the rearing environment. The depression NPGI is consistently associated with mental health symptoms across most sex-stratified sub-samples (best meta-analysis beta = 0.091, p 0.001) but demonstrates 1.6 - 24.5% environmental mediation. Seven other NPGIs and three EPGIs show sample- and sex-specific associations with mental health symptoms. NPGIs for attention deficit hyperactivity disorder, depression and substance use disorder are robustly associated with measures of the rearing environment, which in turn are frequently associated with mental health symptoms. Sensitivity analyses find that NPGI associations vary substantially depending on who is included in the sample. In conclusion, the rearing environment likely mediates a substantial portion of NPGIs' so-called "genetic" effects on mental health symptoms, but EPGIs are not currently powerful enough to replace them.

Physical activity produces widespread benefits to physical and mental health, including protection against stress-related behavioral outcomes. However, the peripheral signals through which physical activity is translated into stress resistance remain incompletely understood. Irisin, an exercise-induced myokine cleaved from the transmembrane protein FNDC5 and released into circulation, has been implicated in improved cognition and neuroprotection, but its role in resistance to behavioral consequences of future adversity has not been examined. Here, we tested whether forced peripheral elevation of irisin is sufficient to protect against stress-induced behavioral outcomes. Adult male C57BL/6 mice received adeno-associated viral (AAV)-mediated peripheral expression of irisin or GFP control. AAV-irisin significantly increased circulating irisin levels, and six weeks later, mice were exposed to inescapable stress, a well-characterized model that produces anxiety-like behaviors, including reducing rodents natural inclination toward sociability. Elevated circulating irisin prevented the stress-induced reduction in social preference without altering general locomotor activity. Moreover, circulating irisin levels positively predicted individual differences in sociability. Additionally, peripheral irisin elevation increased brain-derived neurotrophic factor (Bdnf) expression, which also positively correlated with circulating irisin levels. Finally, we identified expression of the irisin receptor subunit integrin V within the dorsal raphe nucleus, a key brain region implicated in the behavioral outcomes of inescapable stress that is modulated by prior exercise. Together, these findings identify peripheral irisin as a mediator sufficient to confer resistance to future stress, even in the absence of physical activity. Significance StatementPhysical activity protects against the anxiety-like behavioral outcomes of future stress, but the peripheral mediators of this effect remain unclear. Here we show that forced peripheral elevation of circulating irisin, an exercise-induced myokine, is sufficient to produce behavioral stress resistance in mice. Irisin prevented the stress-induced reduction in social preference and positively correlated with individual differences in sociability. Forced expression of peripheral irisin also increased Bdnf expression in the brain, consistent with engagement of central neuroplasticity pathways that support adaptive behavioral responses. These findings demonstrate that an exercise-induced circulating factor can confer resistance to future stress, identifying irisin as a potential prophylactic target for stress-related mental health disorders.

BackgroundEarly life adversity (ELA) is associated with notable negative consequences across development. Experiences of deprivation may affect neurocognitive development, while experiences of threat may alter emotion processing. Deprivation and threat may also differentially influence reward processing. However, unique consequences of deprivation and threat beyond low family resources are debated. MethodsWe employed an exposure vs. control data analytic approach to isolate deprivation and threat influences from socioeconomic resources. Adolescent Brain Cognitive Development (ABCD(R)) Study youth exposed to neither deprivation nor threat (N=2408-2962) were matched to youth exposed to deprivation-only (N=638-721), threat-only (N=198-232), or threat non-exclusively (threat+: N=382-464) based on family income, parental education, race/ethnicity, sex, and age. Multivariate analyses were used to distinguish each ELA group from their respective control groups in the neurocognitive domain (resting-state connectomic maturation, cognitive task performance, and cortical grey matter thickness at two timepoints) and in the neuroaffective domain (nucleus accumbens and caudate activation to reward anticipation and amygdala and insula activation to fearful faces). ResultsIn the neurocognitive domain, similar latent variables (LVs) differentiated the deprivation and threat+ groups from their respective matched control groups. This LV corresponded to neurocognitive maturation, loading positively on cortical functional maturation and task performance, and negatively on cortical grey matter thickness. This LV was weaker in the deprivation and threat+ groups compared to controls. In the neuroaffective domain, no significant LVs were found. ConclusionBoth threat and deprivation exposure during childhood may delay neurocognitive development in early adolescence beyond their co-occurrence with low socioeconomic resources.

Background Prenatal cannabidiol (CBD) consumption is increasing, driven by a perception of safety relative to delta-9-tetrahydrocannabinol (THC). However, the neurodevelopmental risks of gestational CBD remain largely uncharacterized. Methods Using a sex-disaggregated framework, we investigated adult (P100-140) mouse offspring following in utero exposure (GD5-18; 3 mg/kg) to THC or CBD. Behavioral strategies were evaluated through risk-assessment and repetitive behavior tasks, coupled with targeted electrophysiological mapping of medial prefrontal cortex Layer 5 neurons, the primary hub for approach-avoidance arbitration. Results We found that increased repetitive behavior was a universal feature of prenatal cannabinoids exposure. Alterations in risk appraisal emerged uniquely in CBD-exposed females and appeared dissociated from classical anxiety metrics. At the circuit level, THC and CBD were linked to an absence of endocannabinoid long-term depression (eCB-LTD). In males, CBD exposure coincided with a bidirectional plasticity collapse characterized by functional saturation, elevated AMPA/NMDA ratios, and slowed NMDAR activation kinetics. This ceiling effect may represent a top-down constraint on the prefrontal output circuit, potentially limiting the synaptic flexibility typically associated with adaptive behavioral transitions. In contrast, females exhibited compound-specific reorganizations of E/I balance. CBD-exposed females displayed a scaled-up architecture that preserved net E/I balance, whereas THC was associated with a pro-excitatory phenotype through the collapse of inhibitory control. Conclusions Despite a shared loss of eCB-LTD, distinct synaptic remodeling might underlie divergent alterations in risk assessment and behavioral flexibility. This sex-specific circuit rewiring provides a neurobiological framework for the long-term behavioral risks associated with gestational cannabinoid exposure.

Genetic instrumental variable studies can provide stronger insights into the causal relationships between smoking and mental illness than conventional observational studies because they are less susceptible to confounding and reverse causation. However, they still rely on genetic instruments that partly capture genetic influences shared with other substance use and socioeconomic status (SES), potentially biasing estimates of smoking-specific effects. We therefore aim to (1) develop a more specific genetic instrument for smoking that minimizes these shared influences and (2) use this instrument to examine the causal effects of smoking on psychiatric disorders. We applied Genomic Structural Equation Modelling to 19 European-ancestry GWAS summary statistics (7 smoking, 8 substance use and 4 SES phenotypes), deriving a novel smoking-specific genetic factor representing liability to smoking independent of shared substance-use and SES influences. We used this factor as an instrument in Mendelian Randomization analyses to test causal effects of smoking on eight psychiatric disorders. The smoking-specific factor was associated with 52 independent genome-wide significant loci. Genetically predicted smoking-specific liability was significantly causally associated with seven psychiatric disorders. These findings support a causal role of smoking in increasing the risk of multiple psychiatric disorders beyond influences shared with other substance use and SES, providing stronger evidence for smoking-specific effects and informing targeted smoking prevention and intervention strategies. More broadly, our findings highlight that the validity of Mendelian Randomization depends on the specificity of its genetic instruments. Future studies should strive to develop instruments that better isolate the exposure of interest from shared genetic influences, enabling more accurate identification of causal mechanisms.

Background: The widespread prevalence of psychopathology, which affects approximately 50% of the global population, often manifests during adolescence. Understanding why some individuals remain resilient while others experience mental health challenges despite similar environmental risks is essential for developing early interventions. However, past efforts have faced challenges with the retrospective definition of resilience. Here, we aim to address these challenges by quantifying resilience to psychopathology at the individual level. Methods: In the Adolescent Brain and Cognitive Development (ABCD) Study(R) (N = 11,868), we utilized gradient-boosted tree regression to predict 2-year follow-up psychopathology from 208 Social Determinants of Health features. We used the "gap score" method--the difference between model-predicted and reported psychopathology--to quantify individual differences in psychopathology resilience and susceptibility, defined as the Resilience-Susceptibility Gap (RS-Gap). We validated the RS-Gap against independent 3-year follow-up clinical and quality-of-life outcomes. Results: Collinearity between gap scores and reported symptoms was high (r=-0.84), requiring further correction. Four bias-correction techniques were implemented and compared. After appropriate bias-correction, greater RS-Gap scores were associated with a higher likelihood of poor academic and social outcomes one year later, suggesting that early adaptation to adversity may carry a latent long-term cost. Conclusions: Dependency between RS-Gap and psychopathology scores is a statistical challenge for gap score resilience methods. Our comparisons demonstrate that correction is mandatory to separate resilience signal from shared variance with psychopathology scores. Findings converged across different bias correction methods, providing a validated framework for using gap scores to identify high-risk developmental trajectories in youth.