Biological Psychiatry Global Open Science

Adolescence is a critical developmental window for the emergence of substance use and psychosis-spectrum symptoms, yet early risk for these outcomes remains poorly understood. Using longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (n=10,134), we tested whether demographic, clinical, and structural and functional neuroimaging measures assessed in childhood (mean baseline age=9.96 years) predict later adolescent substance use, psychotic-like experiences, and/or their co-occurrence. Multivariate machine learning models reliably predicted later emergence of psychotic-like experiences (AUROC=0.780) and their co-occurrence with substance use (AUROC= 0.828), as well as substance use on its own (AUROC=0.626). Distinct patterns of functional brain connectivity, task-related brain activation, demographic, and clinical factors differentiated each outcome. Findings suggest that partially dissociable developmental risk profiles are detectable as early as childhood, and results underscore the importance of explicitly modeling comorbidity when interrogating risk factors for mental health outcomes.

Impulsivity is a core dimension of ADHD and a transdiagnostic vulnerability factor for a wide range of adverse psychiatric and somatic outcomes, that could be mitigated through more effective screening of at-risk individuals. However, laboratory-based measures of impulsivity show weak convergence across paradigms and limited prediction of real-world behavior, constraining their utility. We tested whether combining repeated ecological assessment with computational modeling of response-time (RT) dynamics improves measurement of impulsivity and its cross-paradigm validity. Sixty participants, including adolescents with ADHD, individuals with 22q11.2 deletion syndrome, and healthy controls, completed a total of 1347 smartphone-based Balloon-Analogue-Risk-Task (D-BART) assessments repeatedly in daily life, alongside a single-session Conners CPT-3. RT was modeled using linear mixed-effects models as a function of objective risk and subjective uncertainty, with random effects capturing between- and within-person variability. Dynamic RT parameters were integrated with conventional performance metrics and related to CPT-3 variables using partial least squares analysis. External validity was evaluated against parent-rated behavioral symptoms. RT increased with both risk and uncertainty, consistent with adaptive modulation of speed-accuracy trade-offs. These effects varied substantially across individuals and repeated assessments. Dynamic RT parameters differentiated clinical from control participants, whereas traditional aggregate metrics did not. A PLS latent component linked D-BART and CPT-3 patterns and was associated with real-world hyperactivity/impulsivity, whereas CPT-3-derived scores alone were not. Experimental manipulation of ecological sampling density directly impacted D-BART predictive accuracy. These findings show that ecological repetition combined with parsimonious RT-dynamics modeling enhances construct validity, cross-paradigm convergence, and behavioral relevance of impulsivity measures, providing a scalable framework for capturing dynamic cognitive-control processes.

Despite their prevalence, the pathophysiology of depression and anxiety remains poorly understood. Although adversity is a known risk factor, the mechanisms and biological contexts through which it contributes to mood disorder symptoms remain unclear. Immune and mitochondrial adaptations have both been implicated in mood disorders, suggesting the biological embedding of adversity may involve both systems. However, inconsistencies in the literature remain, partly due to reliance on mixed peripheral blood mononuclear cell (PBMC) populations despite substantial variability in mitochondrial biology across immune cell subtypes. We therefore investigated associations between adversity, mood disorder symptoms, immune cell proportions, and immune cell-specific mitochondrial bioenergetics (enzyme activities and respirometry) in participants from the Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study (n=105, age 18-60, 68% female, 35% with mitochondrial disease). Depressive and anxiety symptoms were positively associated with the monocyte-to-lymphocyte ratio, suggesting a shift toward greater innate relative to adaptive immunity. Associations between mood disorder symptoms and immune cell count were stronger in those exposed to greater early life adversity. Mood disorder symptoms were negatively associated with lymphocyte maximal mitochondrial respiratory capacity (MRC). As expected, the associations between mood disorder symptoms and lymphocyte mitochondrial bioenergetics (enzyme-based MRC and respiratory measurements) were stronger and more consistent among individuals exposed to higher lifetime adversity compared to those with lower lifetime adversity. Overall, these results suggest a complex interplay between adversity, immune cell mitochondrial bioenergetics, and mood disorder symptoms, highlighting immune mitochondrial biology as a potential allostatic pathway linking adversity to psychiatric disorders.

Childhood obesity remains a pressing global health challenge, yet the impact of dynamic adiposity changes during active developmental window retains poorly understood. Leveraging longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (N=8519 at baseline; N=1873 at 4-year follow-up), our study reveals distinct neurodevelopmental implications of central fat dynamics during adolescence. At baseline, central fat indices (body roundness index, BRI / waist-to-height ratio, WHtR) outperformed BMI in predicting cognitive deficits, showing robust associations with impaired inhibitory control and episodic memory. The prediction effect was partially mediated by cortical changes in prefrontal and temporal regions. Longitudinally, the rate of fat accumulation ({Delta}) emerged as a critical predictor: faster adiposity accrual predicted attenuated cortical thinning (i.e., slower development) in parietal lobes and poorer executive function at follow-up, while baseline adiposity showed no significant effects on the follow-up brain morphology or cognitive development. Notably, subgroup analyses uncovered that obese adolescents with central fat reduction exhibited accelerated cortical thinning in posterior cingulate (change difference p=0.006-0.029) alongside rapid improvement in inhibitory control (Flanker slope difference p<0.05), whereas those with persistent adiposity showed delayed thinning in the postcentral gyrus. The study reveals that central fat (BRI/WHtR) is closely linked to neurocognitive risks, and longitudinal fat accumulation--rather than baseline adiposity--drives cortical alteration. Notably, fat reduction activated adaptive neural change in obese adolescents, underscoring the importance of weigh regulation during neurodevelopment.

Children exposed to severe childhood maltreatment often develop complex mental health disorders where standard treatments show limited efficacy. Current residential approaches combine psychopharmacological with behavioural interventions, yet the feasibility and clinical-neurobiological outcomes of intensive, medication-free psychotherapy have not been investigated in this population. Our prospective study followed severely traumatized children (aged 6-13 years) with documented histories of changes and failures in placement.They completed an intensive 6-8 months inpatient treatment program (5 individual psychotherapy and 3 group therapy sessions per week with high caregiver-patient ratio) grounded in a novel, multimodal, attachment-based therapeutic framework. Medication was discontinued prior to treatment. The intervention group was compared to healthy controls and waitlist controls receiving treatment as usual. Participants in the intervention group achieved high remission rates for dysregulated behaviour (Child Behaviour Checklist (CBCL) >60% post treatment, 50% on follow-up) and trauma-related symptoms (Parent Report of Post-traumatic Stress Symptoms (PROPS) >65% post treatment, >60% on follow-up). Within-group effect sizes for Total Problems Score, Externalising behaviour (both CBCL), Hyperactivity (Strengths and Difficulties Questionnaire) and trauma symptoms (PROPS) each exceeded Cohen's d = 1.0 and were maintained at 6-month follow-up. Resting-state fMRI identified significant functional reorganization in visual processing networks. Atypical correlation patterns between visual network activity and symptom severity resolved following treatment, yielding patterns comparable to those of healthy controls. These pilot findings provide initial evidence of the feasibility and effectiveness of intensive, medication-free, attachment-based inpatient treatment to promote clinical remission and neurobiological normalization in severely traumatized children.

ObjectiveChildhood poverty is a high-risk context that involves diverse adversities, making it difficult to understand how poverty confers later psychopathology risk and why some children remain resilient despite growing up in poverty. To address this heterogeneity, we quantified adversity-linked vulnerability as adversity-psychopathology coupling and tested whether childhood poverty amplifies this coupling and whether multilevel inhibitory-control profiles stratify vulnerability and resilience within poverty-exposed youth. MethodsWe analyzed 10,112 youth (48.4% female; mean age = 9.92 years) from the Adolescent Brain Cognitive Development Study, linking baseline cumulative early-life adversity (ELA) to later behavioral problems across 4 waves. In the stop-signal task fMRI subsample of 7,401 youth, semi-supervised clustering of inhibitory-control activation identified neurofunctional subtypes within poverty-exposed youth. We also tested temperamental inhibitory control as an additional moderator. ResultsChildhood poverty amplified the association between cumulative ELA and behavioral problems at baseline ({Delta}{beta} = 0.088; P < .001) and across follow-up waves. Two neurofunctional subtypes were identified within poverty-exposed youth: subtype-1 showed greater vulnerability than higher-income peers ({Delta}{beta} = 0.149; P < .001), whereas subtype-2 showed attenuated vulnerability and did not differ from higher-income peers ({Delta}{beta} = 0.049; P = .135); this pattern persisted longitudinally. Among poverty-exposed youth in subtype-2 with high temperamental inhibitory control, the association between cumulative ELA and later behavioral problems was no longer significant. ConclusionsChildhood poverty strengthened the translation of adversity burden into later behavioral problems, but inhibitory-control profiles differentiated higher- and lower-risk pathways within poverty, highlighting inhibitory control as a candidate target for prevention.

Early adversity increases vulnerability for adult psychopathology. Across multiple pre-clinical models of early adversity, there are reports of glial dysfunction and disrupted amino acid neurotransmission, along with maladaptive behavioral responses in adulthood. Disrupted G-protein coupled receptor signaling is known to phenocopy specific consequences of early life adversity. Enhanced Gq signaling in the forebrain excitatory neurons in early postnatal life programs anxio-depressive behaviors in adulthood, accompanied by altered neuronal glutamate and GABA metabolism in mouse models. We hypothesized that enhancing Gq signaling in forebrain excitatory neurons in early postnatal life may also impact glial function in adulthood. Our results show that postnatal hM3Dq-mediated chemogenetic activation of CaMKII-positive forebrain excitatory neurons not only increases anxiety-like behavior, but also evokes bidirectional transcriptional regulation of multiple glia-associated genes in the neocortex and hippocampi. While Gfap, Aldh1l1, S100{beta}, Eaat1, Eaat2 and Eaat3, mRNA levels were reduced in the neocortex, they were enhanced in the hippocampus, and a similar pattern was noted for GFAP protein levels. Transient, postnatal chemogenetic activation of CaMKII-positive neurons did not alter astrocyte cell density in both the neocortex and the hippocampus. Using (1H-(13C)) NMR spectroscopy, we observed a significant decline in astrocyte-specific glutamate and GABA neurotransmitter turnover, and a reduction in astrocyte metabolic flux within the neocortex and the hippocampus in adulthood in animals with a history of postnatal chemogenetic activation of forebrain excitatory neurons. Our findings indicate that chemogenetically driving Gq signaling transiently during the postnatal window in forebrain excitatory neurons results in persistent changes well into adulthood, with enhanced anxiety-like behaviors and disrupted glial function and metabolism, phenocopying specific changes in glial function noted following early adversity.

Background: Major depressive disorder (MDD) is the leading cause of non-fatal disability in youth and disproportionately affects adolescent females. Structural MRI studies of adolescent depression have yielded inconsistent findings, potentially reflecting symptom heterogeneity and rapid developmental changes in brain morphology. Methods: In this longitudinal study, we examined associations between specific depressive symptoms and structural brain MRI measures in 9,722 youth (53% male, age range = 10.0-17.7, 24,378 observations) from the Adolescent Brain Cognitive Development (ABCD) Study. A four-wave panel graphical vector autoregression (GVAR) model was estimated to separate within-person (contemporaneous and temporal networks) from stable between-person effects. Brain measures included cortical thickness in the insula, cingulate, medial orbitofrontal cortex (mOFC) and fusiform gyrus, as well as hippocampal volume. Depressive symptoms included parent-reported depressed mood, anhedonia, lethargy, and worthlessness. Additionally, sex-differences in network structures were tested. Results: Strong within-domain associations were observed among brain measures and among symptoms, with the largest effects in the symptom domain. Cross-domain (brain-symptom) associations emerged only at the within-person level, where elevated depressed mood was associated with contemporaneous and subsequent reductions in cingulate and fusiform gyrus thickness (partial r = [-0.02 - 0.04]). No cross-domain associations were detected in the between-person networks. Sex-differences emerged only in the within-person networks. Conclusions: Associations between brain structure and depressive symptoms were subtle, symptom-specific, and dynamic rather than reflecting stable individual differences. Longitudinal within-person approaches are therefore important for understanding neurodevelopmental contributions to adolescent depression risk.

Progress in pharmacological treatment development for neurodevelopmental disorders is hindered by a misalignment between targeted mechanisms, outcome measures, and trial designs. This study was initiated as a post-trial access pathway for bumetanide and later expanded with treatment-naive participants. Within this framework, we implemented a parent-cocreated sensory outcome measure set (PROMset) in an unmasked, multiple-baseline single-case experimental design with randomized baseline periods of 2-12 weeks, followed by 6 months of bumetanide treatment (up to 1.5 mg twice daily). Participants (7-19 years) had atypical sensory reactivity and a diagnosis of ASD, ADHD, epilepsy, or TSC. The primary outcome was a PROMset comprising seven PROMIS item banks assessing anxiety, depressive symptoms, sleep disturbance, fatigue, sleep-related impairment, cognitive function, and peer relationships. Secondary outcomes included SSP, SRS-2, RBS-R, and ABC. Of 113 enrolled participants (mean age 13.2 [SD 2.7], 64% male), 102 completed the trial and 95 had analyzable PROMsets. At baseline, PROMset scores showed substantial impairment across domains (mean deviation [&ge;]9.0 T-score points, p<.001) and correlated with sensory reactivity (SSP; r[&ge;]-0.40, p<.001). Individual-level analyses showed improvement in 24-41% of participants per PROM domain, most frequently in anxiety and depressive symptoms (41% and 38%; mean across-case Cohens d{approx}-1). Overall, 83% improved on at least one domain. Group-level analyses showed improvement across all secondary outcomes (p<.001), with superiority over historic placebo for RBS-R and SSP. Integrating PROMsets with individualized trial designs can reveal clinically meaningful changes, supporting a more sensitive and patient-centered framework for treatment evaluation in heterogeneous populations.

BackgroundNon-suicidal self-injury (NSSI) represents a growing public health concern, particularly in adolescents. Emotion dysregulation is central to prevailing NSSI models, yet it remains unclear whether acceptance-based emotion regulation (ER) and its underlying neural processes are disrupted in naturalistic, dynamic contexts. MethodsPre-registered neuroimaging trial in recently diagnosed and treatment-naive adolescents with NSSI (n=25) and healthy controls (n=25) using an ER paradigm with dynamic video clips and concomitant functional magnetic resonance imaging. Behavioral, neural activity, and connectivity indices during emotion reactivity and acceptance-based regulation were compared between groups. ResultsAdolescents with NSSI experienced elevated negative feelings during neutral clips, reflecting heightened baseline negativity. In comparison to controls, they displayed reduced temporal and ventrolateral prefrontal engagement during emotional reactivity, but increased engagement of regions implicated in both emotion reactivity (right amygdala, insula) and ER (right dlPFC, dmPFC, vlPFC) when utilizing acceptance. Higher activation in the right dlPFC was positively associated with difficulties in accessing ER strategies in everyday life. Adolescents with NSSI showed reduced functional connectivity between the right amygdala and left dlPFC. ConclusionsAdolescents with NSSI exhibited a baseline negativity bias and altered neural engagement during both negative emotional reactivity and acceptance-based regulation, characterized by increased activation and reduced amygdala-dlPFC connectivity. These findings highlight atypical emotion processing in real-life contexts in individuals with NSSI. Targeting acceptance-based regulation and prefrontal-limbic circuitry may represent a promising intervention approach for adolescents with NSSI.

BackgroundMost studies seeking to identify youth at increased risk for depression have developed prediction models using a limited set of risk factors in general population samples. It is unclear whether these models generalize to high-risk youth. Here, we developed machine learning algorithms to predict first-onset depression in youth from the general population and high-risk youth with attention-deficit/hyperactivity disorder (ADHD). MethodsParticipants were 4803 unrelated children from the ABCD study with no prior mood disorder and complete data at baseline (age 9-10 years) and 2-year follow-up. Support Vector Machine, Random Forest, and Elastic Net models were used to predict first-onsets from clinically-relevant risk factors spanning mental and physical health, cognitive, dispositional, interpersonal, and socio-environmental domains. Predictive performance was evaluated in the full sample and separately in participants with ADHD (N=584, 12.16%). ResultsModels trained on the full sample achieved good discriminative predictive power (area under the curve [AUC]=0.70 and accuracy=0.70-0.82). Predictors that replicated across models included earlier pubertal development, higher behavioral inhibition and aggression, and more time spent passively watching media content. In the ADHD subsample, model performance declined (AUC=0.46-0.61) and predictors only partly overlapped with those identified in the full sample. ConclusionsModels effectively predicted depression in the general population but showed poor generalization to high-risk youth with ADHD, suggesting different risk factors in this group. These findings highlight that models trained in general population samples may not generalize to high-risk groups, pointing to the need for more tailored efforts to predict depression in youth at increased risk.

ImportanceEating disorders (EDs) are heritable, yet the developmental pathways through which genetic liability manifests in early life remain unclear. ObjectiveTo investigate the associations between genetic liability for anorexia nervosa (AN) and binge eating (BE) and disordered eating behaviors (DEB) across childhood, and to identify the mediating roles of metabolic and psychosocial traits. Design, Setting, and ParticipantsThis longitudinal observational study used genomic and behavioral data from the Adolescent Brain Cognitive Development SM (ABCD(R)) Study, a multisite, population-based cohort of children recruited between 2016 and 2018 at ages 9 to 10 years from 21 research centers across the United States. A three-wave temporal design was employed, utilizing data from baseline (T0), Year 1 (T1), and Year 2 (T2) follow-ups. Primary analyses focused on 5,618 participants of genetically inferred European (EUR) ancestry, with exploratory analyses conducted in a diverse sample of 9,132 participants. ExposuresPolygenic scores (PGS) for AN and BE were calculated using summary statistics from the most recent genome-wide association studies. Mediators included BMI, ADHD, anxiety/depression, and social problems from the Child Behavioral Checklist assessed at Year 1 follow-up (T1). Main Outcomes and MeasuresParent reported DEB symptoms via the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS). For longitudinal association analyses, DEB were pooled across T0, T1 and T2 to assess the relationship between genetic liability and childhood symptom severity. For mediation analyses, DEB at T2 follow-up were used to ensure a clear temporal sequence between mediators at T1 and the outcomes. ResultsAmong 5,618 EUR participants (mean [SD] age, 9.91 [0.62] years; 47% female), longitudinal association models revealed that higher AN-PGS was associated with increased AN symptoms, while BE-PGS was associated with increased BE and AN symptoms. These patterns were largely consistent in exploratory cross-ancestry analyses. Mediation analyses showed that BMI mediated genetic risks across sexes, while ADHD and anxiety/depression symptoms emerged as additional mediators in females. Conclusions and RelevanceGenetic liabilities to AN and BE contribute to childhood DEB through sex-dependent pathways, highlighting the developmental continuity of ED risk from childhood. Integrating genetic profiles with behavioral markers may facilitate early identification and support multifaceted interventions. Key points QuestionDo genetic risks for anorexia nervosa (AN) and binge eating (BE) contribute to childhood disordered eating behaviors, and what mechanisms mediate these effects? FindingsIn this longitudinal study of 5,618 children of European ancestry, AN polygenic scores (AN-PGS) were associated with early AN symptoms, while BE-PGS showed transdiagnostic associations with both AN and BE symptoms. These links were mediated by BMI and psychosocial traits, including sex-specific pathways through ADHD and anxiety/depression symptoms in females. MeaningOur findings suggest that genetic liability to eating disorders manifests early in life through distinct metabolic and psychosocial pathways, highlighting a window for sex-specific targeted prevention.

Background: Attention problems are common transdiagnostic symptoms of psychiatric illness. Although environmental exposures and experiences influence attention during adolescent development, the underlying neural pathways by which they do so is unclear. Methods: We measured attention problems, attention-related brain networks, and multidimensional environmental experiences (the exposome) using data from the ABCD Study (N = 11,878). We tested whether the exposome is associated with 9-10-year-olds attention-related brain network strength and current and future attention problems. We further examined cross-sectional indirect pathways linking the exposome, brain network strength, and attention problems. Results: The exposome predicted youths current and future self-, caregiver-, and teacher-reported attention problems as well as their current attention-related brain network strength. This brain network signature of sustained attention also predicted attention problems from all three reporters. Indirect effects models revealed that the exposome was associated with current reported attention problems both directly and indirectly though this brain signature. Conversely, predictive brain network strength was related to attention problems both directly and indirectly through the exposome. Conclusion: Interactions between environmental exposures, experiences, and brain network organization are associated with attention problems in early adolescence. These findings support a bidirectional framework linking the environment and functional brain networks in the development of attention problems.

Objective: Autistic individuals may face elevated risk for PTSD, yet the degree to which this risk differs by sex remains unknown. We examined the association between autism and incident PTSD, characterized sex differences in risk, identified high-risk subgroups, and described post-diagnosis clinical trajectories. Method: We conducted a population-based matched cohort study using Swedish national registers. Individuals born 1990 through 2010 were followed from age 6 years through December 31, 2017. Autistic individuals (N=42,862) were matched 1:10 to controls (N=412,251) on sex and birth year. Cox proportional hazards regression estimated hazard ratios (HRs) for incident PTSD. Among those who developed PTSD, we compared care utilization, hospitalization rates, and persistence of care contacts. Results: During mean follow-up of 5.1 years, 401 autistic individuals (0.9%) and 903 controls (0.2%) developed PTSD (incidence rates: 18.3 vs 4.2 per 10,000 person-years). Autism was associated with 4.4-fold increased PTSD risk (HR=4.37; 95% CI, 3.93-4.86). Risk was higher among females (HR=4.79) than males (HR=3.39; P interaction=.006). Among autistic individuals, comorbid ADHD conferred additional risk (HR=1.38; 95% CI, 1.14-1.68). Ten-year cumulative incidence reached 6.0% among autistic females with ADHD. Autistic individuals with PTSD had higher care utilization (mean visits: 5.0 vs 3.9; P<.001), more psychiatric hospitalizations (27.9% vs 19.8%; P=.002), and more persistent courses (24.8% vs 12.3% with contacts in all 3 post-diagnosis years; P=.001). Conclusion: Autism is associated with substantially elevated PTSD risk, particularly among females with comorbid ADHD. When PTSD occurs, autistic individuals experience more severe and persistent clinical courses, supporting targeted screening and sustained follow-up.

Antidepressant efficacy varies widely, yet the circuit-level mechanisms that distinguish treatment responders from non-responders remain poorly understood in humans. Here, we used high-resolution neuroimaging of hippocampal-amygdala networks during an emotional mnemonic discrimination task that taxes hippocampal pattern separation to examine how antidepressant mechanism of action and perceived treatment response shape emotional memory circuitry (N = 117). Participants included individuals taking single-action antidepressants (selective serotonin reuptake inhibitors), multi-action antidepressants (serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, or polypharmacy), and unmedicated controls matched on current depression severity. Antidepressant mechanism and treatment response were associated with distinct patterns of activity in hippocampal subfields (dentate gyrus (DG)/CA3 and CA1) and amygdala subnuclei, including the basolateral amygdala (BLA) and central amygdala (CEA), during emotional mnemonic discrimination. Among non-responders, the relative balance of hippocampal activity differed by antidepressant mechanism: those taking single-action antidepressants showed greater DG/CA3 than CA1 activity, whereas those taking multi-action antidepressants showed the opposite pattern. This suggests mechanistically specific differences in hippocampal computations associated with ineffective treatment. These effects were localized to the anterior hippocampus, with no significant effects observed in posterior regions. In contrast, responders exhibited stronger DG/CA3-BLA coactivation during negative mnemonic discrimination, a pattern absent in non-responders and unmedicated controls. Antidepressant-associated differences in amygdala subnuclei activity persisted beyond current symptom severity, suggesting medication-related modulation of emotional memory circuits rather than effects driven solely by depression severity. These findings provide evidence in humans that antidepressant use is associated with altered hippocampal-amygdala circuitry in a manner that depends on both pharmacological mechanism and treatment efficacy. Identifying circuit-level signatures of treatment response may inform mechanistically guided approaches to antidepressant selection and monitoring.

Mutations in SCN2A, which encodes the voltage-gated sodium channel Nav1.2, are associated with a wide spectrum of neurodevelopmental and neuropsychiatric disorders, including epilepsy, autism spectrum disorder (ASD), and schizophrenia. Although dysfunction of SCN2A-dependent neural circuits has been implicated in these disorders, the circuit mechanisms underlying social behavioral abnormalities remain poorly understood. Here, we investigated the neural circuit basis of social behavioral deficits associated with Scn2a dysfunction, focusing on the nucleus accumbens (NAc), a key hub in cortico-limbic circuits that regulates emotional and motivational behaviors. Using conditional genetic and chemogenetic approaches in mice, we examined the roles of dorsal telencephalic excitatory neurons, including those in the cerebral cortex, hippocampus, and amygdala, as well as parvalbumin-positive fast-spiking interneurons (PV FSIs) in the NAc. Mice with Scn2a haploinsufficiency in dorsal telencephalic excitatory neurons (Scn2afl/+/Emx1-Cre) exhibited reduced sociability in the three-chamber social interaction test. Similarly, chemogenetic inhibition of NAc PV FSIs decreased sociability without affecting locomotor activity or anxiety-like behavior. Scn2afl/+/Emx1-Cre mice also showed a trend toward reduced prepulse inhibition of the acoustic startle response. Notably, dopamine release into the NAc in the Scn2afl/+/Emx1-Cre and systemic Scn2a heterozygous knockout (Scn2a+/-) mice was largely comparable to that in control mice. Together, these findings indicate that reduced activity of dorsal telencephalic excitatory neurons or NAc PV FSIs is sufficient to impair sociability independently of mesolimbic dopamine hypofunction. Our results highlight a potential role of cortico-accumbal circuits in social behavioral deficits associated with SCN2A dysfunction.

Early-life stress elevates the risk of developing neuropsychiatric disorders. However, the mechanism underlying this vulnerability, and how they contribute to sex differences in these disorders, remain to be understood. Here, we use multivariate brain-based predictive models to examine how the number, positive or negative appraisal, and impact of adolescent stressful life events reported either by the youth or their caregivers are reflected in neuroanatomy (cortical thickness, surface area, cortical and subcortical gray matter volume, and T1 intensity measures). We used data from the Adolescent Brain Cognitive Development (ABCD) study at 2-year (N = 6,301, age 11-12), 4-year (N = 5,000, age 13-14) and 6-year (N = 3,226, age 15-16) follow-up time points to examine the sex-independent and sex-specific neural correlates of stressful life events. Our analyses showed mostly non-significant associations between stressful life events and neuroanatomy. However, we did find that the number of positively appraised stressful life events reported by the caregivers at the 4-year follow-up was significantly associated with cortical thickness, independent of sex, and with surface area in females only. Across three developmental timepoints, seven neuroanatomical measures, two reporting perspectives, and both sex-independent and sex-specific analyses, we show that the number, appraisal, and impact of stressful life events are largely not reflected in adolescent neuroanatomy.

Internet gaming disorder (IGD) presents a significant public health challenge, yet its complex biopsychosocial mechanisms and dynamic risk trajectories remain poorly understood due to a scarcity of comprehensive longitudinal and multimodal cohorts. To address this critical gap, we established the Chinese College Student Gamers Cohort (CCSGC), a prospective, multimodal longitudinal study of 793 first-year undergraduates primarily playing Honor of Kings from 2022 Sept. The CCSGC integrates semi-annual psychosocial questionnaires, annual neuroimaging (EEG/fMRI), and biospecimen collection over multiple years. Baseline data revealed individuals with IGD (n=211) exhibited significantly higher gaming craving, psychological distress (depression, anxiety), impulsivity, and maladaptive motivational features compared to non-IGD gamers (regular players (RP) n=400; casual players (CP) n=182). Longitudinal analyses across four waves indicated bidirectional temporal associations between IGD severity and mental symptoms, and a stabilization of IGD incidence after an initial decrease. Furthermore, specific neurophysiological (e.g., N400 amplitude to game cues) and neuroimaging (e.g., superior parietal activation) markers were identified that correlated with IGD severity and predicted one-year outcomes in gaming disorder or social functioning. The CCSGC provides an invaluable resource for dissecting the heterogeneity, comorbidity, and intricate biopsychosocial mechanisms of IGD, holding significant potential to advance risk prediction, early identification, and targeted intervention strategies.

Aim: To determine whether the neural phenotype (whole-brain resting-state functional connectivity pattern) of attention deficit hyperactivity disorder associated with prenatal alcohol exposure (ADHD+PAE) differs from that in unexposed children with ADHD of probable familial origin (ADHD-PAE). Method: Resting-state functional MRI was acquired from 26 children with ADHD+PAE, 25 with ADHD-PAE, and 25 typically developing (TD) children, all aged 8-13 years. Mean connectivity matrices based on the Cole-Anticevic Brainwide Network Parcellation of the brain were compared between the groups. Results: Within the frontoparietal network (FPN), children with ADHD+PAE showed widespread lower group-mean connectivity than children with ADHD-PAE; effects were concentrated primarily in cerebellar-cerebral cortical and cerebral cortical-cerebral cortical connections. Children with ADHD-PAE showed widespread hyperconnectivity relative to TD children. Children with ADHD+PAE showed mixed hyper- and hypoconnectivity relative to TD. Interpretation: These results are consistent with other MRI findings indicating that ADHD+PAE is neurally distinct from ADHD-PAE; PAE may be associated with broadly reduced connectivity, especially across cerebellar-cerebral cortical systems.

Background: While counterfactual thinking ('what could have been') guides adaptive decision-making, it remains unclear how this process is altered by the negative biases and motivational deficits characteristic of Major Depressive Disorder (MDD). Methods: We used a sequential economic decision-making task designed to emulate a volatile stock market to assess choice behavior in adults with or without MDD (Total N=178); a subset of these participants completed the task during functional MRI (N=53). The task allowed participants to make either positive ('invest') or negative ('short') bets, under either positive or negative contextual valence, defined by whether the immediately preceding stock price change was positive or negative. Fictive errors were defined as the difference between realized and best-possible outcomes. Results: Across the full cohort, group differences in behavioral adjustments to fictive error signals emerged exclusively under negative contextual valence, when stock prices decreased. Compared with controls, participants with MDD showed heightened sensitivity to invest-and-loss fictive errors, reflected in a greater reduction in subsequent bets (interaction beta = -0.63, p < .001), but blunted adjustment to short-and-gain fictive errors (beta = -0.86, p < .001). In the imaging cohort, blunted short-and-gain adjustment was accompanied by heightened anterior cingulate (ACC) activity and attenuated ventromedial prefrontal (vmPFC)-to-ACC coupling in MDD. vmPFC activity following negative market returns also tracked depression symptom severity. Conclusions: Depression selectively disrupts the use of counterfactual outcomes to guide adaptive choice under negative contextual valence, implicating altered frontocingulate function in maladaptive decision-making.