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.

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.

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.

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.

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.

Background: Major depressive disorder (MDD) is characterized by disrupted information flow among brain regions. While effective connectivity (EC) captures these causal interactions, the underlying structural and molecular basis remain unclear. This study aims to investigate direction-specific EC alterations in MDD and their associations with laminar structural covariance (SC) and transcriptional and neurotransmitter profiles. Methods: Resting-state fMRI and structural MRI data were analyzed from the REST-meta-MDD consortium (Discovery, N=1627) and an independent cohort (Validation, N=226). We calculated the unsigned and signed EC using Liang Information Flow and laminar SC based on cortical depth, and compared them between MDD patients and healthy controls. The EC alterations were further associated with molecular profiles integrating gene expression (AHBA) and neurotransmitter receptors (PET/SPECT). Then, Chain mediation analyses were performed to map the hierarchical pathways from molecular basis to EC. Finally, we evaluated the clinical potential of EC in its therapeutic responses to medication and neuromodulation in a longitudinal dataset (N = 16 for medication, N = 11 for neuromodulation). Results: Our analysis revealed no significant changes in the EC of first-episode MDD but observed a hyper-driven cerebellar-cerebral EC pattern in recurrent MDD (RMDD), characterized by a direction-specific excitation-inhibition imbalance featuring enhanced inhibitory cerebellar output alongside a concurrent increase in both inhibitory input and excitatory output within sensorimotor/cognitive regions. These alterations were physically constrained by specific laminar SC patterns, particularly involving the middle cortical lamina. Moreover, the input EC changes in RMDD patients were primarily enriched in biological processes related to the modulation of chemical synaptic transmission, whereas output EC changes were linked to synapse structure regulation. These EC alterations were closely associated with serotonergic, GABAergic, and glutamatergic neurotransmitter systems. Importantly, we identified oligodendrocyte precursor cells (OPCs) as a key cellular mediator bridging microscale molecular features to macroscale connectional alterations in RMDD. These findings were reproducible in the validation dataset. Clinically, medication treatment primarily evoked a pattern of decreased input coupled with increased output, whereas neuromodulation elicited a reciprocal shift characterized by enhanced input and attenuated output. Conclusions: These findings underscore a direction-specific gene-neurotransmitter-cell type-laminar SC-EC pathological model in RMDD. By integrating multi-scale biological mechanisms with clinical phenotypes, this study highlights the potential of directional EC as a biomarker for stratifying refractory depression and guiding precision therapeutics.

ImportancePrenatal exposure to gestational diabetes mellitus (GDM) has been associated with adverse metabolic, neurodevelopmental, and psychiatric outcomes in offspring. However, whether GDM-exposed youth exhibit heterogeneous neuroanatomical patterns remains unclear. ObjectiveTo identify distinct cortical thickness subtypes among GDM-exposed youth and examine their associations with anthropometric, neurocognitive, psychiatric/behavioral and neuroimaging measures both cross-sectionally and longitudinally. Design, Setting, and ParticipantsThis cohort study used the Adolescent Brain Cognitive Development (ABCD)(R)data, a multisite longitudinal population study. Subtype and Stage Inference (SuStaIn), an unsupervised machine learning framework, was applied to cross-sectional structural MRI data to identify cortical thickness patterns in 573 GDM-exposed youth and 2854 healthy controls. Posthoc longitudinal analyses included 1,853 observations from a subset of GDM-exposed youth with 1-, 2-, and 4-year follow-up visits to examine subtype differences in developmental trajectories over time. Exposure(s)Prenatal exposure to GDM. Main Outcome(s) and Measure(s)The primary outcomes included identification of cortical thickness subtypes and their inferred regional ordering patterns. Secondary outcomes included subtype-specific anthropometric, neurocognitive, psychiatric/behavioral and neuroimaging measures. ResultsThe GDM-exposed sample had a mean age of 119.02 {+/-} 7.34 months and was 47.5% female. Two cortical thickness subtypes were identified. Between subtypes, Subtype 1 (63.2%) was characterized by earlier inferred insula involvement and was associated with greater height (d = 0.36, pFDR < 0.001) and weight (d = 0.26, pFDR = 0.007), whereas Subtype 2 exhibited earlier inferred frontal involvement and nominally higher Attention-Deficit/Hyperactivity Disorder (ADHD) prevalence (d = 0.08, p = 0.036), steeper longitudinal cortical thinning across all six cortical regions of interest ({beta} range: -0.05 to -0.13, all pFDR < 0.05), and a smaller decline in Obsessive-Compulsive Disorder (OCD) prevalence over time ({beta} = -1.02, pFDR = 0.049). Conclusions and RelevanceGDM exposure was associated with two distinct offspring cortical thickness subtypes, each showing different inferred regional ordering patterns and clinical associations. One subtype showed an insula-cingulate-predominant pattern associated with anthropometric measures, whereas the other showed a frontal-predominant pattern associated with nominally higher psychiatric measures and faster cortical thinning over time.

The ability to adjust to changing environments (cognitive flexibility) and optimal decision-making are pivotal brain functions that govern successful human behavior. Anxiety and depressive disorders are strongly pervasive psychiatric conditions across the lifespan that profoundly disrupt mechanisms of attention, working memory, and decision-making. Although existing task evidence documents impaired decision-making and flexibility outcomes for both anxiety and depression, there is a growing need to systematically evaluate the role of anxiety and depression and to quantitatively compare the effects of these disorders on these domains. In the present study, we conducted a meta-analysis of anxiety and depression on decision-making and cognitive flexibility. We utilized a random-effects approach, given that a large amount of between-subject heterogeneity was anticipated. Given the scope of this meta-analysis, we used the machine learning tool asReview to more efficiently conduct a meta-analytic search. Across all outcomes, results showed anxiety and depression were associated with reduced cognitive flexibility and decision-making. These effect sizes were then tested for significance using a fixed-effects (plural) model. Subgroup analyses revealed no significant differences between anxiety and depression for either decision-making or flexibility outcomes, consistent with a transdiagnostic perspective. Results are contextualized in light of the biopsychosocial model and potential transdiagnostic factors.

I ntroduction: Prospective memory (PM) deficits in children with attention-deficit/hyperactivity disorder (ADHD) significantly impact academic and daily functioning. Through two experiments, this study investigated how cognitive load and encoding strategies modulate PM performance. Methods: Experiment 1 included 43 children (21 ADHD, 22 typically developing) who completed an n-back task under high and low cognitive load. Experiment 2 included 44 children with ADHD who were randomly assigned to either a standard encoding group or an implementation intention encoding group, also completing the n-back task under both load conditions. Results: Experiment 1 showed that children with ADHD had significantly lower PM accuracy than typically developing peers. Signal detection analysis revealed that this deficit stemmed from a more conservative response bias rather than impaired perceptual sensitivity. Unexpectedly, PM accuracy and perceptual sensitivity were higher under high cognitive load than low load for both groups. Experiment 2 demonstrated that implementation intention encoding significantly enhanced PM accuracy and perceptual sensitivity in children with ADHD, with stable effects across load conditions and no interference with ongoing task performance. Discussion: These findings indicate that PM deficits in children with ADHD reflect a conservative response strategy rather than an inability to detect target cues. Implementation intention encoding provides an effective, load-independent cognitive strategy for enhancing PM performance. These results offer novel insights into the cognitive mechanisms underlying PM deficits in ADHD and provide evidence-based guidance for targeted interventions.

Dopamine signaling plays critical roles in postnatal brain development, yet the molecular consequences of early dopaminergic disturbance remain incompletely understood. Here, we investigated transcriptomic alterations in the prefrontal cortex (PFC) and striatum (STR) of mice subjected to early postnatal dopaminergic disturbance by 6-hydroxydopamine (6-OHDA) treatment. Using bulk RNA sequencing (RNA-seq) and weighted gene co-expression network analysis (WGCNA), we identified 369 differentially expressed genes (DEGs) in the PFC, 493 DEGs in the STR, and 32 co-expression modules with region-specific expression patterns. Functional enrichment analyses showed that PFC DEGs were associated with cortical development, plasma membrane signaling, and transcriptional regulation, whereas STR DEGs were enriched for striatal development, locomotion, extracellular matrix organization, and amphetamine response. Co-expression network analysis further identified module-specific enrichments related to developmental, synaptic, metabolic, immune-related, and transcriptional programs. DEG sets from both regions also overlapped with genes implicated in attention-deficit/hyperactivity disorder (ADHD) and other neuropsychiatric disorders. Together, these findings reveal region-specific cortico-striatal transcriptomic remodeling following early postnatal dopaminergic disturbance and identify molecular programs that may link developmental dopaminergic perturbation to later behavioral phenotypes. HighlightsO_LIEarly dopaminergic disturbance reshapes cortico-striatal transcriptomes C_LIO_LIPFC changes were linked to developmental and transcriptional programs C_LIO_LISTR changes were linked to locomotion and extracellular matrix programs C_LIO_LINetwork analysis revealed region-specific developmental and synaptic programs C_LI

Objective. Persistent, distressing psychotic-like experiences (PLEs) are associated with neurobiological alterations and increased psychosis risk. We combined individual-level neuroimaging measures with effect sizes from large neuroimaging studies to create a summary score ('Psychosis Neuroscore') reflecting neuroanatomic liability for psychosis, and examined its ability to predict PLE trajectories in young adolescents. Method. Using latent growth mixture models, we estimated PLE trajectories from four annual visits of the Adolescent Brain Cognitive Development Study (N=9584, ages 9-10 at baseline). Using baseline T1-weighted and diffusion-weighted imaging data, we calculated Psychosis Neuroscores, as well as Neuroscores for two psychiatric disorders with late adolescent/adult onset (Major Depressive Disorder, Bipolar Disorder). We compared Psychosis Neuroscores to i) other psychiatric Neuroscores, ii) modifiable risk factors, and iii) established risk factors in predicting trajectory membership. Results. We identified four trajectories of distressing PLEs: Persistent Elevated (N=1,968, 21%), Gradual Decreasing (N=3,424, 36%), Rapid Decreasing (N=1,593, 17%) and Low/No Distress (N=2,599, 27%). Adolescents with Persistent Elevated PLEs had significantly higher Multimodal (combined T1 and diffusion-weighted) and T1-weighted Psychosis Neuroscores than all other trajectories (Odds Ratios [ORs] 1.27-1.34,pFDR<.01). Bipolar Disorder Neuroscores showed a similar pattern (ORs 1.16-1.23,pFDR<.01). Psychosis Neuroscores showed comparable associations with established risk factors in predicting trajectory membership, but smaller associations than modifiable risk factors, including screen time, physical activity, and sleep disturbances. Conclusion. Psychosis Neuroscores differentiate youth with persistent PLEs from those with decreasing, remitting or low PLEs, demonstrating their potential utility for early risk stratification. Integration with established risk factors may enhance psychosis risk prediction in youth.

Hypomanic tendencies are associated with elevated goal-directed behavior, creativity, charisma, sociability, and entrepreneurial drive, but also with mood instability, irritability, impulsive persistence, and elevated risk for bipolar disorder and other psychopathology. Existing models often emphasize unidimensional constructs such as reward sensitivity or behavioral activation, yet these approaches incompletely capture the dynamic and often contradictory nature of the hypomanic temperament. We propose the Limbic Overload Hypothesis of Hypomanic Vulnerability, a dynamic biosocial framework suggesting that hypomanic tendencies reflect a persistent pattern of elevated engagement despite potential loss, coupled with reduced integration of negative emotional experience into subsequent behavioral regulation. Over time, this pattern may contribute to progressive "limbic overload," characterized by increasing emotional dysregulation, hypersensitivity to salient experiences, and vulnerability to psychopathology. Integrating evidence from personality research, affective neuroscience, and preliminary neuroimaging findings, we propose a dynamic cortico-limbic model linking prefrontal-limbic coordination, loss tolerance, emotional updating, and social reinforcement cycles. Preliminary pilot data suggest that individual differences in hypomanic tendencies are reflected not simply in baseline cortico-limbic organization, but in dynamic neural reconfiguration across pre-task resting-state [-&gt;] task [-&gt;] post-task resting-state transitions during loss-related decision making. Specifically, elevated hypomanic tendencies were associated with persistently elevated tolerance of potential losses and reduced integration of negative emotional information into subsequent behavioral regulation. We further propose that social connectedness and cognitive-emotional integration may mitigate progressive limbic overload and contribute to resilience. Together, this framework generates experimentally testable predictions regarding the neural, behavioral, and social processes underlying hypomanic vulnerability and resilience.

Background: Aberrations in neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways are implicated in major depressive disorder (MDD). First-episode simple dysmood disorder (FE-SDMD) without metabolic syndrome offers a unique model to investigate early lipid alterations underlying NIMETOX pathophysiology. Methods: Plasma samples were collected from 88 university students (44 FE-SDMD, 44 healthy controls). Participants underwent comprehensive psychiatric and psychological assessments, including adverse childhood experiences (ACEs), negative life events (NLEs), depression, anxiety, suicidal behaviors, and insomnia. Untargeted lipid profiling was performed using LC-QTOF-MS, while indices of oxidative and nitrosative stress (ONS) and lecithin-cholesterol acyltransferase (LCAT) activity were assessed. Data was analyzed using machine learning approaches with recursive feature elimination and cross-validation. Results: FE-SDMD was characterized by increased ceramides (CER), diacylglycerides (DAG), triacylglycerides (TG), sphingomyelins (SM), bis-monoacylglycerol phosphates (BMP), cholestone, and fatty-acyl amino acids (FAAA). DAG, CER, and BMP were the strongest predictors of depression severity and physiosomatic symptoms, whereas cholestone, CER, and SM predicted suicidal behaviors. These lipid modules, together with lowered LCAT and increased ONS, explained substantial variance in depression severity (46.4%), physiosomatic symptoms (42.4%), cognitive-affective symptoms (37.9%), suicidal behaviors (30.1%), insomnia (32%), and anxiety (19.5%). ACEs and NLEs were strongly associated with CER (p<0.001), DAG (p<0.01), and cholestone (p<0.01). Conclusion: Early-stage MDD is characterized by distinct lipid dysregulations linked to psychosocial stress exposure, oxidative and nitrosative stress, and an indicant of impaired reverse cholesterol transport. These lipid modules may serve as early biomarkers and therapeutic targets in vulnerable populations.

Background and Objectives In ADHD, a heterogeneous neurodevelopmental condition, behavioral and motor manifestations may reflect multiple inefficient or perturbed inhibitory systems. To evaluate Transcranial Magnetic Stimulation (TMS) evoked cortical silent period (CSP) duration, an indicator of GABA(B) receptor-mediated inhibition in motor cortex, as a potential biomarker of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. Method We retrospectively analyzed TMS data, obtained using both round and figure-of-8 coils, from three cross-sectional studies conducted in 8- to 12-year-old children with ADHD (n=79; 10.7 +/- 1.5 years old) and age-and-sex-matched typically developing controls (n=96; 10.5 +/- 1.4 years old). Results Median CSP was 32% shorter in ADHD (p=0.02). Regression analysis demonstrated a relationship between shorter CSP and both lower active motor thresholds (p < 0.0001) and more severe hyperactivity symptom rating (p = 0.026). Test-retest CSP measures in 83 children showed moderate reliability (intraclass correlation 0.77 [ADHD], 0.75 [controls]). Conclusion TMS-evoked CSP may be a useful biomarker in future investigations of ADHD subtypes, domains of impaired function, or treatment outcomes.

Background: Individuals diagnosed with depression during pregnancy are more likely to develop cardiovascular disease (CVD) later in life. However, it remains unclear whether subclinical depressive symptoms or symptom trajectories across time are associated with indicators of cardiovascular health (CVH). Therefore, the present study evaluated the relationship between longitudinal depressive symptom trajectories beginning in pregnancy and future CVH. Methods: This secondary analysis of the multisite prospective nuMoM2b-Heart Health Study and included participants with complete longitudinal data from early pregnancy to 2-7 years post-delivery. Participants self-reported depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) at 6-13 weeks gestation (early pregnancy), 22-29 weeks gestation (mid- to late-pregnancy), and 2-7 years post-delivery. Latent class mixture modeling was conducted to identify longitudinal patterns of depressive symptoms across early pregnancy, mid-late pregnancy, and extended postpartum follow-up. Structural equation modeling was used to test whether EPDS trajectories were associated with latent CVH, adjusted for length of follow-up interval, pre-pregnancy BMI, gravidity, adverse pregnancy outcomes, smoking history, age, education, income, and use of psychiatric medications. Results: A total of 3,934 participants (mean (M) {+/-} standard deviation (SD) age=27.6{+/-}5.6 years) met inclusion criteria with a mean follow-up interval of 3.2{+/-}0.9 years. A 4-class model, which provided the best fit to the EPDS data (mean posterior probability across classes=0.81), produced the following trajectories: (1) stable low (n=2412; 61.1%), (2) increasing severity (n=848; 21.5%), (3) decreasing severity (n=476; 12.1%), and (4) stable high (n=212; 5.4%). Compared to the stable low group, all groups exhibited significantly lower CVH (stable high: {beta}=0.06, p<0.01; decreasing severity: {beta}=0.05, p=0.02; increasing severity: {beta}=0.08 p<0.01). Pairwise comparisons among the three elevated-symptom groups revealed no significant differences in latent CVH (all ps >0.24). Discussion: The longitudinal course of depressive symptoms from pregnancy to 2-7 years post-delivery varied across individuals. Compared to those with consistently low depressive symptoms, individuals with higher severity symptoms at any point all exhibited lower CVH, regardless of the specific trajectory of symptoms. These findings support a life-course perspective in which depressive symptom patterns may represent an early indicator of cardiometabolic vulnerability.

Young people with major depressive disorder (MDD) exhibit altered thermoregulation, which has also been linked to vigilance and sustained attention. However, whether peripheral skin temperature is associated with cognitive vulnerability around sleep onset is unknown. We examined the relationship between the distal-proximal skin temperature gradient (DPG) and vigilance in 38 young people with MDD (20.1{+/-}3.7 years, 65.9% female) using an in-laboratory protocol spanning 4h before, to 2h after, habitual sleep time. Participants were classified into DPGwarm and DPGcold subgroups based on being above or below median DPG before sleep onset. Linear mixed models adjusted for age and sex examined psychomotor vigilance task performance across timepoints. The DPGwarm subgroup (n=19) showed significantly worse performance than DPGcold (n=19) across the evening for mean reaction time (RT), reciprocal reaction time, number of lapses, and fastest 10% of RT (all p[&le;]0.003). Significant GroupxTime interactions were observed for mean RT (F(3,90.4)=5.00, p=0.003) and lapses (F(3,93.6)=6.73, p<0.001), with DPGwarm participants showing progressively worse performance approaching sleep onset. At 2h post-habitual sleep onset, DPGwarm participants exhibited slower RT ({Delta}=129ms, p<0.001) and nearly four times more lapses (14.9 vs 4.1, p<0.001). Performance decrements were not accompanied by differences in melatonin timing, subjective sleepiness or mood, suggesting DPG may index cognitive vulnerability independently. Of note, younger age was associated with greater vigilance decrements. These findings demonstrate that elevated peripheral skin temperature before sleep onset is associated with reduced vigilance in young people with MDD, and may therefore have potential utility as a non-invasive thermoregulatory biomarker of cognitive vulnerability.

Background: Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) exhibit high clinical overlap, but categorical diagnostic boundaries obscure their shared, dynamic physiological vulnerabilities during real-world sensory processing. Methods: We analyzed multimodal eye-tracking synchrony in a large transdiagnostic pediatric cohort (N = 2,026) during naturalistic viewing of four distinct media paradigms. A novel 2D complex correlation framework captured gaze inter-subject correlation (ISC) magnitude and spatiotemporal phase divergence, while 1D pupil ISC measured autonomic arousal synchrony. Linear models evaluated dimensional (RDoC) and categorical (2x2 ANCOVA) diagnostic frameworks alongside rigorous medication and severity controls. Results: Dimensional models revealed a domain-general vulnerability: autistic traits independently predicted widespread reductions across gaze synchrony in all media contexts, and pupillary synchrony in narrative-driven contexts, whereas continuous ADHD traits showed minimal independent effects. In contrast, severe spatiotemporal misalignment (phase divergence) did not scale dimensionally but emerged strictly at clinical boundaries, reflecting highly idiosyncratic spatial locking in isolated ASD. Furthermore, categorical models demonstrated a robust, non-additive interaction: the clinical co-occurrence of ADHD paradoxically buffered against this severe spatiotemporal decoupling. Crucially, this protective phenotype was localized strictly to character-driven social narratives and remained highly significant after rigorously adjusting for daily stimulant medication, outlier instability, and baseline autism trait severity. Conclusions: These findings validate model-free physiological synchrony as a candidate transdiagnostic biomarker. Rather than compounding impairment, comorbid ASD and ADHD reflect competing, non-additive neurocognitive strategies that yield distinct, context-dependent visual phenotypes.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by symptoms that emerge in childhood and often improve or even disappear in adulthood, providing a model for understanding how altered brain development shapes neural structure and function. We investigate brain structural alterations in TS and Chronic Tic Disorders (TS/CTD) across development, presenting the largest structural neuroimaging analysis for TS/CTD to date (1,803 individuals from the ENIGMA-TS Working Group), and integrating with large-scale genomewide association studies. Nonlinear age effects were observed in cortical thickness across development and in thalamic volume in children, indicating altered trajectories of brain maturation . Pediatric and adult TS/CTD showed distinct structural patterns, with widespread alterations in childhood and more focal changes in adulthood. Children also showed the most prominent effects highlighting the involvement of orbitofrontal cortex and putamen, alongside additional regions such as frontal and paralimbic areas. Genetic pleiotropy analyses identified overlap between TS/CTD-associated genetic effects on brain structure and neuroanatomical differences. Cross-disorder comparisons revealed correlations with ADHD and OCD and age-related patterns. These findings demonstrate altered neurodevelopmental trajectories in TS/CTD and implicate systems underlying inhibitory control and urge regulation.

Background: Obsessive-compulsive disorder (OCD) is characterized by disturbing thoughts (obsessions) that initiate anxiety-reducing thoughts or behaviors (compulsions). For patients with treatment-resistant OCD (tr-OCD), neuromodulation techniques, like capsulotomy (a lesion in the anterior limb of the internal capsule) and deep brain stimulation (DBS), have emerged as interventions that likely regulate connectivity between the prefrontal cortex (PFC) and subcortical targets. Three patients (Cap-DBS1-3) underwent a failed capsulotomy followed by successful DBS. Here, we aimed to understand the brain connections disrupted by failed capsulotomy vs modulated by successful DBS. Methods: We used diffusion-weighted magnetic resonance imaging (dMRI) tractography in a control cohort with tr-OCD (n=12) and in two of the Cap-DBS patients themselves to determine connectivity profiles of the capsulotomy, volume of tissue activated (VTA), and potentially necessary tracts (VTA minus capsulotomy tracts). We used whole-brain, PFC-focused, and subcortically-focused tractography algorithms to fully explore the space of possible connections. Results: Capsulotomy regions-of-interest (ROIs) connected with a variety of PFC and subcortical regions. VTA ROIs and potentially necessary tracts had limited and inconsistent PFC connectivity but substantial subcortical connectivity. While correlated to the average OCD connectome (r = 0.214, 95% CI [0.177, 0.251]; r = 0.756, 95% CI [0.739, 0.772]), the Cap-DBS connectomes had many edges that were stronger (z-score > 3). Conclusions: The connectivity profile of potentially necessary tracts for successful DBS treatment after failed capsulotomy revealed a surprising proportion of subcortical regions and inconsistent PFC involvement, highlighting an often-ignored set of connections that may be critical to effective DBS.