Background and Aims: Impulsivity and neural reward reactivity are considered important factors in the development and maintenance of substance use disorders (SUDs) and may be predictive of treatment response. However, relationships between treatment response, impulsivity, and reward reactivity are understudied in women with SUDs, where there may be unique clinical concerns such as higher incidences of trauma than men. Our study aimed to characterize relationships between neural responses to reward anticipation and changes in behavioral and clinical outcomes following treatment. Design: Multimodal longitudinal, within-subjects study. Follow-up measurement took place one year after the start of a criminal diversion SUD treatment program. Setting: The study was conducted in Tulsa, Oklahoma. Participants: Eighty-three adult women who completed a criminal diversion program that included comprehensive treatment for SUDs. Measurement: The primary variable of interest was nucleus accumbens (NAc) reactivity to reward and loss anticipation during a monetary incentive delay (MID) task examined via functional magnetic resonance imaging (fMRI) early in treatment (baseline) and one year later (follow-up). Outcomes included measures of substance use severity, positive and negative urgency, and posttraumatic stress disorder (PTSD) symptoms. Findings: At baseline, more severe substance use symptoms were associated with elevated NAc reward anticipation while greater PTSD symptoms were associated with lower NAc loss anticipation. Symptoms of PTSD, substance use, and urgency significantly decreased by one-year follow-up (η_p^2>0.22). Increases in NAc reward anticipation over time were associated with lower urgency at follow-up, regardless of PTSD symptom levels (η_p^2>0.03). Whole-brain analyses also showed that increased striatal reward anticipation over time was associated with lower positive urgency at follow-up. PTSD symptom severity moderated the relationship between changes in NAc loss anticipation and negative urgency. Conclusions: Following a one-year SUDs treatment program , a sample of women showed lower impulsivity associated with increased striatal responses to reward anticipation. This suggests that NAc reactivity to anticipation of non-drug outcomes may offer a potential neural target for enhancing SUDs treatment outcomes for women, while loss-related reactivity may be particularly relevant in the presence of co-occurring PTSD.

Background:Major depressive disorder (MDD) is heterogeneous in clinical presentation and treatment response. The COORDINATE-MDD consortium identified two magnetic resonance imaging (MRI)-derived neuroanatomical profiles: dimension 1 (D1), with relatively preserved gray and white matter, and dimension 2 (D2), showing widespread reductions aligned with immunometabolic profile. Profiles were associated with distinct responses to selective serotonin reuptake inhibitor (SSRI) antidepressant and placebo (PLA). In this study, we examined electrophysiological correlates of the neuroanatomical profiles and their relationship to treatment outcome. Methods:Baseline resting-state, eyes-closed electroencephalography (EEG) was acquired from 237 medication-free participants with MDD who were in a current depressive episode (155 women; mean age [SD] = 37.47 [13.36] years) from CAN-BIND (Canadian Biomarker Integration Network in Depression) (SSRI) and EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) (SSRI or PLA). EEG features included spectral power, frontal alpha asymmetry (FAA), multiscale sample entropy, and intersite phase clustering. Effects of profile (D1 and D2) and clinical outcome (responder, nonresponder; defined as ≥50% symptom improvement) were examined with age, sex, and site as covariates. Results:No significant electrophysiological differences were observed after covariate adjustment. However, among participants who subsequently responded to treatment, D1 showed greater baseline alpha power in frontal and central regions and lower relative delta posteriorly compared with D2. In PLA-treated responders, D2 showed spectral slowing, elevated low-frequency power, reduced gamma, and coarse-scale entropy compared with D1. Baseline FAA was lower in responders than nonresponders, independent of the neuroanatomical profile. Conclusions:EEG differences between MRI-defined neuroanatomical profiles emerged in relation to clinical outcome. D1 was associated with electrophysiological patterns consistent with flexible, globally regulated cortical dynamics in SSRI responders, whereas D2 showed a distinct pattern in PLA responders, indicating partially separable neural mechanisms underlying pharmacological and PLA treatment effects.

BACKGROUND:Bipolar disorder (BD) is associated with clinical and biological markers of premature aging. In this largest study of brain age in BD to date, with 2919 participants, we compared brain-predicted age difference (brain-PAD) in individuals with BD and healthy comparison (HC) participants. Brain-PAD is a machine learning-estimated metric that quantifies the difference between an individual's predicted brain age and their chronological age, a potential clinical bio-signature of premature brain aging. Within individuals with BD, we also examined how medication and clinical characteristics were related to brain-PAD. METHODS:Age was predicted from 77 MRI measures of regional subcortical and lateral ventricle volumes, cortical thickness, and surface area for 1342 BD and 1577 HC adult participants, aged 18-75 yrs. old (μ = 37.2; SD = 12.3), from the curated ENIGMA Bipolar Disorder working group (ENIGMA-BD) and leveraging an ENIGMA machine learning model previously trained and validated using independent samples. Chronological age was subtracted from predicted age to produce an individual-level estimate known as brain-PAD. Linear mixed models (adjusting for sex and age as fixed effects and site as a random effect) were used to examine group differences and clinical associations. RESULTS:BD was associated with higher brain-PAD, compared to HC, primarily among older patients, as demonstrated by a significant age by diagnosis interaction (+0.05 [SE: 0.02] years). Individuals with BD on antiepileptic (AED) medications only (+3.20 [SE: 0.78] years) or on both AED and second-generation antipsychotics (SGA) (+3.74 [SE: 0.89] years) demonstrated greater brain-PAD compared to individuals who were not on any of the examined medications. Those taking lithium, whether alone or with AED and SGA independently, showed no difference in brain-PAD compared to individuals not taking any of the examined medications. However, individuals who were taking lithium showed lower brain-PAD compared to those on AED (-4.48 [SE: 0.84] years) or AED and SGA (-5.01 [SE:0.92] years). Individuals with a BD I subtype diagnosis had a higher brain-PAD (+1.50 [SE:0.55] years) compared to those with BDII or subtypes that are not otherwise specified (NOS). CONCLUSIONS:Results from this study suggest compounding effects of BD diagnosis and older age on brain-PAD, an ML-derived summary metric of structural alterations. Within BD, brain-PAD was differentially related to medication use, consistent with prior findings from ENIGMA-BD. Notably, AED use was generally related to more advanced brain age. Lithium use, alone or in combination with other medications, was not associated with advanced brain age, suggesting a possible neuroprotective effect of lithium. Brain-PAD as an ML-derived summary metric of structural alterations of the brain may provide clinical utility in assessing long-term holistic brain health to monitor the effectiveness of lifestyle modifications or treatments over time. LIMITATIONS:The cross-sectional nature of the study design and the limited granularity of the clinical data limit interpretation. Longitudinal studies with detailed chronicity data, medications and clinical measures overtime will improve brain-PAD modeling in BD.

Abstract Background Major depressive disorder (MDD) is clinically heterogeneous, hindering identification of reproducible biomarkers. Using a semi-supervised machine learning approach, HYDRA, we previously identified two neuroanatomical dimensions from structural MRI in medication-free MDD from COORDINATE-MDD consortium. These dimensions (D1, D2) showed differential responses to selective serotonin reuptake inhibitor (SSRI) antidepressants and placebo. External replication in UK Biobank linked D2, characterized by widespread subtle neuroanatomical reductions, to an immuno-metabolic profile. Here, we examined whether these dimensions are detectable early in the course of illness. Methods We applied the pre-trained model to structural MRI data from the multisite PRONIA cohort, comprising individuals with recent-onset depression (ROD; n = 377; mean age 25.8 years, SD 6.0; 51.3% female) and healthy controls (n = 267; mean age 25.5 years, SD 6.4; 61.0% female). Participants were assigned to clusters (C1, C2) corresponding to the previously identified dimensions (D1, D2). Clusters were compared on clinical symptom profiles, peripheral inflammatory markers, and in a subset (n = 107), proteomic ageing indices. Results Two neuroanatomical clusters were identified in PRONIA. C1 (n = 265) showed higher negative symptom severity and elevated interleukin-2 levels. C2 (n = 140) was associated with higher residual proteomic age. Overall depressive symptom severity did not differ significantly between clusters. Conclusions Neuroanatomical dimensions of MDD are reproducible and detectable at illness onset. Associations with negative symptom severity, inflammatory signalling, and proteomic ageing suggest these dimensions capture biologically meaningful heterogeneity early in depression. These findings support a biologically informed framework for stratified treatment approaches in MDD.

Importance Childhood trauma is associated with increased risk for bipolar disorder, but the biological mechanisms of this association remain incompletely defined. Gray matter differences observed after trauma exposure overlap with those reported in bipolar disorder, suggesting that the association of childhood trauma with bipolar disorder might be mediated through brain morphology. Objective To determine whether cortical thickness, cortical surface, or subcortical volume mediate the association of childhood trauma with bipolar disorder. Design, Setting, and Participants This case-control study conducted a cross-sectional analysis of individuals with bipolar disorder and healthy controls from 19 international cohorts (Enhancing NeuroImaging Genetics Through Meta-Analyses [ENIGMA] Bipolar Disorder Working Group) from January 2010 to December 2022. Data were analyzed from January 2025 to January 2026. Exposures The primary exposure was the severity of total childhood trauma assessed with the Childhood Trauma Questionnaire, with secondary analyses of 5 subscales (emotional neglect and abuse, physical neglect and abuse, and sexual abuse). Main Outcomes and Measures The primary outcome was bipolar disorder diagnosis (case vs control). The primary measure was the mediation effects of childhood trauma on diagnosis via gray matter (75 bilateral-averaged cortical thickness, surface, and subcortical volume measures). The mediation pathway from severity of childhood trauma to bipolar disorder through brain morphology was specified a priori. High-dimensional mediation analysis, with leave-one-site-out cross-validation and permutation testing for significance (false discovery rate [FDR]), was conducted. Results The final sample included 2221 healthy controls (mean [SD] age, 35.6 [13.2] years; 1274 female [57%]) and 1031 participants with bipolar disorder (mean [SD] age, 38.6 [13.7] years; 579 female [56%]). Severity of childhood trauma was directly associated with higher likelihood of having a bipolar disorder diagnosis (median coefficient, 0.841; 95% CI, 0.834-0.851; range, 0.776-0.893; FDR P < .001). Less than 1% of the association between childhood trauma and bipolar disorder was mediated by brain morphology. Statistically significant mediators were hippocampal volume (median coefficient, 0.004; 95% CI, 0.002-0.005; range, 0-0.008; FDR P < .001), medial orbitofrontal gray matter thickness (median coefficient, 0.002; 95% CI, 0.002-0.003; range, 0-0.004; FDR P < .001), and superior frontal gyrus gray matter thickness (median coefficient, 0.002; 95% CI, 0.002-0.003; range, 0-0.005; FDR P < .001). Conclusions and Relevance This study found that severity of childhood trauma exposure was associated with bipolar disorder diagnosis in part through a smaller hippocampus, thinner cortex in the medial orbitofrontal gyrus, and thinner cortex in the superior frontal gyrus. The identification of this mechanistic pathway improves understanding of the disorder, could help to identify those at risk, and enable the development of new interventions.

Background:Major depressive disorder (MDD) is associated with altered brain structure and evidence of accelerated brain aging. However, previous studies have been limited by clinical samples with mixed medication status and multiple mood states, modest sample sizes, small percentage of MDD individuals older than 65 years of age, and/or reliance on summary-level data. Methods:Harmonized T1-weighted MRI from MDD (n = 645), all medication-free and in a current depressive episode, and matched healthy controls (n = 645), segmented into 145 regional volumes, from 11 sites in COORDINATE-MDD consortium. Brain age gap (BAG) was estimated using gradient boosting regression with nested cross-validation. Group differences in BAG (and age-corrected BAG [cBAG]) were examined across age strata. Regional contributions were evaluated using Shapley Additive exPlanations. Results:MDD was associated with significantly elevated cBAG compared with healthy controls (mean difference + 2.01 years). Age-stratified analyses showed no differences before mid-30s, with progressively larger gaps thereafter, reaching +6.85 years in MDD aged 55 and older. cBAG differed across neuroanatomical phenotypes associated with differential antidepressant response, cognitive impairment, increased adverse life events, increased self-harm and suicide attempts, and a pro-atherogenic metabolic profile. Key contributing regions included lateral and medial prefrontal regions, middle temporal gyrus, putamen, supplementary motor cortex, central operculum, and cerebellum. Conclusions:Accelerated structural brain aging in MDD is age-dependent and is most pronounced in a neuroanatomical phenotype associated with worse key clinical outcomes. The findings support neuroprogression models of MDD while demonstrating that cBAG is not a uniform feature of MDD and seem to be more strongly expressed in a specifically clinically vulnerable disease phenotype.

Neuroimaging and blood-based biomarkers are increasingly utilized to identify long-term effects of concussion and contact-sport exposure (CSE), but female athletes are underrepresented in this work, despite potential sex-related differences. Early research indicates that widely used oral contraceptives (OCs) influence brain structure and function and concussion-related biomarkers. This study investigated whether current oral contraceptive (OC) use moderates associations of concussion history and CSE with magnetic resonance imaging (MRI) measures and brain injury biomarkers in female athletes. Part of a larger cross-sectional study, 68 collegiate-aged female athletes (30 OC users, 38 with no hormonal contraceptive use [NoHC]), completed interviews to retrospectively determine the number of prior concussions (last injury at least 6 months before study enrollment) and years of CSE. Serum glial fibrillary acidic protein, neurofilament light, and total tau levels were measured, along with hippocampal volume, cortical thickness, and Neurite Orientation Dispersion and Density Imaging metrics. Linear regression and Bayesian multilevel modeling tested interactions between OC use and concussion history or CSE on outcomes. Number of prior concussions was negatively associated with hippocampal volumes and cortical thickness. OC use moderated relationships between CSE and cortical thickness, isotropic volume fraction (ISO), and intracellular volume fraction, and between concussion history and orientation dispersion index (ODI). OC users had lower tau levels than the NoHC group. Exploratory models suggested OC pill formulation may moderate associations of concussion history and/or CSE with outcomes and directly affect cortical thickness, ODI, and ISO. These results suggest OC use deserves consideration as an influencing factor in future research and personalized treatment for female athletes.

Importance:Childhood trauma is associated with increased risk for bipolar disorder, but the biological mechanisms of this association remain incompletely defined. Gray matter differences observed after trauma exposure overlap with those reported in bipolar disorder, suggesting that the association of childhood trauma with bipolar disorder might be mediated through brain morphology. Objective:To determine whether cortical thickness, cortical surface, or subcortical volume mediate the association of childhood trauma with bipolar disorder. Design, Setting, and Participants:This case-control study conducted a cross-sectional analysis of individuals with bipolar disorder and healthy controls from 19 international cohorts (Enhancing NeuroImaging Genetics Through Meta-Analyses [ENIGMA] Bipolar Disorder Working Group) from January 2010 to December 2022. Data were analyzed from January 2025 to January 2026. Exposures:The primary exposure was the severity of total childhood trauma assessed with the Childhood Trauma Questionnaire, with secondary analyses of 5 subscales (emotional neglect and abuse, physical neglect and abuse, and sexual abuse). Main Outcomes and Measures:The primary outcome was bipolar disorder diagnosis (case vs control). The primary measure was the mediation effects of childhood trauma on diagnosis via gray matter (75 bilateral-averaged cortical thickness, surface, and subcortical volume measures). The mediation pathway from severity of childhood trauma to bipolar disorder through brain morphology was specified a priori. High-dimensional mediation analysis, with leave-one-site-out cross-validation and permutation testing for significance (false discovery rate [FDR]), was conducted. Results:The final sample included 2221 healthy controls (mean [SD] age, 35.6 [13.2] years; 1274 female [57%]) and 1031 participants with bipolar disorder (mean [SD] age, 38.6 [13.7] years; 579 female [56%]). Severity of childhood trauma was directly associated with higher likelihood of having a bipolar disorder diagnosis (median coefficient, 0.841; 95% CI, 0.834-0.851; range, 0.776-0.893; FDR P < .001). Less than 1% of the association between childhood trauma and bipolar disorder was mediated by brain morphology. Statistically significant mediators were hippocampal volume (median coefficient, 0.004; 95% CI, 0.002-0.005; range, 0-0.008; FDR P < .001), medial orbitofrontal gray matter thickness (median coefficient, 0.002; 95% CI, 0.002-0.003; range, 0-0.004; FDR P < .001), and superior frontal gyrus gray matter thickness (median coefficient, 0.002; 95% CI, 0.002-0.003; range, 0-0.005; FDR P < .001). Conclusions and Relevance:This study found that severity of childhood trauma exposure was associated with bipolar disorder diagnosis in part through a smaller hippocampus, thinner cortex in the medial orbitofrontal gyrus, and thinner cortex in the superior frontal gyrus. The identification of this mechanistic pathway improves understanding of the disorder, could help to identify those at risk, and enable the development of new interventions.

A substantial literature links depression with immune activation, typically indexed by modest elevations in circulating inflammatory mediators such as C-reactive protein and interleukin-6. While these associations are well documented, less attention has been paid to a more fundamental question: why immune responses that are normally transient become repeated, prolonged, or insufficiently resolved in depression despite their substantial energetic and physiological costs. Addressing this question requires moving beyond descriptive associations toward frameworks that explain the evolutionary origins and regulation of depression-associated immune activity. In this review, we integrate findings from psychoneuroimmunology with evolutionary theory to examine how conserved defense programs, metabolic tradeoffs, and developmental plasticity may jointly contribute to immune-related phenotypes observed in depression. We briefly summarize converging epidemiological, experimental, and clinical trial evidence supporting a link between immune signaling and depressive symptoms, and then discuss upstream drivers of repeated or poorly resolved immune activation, including metabolic dysfunction, infection burden, psychological stress, and sleep and circadian disruption. These factors frequently co-occur in modern environments and may engage immune pathways in the absence of discrete, self-limiting threats. We subsequently discuss four complementary evolutionary frameworks - defense-system models, antagonistic pleiotropy, mismatch between ancestral and modern environments, and developmental programming - to explain how patterns of immune activation and regulation are shaped across the lifespan. Together, these perspectives suggest that immune responses that enhanced survival in pathogen-dense and threatening ancestral contexts incur downstream costs when repeatedly engaged or insufficiently resolved in contemporary settings characterized by abundant energy availability, prolonged psychosocial stress, and reduced exposure to immunoregulatory organisms that historically helped calibrate immune tolerance and support effective resolution of inflammatory responses. This account highlights the importance of timing and regulation: immune and metabolic responses that are adaptive when brief may become pathological when sustained or recurrent. Framing depression in terms of variation in the frequency, duration, resolution, and type of immune activation provides a conceptual foundation for more mechanistically informed models of heterogeneity and supports stratified approaches to prevention and treatment.

Behavioral activation therapy (BA) is an efficacious treatment for major depressive disorder (MDD). However, the neurobiological mechanism of action is unclear. The present study is a secondary, multimodal analysis of data from two BA clinical trials, integrating previously reported kynurenine pathway (KP) measures with structural MRI. We tested (a) whether BA is associated with pre-post changes in gray matter volume (GMV) within a priori regions of interest (hippocampus, amygdala, and striatum), and (b) whether BA-associated changes in KP metabolites including kynurenic acid (KynA), quinolinic acid (QA), and KynA/QA relate to concomitant changes in GMV. Twenty-seven participants with mood and anxiety disorders and clinically significant depressive symptoms underwent 10 weeks of BA with pre- and post-treatment blood sampling and MRI. KP metabolites were measured with high-performance liquid chromatography and tandem mass spectrometry. Data were analyzed using linear mixed effects and regression models controlling for age, sex, BMI, therapy group, and intracranial volume (for MRI outcomes). All reported p-values were FDR-corrected. BA was associated with a pre- to post-treatment reduction in left putamen volume (β = -0.11, p < 0.05). At baseline, QA was negatively correlated with bilateral caudate volumes (left: r = -0.47, p < 0.05; right: r = -0.49, p < 0.05). Pre-post BA increases in KynA (β = 0.183, p < 0.01) and KynA/QA (β = 0.159, p < 0.05) were associated with increases in right hippocampal volume, and KynA changes were also positively associated with increases in right amygdala volume (β = 0.234, p < 0.05). Furthermore, QA increases were associated with GMV increases in both the right hippocampus (β = 0.148, p < 0.05) and nucleus accumbens (β = 0.224, p < 0.05). Exploratory analyses revealed additional associations between other KP metabolites (e.g., 3-hydroxykynurenine, tryptophan) and volumetric changes. Baseline KP metabolites and baseline GMV did not predict concurrent symptom change. In targeted prospective tests, larger pre- to post-treatment QA decreases predicted lower depression and anxiety symptoms at 3 months, whereas ΔGMV within a priori ROIs did not predict 3-month symptoms. Our findings suggest that BA is associated with changes in KP metabolism and GMV within affective neural circuitry, and that changes in QA may predict longer-term clinical outcomes. However, given the modest sample size and absence of a control group, these findings should be considered preliminary and cannot establish whether observed changes reflect BA-specific effects or nonspecific effects of time. Future research using randomized clinical designs, larger samples, and multimodal approaches will be critical to delineate the role of KP metabolites in supporting neuroplasticity with BA specifically, and psychotherapy more generally.

MRI studies in bipolar disorder (BD) have yielded inconsistent findings, partly due to the varied use of psychotropic medications. This study utilised a mega-analysis approach, accounting for concurrent medication status (syndrome-based and Neuroscience-based Nomenclature (NbN) classifications), in order to assess the association of medication status with subcortical brain volumes in BD. Data from 2,664 BD patients and 4,065 controls (CN) were pooled from 34 research groups as part of the ENIGMA Bipolar Disorder Working Group. Standardized ENIGMA protocols were used to measure subcortical brain volumes. Linear-mixed-effects regression evaluated the association between psychotropic medications and subcortical volumes, and moderation analyses explored interactions. Medication-free patients (n = 410) showed mild ventricular enlargement (d = 0.07) and increased putamen volume (d = 0.06) compared to CN. Patients taking psychotropic medications exhibited smaller subcortical volumes (d = -0.06 to -0.11) and larger ventricles (d = 0.11 to 0.19). Use of antiepileptic and antipsychotic medications was associated with smaller hippocampal and thalamic volumes (d = -0.07 to -0.14), while NbN classification indicated that the categories of ‘valproate’ and ‘dopamine and other monoamine receptor antagonists’ are key variables when considering volume differences between BD and CN. Concurrent lithium use weakened the negative association between antiepileptic use and hippocampal volume (β = 0.19, q = 0.038) in patients. Medication status is associated with altered subcortical brain volumes in BD. The NbN classification provides a useful framework for future studies, emphasizing the need for comprehensive longitudinal research to further unravel complex clinical-pharmacological-neurobiological interactions in BD.

Background: Astrocytes play a critical role in the pathophysiology of major depressive disorder (MDD) and astrocyte-enriched extracellular vesicles (AEEVs) provide a minimally invasive window into central nervous system (CNS) processes. To date, relatively few laboratories have applied AEEV-based transcriptomics to examine microribonucleic acid (miRNA) dysregulation and associated pathways in MDD. Thus, we aimed to identify differentially expressed (DE) miRNAs in AEEVs and characterize astrocyte-relevant gene targets and biological pathways associated with MDD in a case-control cohort of individuals with MDD and healthy controls (HC). Methods: Participants were propensity-score matched on age, sex, and body mass index, yielding 71 adult MDD without psychiatric comorbidity and 71 HC. Plasma extracellular vesicles (EVs) were isolated and subsequently enriched for AEEVs with immunocapture targeting astrocyte cell surface antigen-1 (ACSA-1 or GLAST). Following AEEV characterization, AEEV miRNA was sequenced using next-generation sequencing. After quality control exclusions, 139 samples [MDD: n=69; HC: n=66] were analyzed for DE with significance defined as p-adjusted (p-adj) < 0·05 and absolute log2 fold-change (|log2FC|) ≥ 1. Experimentally validated gene targets were identified and unique gene targets pooled across all DE miRNAs for over-representation analysis (ORA) of Gene Ontology (GO), KEGG biochemical pathways, and DisGENet disease associations. Findings: Twelve miRNAs were DE in MDD [2 downregulated and 10 upregulated (log2FC ranging from -1·46 to 1·43)]. GO showed significantly (p-adj < 0·05) enriched genes related to synaptic development and signaling in neurons. KEGG pathway analysis revealed 193 significantly enriched pathways, including axon guidance and pathways related to neurodegeneration. Finally, significantly enriched disease states ranged from neurodegenerative conditions (i.e., Familial Alzheimer Disease (FAD); p-adj<0·0001; and Amyotrophic Lateral Sclerosis, Familial; p-adj<0·0001) to depression-related phenotypes [(i.e., Depression, Bipolar; p-adj=0·0005; and Endogenous depression; p-adj=0·0019)]. Interpretation: The predominance of upregulated AEEV miRNAs and pathways related to excitatory synaptic function, neuroplasticity, and astrocyte-neuron interactions suggests coordinated shifts in post-transcriptional regulation that may impact neuronal microenvironment. These findings support a model of MDD involving dysregulated astrocyte–mediated synaptic modulation and highlight AEEVs as a promising liquid-based approach for understanding CNS alterations in MDD.

Adolescence is a sensitive period of brain development marked by rapid cortical thinning and increased risk for psychiatric disorders, yet the biological drivers of atypical trajectories remain unclear. Here, using longitudinal data from the Adolescent Brain Cognitive Development Study, we examined whether genetic predisposition to systemic inflammation, indexed by polygenic scores for C-reactive protein (PGS-CRP), influences brain development and psychopathology. Higher PGS-CRP was associated with accelerated cortical thinning, particularly in medial temporal and insular regions, and with increased externalizing symptoms. Early-life infections independently predicted greater depressive and externalizing symptoms but did not interact with genetic risk. Mediation analyses indicated that cortical thinning partially accounted for the association between PGS-CRP and externalizing psychopathology. Biological annotation further identified the regional similarity between cortical effects of PGS-CRP and several neurotransmitter systems. Together, these findings suggest that genetic susceptibility to inflammation may shape adolescent brain maturation and contribute to mental health vulnerability via neuroimmune pathways.

Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Concussion history is linked to increased risk of psychological symptoms, potentially through inflammation-driven activation of the kynurenine pathway (KP). Use of oral contraceptives (OC) is also associated with increased inflammation, reduced protective kynurenic acid (KynA), and, in some cases, increased psychological symptoms. Despite this evidence and the fact that around half of all female collegiate athletes use OCs, existing research in this area does not account for OC use among female athletes. In this study, we tested the hypothesis that OC use moderates the association of number of prior concussions with serum inflammatory markers and KP metabolites and self-reported psychological symptoms. Collegiate female athletes (N = 69; 30 using OC) participating in a larger cross-sectional study completed semi-structured interviews to retrospectively determine the number of prior concussions (last injury at least 6 months before study enrollment). Linear models assessed associations between the number of prior concussions, OC use, and their interaction with outcomes, controlling for contact-sport exposure. Split analyses tested these associations in athletes using OC versus those not using hormonal contraception (NoHC). Additional exploratory linear models assessed associations between the number of prior concussions, hormonal activity levels of OC, and their interaction on outcomes, controlling for contact-sport exposure. Higher number of prior concussions was associated with elevated quinolinic acid (QuinA), interleukin (IL)-1 receptor antagonist, and psychological symptoms. Although there was no significant interaction, split analyses showed these relationships held only in the NoHC group. Moreover, compared to the NoHC group, OC users exhibited higher C-reactive protein and IL-6 and lower KynA, KynA/QuinA, and KynA/3-hydroxykynurenine. OC formulation moderated biomarker associations in this cohort, with higher progestational and androgenic activity linked to a more proinflammatory profile and greater KP activation with more prior concussions. The results highlight OC use as a potential moderator of the cumulative psychological/immunological effects of repeat concussion in female athletes that should be considered when personalizing treatment for individuals with multiple injuries.

Childhood trauma is a risk factor for bipolar disorder, but the biological mechanisms of this association remain incompletely defined. Gray matter differences observed after trauma exposure overlap with those reported in bipolar disorder, suggesting that the association between childhood trauma and bipolar disorder might be mediated through brain morphology. Our goal was to determine whether cortical thickness, cortical surface or subcortical volume mediate the association between childhood trauma and bipolar disorder. We leveraged a large multi-site dataset from the ENIGMA Bipolar Disorder Working Group, comprising of 1,031 participants with bipolar disorder and 2,221 controls from 19 international cohorts. To identify brain morphology mediators of the association of childhood trauma and bipolar disorder, we used high-dimensional mediation analysis and validated our results using leave-one-site-out cross-validation and permutation testing for significance. Severity of childhood trauma was directly associated with higher likelihood of having a bipolar disorder diagnosis (median coefficient 0.841, 95% CI: [0.834, 0.851], p<0.001). Significant mediators were hippocampal volume (0.004, 95% CI: [0.002, 0.005], p<0.001), medial orbitofrontal gray matter thickness (0.002, 95% CI: [0.002, 0.003], p<0.001), and superior frontal gyrus gray matter thickness (0.002, 95% CI: [0, 0.005], p<0.001). Our results show that the severity of childhood trauma exposure is associated with bipolar disorder diagnosis in part through a smaller hippocampus, thinner cortex in the medial orbitofrontal gyrus and thinner cortex in the superior frontal gyrus. The identification of this mechanistic pathway improves our etiologic understanding of bipolar disorder and could help to identify those at risk and enable the development of new interventions.

Adolescence is a critical neurodevelopmental window characterized by rapid cortical thinning, during which vulnerability to psychiatric disorders significantly increases. Although increased rates of cortical thinning have been associated with adverse mental health outcomes, the biological mechanisms underlying atypical neurodevelopment remain unclear. This study investigates whether genetic predisposition to systemic inflammation, assessed via polygenic scores for C-reactive protein (PGS_CRP), influences cortical thinning trajectories and psychopathology risk in adolescents. Using longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (baseline n=11,214; follow-up n=7,823), we found that higher genetic susceptibility to inflammation was associated with accelerated cortical thinning, particularly in medial temporal and insular regions (β = -0.013 ~ -0.018, p.FDR < 0.05), and increased externalizing psychopathology symptoms (β = 0.167, p.FDR < 0.05). Early-life infections independently predicted greater depressive and externalizing symptoms (β = 0.511 ~0.608, p.FDR < 0.05) but did not interact significantly with genetic predisposition. Structural equation modeling revealed that cortical thinning partially mediated the relationship between genetic inflammation risk and externalizing symptoms. Moreover, neurobiological annotation showed regional overlaps between inflammation-linked cortical thinning and neurotransmitter receptor gradients involving serotonin, GABA, cannabinoid, and glutamate systems. These findings provide evidence for genetic predisposition to inflammation as a factor in adolescent cortical maturation and behavioral outcomes, highlighting potential neuroimmune mechanisms underpinning vulnerability to mental health disorders during this sensitive developmental period.

Recent associations between Major Depressive Disorder (MDD) and measures of premature aging suggest accelerated biological aging as a potential biomarker for MDD susceptibility or MDD as a risk factor for age-related diseases. Residuals or "gaps" between the predicted biological age and chronological age have been used for statistical inference, such as testing whether an increased age gap is associated with a given disease state. Recently, a gene expression-based model of biological age showed a higher age gap for individuals with MDD compared to healthy controls (HC). In the current study, we propose an approach that simplifies gene selection using a least absolute shrinkage and selection operator (LASSO) penalty to construct an expression-based Gene Age Gap Estimate (GAGE) model. We train a LASSO gene age model on an RNA-Seq study of 78 unmedicated individuals with MDD and 79 HC, resulting in a model with 21 genes. The L-GAGE shows higher biological aging in MDD participants than HC, but the elevation is not statistically significant. However, when we dichotomize chronological age, the interaction between MDD status and age has a significant association with L-GAGE. This effect remains statistically significant even after adjusting for chronological age and sex. Using the 21 age genes, we find a statistically significant elevated biological age in MDD in an independent microarray gene expression dataset. We find functional enrichment of infectious disease and SARS-COV pathways using a broader feature selection of age related genes.