Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD ( β diagnosis (SE)=0.70 (0.37) years, p =0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohen's d =0.23, p FDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.

Perinatal depression (PD) is common and disabling, yet its longitudinal comorbidity patterns and predictability remain poorly understood. This study leveraged 8,804 women with delivery records in the All of Us cohort, including 438 with clinically diagnosed postpartum depression (PPD), to characterize multimorbidity trajectories and develop integrated prediction models. Comorbidities were grouped into 38 conditions across psychiatric, autoimmune, metabolic, neurological/pain, and reproductive/gynecological categories and examined both cross-sectionally and in monthly time bins from 250 months before to 500 months after delivery. Latent class analysis identified three pre- and post-delivery multimorbidity profiles and transitions between classes, while polygenic risk scores for depression and obstetric, clinical and socioeconomic variables were combined in machine learning models to predict PPD, post-delivery class membership, and symptom worsening among initially low-burden women. PPD cases showed higher odds of several psychiatric, autoimmune, and metabolic conditions and a tendency toward greater post-delivery comorbidity accumulation, particularly among women who were healthy pre-pregnancy. Multimorbidity profiles based on latent classes captured clinically meaningful risk gradients, and transition analyses revealed that incident PPD in previously healthy women marked a shift toward more symptomatic post-delivery profiles. Machine learning models achieved moderate discrimination for PPD and comorbidity outcomes and highlighted the importance of genetic liability, obstetric complications, and socioeconomic disadvantage, but low positive predictive values limit clinical implementation. These findings position PPD as a critical event in women's psychiatric, cardiometabolic, and pain-related health trajectories and support life-course, multimorbidity-informed screening and prevention strategies that extend beyond the traditional postpartum period.

Abstract Elucidating the neurobiological basis of neurodevelopmental and psychiatric conditions (NDPCs) remains challenging because brain alterations vary within diagnoses and overlap across them. Whether diverse alterations follow a systematic organization that may reflect shared vulnerabilities remains unknown. Here, we assembled 10,135 individuals with schizophrenia, autism, bipolar, obsessive-compulsive, generalized anxiety, and major depressive disorders, and 11,998 reference participants across six continents through the ENIGMA consortium. Using normative modeling, we quantified individual deviations in cortical thickness, surface area, and subcortical volumes relative to lifespan reference trajectories (5 to 80 years). We show that structural deviations converged along cortical axes reflecting connectome organization, maturation, and cytoarchitectonic diversity. These axes mirrored typical population variation, but their expression differed across diagnoses and partly scaled with symptom severity. Even rare and highly individualized extreme deviations followed this organization, concentrating in densely connected regions. Finally, brain structural deviations overlapped substantially across diagnoses, while differences between them increased toward the association cortex. Together, we provide large-scale evidence that structural deviations across NDPCs are systematically constrained by the brain’s intrinsic architecture. This shared organization provides a framework for reconciling individual variability with transdiagnostic similarities and motivates an integrative, systems-level understanding of mental health.

Specific phobia (SPH) is a prevalent anxiety disorder and may involve advanced biological aging. However, limited brain age research has been conducted in anxiety disorders. This mega-analysis investigated brain aging in SPH participants within the ENIGMA-Anxiety Working Group. 3D brain structural MRI scans from 17 international samples (600 SPH individuals, of whom 504 formally diagnosed and 96 questionnaire-based cases; 1134 controls; age range: 22-75 years) were processed with FreeSurfer. Brain age was estimated from 77 subcortical and cortical regions with a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as brain age minus chronological age. Linear mixed-effects models examined group differences in brain-PAD and moderation by age. No significant group difference in brain-PAD manifested (βdiagnosis [SE] = 0.37 years [0.43], p = 0.39). A negative diagnosis-by-age interaction was identified, which was most pronounced in formally diagnosed SPH (βdiagnosis-by-age = -0.08 [0.03], pFDR = 0.02). This interaction remained significant when excluding participants with anxiety comorbidities, depressive comorbidities, and medication use. Post hoc analyses revealed a group difference for formal SPH diagnosis in younger participants (22-35 years; βdiagnosis = 1.20 [0.60], p < 0.05, mixed-effects d [95% confidence interval] = 0.14 [0.00-0.28]), but not older participants (36-75 years; βdiagnosis = 0.07 [0.65], p = 0.91). Brain aging did not relate to SPH in the full sample. However, a diagnosis-by-age interaction was observed across analyses, and was strongest in formally diagnosed SPH. Post hoc analyses showed subtle advanced brain aging in young adults with formally diagnosed SPH. Taken together, these findings indicate the importance of clinical severity, impairment, and persistence, and may suggest a slightly earlier end to maturational processes or subtle decline of brain structure in SPH.

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.

Higher predicted brain age difference has been associated with several psychiatric disorders. Generalized anxiety disorder (GAD) is associated with markers of accelerated aging. In this study, we determined brain predicted age difference (PAD) in individuals with GAD and healthy controls (HC) as well as group differences in PAD variability using voxel-wise structural MRI. The training dataset included 3,511 controls, and the testing dataset included 1,595 individuals with GAD and 4,552 HC from the ENIGMA-Anxiety GAD Working Group. A convolutional neural network model using four input modalities per subject and a model ensemble approach was used to predict brain age. The PAD was then calculated by subtracting chronological age. Model performance was consistent with other image-based brain age prediction models with similar accuracy across the training set (mean absolute error (MAE) = 2.95 years) and HC in the testing set (MAE = 2.94). We found no evidence of accelerated brain aging in individuals with GAD, though we did find evidence for greater variation in PAD for individuals with GAD (Levene's test: W = 442.98, p < .001) and evidence for greater variability in PAD of those with GAD over 25 years of age. No relationships between PAD and clinical or demographic measures were found. To conclude, using large training and testing samples, the study found no significant association between GAD and PAD, although individuals with GAD had greater heterogeneity in brain-predicted age.

Introduction:Specific phobia (SPH) is a prevalent anxiety disorder and may involve advanced biological aging. However, brain age research in psychiatry has primarily examined mood and psychotic disorders. This mega-analysis investigated brain aging in SPH participants within the ENIGMA-Anxiety Working Group. Methods:3D brain structural MRI scans from 17 international samples (600 SPH individuals, of whom 504 formally diagnosed and 96 questionnaire-based cases; 1,134 controls; age range: 22-75 years) were processed with FreeSurfer. Brain age was estimated from 77 subcortical and cortical regions with a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as brain age minus chronological age. Linear mixed-effect models examined group differences in brain-PAD and moderation by age. Results:No significant group difference in brain-PAD manifested (β diagnosis (SE)=0.37 years (0.43), p=0.39). A negative diagnosis-by-age interaction was identified, which was most pronounced in formally diagnosed SPH (β diagnosis-by-age=-0.08 (0.03), pFDR=0.02). This interaction remained significant when excluding participants with anxiety comorbidities, depressive comorbidities, and medication use. Post-hoc analyses revealed a group difference for formal SPH diagnosis in younger participants (22-35 years; β diagnosis=1.20 (0.60), p<0.05, mixed-effects d (95% confidence interval)=0.14 (0.00-0.28)), but not older participants (36-75 years; β diagnosis=0.07 (0.65), p=0.91). Conclusions:Brain aging did not relate to SPH in the full sample. However, a diagnosis-by-age interaction was observed across analyses, and was strongest in formally diagnosed SPH. Post-hoc analyses showed a subtle advanced brain aging in young adults with formally diagnosed SPH. Taken together, these findings indicate the importance of clinical severity, impairment and persistence, and may suggest a slightly earlier end to maturational processes or subtle decline of brain structure in SPH.

Introduction: Obsessive-compulsive disorder (OCD) is a chronic condition where many patients remain symptomatic despite first-line treatments such as cognitive behavioural therapy and selective serotonin reuptake inhibitors. This randomised controlled trial evaluated mindfulness-based cognitive therapy (MBCT) efficacy as an augmentation strategy and its impact on brain functional connectivity. Methods: Sixty-eight participants with moderately symptomatic OCD were randomised into MBCT or treatment as usual (TAU). Clinical outcomes were evaluated using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Obsessive-Compulsive Inventory, alongside other relevant secondary outcomes. Data were analysed using repeated-measures ANOVA to assess time * group effects. Neuroimaging functional measures (resting-state network connectivity) were collected before and after the intervention and analysed using independent component analysis. Results: Primary outcome: MBCT significantly reduced OCD symptoms compared to TAU (31.73% vs. 8.07% Y-BOCS reduction). Secondary outcomes: the MBCT group also experienced reductions in depressive symptoms, rumination, perceived stress, and quality of life. No significant post-treatment changes were observed in resting-state connectivity. However, baseline connectivity demonstrated significant predictive value, with lower connectivity in preselected networks of interest, including the fronto-striatal, salience, and default mode networks, associated with greater reductions in Y-BOCS scores. Conclusion: MBCT is an effective strategy for individuals with moderately symptomatic OCD who continue to experience symptoms despite prior gold-standard treatments. While no post-treatment changes in brain functional connectivity were observed, baseline connectivity patterns predicted symptom reduction, suggesting a neural basis for MBCT response.

Electroconvulsive therapy (ECT)-mediated hippocampal volumetric increase is consistently reported, though its clinical relevance remains debated. This study evaluates if ECT-related cognitive side effects are associated with regional volumetric changes along the hippocampal longitudinal axis. Longitudinal T1-weighted MRI scans in 435 patients (54.0 ± 15.0 years, 261 female) with major depression from the Global ECT-MRI Research Collaboration (GEMRIC) were used to measure changes in right global and longitudinal axis hippocampal subdivisions (head, body, tail) from baseline to post-treatment. Cognitive side effects were evaluated using pre-to-post treatment changes in two different verbal fluency tests available for 124 patients. Electric field modelling was applied to explore whether the regional hippocampal electric field strength related to individual changes in cognitive performance. Global hippocampal enlargement is observed pre-to-post ECT (pFDR < 0.001), but enlargement of the hippocampal head significantly exceeds the volumetric change in the hippocampal body and tail (pFDR < 0.001). Volumetric expansion of the hippocampal body and tail significantly associates with reduced verbal fluency scores (pFDR< 0.05). Moreover, volumetric reduction of the hippocampal tail at 6 months post-ECT associates with improved cognitive performance (pFDR < 0.05, N = 24). Finally, patients performing worse on verbal fluency tests following treatment have greater electric field during ECT in the right hippocampal body (puncorrected < 0.05). The findings support that cognitive performance following ECT relates to macrostructural changes in the posterior cognitive hippocampus. Thus, there may be a threshold of ECT induced posterior hippocampal volumetric change, beyond which cognitive side effects occur. Electroconvulsive Therapy (ECT) is a procedure that sends small electric currents through the brain and remains the most effective acute treatment for severe depressive episodes. However, we still do not fully understand how ECT works. Studies using brain scans (MRI) before and after ECT have shown that a part of the brain called the hippocampus often becomes larger after treatment. However, the clinical relevance of the volumetric change remains unknown. In this study, we looked at whether the increase in hippocampus size is linked to cognitive side effects. We found that a larger hippocampal volumetric increase after ECT was associated with reduced performance in verbal fluency tests, which measures our ability to rapidly produce words. These results suggest that big changes in the hippocampus after ECT may be related to short-term cognitive side effects. Ousdal et al. investigate whether global or regional hippocampal volume increase after Electroconvulsive therapy (ECT) for major depressive episodes relate to cognitive side effects. Their findings suggest that pronounced structural change in the posterior hippocampus (i.e., body and tail) associates with reduced cognitive performance following ECT.

BACKGROUND:Anorexia nervosa (AN) is a severe and disabling disorder, with relapse rates as high as 50% after the first episode, posing a significant challenge for clinicians. Most therapies excessively focus on nourishment, resulting in temporary weight restoration but with no improvements in general well-being and quality of life. Radically Open Dialectical Behavior Therapy (RO-DBT) is a transdiagnostic treatment designed to address overcontrol, a key aspect in the functioning of patients with AN. To date, no clinical trial (CT) has shown its efficacy in these patients or evaluated its neurobiological mechanism of action. METHODS:A randomized CT in weight restored adult AN patients will be conducted, with one group receiving treatment as usual (TAU) and the other TAU plus RO-DBT, with the main outcome being quality of life. Secondary variables will include eating disorders (EDs) symptoms, overcontrol characteristics, autistic traits, and neuroimaging changes. DISCUSSION:The results will address a gap in knowledge regarding AN treatment, with the expectation that patients receiving TAU with RO-DBT will exhibit improved quality of life and experience fewer relapses at the one-year follow-up. This is the first study examining neuroimaging changes in RO-DBT to better understand its underlying mechanisms. TRIAL REGISTRATION:The study has been registered in ClinicalTrials.gov in September 22, 2023. It can be found in https://classic. CLINICALTRIALS:gov/ct2/show/NCT06050421 . TRIAL REGISTRATION NUMBER:NCT06050421.

BACKGROUND:Externalizing and internalizing disorders are common in youth but are often studied separately, preventing researchers from identifying shared (i.e., transdiagnostic) alterations in brain structure. Using data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium, we conducted a mega-analysis to identify shared and distinct cortical and subcortical brain alterations across internalizing (anxiety disorders and depression) and externalizing (attention-deficit/hyperactivity disorder [ADHD] and conduct disorder [CD]) disorders in youth. METHODS:3D T1-weighted magnetic resonance imaging data from youths (age range 4-21 years) with anxiety disorders (n = 1044), depression (n = 504), ADHD (n = 1317), and CD (n = 1172) along with healthy control participants (n = 4743) were analyzed. We assessed group differences in regional cortical thickness, surface area (SA), and subcortical volume using linear models, adjusted for site, age, and sex, as well as total intracranial volume in the SA and subcortical volume models. RESULTS:We observed transdiagnostic associations, with both internalizing and externalizing disorders characterized by lower SA in the insula, entorhinal cortex, and middle temporal gyrus and lower amygdala volume (Cohen's ds = -0.07 to -0.24) as well as total SA and intracranial volume (ds = -0.11 to -0.25). Externalizing-specific reductions in SA were observed in frontoparietal regions (ds = -0.08 to -0.13), but no internalizing-specific associations were identified. Disorder-specific alterations were identified for ADHD, CD, and anxiety disorders but not depression. CONCLUSIONS:Both common and disorder-specific alterations were identified, with regions involved in salience attribution and emotion processing implicated across internalizing and externalizing disorders. These novel findings can guide future research targeting common biological processes across youth psychiatric disorders as well as features unique to individual disorders.

Pavlovian fear conditioning is a fundamental process in both health and disease. We investigate its neural correlates and sources of variability using harmonized functional magnetic resonance imaging data from 2199 individuals across nine countries, including 1888 healthy individuals and 311 with anxiety-related or depressive disorders. Using mega-analysis and normative modeling, we show that fear conditioning consistently engages brain regions within the "central autonomic-interoceptive" or "salience" network. Several task variables strongly modulate activity in these regions, contributing to variability in neural responses. Additionally, brain activation patterns differ between healthy individuals and those with anxiety-related or depressive disorders, with distinct profiles characterizing specific disorders such as post-traumatic stress disorder and obsessive-compulsive disorder. While the neural correlates of fear conditioning are highly generalizable at the population level, variability arises from differences in task design and clinical status, highlighting the importance of methodological diversity in capturing fear learning mechanisms.

OBJECTIVE:Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults).METHODS:Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis.RESULTS:Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents.CONCLUSIONS:Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.

BackgroundBipolar disorder (BD) is characterized by episodic mood dysregulation, although a significant portion of patients suffer persistent cognitive impairment during euthymia. Previous magnetic resonance imaging (MRI) research suggests BD patients may have accelerated brain aging, observed as lower grey matter volumes. How these neurostructural alterations are related to the cognitive profile of BD is unclear.MethodsWe aim to explore this relationship in euthymic BD patients with multimodal structural neuroimaging. A sample of 27 euthymic BD patients and 24 healthy controls (HC) underwent structural grey matter MRI and diffusion-weighted imaging (DWI). BD patient's cognition was also assessed. FreeSurfer algorithms were used to obtain estimations of regional grey matter volumes. White matter pathways were reconstructed using TRACULA, and four diffusion metrics were extracted. ANCOVA models were performed to compare BD patients and HC values of regional grey matter volume and diffusion metrics. Global brain measures were also compared. Bivariate Pearson correlations were explored between significant brain results and five cognitive domains.ResultsEuthymic BD patients showed higher ventricular volume (F(1, 46) = 6.04; p = 0.018) and regional grey matter volumes in the left fusiform (F(1, 46) = 15.03; pFDR = 0.015) and bilateral parahippocampal gyri compared to HC (L: F(1, 46) = 12.79, pFDR = 0.025/ R: F(1, 46) = 15.25, pFDR = 0.015). Higher grey matter volumes were correlated with greater executive function (r = 0.53, p = 0.008).LimitationsWe evaluated a modest sample size with concurrent pharmacological treatment.ConclusionsHigher medial temporal volumes in euthymic BD patients may be a potential signature of brain resilience and cognitive adaptation to a putative illness neuroprogression. This knowledge should be integrated into further efforts to implement imaging into BD clinical management.

Exposure to acute and chronic stress has a broad range of structural effects on the brain. The brain areas commonly targeted in the stress response models include the hippocampus, the amygdala, and the prefrontal cortex. Studies in patients suffering from the so-called stress-related disorders -embracing post-traumatic stress, major depressive and anxiety disorders- have fairly replicated animal models of stress response -particularly the neuroendocrine and the inflammatory models- by finding alterations in different brain areas, even in the early neurodevelopment. Therefore, this narrative review aims to provide an overview of structural neuroimaging findings and to discuss how these studies have contributed to our knowledge of variability in response to stress and the ulterior development of stress-related disorders. There are a gross number of studies available but neuroimaging research of stress-related disorders as a single category is still in its infancy. Although the available studies point at particular brain circuitries involved in stress and emotion regulation, the pathophysiology of these abnormalities -involving genetics, epigenetics and molecular pathways-, their relation to intraindividual stress responses -including personality characteristics, self-perception of stress conditions…-, and their potential involvement as biomarkers in diagnosis, treatment prescription and prognosis are discussed.