The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Decades of research have consistently demonstrated the efficacy of electroconvulsive therapy (ECT) for the treatment of major depressive disorder (MDD), but its clinical use remains somewhat restricted because of its cognitive side effects. The aim of this systematic review is to comprehensively summarize current evidence assessing potential biomarkers of ECT-related cognitive side effects. Based on our systematic search of human studies indexed in PubMed, Scopus, and Web of Knowledge, a total of 29 studies evaluating patients with MDD undergoing ECT were reviewed. Molecular biomarkers studies did not consistently identify concentration changes in plasma S-100 protein, neuron-specific enolase (NSE), or Aβ peptides significantly associated with cognitive performance after ECT. Importantly, these findings suggest that ECT-related cognitive side effects cannot be explained by mechanisms of neural cell damage. Notwithstanding, S-100b protein and Aβ40 peptide concentrations, as well as brain-derived neurotrophic factor (BDNF) polymorphisms, have been suggested as potential predictive biomarkers of cognitive dysfunction after ECT. In addition, recent advances in brain imaging have allowed us to identify ECT-induced volumetric and functional changes in several brain structures closely related to memory performance such as the hippocampus. We provide a preliminary framework to further evaluate neurobiological cognitive vulnerability profiles of patients with MDD treated with ECT.

It remains unexplored in the field of fear memory whether functional neuronal connectivity between two brain areas is necessary for one sex but not the other. Here, we show that chemogenetic silencing of centromedial (CeM)– Tac2 fibers in the lateral posterior BNST (BNSTpl) decreased fear memory consolidation in male mice but not females. Optogenetic excitation of CeM- Tac2 fibers in the BNSTpl exhibited enhanced inhibitory postsynaptic currents in males compared to females. In vivo calcium imaging analysis revealed a sex-dimorphic fear memory engram in the BNSTpl. Furthermore, in humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) ( TAC3R ) decreased CeM-BNST connectivity in a fear task, impaired fear memory consolidation, and increased the expression of the TAC3R mRNA in AA-carrier men but not in women. These sex differences in critical neuronal circuits underlying fear memory formation may be relevant to human neuropsychiatric disorders with fear memory alterations such as posttraumatic stress disorder.

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.

Background: Primary care plays a central role in the treatment of depression. Nonetheless, shortcomings in its management and suboptimal outcomes have been identified. Collaborative care models improve processes for the management of depressive disorders and associated outcomes. We developed a strategy to implement the INDI collaborative care program for the management of depression in primary health care centers across Catalonia. The aim of this qualitative study was to evaluate a trial implementation of the program to identify barriers, facilitators, and proposals for improvement. Methods: One year after the implementation of the INDI program in 18 public primary health care centers we performed a qualitative study in which the opinions and experiences of 23 primary care doctors and nurses from the participating centers were explored in focus groups. We performed thematic content analysis of the focus group transcripts. Results: The results were organized into three categories: facilitators, barriers, and proposals for improvement as perceived by the health care professionals involved. The most important facilitator identified was the perception that the INDI collaborative care program could be a useful tool for reorganizing processes and improving the management of depression in primary care, currently viewed as deficient. The main barriers identified were of an organizational nature: heavy workloads, lack of time, high staff turnover and shortages, and competing demands. Additional obstacles were inertia and resistance to change among health care professionals. Proposals for improvement included institutional buy-in to guarantee enduring support and the organizational changes needed for successful implementation. Conclusions: The INDI program is perceived as a useful, viable program for improving the management of depression in primary care. Uptake by primary care centers and health care professionals, however, was poor. The identification and analysis of barriers and facilitators will help refine the strategy to achieve successful, widespread implementation. Trial registration: ClinicalTrials.gov identifier: NCT03285659; Registered 18th September, 2017.