Charles B. Nemeroff

Major depressive disorder (MDD) involves frontal cortical dysfunction, with emerging evidence implicating gliovascular and immune mechanisms, yet its transcriptional signatures across subregions, cell-types, and molecular layers remain poorly defined. Here, we integrated bulk-tissue RNA-seq data from dlPFC, mPFC, and dACC (n = 286) to identify a conserved core transcriptional profile, anchored in downregulated interneuron markers, and upregulated immune and vascular genes, spatially enriched in leptomeninges and white matter. Concordantly, multiomic factor analysis revealed immune activation, stress-response, and accelerated aging in MDD. Analysis of snRNA-seq data from dlPFC, mPFC, and oFC (863,511 nuclei; n = 204) revealed most pronounced MDD signatures in excitatory neurons, accompanied by coordinated disruption of glucocorticoid receptor machinery across cell-types, including FKBP5 upregulation. Glial, immune, and perivascular populations exhibited signatures of oxidative stress, ECM remodeling, and reduced neuronal support, and greater concordance with bulk-tissue MDD signals than neurons. A global reduction in cell-to-cell communications in MDD revealed a shift from homeostatic neuronal signaling toward endothelial and myelination-associated pathways. Ephrin-Eph signaling was consistently dysregulated, implicating disrupted axonal guidance, synaptic remodeling, and neurovascular integrity. Notably, MDD signatures were shared between MDD-only and PTSD comorbid cases at bulk-tissue analyses, while diverging at single-cell resolution. Together, these findings reframe MDD as a distributed frontal cortex disorder, driven by disrupted neuroglial and neurovascular communication.

Examining risk factors for the development of dementia, a devastating condition, is of increasing importance in clinical research. Adverse childhood experiences (ACEs) represent one set of potentially modifiable dementia risk factors with known impacts on neurodevelopment and health. Refining approaches used in previous reviews, the authors of this review and meta-analysis sought to answer the question, What is the strength of the association between ACEs and dementia in later life? The authors searched PubMed, EMBASE, and Web of Science, including peer-reviewed studies involving adults exposed to ACEs and a comparison group of unexposed adults. The outcome of interest was dementia of any etiology, and study quality was assessed. Separate meta-analyses were performed with odds ratios and hazard ratios (HRs). The literature search yielded 2,032 articles, of which 13 were included for analysis. ACE exposure (OR=1.54, 95% CI=1.38-1.71, p<0.001; HR=1.51, 95% CI=1.24-1.84, p<0.001) and exposure to parental death in childhood (OR=1.42, 95% CI=1.16-1.74, p<0.001) were associated with increased odds of or risk for developing dementia, respectively. This meta-analytic review is the most extensive examination of the ACE-dementia relationship to date, and its findings suggest that several ACEs are associated with increased dementia odds and risk. Although the number of studies reviewed was small and the studies were mostly of fair quality, necessitating caution in interpretation, nearly all of their results supported the association between ACE and dementia. High-quality prospective cohort studies incorporating biomarkers to measure ACE outcomes will be essential.

Because extinction forms the empirical foundation of exposure therapy, strategies to enhance extinction could lead to more effective interventions for posttraumatic stress disorder (PTSD). Here, we used functional MRI to compare immediate and long-term efficacy of enhanced versus standard extinction in 54 adults with (n = 32) and without (n = 22) PTSD. In both control and PTSD groups, counterconditioning—an enhanced form of extinction that replaces threat with positive outcomes—was more effective than standard extinction. It reduced threat-related neural activity and promoted reinstatement of safety (extinction) patterns in the ventromedial prefrontal cortex (a region involved in learning and retrieving safety associations). However, the PTSD group continued to reinstate both threat- and safety-related neural patterns in the dorsal anterior cingulate cortex (a region involved in learning and retrieving threat associations). These findings represent novel evidence that enhanced extinction outperforms standard extinction in promoting more rapid and persistent neural representations of safety in PTSD.

Background: The relationship between media portrayal of psychedelic drugs, scientific research and drug policy is an area of debate. Aims: To apply artificial intelligence technology to measure trends in media sentiment towards the therapeutic potential of psychedelic drugs. Method: Up to 300 of the most relevant articles from Google News searches for the term ‘psychedelics’ were sampled for each year from 2000 to 2025. A large language model, ChatGPT, evaluated subject matter and sentiment. Results: In total, 88.3% of screened URLs (3308 of 3747) were included in the analysis. The proportion of articles focusing on the therapeutic potential of psychedelics increased from 13.3% (26 of 198) from 2000 to 2009 to 85.3% (1254 of 1470) from 2020 to 2025. The average sentiment score from 2000 to 2025 for articles from all publications ( N = 2168) was 78.5 ± 9.3 (mean ± s.d.) (possible range: 1–100). 1.3% (29 of 2168) of articles carried negative sentiment (P < 0.00001, Mann–Whitney U -test). The proportion of negative-neutral articles (≤65) increased annually from a trough of 3.6% (8 of 267) in 2020 to a peak of 20.9% (43 of 253) in 2024. Artificial intelligence sentiment scores were correlated and concordant with average human rater scores ( r = 0.88, concordance correlation coefficient 0.84). Conclusions: Although most 21st-century media coverage of psychedelic drugs has been positively framed, negative and neutral coverage has increased in frequency since 2020. Researchers, clinicians, regulators and policy-makers should be mindful of the complex relationship between media portrayals of psychedelics and the results of scientific research.