John Krystal

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with …

Correction: Psychosocial moderators of polygenic risk scores of inflammatory biomarkers in relation to GrimAge - PMC Back to Top Skip to main content NIH NLM Logo Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List Neuropsychopharmacology v.49(4); 2024 Mar PMC10876612 Other Formats PDF (405K) Actions Cite Collections Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List Neuropsychopharmacology v.49(4); 2024 Mar PMC10876612 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Logo of nppharm Neuropsychopharmacology. …

BackgroundOpioid misuse is highly comorbid with PTSD and individuals with this comorbidity exhibit a higher severity of PTSD symptomatology and poorer treatment efficacy. However, the underlying biological mechanisms are unknown.MethodsHere, we present a study utilizing multiple bioinformatics approaches to comprehensively characterize the transcriptional landscape of opioid misuse, PTSD, and its comorbidity in 212 postmortem brain samples from four human prefrontal cortex (PFC) regions.ResultsOur findings indicate that individuals with comorbid opioid misuse and PTSD exhibit a higher number of differentially expressed genes at a false discovery rate of< 0.05 in the PFC compared to those with PTSD, or opioid misuse only. Particularly, we identified a set of genes with distinct expression profiles, specifically in the orbitofrontal cortex and subgenual prefrontal cortex. These genes were enriched in …

GrimAge acceleration has previously predicted age-related morbidities and mortality. In the current study, we sought to examine how GrimAge is associated with genetic predisposition for systemic inflammation and whether psychosocial factors moderate this association. Military veterans from the National Health and Resilience in Veterans study, which surveyed a nationally representative sample of European American male veterans, provided saliva samples for genotyping (N = 1135). We derived polygenic risk scores (PRS) from the UK Biobank as markers of genetic predisposition to inflammation. Results revealed that PRS for three inflammatory PRS markers—HDL (lower), apolipoprotein B (lower), and gamma-glutamyl transferase (higher)—were associated with accelerated GrimAge. Additionally, these PRS interacted with a range of potentially modifiable psychosocial variables, such as exercise and …

It is widely hoped that statistical models can improve decision-making related to medical treatments. Because of the cost and scarcity of medical outcomes data, this hope is typically based on investigators observing a model’s success in one or two datasets or clinical contexts. We scrutinized this optimism by examining how well a machine learning model performed across several independent clinical trials of antipsychotic medication for schizophrenia. Models predicted patient outcomes with high accuracy within the trial in which the model was developed but performed no better than chance when applied out-of-sample. Pooling data across trials to predict outcomes in the trial left out did not improve predictions. These results suggest that models predicting treatment outcomes in schizophrenia are highly context-dependent and may have limited generalizability.

BackgroundPosttraumatic stress disorder (PTSD) is a complex mental illness that can be developed in individuals exposed to trauma. While recent epigenome-wide association analysis (EWAS) studies have revealed differential methylation associated with PTSD, this work has mostly examined peripheral tissue. In this study, we map CpG and non-CpG methylome (5mC) and hydroxymethylome (5hmC) in cortical neurons of individuals with PTSD and healthy controls.MethodsReduced-representation oxidative bisulfite sequencing was conducted on 38 postmortem brain samples (25 PTSD, 13 controls) from the National PTSD Brain Bank.ResultsBy using methylKit R package, we identified hundreds of differential 5mC and 5hmC sites significantly associated with PTSD after multiple test correction (FDR< 0.5). Discernible variations between CpG and non-CpG sites in terms of gene feature annotation and directional …

Recent advances in our understanding of how to treat TRD have largely expanded our knowledge of best practices in, and efficacy of, interventional psychiatric approaches. Recent research has used a variety of TRD definitions for study inclusion criteria; research on TRD should adhere to inclusion criteria based on internationally defined guidelines for more meaningfully generalizable results.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with …