Dysfunctional large-scale networks linking PTSD and cognitive impairment

Post-traumatic stress disorder (PTSD) is associated with increased risk of cognitive impairment (CI), but how large-scale network disruption relates to this vulnerability remains unclear. We examined whether PTSD and cognitive status interact to shape brain network organization.

Resting-state fMRI from 178 age-matched male participants (ADNI-DOD and ADNI cohorts) was analyzed within a 2 × 2 factorial design defined by PTSD status and cognitive status. Cognitive status was classified using the Montreal Cognitive Assessment (MoCA), with CI defined by a MoCA score of 18-26 and cognitively normal (CN) status by a MoCA score >26, yielding four groups; PTSD status was established using the Clinician-Administered PTSD Scale (CAPS), requiring a score ≥40 for the PTSD group and ≤30 for non-PTSD (NPTSD) controls. These criteria yielded four groups: PTSD-CI (n = 46), PTSD-CN (n = 14), NPTSD-CI (n = 55), and NPTSD-CN (n = 63). Functional connectivity matrices (32 regions, Harvard-Oxford atlas) underwent graph-theoretical analysis. General linear models tested main effects and the PTSD × cognitive status interaction for global efficiency, eigenvector centrality, clustering coefficient, local efficiency, degree, and betweenness centrality, adjusting for age, education, APOE ε4 status, and depressive symptoms (FDR-corrected).

A significant PTSD × cognitive status interaction was observed across all four dorsal attention network (DAN) nodes-bilateral frontal eye fields and intraparietal sulci-for global efficiency, eigenvector centrality, cost, and degree. These effects were driven exclusively by PTSD-CI versus PTSD-CN differences and were absent in non-PTSD groups, reflecting a reversal of the normally right-lateralized DAN organization. Further interaction effects emerged in the right supramarginal gyrus (salience network) and medial visual network. A PTSD main effect reduced language-network hub function (left inferior frontal gyrus, left posterior superior temporal gyrus), and a cognitive-status main effect involved the left supramarginal gyrus.

PTSD and cognitive impairment interact, rather than summate, to produce a distinct network signature characterized by DAN lateralization reversal, identifying PTSD-CI as a neurobiologically distinct phenotype and highlighting the DAN, salience, and language networks as targets.