Background: Post-traumatic stress disorder can be viewed as a memory disorder, with trauma-related flashbacks being a core symptom. Given the central role of the hippocampus in autobiographical memory, surprisingly, there is mixed evidence concerning altered hippocampal functional connectivity in PTSD. We shed light on this discrepancy by considering the distinct roles of the anterior versus posterior hippocampus and examine how this distinction may map onto whole-brain resting-state functional connectivity patterns among those with and without PTSD. Methods: We first assessed whole-brain between-group differences in the functional connectivity profiles of the anterior and posterior hippocampus within a publicly available data set of resting-state fMRI data from n =31 male Vietnam War veterans diagnosed with PTSD and n =29 age-matched combat-exposed male controls. Next, the connectivity patterns of each subject within the PTSD group were correlated with their PTSD symptom scores. Finally, the between-group differences in whole-brain functional connectivity profiles discovered for the anterior and posterior hippocampal seeds were used to prescribe post-hoc ROIs, which were then used to perform ROI-to-ROI functional connectivity and graph-theoretic analyses. Results: The PTSD group showed increased functional connectivity of the anterior hippocampus with affective brain regions (anterior/posterior insula, orbitofrontal cortex, temporal pole) and decreased functional connectivity of the anterior/posterior hippocampus with regions involved in processing bodily self-consciousness (supramarginal gyrus). Notably, decreased anterior hippocampus connectivity with the posterior cingulate cortex /precuneus was associated with increased PTSD symptom severity. The left anterior hippocampus also emerged as a central locus of abnormal functional connectivity, with graph-theoretic measures suggestive of a more central hub-like role in those with PTSD compared to trauma-exposed controls. Conclusions: Our results highlight that the anterior hippocampus plays a critical role in the neurocircuitry underlying PTSD and underscore the importance of the differential roles of hippocampal sub-regions in serving as biomarkers of PTSD.

The authors have declared no competing interest.

This research was supported by a Discovery Grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada to S.B., MacDATA Graduate Fellowship from the MacDATA Institute to M.CH., a MITACS Elevate Postdoctoral Fellowship to S.B.S, Canadian Institues of Health Research (CIHR) grants to M.M., R.L., and A.A.N. M.M. and A.A.N. were also supported by the Homewood Chair in Mental Health and Trauma at McMaster University, and by the Banting Research Foundation, respectively.

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