Abstract
OBJECTIVE: Hippocampal dysfunction is implicated in posttraumatic stress disorder (PTSD), particularly intrusive reexperiencing symptoms, and may be mediated by glutamatergic excitotoxicity. Markers of glutamate dysfunction (higher glutamate to N-acetyl aspartate levels; Glu/NAA) in the hippocampus (HPC) have been linked to reexperiencing symptoms. However, the HPC demonstrates heterogeneity along its anterior-posterior axis, with different functional connectivity patterns and PTSD symptom associations, motivating investigations into glutamate metabolism in anterior and posterior HPC subregions (a/pHPC). METHODS: 121 symptomatic trauma-exposed adults (93 female) with current trauma reexperiencing symptoms completed magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging to examine the regional specificity of HPC Glu/NAA associations with reexperiencing, and the link to a/pHPC functional connectivity. PTSD symptoms were assessed with the Clinician-Administered PTSD Scale for DSM-5. RESULTS: Reexperiencing symptom severity was associated with greater Glu/NAA in the pHPC, but not aHPC. pHPC Glu/NAA was further linked to stronger functional connectivity between the pHPC and visual cortex (VC), which in turn correlated with more severe reexperiencing symptoms. This strengthened pHPC-VC connectivity explained the shared variance between pHPC Glu/NAA and reexperiencing severity, suggesting dysregulated glutamate metabolism in the pHPC may contribute to reexperiencing symptoms through functional connectivity with the VC. CONCLUSIONS: These findings replicate prior work linking HPC Glu/NAA to trauma reexperiencing symptoms and provide novel evidence this association may be specific to the pHPC and mediated by its functional connectivity with the VC. This multimodal investigation supports translational models of glutamatergic dysfunction in trauma-related disorders and highlights new targets for pharmacological and neuromodulatory interventions.