Anterior hippocampal dysconnectivity in posttraumatic stress disorder: a dimensional and multimodal approach

Abstract

The anterior hippocampus (aHPC) has a central role in the regulation of anxiety-related behavior, stress response, emotional memory and fear. However, little is known about the presence and extent of aHPC abnormalities in posttraumatic stress disorder (PTSD). In this study, we used a multimodal approach, along with graph-based measures of global brain connectivity (GBC) termed functional GBC with global signal regression (f-GBCr) and diffusion GBC (d-GBC), in combat-exposed US Veterans with and without PTSD. Seed-based aHPC anatomical connectivity analyses were also performed. A whole-brain voxel-wise data-driven investigation revealed a significant association between elevated PTSD symptoms and reduced medial temporal f-GBCr, particularly in the aHPC. Similarly, aHPC d-GBC negatively correlated with PTSD severity. Both functional and anatomical aHPC dysconnectivity measures remained significant after controlling for hippocampal volume, age, gender, intelligence, education, combat severity, depression, anxiety, medication status, traumatic brain injury and alcohol/substance comorbidities. Depression-like PTSD dimensions were associated with reduced connectivity in the ventromedial and dorsolateral prefrontal cortex. In contrast, hyperarousal symptoms were positively correlated with ventromedial and dorsolateral prefrontal connectivity. We believe the findings provide first evidence of functional and anatomical dysconnectivity in the aHPC of veterans with high PTSD symptomatology. The data support the putative utility of aHPC connectivity as a measure of overall PTSD severity. Moreover, prefrontal global connectivity may be of clinical value as a brain biomarker to potentially distinguish between PTSD subgroups.

Altered White Matter Diffusivity of the Cingulum Angular Bundle in Posttraumatic Stress Disorder

“…Structural MRI included 2 T1-weighted MPRAGE scans (TR = 2,530 ms; TE = 2. . Consistent with prior literature [21,32,37,38], and described in greater detail in the online supplementary Materials (for all online suppl. material, see www.karger.com/ doi/10.1159/000490464), DTI processing was conducted using FMRIB Software Library (FSL; https://fsl.fmrib.ox.ac.uk/fsl/fslwiki) [39], and TRACULA (FreeSurfer; https://surfer.nmr.mgh.harvard.edu) [40].…”

“…The CAB connects the hippocampus and other regions of the medial temporal lobe with the posterior cingulate [43], an area that has been shown to exhibit alterations of gray matter integrity (thinning) in this group of participants [30]. Of similar relevance, we have previously reported various associations between PTSD symptom severity and the anterior hippocampus, including differences in morphometry [29], lower volume of the hippocampus-amygdala transition area [31], and both structural and anatomical dysconnectivity [32]. Given the purported associations with key regions of emotion, memory, and cognition, it is interesting to consider the implications of altered CAB integrity in the context of our earlier work with this cohort.…”

“…All 67 participants were combat-exposed, of which 33 PTSD subjects and 34 CCs were well matched in terms of age, sex, and IQ. This group of participants has been discussed in prior publications from our group, in which we reported on PTSD associations with: gray matter integrity [29,30], volumetric alterations [31], and functional dysconnectivity [32]. In this manuscript, we present the first DTI results from this cohort.…”

Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

“…functional connectivity strength, have been used to identify major brain networks (30), were found to predict cognitive functioning and intelligence (31), and were shown to significantly correlate with regional cerebral blood flow (32, 33). Accumulating evidence has consistently shown reduced PFC GBCr across various psychiatric disorders marked by chronic stress (15, 34–39). Thus, it was proposed that these PFC GBCr abnormalities may reflect depression and stress-induced glutamate alterations (16, 17, 34).…”

“…Accumulating evidence has consistently shown reduced PFC GBCr across various psychiatric disorders marked by chronic stress (15, 34–39). Thus, it was proposed that these PFC GBCr abnormalities may reflect depression and stress-induced glutamate alterations (16, 17, 34). Depressive features and chronic stress in animal models reduce prefrontal glutamate synaptic density and strength, abnormalities that are reversed by ketamine treatment (40).…”