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

C G Abdallah,J H Krystal,A Roy,C L Averill,T Akiki,J C Scott,K M Wrocklage,B Martini,S M Southwick,B Schweinsburg

doi:10.1038/tp.2017.12

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.

Highlights

Posttraumatic stress disorder (PTSD) is a disabling mental illness, with limited treatment options and a pathophysiology that is not well understood.[1]
Our functional global brain connectivity (GBC) with global signal regression (f-GBCr) methods minimize the effects of gray matter (GM) variability between participants, we did examine the effect of hippocampal volume on anterior hippocampus (aHPC) f-GBCr to rule out the possibility that the observed dysconnectivity is primarily driven by the welldocumented hippocampal reduction in posttraumatic stress disorder (PTSD)
To determine the presence of aHPC anatomical dysconnectivity, we first examined the relationship between Clinician Administered PTSD Scale (CAPS) and diffusion GBC (d-GBC), followed by seed-based anatomical connectivity using the aHPC as seed and the whole-brain GM as target

Summary

INTRODUCTION

Posttraumatic stress disorder (PTSD) is a disabling mental illness, with limited treatment options and a pathophysiology that is not well understood.[1]. Together with preclinical data, such studies have encouraged the development of putative circuit-based models of PTSD, which propose altered activity and connectivity in critical brain regions as the underlying mechanism of PTSD abnormalities in stress response, fear conditioning and emotion regulation.[9,10,11,12] A complementary synaptic model of traumatic stress suggests that severe traumatic events, and the ensuing chronic stress experience, reduce synaptic connectivity in the PFC and HPC by reducing synaptic strength, spine density and dendritic arborization and length.[13,14] Supporting the preclinical data, a number of individual studies have reported PFC and HPC gray matter (GM) structural alterations in PTSD, which have been supported by systematic reviews and meta-analyses.[15,16] While prefrontal deficits appear to be mostly acquired post trauma,[17] HPC structural alterations are believed to be both predisposing and acquired features.[17,18] HPC structural deficits show a pattern of normalization following PTSD treatment.[19]. Premorbid intellectual functioning was assessed using Wechsler Test of Adult Reading.[41] whether f-GBCr alterations exist in PTSD; (b) to what extent these alterations are associated with anatomical dysconnectivity; and (c) whether such alterations are disorder-specific or stress-related abnormalities

Neuroimaging methods

Participants and clinical assessments

Findings

DISCUSSION