Smaller hippocampal CA1 subfield volume in posttraumatic stress disorder

Abstract

Background: Smaller hippocampal volume in patients with posttraumatic stress disorder (PTSD) represents the most consistently reported structural alteration in the brain. Subfields of the hippocampus play distinct roles in encoding and processing of memories, which are disrupted in PTSD. We examined PTSD-associated alterations in 12 hippocampal subfields in relation to global hippocampal shape, and clinical features.

Methods: Case-control cross-sectional studies of U.S. military veterans (n = 282) from the Iraq and Afghanistan era were grouped into PTSD (n = 142) and trauma-exposed controls (n = 140). Participants underwent clinical evaluation for PTSD and associated clinical parameters followed by MRI at 3 T. Segmentation with FreeSurfer v6.0 produced hippocampal subfield volumes for the left and right CA1, CA3, CA4, DG, fimbria, fissure, hippocampus-amygdala transition area, molecular layer, parasubiculum, presubiculum, subiculum, and tail, as well as hippocampal meshes. Covariates included age, gender, trauma exposure, alcohol use, depressive symptoms, antidepressant medication use, total hippocampal volume, and MRI scanner model.

Results: Significantly lower subfield volumes were associated with PTSD in left CA1 (P = 0.01; d = 0.21; uncorrected), CA3 (P = 0.04; d = 0.08; uncorrected), and right CA3 (P = 0.02; d = 0.07; uncorrected) only if ipsilateral whole hippocampal volume was included as a covariate. A trend level association of L-CA1 with PTSD (F_{4, 221} = 3.32, P = 0.07) is present and the other subfield findings are nonsignificant if ipsilateral whole hippocampal volume is not included as a covariate. PTSD-associated differences in global hippocampal shape were nonsignificant.

Conclusions: The present finding of smaller hippocampal CA1 in PTSD is consistent with model systems in rodents that exhibit increased anxiety-like behavior from repeated exposure to acute stress. Behavioral correlations with hippocampal subfield volume differences in PTSD will elucidate their relevance to PTSD, particularly behaviors of associative fear learning, extinction training, and formation of false memories.

Figure 1.. Hippocampal Subfield Segmentation.

Automated segmentation of the hippocampus into 12 subfields in each hemisphere of the brain was performed with FreeSurfer v6.0. Subfield images of CA1, CA2/3, CA4, dentate gyrus, hippocampal-amygdala transition area (HATA), subiculum, tail, fissure, presubiculum, parasubiculum, molecular layer, and fimbria are shown in magnified (a) sagittal, (b) coronal, and (c) sagittal planes.

Figure 2.

The L-CA1, L-CA3, and R-CA3 residualized values for the covariates included in the regression model, which includes the ipsilateral whole hippocampal volume covariate.

Figure 3.

Results of the association between lifetime trauma exposure (TLEQ score) and subfield volumes for (A) L-CA1, (B) L-CA3, and (C) R-CA3, were weak and were not significantly different in the PTSD group (red trend line) compared to the trauma-exposed Control group (blue trend line).

Figure 4.

The results of 3D shape analysis at 2,502 vertices for PTSD < Control and PTSD > Control at the FDR corrected significance level of p < 0.2 display of (A) β-map (B) p-map.