Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder

Abstract

Background: Controversy exists over the nature and origin of reduced regional brain volumes in posttraumatic stress disorder (PTSD). At issue is whether these reductions represent preexisting vulnerability factors for developing PTSD upon traumatic exposure or acquired PTSD signs due to the traumatic stress that caused the PTSD or the chronic stress of having the disorder (or both). We employed a case-control design in monozygotic twin pairs discordant for combat exposure to address the preexisting versus acquired origin of brain morphometric abnormalities in PTSD.

Methods: We used voxel-based morphometry to search for gray matter density reductions in magnetic resonance imaging (MRI) data obtained in a previous study of combat-exposed Vietnam veteran twins with (n = 18) versus without (n = 23) PTSD and their "high-risk" versus "low-risk" (respectively) identical combat-unexposed cotwins.

Results: Compared with the combat-exposed twins without PTSD, the combat-exposed twins with PTSD showed significant gray matter density reductions in four predicted brain regions: right hippocampus, pregenual anterior cingulate cortex (ACC), and left and right insulae. There was a significant PTSD Diagnosis x Combat Exposure interaction in pregenual ACC in which combat-exposed PTSD twins had lower gray matter density than their own combat-unexposed cotwins as well as than the combat-exposed twins without PTSD and their cotwins.

Conclusions: The results point to gray matter volume diminutions in limbic and paralimbic structures in PTSD. The pattern of results obtained for pregenual ACC suggests that gray matter reduction in this region represents an acquired sign of PTSD consistent with stress-induced loss.

Figure 1. Brain regions showing diminution in gray matter density in combat-exposed twins with PTSD versus without PTSD

A.) SPM analysis with 4-mm Gaussian smoothing kernel revealed statistically significant reduced gray matter density shown in the axial projection. A-1.) Regional gray matter density reduction in the right hippocampus is rendered onto orthogonal slices of the averaged magnetic resonance image of the present study’s subjects. B.) SPM analysis with 12-mm Gaussian smoothing kernel revealed statistically significant reduced gray matter density shown in the axial projections. Regional gray matter density reductions in the following areas are rendered: B-1.) Pregenual anterior cingulate cortex; B-2.) Left insula; B-3.) Right insula. Abbreviations: L: left hemisphere, R: right hemisphere, ACC: anterior cingulate cortex.

Figure 2. Brain region showing PTSD Diagnosis × combat Exposure interaction

Regional interaction for gray matter density in pregenual anterior cingulate cortex is rendered onto orthogonal slices of the averaged magnetic resonance image of the present study’s subjects. Cross hairs indicate the peak coordinate of the interaction ([ 8 50 12]). Abbreviations: L: left hemisphere, R: right hemisphere.

Figure 3. Scatterplots of individual subjects’ adjusted VBM responses

Shown at the site of the PTSD Diagnosis × Combat Exposure interaction in pregenual anterior cingulate cortex ([ 8 50 12]). Means are represented by solid horizontal lines drawn on each group’s distribution.