Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma

Abstract

In animals, exposure to severe stress can damage the hippocampus. Recent human studies show smaller hippocampal volume in individuals with the stress-related psychiatric condition posttraumatic stress disorder (PTSD). Does this represent the neurotoxic effect of trauma, or is smaller hippocampal volume a pre-existing condition that renders the brain more vulnerable to the development of pathological stress responses? In monozygotic twins discordant for trauma exposure, we found evidence that smaller hippocampi indeed constitute a risk factor for the development of stress-related psychopathology. Disorder severity in PTSD patients who were exposed to trauma was negatively correlated with the hippocampal volume of both the patients and the patients' trauma-unexposed identical co-twin. Furthermore, severe PTSD twin pairs-both the trauma-exposed and unexposed members-had significantly smaller hippocampi than non-PTSD pairs.

Fig. 1

Discordant monozygotic twin paradigm for assessing MRI differences in PTSD. Sample coronal MRI images of right (red) and left (blue) hippocampi in a PTSD and a non-PTSD twin pair. Images represent four subject groups: (1) combat-exposed (Ex) subjects who developed chronic PTSD (ExP+); (2) their combat-unexposed (Ux) co-twins with no PTSD themselves (UxP+); (3) Ex subjects who never developed PTSD (ExP−) and (4) Ux co-twins also with no PTSD (UxP−). Contrast (a) provides a replication of previous work demonstrating smaller hippocampal volumes in combat veterans with versus without PTSD. Contrast (b) identifies the neurotoxicity effect—hippocampal reduction—as environmentally acquired, by contrasting hippocampal volumes in combat-exposed PTSD veterans with their unexposed co-twins. Contrast (c) examines pre-existing vulnerability by contrasting hippocampal volumes in the two groups of combat-unexposed co-twins whose combat-exposed brothers did versus did not develop PTSD. Model is tested by a diagnosis (P+ versus P−) × exposure (Ex versus Ux) ANOVA. Diagnosis refers to combat-exposed twin only. If hippocampal volume represents a vulnerability factor, the model predicts a significant main effect of diagnosis in the absence of a diagnosis × exposure interaction (that is, PTSD combat-exposed veterans and their unexposed co-twins show the same pattern). If hippocampal reduction results from neurotoxicity, the model predicts a significant main effect of exposure and/or a significant diagnosis × exposure interaction.

Fig. 2

Hippocampal volume correlations with post-trauma symptoms. Scatter plots illustrate relationship of symptom severity in combat veterans with PTSD to: (a) their own hippocampal volumes and (b) the hippocampal volumes of their identical twin brothers who were not exposed to combat. Symptom severity represents the total score received on the Clinician-Administered PTSD Scale (CAPS).

Fig. 3

Total hippocampal volumes for four subject groups. Scatter plot illustrates absolute hippocampal volumes (ml) for combat-exposed individuals with and without PTSD, as well as for their respective unexposed co-twins. Data are only presented for PTSD twin pairs in which the combat-exposed twin had a CAPS score >65.