Consistent with previous reports5–8
, we found smaller hippocampal volume in trauma-exposed persons diagnosed with more severe, unremitting PTSD. The finding of a 10% difference in total hippocampal volume between individuals with versus without PTSD is in line with previously reported volumetric differences, as is the finding of predominantly right hippocampal differences5,19,20
The key finding here concerns the identical twins of the higher-severity PTSD combat veterans who were not themselves exposed to combat; they showed hippocampal volumes that were comparable to their combat-exposed brothers but significantly smaller than those of combat veterans without PTSD and their non-combat–exposed twins. These data indicate that smaller hippocampi in PTSD represent a pre-existing, familial vulnerability factor rather than the neurotoxic product of trauma exposure per se. Further support for this conclusion comes from the highly significant correlation that we found between the hippocampal volume of combat-unexposed co-twins and the PTSD severity of their combat-exposed brothers. The high concordance of hippocampal volume within twin pairs, as well as the lack of a significant combat exposure effect or diagnosis × exposure interaction in our statistical model, provide clear evidence against the neurotoxicity hypothesis, as monozygotic co-twins provide the ideal biological control for detecting exposure-based differences. In light of the current findings, reference to hippocampal ‘atrophy’ in PTSD may be a misnomer.
We have also addressed the potential impact of confounding factors in the interpretation of hippocampal volume differences. In most non-twin studies, the presence of comorbid conditions precludes clear attribution of biological alterations to the psychiatric condition of PTSD alone. Most notably, major depression and alcohol abuse constitute comorbid conditions with high prevalence rates in PTSD21
that could ostensibly also influence hippocampal volume22–25
. Although previous studies have attempted to statistically control for such confounds, the controls can still be unsound if the covariate differs between groups26
. If alcohol abuse and depression are secondary consequences of more severe PTSD, the effect of ‘controlling for’ these variables may simply be to remove variance associated with more severe PTSD. Our study design uniquely circumvented these difficulties. Specifically, the PTSD combat veterans with smaller hippocampi predictably showed higher rates of major depression and more severe alcohol histories, but their combat-unexposed twin brothers, who showed comparably small hippocampi, did not. These results effectively exclude these comorbid conditions as a source of hippocampal volume differences in PTSD. Moreover, the association of hippocampal volume with PTSD remained significant after adjusting for combat severity, which in this study was not significantly associated with hippocampal volume. This argues against the possibility that subjects with smaller hippocampi were more likely to be selected for high combat roles. These data do not counter the idea that more severe combat exposure results in more severe PTSD; rather, they suggest hippocampal volume to be a predictor of PTSD severity independent of combat severity.
A limitation of the present study relates to the fact that hippocampal differences, as revealed by structural MRI, may not apply to all populations of individuals diagnosed with PTSD. More specifically, pre-existing decreased hippocampal volume may only be related to severe and unremitting forms of post-traumatic stress responses. All studies to date that have found smaller hippocampal volume in PTSD, including the findings reported here, have involved individuals with chronic, unremitting forms of the disorder; that is, intense symptoms which persist for years, and in many cases, decades. In fact, group differences in hippocampal volume only emerged in our sample when we examined PTSD individuals with a CAPS symptom severity score above 65. Failures to replicate findings of reduced hippocampal volume in PTSD have typically been reported in studies that involved subjects with PTSD of lower severity and/or shorter duration27–29
. Over 40% of those diagnosed with PTSD show remission within the first year after traumatic exposure30,31
, with a continued, more gradual remission rate for approximately six years14
. Such individuals may clearly differ from those who develop long-standing, unremitting posttraumatic symptoms.
Hippocampal morphology and function have been implicated in conditioning and extinction of fear responses in animals, and may be involved in the contextual processing of fear32,33
. Rodents with hippocampal lesions show stronger conditioned fear, as evidenced by more rapid acquisition of an avoidance response to an auditory cue paired with shock, as well as more fear behavior following acquisition, than do non-lesioned animals34,35
. Similar alterations in fear-mediated performance have also been shown in mice with genetically smaller hippocampi15–17
. Smaller hippocampal volume may also predispose an animal to diminished neuroendocrine regulation of the hypothalamic–pituitary–adrenal axis, as has been shown in monkeys who inherit smaller hippocampi and respond to stressful rearing conditions with larger cortisol elevations18
. As a vulnerability factor for PTSD, smaller hippocampal volume might therefore predispose individuals to acquire stronger and/or more persistent conditioned emotional responses, or stronger hormonal stress responses, when exposed to a traumatic event36
Heredity is the most likely explanation for the origin of the smaller hippocampi observed in PTSD combat veterans and their twins in this study18,37–40
. In the absence of dizygotic twin subjects, however, the effects of heredity could not be separated from those of shared environment. We did find a non-significant trend for P+ pairs to share higher rates of childhood abuse, but this did not account for the observed hippocampal differences. Additionally, unexposed co-twins of PTSD veterans did not share with their brothers a general increase in lifetime number of reported non-combat trauma or stressor incidents, further diminishing the relevance of shared environment. Moreover, any stress-based interpretation of the smaller hippocampal volume observed in the combat-unexposed co-twins of the PTSD veterans would need to explain why the extra stress of military combat and consequent PTSD did not exert any further reduction in hippocampal volume in the PTSD veterans. Indeed, the finding that individuals who were exposed to combat, but did not develop PTSD, had larger hippocampi than individuals who were not exposed to combat but were merely the brothers of combat veterans with PTSD argues strongly against a stress–neurotoxic interpretation of the hippocampal diminution. Nevertheless, further research that includes dizygotic twin pairs is needed to tease apart the contributions of genetics and shared environment to smaller hippocampi in PTSD.