The present study found diminished left and right hippocampal volume in PTSD combat veteran subjects in comparison to both combat and noncombat control subjects. These results remained significant after statistically adjusting for age, total brain volume, lifetime months of excessive drinking, and, for left hippocampus, severity of combat exposure. This finding supplements previous evidence of neurologic compromise in PTSD. It is also consistent with other findings of diminished hippocampal volume in subjects with PTSD resulting from combat in Vietnam (Bremner et al 1995a
) and child abuse (Bremner et al 1995b
; Stein et al 1995
) in comparison only to nontrauma exposed control subjects. The 26% total hippocampal diminution in the present study was manifest bilaterally and larger than the percent diminutions described in other studies. This may in part be accounted for by the greater resolution afforded by the larger number of thinner MRI slices employed, and the greater extent of hippocampal structure measured, in the present study.
Results of the present study present modest evidence of an association between hippocampal volume reduction and impaired memory functioning, e.g., in the correlation between hippocampal volume and delayed recall errors.
The present investigation suffers from limitations typical of pilot studies of this nature. Subjects from the different groups were not intermingled in the MRI analyses, so the possibility of subtle methodologic differences between groups cannot be excluded. Sample sizes were small, and the groups were imperfectly matched on age and past alcohol abuse, although when statistically controlled, group differences on these factors did not account for the significantly smaller hippocampi in the PTSD subjects. Furthermore, the credibility of this finding is heightened by its convergence with the results of three other investigations performed in two other laboratories. Nevertheless, replication of the present results is called for in a larger, more carefully controlled study. The greater volume of cerebrospinal fluid in both the PTSD and combat control subjects relative to the normal nonveteran subjects may at least partially have resulted from greater age and past alcohol use.
Additional studies are also required to test the anatomic specificity of lower hippocampal volume in PTSD. The present study included only one comparison structure, viz., amygdala. Bremner et al (1995a)
compared hippocampus with caudate nucleus and temporal lobe. Although only the right hippocampus was found to be significantly smaller in the PTSD subjects, its differential reduction over the comparison structures was less apparent when expressed in percentage terms than in terms of statistical effect size. Stein et al (1995)
did not measure any comparison brain structures. It remains to be investigated whether the volume of other structures, e.g., the frontal lobes, may also be lower in PTSD.
In light of the strong negative correlation between severity of past combat exposure and hippocampal volume, a straightforward interpretation of the results of the present study is that the severe stress of military combat both damages the hippocampus and causes PTSD. This conclusion would bring the present findings in line with those from studies indicating that stress and glucocorticoids damage the rodent and primate hippocampus. Bremner et al (1995a)
did not find a significant correlation between hippocampal volume and combat exposure within the PTSD veterans they studied. However, the power to detect such a correlation in that study may have been reduced by the smaller decreases in hippocampal volume that were observed, and by a narrower range of combat exposure scores due to the absence of a nonPTSD combat control group.
There are, however, at least three alternative explanations for the association between combat exposure and smaller hippocampi found here. First, it may be that this relationship is not directly causal but rather results from the association of both these variables with a third factor, i.e., PTSD. Indeed, the correlation between combat exposure and hippocampal volume lost its significance after adjusting for PTSD severity. This makes sense, because a psychologic stressor can only impact on the organism insofar as it induces a stress response. It may be that combat stress causes PTSD, and PTSD, and/or its biopsychosocial concomitants, causes shrinkage of the hippocampus.
Second, it is possible that diminished hippocampal volume represents a risk factor for exposure to combat. In this regard, the history of significantly more precombat enuresis, and the nonsignificant trends toward more delayed walking/talking, attention deficit, and learning difficulties, in the PTSD subjects, is worth noting. In a previous neuropsychiatric study of PTSD, Gurvits et al (1993)
also found evidence of pretrauma, neurodevelopmental impairment in PTSD Vietnam veterans. Individuals with neurodevelopmental impairment, possibly including smaller hippocampi, may be less likely to be assigned to higher-skill military occupational specialties that isolate them from combat as opposed to infantry or other high-combat units.
Third, low hippocampal volume may represent a precombat vulnerability factor for the development of PTSD upon combat exposure. Theoretically, this possibility would not predict a statistical association between combat exposure and decreased hippocampal volume; however, if precombat vulnerability, manifest (among other things) in smaller hippocampi on the one hand, and high combat exposure on the other hand, were independently to increase the likelihood of PTSD, the selective recruiting of PTSD subjects in the present study might have led to a spurious, i.e., noncausal, association between combat exposure and hippocampal volume. Such an explanation could potentially be disproven in a study that selected subjects independent of PTSD status. Although no such study has yet been undertaken in combat veterans, Stein et al (1995)
selected their subjects on the basis of a history of exposure vs. no exposure to child abuse, irrespective of PTSD. Thus their finding of smaller hippocampi in the exposed group is supportive of a causal relationship between traumatic exposure and hippocampal reduction.
The ultimate test of whether combat, or any other traumatic exposure, causes hippocampal damage, must be a prospective study employing a within subjects, repeated measures design that examines the development of de novo
hippocampal reduction, and possibly PTSD, following exposure to traumatic stress. Meanwhile, animal studies indicate that stress and steroid induced hippocampal damage may be prevented by the administration of certain pharmacologic agents, e.g., phenytoin (Watanabe et al 1992a
) or tianeptine (Watanabe et al 1992b
). Should it be established that traumatic stress does indeed damage the human hippocampus, these animal findings raise the intriguing possibility of secondary, i.e., posttraumatic event, pharmacologic prevention of hippocampal damage and possibly PTSD.