Hippocampal Volumes in Patients With Chronic Combat-Related Posttraumatic Stress Disorder: A Systematic Review

We used the PubMed database to search for the term PTSD in combination with any of the following terms: physical changes, neuroanatomical, frontal, parietal, temporal, hippocampal, cortical, prefrontal, amygdala, and locus coeruleus. The literature search extended to 08/11/2011 (range: earliest returned article, 1966 – latest returned article, 2011), and the articles produced for each of the above search combinations were merged to form a catalog of 1,084 articles. This initial query was filtered by including only human adult (age 19+ years) studies published in English (488 articles).

The resulting collection of articles was then reviewed for focus, demographics, and duration of PTSD by researcher personnel (JC). Each study had to 1) be an original study; 2) investigate structural neuroanatomy; 3) use veterans with chronic CR-PTSD, defined as PTSD of ≥6 months’ duration resulting from trauma in combat; and 4) compare the veteran group with a control group. This process produced 22 articles^18–39 that covered 21 cross-sectional studies^18–38 and one longitudinal study.³⁹ The bibliographies of these 22 articles were searched to identify relevant studies not captured by our search net, but none were identified (Figure 1).

Of the 1,084 articles initially reviewed, 22 studies^18–39 were found to meet all of our inclusion criteria and were assigned a quality score (QS). These resulting articles were all magnetic resonance imaging (MRI) studies. All significant results were then sorted by QS and included in the attached tables. See Table 1 for a list of brain regions and QS differences between positive and negative studies. Table 2, Table 3, Table 4, and Table 5 include the significant results pertaining to specific brain anatomical regions.

In the 22 studies reviewed, the most frequently cited neuroanatomical differences found in patients with chronic CR-PTSD were in the hippocampus, involving either smaller total or right hippocampal volumes. Although volumetric differences were reported in other regions, including the frontal cortex, temporal cortex, and ACC, the findings for these areas were less conclusive and preclude a firm conclusion.

The reductions in hippocampal volume observed in these studies offer a potential explanation for the increased rates of dementia we and others observe in veterans with chronic CR-PTSD.^14,15 Dementia is a loss of cognitive faculties in a person who was previously cognitively normal. Its etiologies include neurodegenerative disorders such as AD and Lewy-body dementia. AD, in particular, is associated with reduced hippocampal volumes. In a metaanalysis of potential neurostructural predictors for the progression from mild cognitive impairment (MCI) to AD, volume reductions in the hippocampus and parahippocampal gyrus were the most consistent predictors of conversion from MCI to AD.⁴⁵ One could hypothesize that the smaller hippocampal volumes in chronic CR-PTSD noted in the studies reviewed here would put patients at greater risk for AD.

However, two of the reviewed studies suggest a different interpretation. The sole longitudinal study³⁹ did not find increased hippocampal atrophy rates in PTSD patients, suggesting that the PTSD disease process does not lead to reduced hippocampal volumes. Accordingly, it is possible that smaller hippocampal volumes pre-dated the traumatic event, in which case reduced hippocampal volume could, in fact, be a risk for PTSD. Indeed, a twin study on CR-PTSD appears to also support this interpretation. Gilbertson et al.²¹ compared two types of monozygotic twin pairs: 1) combat veterans with CR-PTSD and their non-combat twins; and 2) combat veterans without PTSD and their non-combat twins. Hippocampal size correlated well between twin brothers; moreover, both the CR-PTSD veterans and their twins had smaller hippocampi than the combat veterans who never developed PTSD. This study, too, suggests that smaller hippocampi may be a risk factor for CR-PTSD. Together, these findings support the hypothesis that reduced hippocampal volumes are a risk factor for PTSD and AD, rather than one causing the other.

Nevertheless, these data are not definitive because other potential mechanisms may play a role. In one study, the hippocampal volumes of recent trauma-exposed individuals (within 1 week) did not differ in those who would subsequently develop PTSD at a 6-month follow-up assessment, as compared with those who would not develop such symptoms.⁴⁶ Also, if the hippocampal volumes were entirely determined by genetic predisposition, the Gilbertson et al.²¹ data should show hippocampal differences between the CR-PTSD+ and CR-PTSD− veterans mirroring the differences between the non-combat individuals. In fact, whereas the difference in total hippocampal volume was significant between the veteran groups, the difference between the non-veteran groups was not significant, which suggests that an additional environmental factor may play a role in the volumetric differences.

Concerning the negative studies included in this review, two reported no significant results in their respective regions of interest.^29,32 One study³² found slightly reduced, but nonsignificant, right hippocampal volume reductions in PTSD veterans versus normal controls; however, they did show reduced N-acetylaspartate (NAA) levels, a marker of neuronal integrity, in the right hippocampus nearly meeting significance levels (p=0.06). Importantly, the small sample size (N: 7 PTSD+; N: 7 PTSD−) represents a notable limitation in this study, and the study received a QS rating of 0 for the purposes of this review. Similarly, a second study²⁹ found no differences between veterans with PTSD and veterans without PTSD in hippocampal or entorhinal cortical volumes, but did find significant bilateral reductions in NAA density (Left: p=0.019; Right: p=0.012) in the PTSD cohort. Notably, in their linear-regression models, further accounting for left hippocampal and entorhinal cortical volumes accounted for 15.3% of incremental variance (p=0.023). Although these two studies failed to report associations between PTSD and reduced hippocampal volumes, they do provide evidence that PTSD effects on hippocampal neuronal integrity represent either a plausible risk factor or potential modifier for subsequent dementia.

Clearly, more longitudinal studies are needed to differentiate between these hypotheses and to determine whether treating PTSD reduces the risk of subsequent dementia. If reduced hippocampal volume is a risk for both, then treating PTSD will not prevent dementia. Clinicians would instead focus on early detection and treatment of dementia in those with PTSD.

Our review has certain limitations. Like all reviews, our results are limited by the “file-drawer” problem, the idea that researchers may not report or publish negative results.⁴⁷ Also, we only examined studies that were published in English, which reduces the number of studies meeting our methodological criteria. The imaging methodologies of the studies included (e.g., strength of the MRI field, thickness of structural slices, interrater reliability for morphometry, preprocessing/enhancement of images, and delineation of anatomical landmarks) were not consistent, and, in general, studies were inconsistent with regard to the quality of their confirmation of PTSD diagnosis and exclusion/inclusion criteria, as well as types and severity of both the severity of the experienced trauma and PTSD symptomatology. Moreover, there may be differences between studies in the veterans’ experiences of war and combat-related trauma, such as differences related to the particular combat in which they were involved and the evolution of warfare. Most studies also differed with regard to controlling for associated disorders, such as severe depression and alcohol abuse, both of which are frequently concomitant with PTSD and have been shown to reduce hippocampal volume.^48–52 Some studies were also performed by the same authors over time, which could potentially introduce bias. Certain premorbid factors, such as previous trauma exposure, including both adult and early-life stress, or preexisting psychiatric/neurological disorders, may influence PTSD development^53–55 but were not consistently controlled for in the studies reviewed. Also, this review was unable to control for presence of traumatic brain injury (TBI). Over 40% of returning U.S. Iraqi veterans with mild TBI met PTSD criteria,⁵⁶ whereas lower, but still significant, correlations appear between PTSD and severe TBI.^57,58 These associations are significant, as TBI has also been shown to be a risk factor for dementia in two large veteran cohorts.^59,60 Finally, this review focused on studies evaluating veterans with combat-related PTSD, including studies primarily or exclusively using male subjects; therefore, these results may not be directly applicable to female veterans with PTSD or civilian PTSD populations.

Most studies reviewed suggest that the hippocampi are smaller in veterans with chronic CR-PTSD. However, it is unclear whether smaller hippocampi are a risk factor for the development of PTSD or they are the result of chronic PTSD. In either event, smaller hippocampi may explain the increase in dementia that we and others have observed in chronic CR-PTSD.^14,15

The implications are important: if smaller hippocampi are a pre-existing risk factor for PTSD, imaging them could serve as an important tool in identifying military personnel vulnerable to developing PTSD after combat exposure. Perhaps their combat experiences could be tailored to prevent PTSD. Moreover, smaller hippocampi would suggest that older veterans with PTSD should be screened more regularly for cognitive changes.

The views expressed reflect those of the authors and do not necessarily represent those of the Department of Veterans Affairs, Baylor College of Medicine, and/or UTHealth.