Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma

Mark Gilbertson

Martha Shenton

Aleksandra Ciszewski

Kiyoto Kasai

Natasha Lasko

Scott Orr

Roger Pitman

^{Research Service, Veterans Administration Medical Center, 718 Smyth Road, Manchester, New Hampshire 03104, USA}

^{Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA}

^{Psychiatry Service, Veterans Administration Boston Healthcare System, Brockton, Massachusetts 02301, USA}

^{Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA}

^{Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02129, USA}

Correspondence should be addressed to M.W.G. (vog.av.dem@nostreblig.kram)

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.

Abstract

Animal research has provided compelling evidence that exposure to severe and chronic stress can damage the hippocampal formation¹2, a region best known for its role in declarative memory³4. Such studies point to a neurotoxic role for corticosteroids, elevated levels of which cause atrophy and/or cell death in hippocampal neurons. This has led to the proposal that a similar process may occur in humans, and thereby mediate specific stress-related disease processes. Of particular relevance is the psychiatric condition of posttraumatic stress disorder (PTSD), a constellation of disabling behavioral and emotional symptoms that occur in some individuals who experience severe psychological trauma such as combat, sexual abuse or natural disaster. Indeed, several structural magnetic resonance imaging (MRI) studies report smaller hippocampal volume in patients diagnosed with chronic, unremitting forms of PTSD⁵8. These results have generated intense interest regarding a potential pathogenesis for this disorder, and they raise the possibility that psychological trauma may in fact induce neurological damage in humans.

Controversy exists, however, over the nature and source of smaller hippocampal volume in PTSD⁹12. The fundamental question at the heart of this controversy is whether volumetric differences represent the consequence of traumatic exposure or a pre-existing trait that predisposes people to pathological stress reactions to a traumatic event. This latter formulation is consistent with the fact that only some individuals exposed to trauma go on to develop PTSD¹³14. The National Vietnam Veterans Readjustment Study¹³, for example, has estimated the prevalence of PTSD in Vietnam combat veterans to be 30.6%. Furthermore, animal research shows that inherited variations in hippocampal size can influence behavioral outcomes in stress-mediated conditioning procedures¹⁵17 and can alter neuroendocrine responses to stress¹⁸. To date, there have been no human studies that directly address this important controversy.

In the present study, we used a ‘case-control’ design (Fig. 1) to examine samples of male monozygotic twin pairs in which one twin was a Vietnam combat veteran (exposed, Ex) and his identical co-twin had no combat exposure (unexposed, Ux). In some twin pairs, the combat-exposed brother developed chronic PTSD, whereas in other twin pairs the combat veteran never developed PTSD. Based on the diagnosis of the combat-exposed brother, we classified twin pairs into two groups: PTSD (P+) and non-(that is, never had) PTSD (P−). The P+ or P− designation always refers to the combat-related PTSD status of the exposed twin (no unexposed twin in this study had PTSD). Because monozygotic twins are genetically identical, any differences in hippocampal volume between brothers were interpreted as evidence for environmental effects, such as stress-induced neurotoxicity. Alternatively, any differences in hippocampal volume between the unexposed brothers of PTSD combat veterans (UxP+) versus the unexposed brothers of non-PTSD combat veterans (UxP−) were taken as evidence for a pre-existing trait. Amygdala and total brain volume served as controls. Our results indicate that smaller hippocampal volume constitutes a pre-existing vulnerability factor for pathological response to stress.

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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.

Footnotes

Note: Supplementary information is available on the Nature Neuroscience website.

Competing interests statement

The authors declare that they have no competing financial interests.

Footnotes

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