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.Animal research has provided compelling evidence that exposure to severe and chronic stress can damage the hippocampal formation 1,2 , a region best known for its role in declarative memory 3,4 . 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 stressrelated 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 PTSD [5][6][7][8] . These results have generated intense interest Correspondence should be addressed to M.W.G. (mark.gilbertson@med.va.gov). Note: Supplementary information is available on the Nature Neuroscience website. Competing interests statementThe authors declare that they have no competing financial interests. regarding a potential pathogenesis for this disorder, and they raise the possibility that psychological trauma may in fact induce neurological damage in humans. NIH Public AccessControversy exists, however, over the nature and source of smaller hippocampal volume in PTSD 9-12 . 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 PTSD 13,14 . The National Vietnam Veterans Readjustment Study 13 , 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 behav...

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

“…106,107 However, it has been argued that smaller hippocampal volume may reflect a pre-existing vulnerability rather than resulting from the traumatic event. 108 It is believed that PTSD symptoms result from a hypoactive medial prefrontal cortex and a hyperactive amygdala, which is supported by experimental findings in animals and humans. 109 However, comparative studies are needed to determine if this imaging marker is uniquely associated with PTSD, but not with MTBI or chronic stress.…”

Neuroimaging in borderline personality disorder

“…There is an ongoing debate as to whether this volume reduction is due to an elevated activity of stress-associated neurobiological systems, such as the HPA axis or is genetically determined (Gilbertson et al, 2002). In contrast to the finding of reduced hippocampal volume, all published studies investigating amygdala volumes in patients with PTSD did not find any significant amygdala volume difference compared to controls (Bonne et al, 2001;Bremner et al, 1997;De Bellis et al, 1999;Gilbertson et al, 2002;Gurvits et al, 1996).…”

“…A major neurobiological finding of the last decade is a reduction in hippocampal volume as assessed by MR-based volumetry in combat-related (Bremner et al, 1995;Gilbertson et al, 2002;Gurvits et al, 1996) as well as abuse-related PTSD (Bremner et al, 1997;Bremner et al, 2003;Stein et al, 1997). There is an ongoing debate as to whether this volume reduction is due to an elevated activity of stress-associated neurobiological systems, such as the HPA axis or is genetically determined (Gilbertson et al, 2002).…”

“…A major neurobiological finding of the last decade is a reduction in hippocampal volume as assessed by MR-based volumetry in combat-related (Bremner et al, 1995;Gilbertson et al, 2002;Gurvits et al, 1996) as well as abuse-related PTSD (Bremner et al, 1997;Bremner et al, 2003;Stein et al, 1997). There is an ongoing debate as to whether this volume reduction is due to an elevated activity of stress-associated neurobiological systems, such as the HPA axis or is genetically determined (Gilbertson et al, 2002). In contrast to the finding of reduced hippocampal volume, all published studies investigating amygdala volumes in patients with PTSD did not find any significant amygdala volume difference compared to controls (Bonne et al, 2001;Bremner et al, 1997;De Bellis et al, 1999;Gilbertson et al, 2002;Gurvits et al, 1996).…”

Anxiety and Hippocampus Volume in the Rat

“…Hippocampal volume is reduced in patients with longstanding depression (Campbell et al, 2004;Videbech and Ravnkilde, 2004) and severe, unremitting post-traumatic stress disorder (PTSD; Bremner et al, 1995Bremner et al, , 1997Gilbertson et al, 2002;Gurvits et al, 1996;Lindauer et al, 2004;Stein et al, 1997;Villarreal et al, 2002).…”