Preface Posttraumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known, viz., an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness, or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular, and molecular levels. The present review attempts to present the current state of this understanding, based upon psychophysiological, structural and functional neuroimaging, endocrinological, genetic, and molecular biological studies in humans and in animal models.

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...

This study used quantitative volumetric magnetic resonance imaging techniques to explore the neuroanatomic correlates of chronic, combat-related posttraumatic stress disorder (PTSD) in seven Vietnam veterans with PTSD compared with seven nonPTSD combat veterans and eight normal nonveterans. Both left and right hippocampi were significantly smaller in the PTSD subjects compared to the Combat Control and Normal subjects, even after adjusting for age, whole brain volume, and lifetime alcohol consumption. There were no statistically significant group differences in intracranial cavity, whole brain, ventricles, ventricle:brain ratio, or amygdala. Subarachnoidal cerebrospinal fluid was increased in both veteran groups. Our finding of decreased hippocampal volume in PTSD subjects is consistent with results of other investigations which utilized only trauma-unexposed control groups. Hippocampal volume was directly correlated with combat exposure, which suggests that traumatic stress may damage the hippocampus. Alternatively, smaller hippocampi volume may be a pre-existing risk factor for combat exposure and/or the development of PTSD upon combat exposure.

Background-Controversy exists over the nature and origin of reduced regional brain volumes in post-traumatic stress disorder (PTSD). At issue is whether these reductions represent pre-existing vulnerability factors for developing PTSD upon traumatic exposure or acquired PTSD signs due to the traumatic stress that caused the PTSD and/or the chronic stress of having PTSD. We employed a case-control design in monozygotic twin pairs discordant for combat exposure to address the preexisting vs. acquired origin of brain morphometric abnormalities in this disorder.

Declarative memory impairment is a frequent complaint of patients suffering from posttraumatic stress disorder (PTSD). We assessed memory, attention, visual spatial skills, and executive function in Vietnam combat veterans with (n = 19) and without (n = 13) PTSD. Although PTSD subjects demonstrated a "generalized impairment" relative to non-PTSD subjects on a majority of tasks, only attention and memory provided unique and independent prediction of PTSD versus non-PTSD status. Our findings suggest that memory functioning represents a neurocognitive domain of specific relevance to the development of PTSD in trauma-exposed individuals, which can be distinguished from generalized attentional impairment as well as the effects of trauma exposure severity, IQ, comorbid depression, history of alcohol use, and history of developmental learning problems.

Neuropsychological deficits have been reported among trauma survivors with posttraumatic stress disorder (PTSD). It is often assumed that these cognitive difficulties are toxic consequences of trauma exposure. Alternatively, they may reflect preexisting characteristics that contribute to the likelihood of developing PTSD. To address this possibility, the authors evaluated cognitive performance in monozygotic twin pairs who were discordant for combat exposure. Pairs were grouped according to whether the combat-exposed brother developed PTSD. The combat-unexposed cotwins of combat veterans with PTSD largely displayed the same performance as their brothers, which was significantly lower than that of non-PTSD combat veterans and their brothers. The results support the notion that specific domains of cognitive function may serve as premorbid risk or protective factors in PTSD.

Background-A significant subgroup of individuals with posttraumatic stress disorder (PTSD) exhibits chronic, unremitting symptomatology that has also been associated with smaller hippocampal volume. The hippocampus plays a significant role in configural processing of contextual cues that facilitates context-appropriate extinction of conditioned fear. We test the hypothesis that hippocampus-based configural processing deficits are a pre-existing vulnerability factor for unremitting forms of PTSD.

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