Greater avoidance behavior in individuals with posttraumatic stress disorder symptoms.

While avoidance is a core symptom of PTSD, little is known about whether individuals with PTSD show a general cognitive bias to acquire and express avoidance, in situations not related to trauma or fear. Here, we used a computer-based task to examine operant acquisition and extinction of avoidance in participants with and without severe self-reported PTSD symptoms. A total of 119 participants (77 male, 42 female; 74 veteran, 45 civilian) with symptoms (PTSS; n = 63) or with few/no symptoms (noPTSS; n = 56) performed a task, in which they controlled a spaceship and could shoot a target to gain points or hide in "safe areas" to escape or avoid on-screen aversive events. Results show that participants with PTSS exhibited more avoidance across trials than noPTSS participants, particularly due to more avoidance behavior in PTSS females compared to noPTSS females. Avoidance behavior decreased across extinction trials but interactions with PTSS and gender fell short of significance. Overall, PTSD symptoms were associated with propensity to acquire and express avoidance behavior, in both civilians and veterans, and even in a cognitive task that does not explicitly involve trauma or fear. This effect was more pronounced in females, highlighting the role of gender differences in PTSD symptomatology. Importantly, this study also demonstrates the potential of an objective assessment of avoidance behavior, which could be used to supplement the common but limited self-report tools.

Post-traumatic stress disorder symptom burden and gender each affect generalization in a reward- and punishment-learning task.

Post-traumatic stress disorder (PTSD) can develop following exposure to a traumatic event. Re-experiencing, which includes intrusive memories or flashbacks of the trauma, is a core symptom cluster of PTSD. From an associative learning perspective, this cluster may be attributed to cues associated with the trauma, which have come to elicit symptoms in a variety of situations encountered in daily life due to a tendency to overgeneralize. Consistent with this, prior studies have indicated that both individuals with clinically diagnosed with PTSD, and those with self-reported symptoms who may not meet full diagnostic criteria, show changes in generalization. Building on prior research, the current study examined whether PTSD symptom burden, but also gender, veteran status, and combat experience-all associated with PTSD vulnerability-modulate learning and generalization in a computer-based task. Participants were presented with stimulus compounds consisting of a foreground and background that could be predictive of reward, punishment or no outcome. Learning was followed by a generalization test where these components were recombined to form novel configurations. An interaction between PTSD symptom burden and gender was found where females with more severe PTSD symptoms showed no evidence of sensitivity to the background. This result is consistent with increased generalization, and may indicate a decrease in the ability to process cue configurations leading to re-experiencing in a variety of situations. Further work is indicated to help elucidate the cognitive processes driving gender differences that may confer vulnerability to PTSD.

Beyond symptom self-report: use of a computer "avatar" to assess post-traumatic stress disorder (PTSD) symptoms.

Post-traumatic stress disorder (PTSD) can occur in the wake of exposure to a traumatic event. Currently, PTSD symptoms are assessed mainly through self-report in the form of questionnaire or clinical interview. Self-report has inherent limitations, particularly in psychiatric populations who may have limited awareness of deficit, reduced attention span, or poor vocabulary and/or literacy skills. Diagnosis and evaluation of treatment efficacy would be aided by behavioral measures. A viable alternative may be virtual environments, in which the participant guides an on-screen "avatar" through a series of onscreen events meant to simulate real-world situations. Here, a sample of 82 veterans, self-assessed for PTSD symptoms was administered such a task, in which the avatar was confronted with situations that might evoke avoidant behavior, a core feature of PTSD. Results showed a strong correlation between PTSD symptom burden and task performance; in fact, the ability to predict PTSD symptom burden based on simple demographic variables (age, sex, combat exposure) was significantly improved by adding task score as a predictor variable. The results therefore suggest that virtual environments may provide a new way to assess PTSD symptoms, while avoiding at least some of the limitations associated with symptom self-report, and thus might be a useful complement to questionnaire or clinical interview, potentially facilitating both diagnosis and evaluation of treatment efficacy.

Increased generalization of learned associations is related to re-experiencing symptoms in veterans with symptoms of post-traumatic stress.

One interpretation of re-experiencing symptoms in post-traumatic stress disorder (PTSD) is that memories related to emotional information are stored strongly, but with insufficient specificity, so that stimuli which are minimally related to the traumatic event are sufficient to trigger recall. If so, re-experiencing symptoms may reflect a general bias against encoding background information during a learning experience, and this tendency might not be limited to learning about traumatic or even autobiographical events. To test this possibility, we administered a discrimination-and-transfer task to 60 Veterans (11.2% female, mean age 54.0 years) self-assessed for PTSD symptoms in order to examine whether re-experiencing symptoms were associated with increased generalization following associative learning. The discrimination task involved learning to choose the rewarded object from each of six object pairs; each pair differed in color or shape but not both. In the transfer phase, the irrelevant feature in each pair was altered. Regression analysis revealed no relationships between re-experiencing symptoms and initial discrimination learning. However, re-experiencing symptom scores contributed to the prediction of transfer performance. Other PTSD symptom clusters (avoidance/numbing, hyperarousal) did not account for significant additional variance. The results are consistent with an emerging interpretation of re-experiencing symptoms as reflecting a learning bias that favors generalization at the expense of specificity. Future studies will be needed to determine whether this learning bias may pre-date and confer risk for, re-experiencing symptoms in individuals subsequently exposed to trauma, or emerges only in the wake of trauma exposure and PTSD symptom development.

Acquired equivalence in U.S. veterans with symptoms of posttraumatic stress: reexperiencing symptoms are associated with greater generalization.

The severity and number of reexperiencing symptoms (e.g., flashbacks) show considerable variability across individuals with posttraumatic stress disorder (PTSD). One interpretation of reexperiencing symptoms invokes generalization: Specifically, the traumatic memory may be stored in such a way that neutral stimuli that only vaguely resemble some feature of the traumatic event are sufficient to trigger the memory. If this is the case, then individuals with higher levels of reexperiencing symptoms might show greater generalization, even in contexts unrelated to trauma. In the current study, an acquired equivalence test was used to assess associative learning and generalization in 114 U.S. veterans who were also given a test of declarative memory. PTSD symptoms were rated by the veteran. After adjusting for demographic variables, psychoactive medication use, and initial learning, regression analyses showed that the number of PTSD reexperiencing symptoms significantly improved the model for generalization (ß = -.23, R(2) = .34) but not associative learning or declarative memory. The results support the idea that generalization is linked to reexperiencing symptoms, is not limited to learning about traumatic events, and can emerge even in a relatively innocuous computer-based learning task.

Learning to obtain reward, but not avoid punishment, is affected by presence of PTSD symptoms in male veterans: empirical data and computational model.

Post-traumatic stress disorder (PTSD) symptoms include behavioral avoidance which is acquired and tends to increase with time. This avoidance may represent a general learning bias; indeed, individuals with PTSD are often faster than controls on acquiring conditioned responses based on physiologically-aversive feedback. However, it is not clear whether this learning bias extends to cognitive feedback, or to learning from both reward and punishment. Here, male veterans with self-reported current, severe PTSD symptoms (PTSS group) or with few or no PTSD symptoms (control group) completed a probabilistic classification task that included both reward-based and punishment-based trials, where feedback could take the form of reward, punishment, or an ambiguous "no-feedback" outcome that could signal either successful avoidance of punishment or failure to obtain reward. The PTSS group outperformed the control group in total points obtained; the PTSS group specifically performed better than the control group on reward-based trials, with no difference on punishment-based trials. To better understand possible mechanisms underlying observed performance, we used a reinforcement learning model of the task, and applied maximum likelihood estimation techniques to derive estimated parameters describing individual participants' behavior. Estimations of the reinforcement value of the no-feedback outcome were significantly greater in the control group than the PTSS group, suggesting that the control group was more likely to value this outcome as positively reinforcing (i.e., signaling successful avoidance of punishment). This is consistent with the control group's generally poorer performance on reward trials, where reward feedback was to be obtained in preference to the no-feedback outcome. Differences in the interpretation of ambiguous feedback may contribute to the facilitated reinforcement learning often observed in PTSD patients, and may in turn provide new insight into how pathological behaviors are acquired and maintained in PTSD.

A model of amygdala-hippocampal-prefrontal interaction in fear conditioning and extinction in animals.

Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus in classical conditioning to include interactions with the amygdala and prefrontal cortex. We apply the model to fear conditioning, in which animals learn physiological (e.g. heart rate) and behavioral (e.g. freezing) responses to stimuli that have been paired with a highly aversive event (e.g. electrical shock). The key feature of our model is that learning of these conditioned responses in the central nucleus of the amygdala is modulated by two separate processes, one from basolateral amygdala and signaling a positive prediction error, and one from the vmPFC, via the intercalated cells of the amygdala, and signaling a negative prediction error. In addition, we propose that hippocampal input to both vmPFC and basolateral amygdala is essential for contextual modulation of fear acquisition and extinction. The model is sufficient to account for a body of data from various animal fear conditioning paradigms, including acquisition, extinction, reacquisition, and context specificity effects. Consistent with studies on lesioned animals, our model shows that damage to the vmPFC impairs extinction, while damage to the hippocampus impairs extinction in a different context (e.g., a different conditioning chamber from that used in initial training in animal experiments). We also discuss model limitations and predictions, including the effects of number of training trials on fear conditioning.

The relationship between Hippocampal asymmetry and working memory processing in combat-related PTSD - a monozygotic twin study.

BACKGROUND: PTSD is associated with reduction in hippocampal volume and abnormalities in hippocampal function. Hippocampal asymmetry has received less attention, but potentially could indicate lateralised differences in vulnerability to trauma. The P300 event-related potential component reflects the immediate processing of significant environmental stimuli and has generators in several brain regions including the hippocampus. P300 amplitude is generally reduced in people with PTSD. METHODS: Our study examined hippocampal volume asymmetry and the relationship between hippocampal asymmetry and P300 amplitude in male monozygotic twins discordant for Vietnam combat exposure. Lateralised hippocampal volume and P300 data were obtained from 70 male participants, of whom 12 had PTSD. We were able to compare (1) combat veterans with current PTSD; (2) their non-combat-exposed co-twins; (3) combat veterans without current PTSD and (4) their non-combat-exposed co-twins. RESULTS: There were no significant differences between groups in hippocampal asymmetry. There were no group differences in performance of an auditory oddball target detection task or in P300 amplitude. There was a significant positive correlation between P300 amplitude and the magnitude of hippocampal asymmetry in participants with PTSD. CONCLUSIONS: These findings suggest that greater hippocampal asymmetry in PTSD is associated with a need to allocate more attentional resources when processing significant environmental stimuli.

Biological studies of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known: that is, 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. This Review attempts to present the current state of this understanding on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.

Individuals with posttraumatic stress disorder show a selective deficit in generalization of associative learning.

OBJECTIVE: Drawing on two different populations, Israeli police and Hungarian civilians, the present study assessed the ability of individuals with posttraumatic stress disorder (PTSD) to generalize previous learning to novel situations. Past neuroimaging studies have demonstrated diminished medial temporal lobe (MTL) activation and/or reduced hippocampal volume in individuals with PTSD. Our earlier computational models of cortico-hippocampal function and subsequent experimental tests of these models in MTL-impaired clinical populations argue that even mild hippocampal dysfunction may result in subtle impairments in generalization. Therefore, we predicted that individuals with PTSD would show impaired generalization. METHOD: We compared the performance of five groups from two countries, including 19 Israeli police with PTSD and 22 trauma-exposed police without PTSD, and 22 Hungarian civilians with PTSD, 25 trauma-exposed civilians without PTSD, and 25 individuals without PTSD unexposed to the same trauma. Participants were tested on a two-phase learning paradigm, the Acquired Equivalence Task, which measures the ability to generalize past learning to novel situations. RESULTS: We found that both PTSD and non-PTSD participants were capable of learning the initial stimulus-outcome associations, F(4, 108) = 1.79, p = .14. However, as predicted, only individuals with PTSD showed a selective deficit in generalization of this learning to novel situations (F(4, 108) = 8.35, p < .001, Partial η2 = 0.26). CONCLUSIONS: Individuals with PTSD show a selective impairment in generalization of past learning similar to other clinical populations with MTL/hippocampal dysfunction. This is consistent with an emerging view of PTSD as being not only an anxiety disorder but also a learning disorder.

Is trauma a causal agent of psychopathologic symptoms in posttraumatic stress disorder? Findings from identical twins discordant for combat exposure.

OBJECTIVE: The diagnosis of posttraumatic stress disorder (PTSD) is unique in that its criteria are embedded with a presumed causal agent, viz, a traumatic event. This assumption has come under scrutiny as a number of recent studies have suggested that many symptoms of PTSD may not necessarily be the result of trauma and may merely represent general psychiatric symptoms that would have existed even in the absence of a trauma event but are subsequently misattributed to it. The current study tests this hypothesis. METHOD: A case-control twin study conducted between 1996-2001 examined psychopathologic symptoms in a national convenience sample of 104 identical twin pairs discordant for combat exposure in Vietnam, with (n = 50) or without (n = 54) combat-related PTSD (DSM-IV-diagnosed) in the exposed twin. Psychometric measures used were the Symptom Checklist-90-Revised, the Clinician-Administered PTSD Scale, and the Mississippi Scale for Combat-Related PTSD. If a psychopathologic feature represents a factor that would have existed even without traumatic exposure, then there is a high chance that it would also be found at elevated rates in the non-trauma-exposed, identical cotwins of trauma-exposed twins with PTSD. In contrast, if a psychopathologic feature is acquired as a result of an environmental factor unique to the exposed twin, eg, the traumatic event, their cotwins should not have an increased incidence of the feature. RESULTS: Combat veterans with PTSD demonstrated significantly higher scores (P < .0001) on the Symptom Checklist-90-Revised and other psychometric measures of psychopathology than their own combat-unexposed cotwins (and than combat veterans without PTSD and their cotwins). CONCLUSIONS: These results support the conclusion that the majority of psychiatric symptoms reported by combat veterans with PTSD would not have been present were it not for their exposure to traumatic events.

Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder.

BACKGROUND: Controversy exists over the nature and origin of reduced regional brain volumes in posttraumatic stress disorder (PTSD). At issue is whether these reductions represent preexisting vulnerability factors for developing PTSD upon traumatic exposure or acquired PTSD signs due to the traumatic stress that caused the PTSD or the chronic stress of having the disorder (or both). We employed a case-control design in monozygotic twin pairs discordant for combat exposure to address the preexisting versus acquired origin of brain morphometric abnormalities in PTSD. METHODS: We used voxel-based morphometry to search for gray matter density reductions in magnetic resonance imaging (MRI) data obtained in a previous study of combat-exposed Vietnam veteran twins with (n = 18) versus without (n = 23) PTSD and their "high-risk" versus "low-risk" (respectively) identical combat-unexposed cotwins. RESULTS: Compared with the combat-exposed twins without PTSD, the combat-exposed twins with PTSD showed significant gray matter density reductions in four predicted brain regions: right hippocampus, pregenual anterior cingulate cortex (ACC), and left and right insulae. There was a significant PTSD Diagnosis x Combat Exposure interaction in pregenual ACC in which combat-exposed PTSD twins had lower gray matter density than their own combat-unexposed cotwins as well as than the combat-exposed twins without PTSD and their cotwins. CONCLUSIONS: The results point to gray matter volume diminutions in limbic and paralimbic structures in PTSD. The pattern of results obtained for pregenual ACC suggests that gray matter reduction in this region represents an acquired sign of PTSD consistent with stress-induced loss.

Configural cue performance in identical twins discordant for posttraumatic stress disorder: theoretical implications for the role of hippocampal function.

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. METHODS: Participants included male monozygotic twin pairs who were discordant for combat trauma. In 18 twin pairs the combat-exposed brother developed unremitting PTSD, whereas in 23 pairs the combat-exposed brother never developed PTSD. Participants were compared in the capacity to solve allocentric spatial processing tasks, and this performance was examined for its relationship to the severity of PTSD symptomatology and hippocampal volume. RESULTS: Although not completely differentiated from overall IQ, PTSD combat veterans demonstrated significantly impaired performance in configural processing relative to non-PTSD combat veterans. Despite having neither combat-exposure nor PTSD, the unexposed co-twins of combat veterans with PTSD displayed the same decrements as their brothers. Deficits were significantly related to PTSD severity and hippocampal volume. CONCLUSIONS: The current study provides the first evidence that the relevance of the hippocampus in PTSD might be related to pre-existing configural cue processing deficits that predispose individuals to develop unremitting forms of the disorder.

Volume of cerebellar vermis in monozygotic twins discordant for combat exposure: lack of relationship to post-traumatic stress disorder.

Several functional neuroimaging studies have implicated the cerebellar vermis in post-traumatic stress disorder (PTSD), but there have been no structural neuroimaging studies of this brain structure in PTSD. We utilized magnetic resonance imaging (MRI) with manual tracing to quantify the volumes of three divisions of the mid-sagittal vermis, and their total, within an identical, co-twin control design that employed Vietnam veterans discordant for combat exposure in Vietnam. Each structure's volume was significantly correlated between twins, indicating a partial familial determination: for anterior superior vermis, r=0.73; for posterior superior vermis, r=0.47; for inferior posterior vermis, r=0.51; and for total vermis, r=0.57. There were no significant differences between the PTSD and non-PTSD veterans for any vermis volume, and no significant main effects or interactions when their non-combat-exposed co-twins were added to the analyses. Thus, the results do not support the structural abnormality of cerebellar vermis in combat-related PTSD.

Clarifying the origin of biological abnormalities in PTSD through the study of identical twins discordant for combat exposure.

A biological abnormality found to be associated with posttraumatic stress disorder (PTSD) may be, among other things, a pretrauma vulnerability factor, that is, it may have been present prior to the event's occurrence and increased the individual's likelihood of developing PTSD upon traumatic exposure. Alternately, it may be an acquired PTSD sign, that is, it may have developed after the traumatic exposure, along with the PTSD. We have studied pairs of Vietnam combat veterans and their noncombat-exposed, identical twins in an effort to resolve these competing origins. Combat veterans were diagnosed as current PTSD or non-PTSD (i.e., never had). Average heart rate responses (HRRs) to a series of sudden, loud-tone presentations were larger in Vietnam combat veteran twins with PTSD, but these larger responses were not shared by their noncombat-exposed cotwins, whose responses were similar to those of the non-PTSD combat veterans and their noncombat-exposed cotwins. These results suggest that larger HRRs to sudden, loud tones represent an acquired sign of PTSD. In contrast, increased neurological soft signs (NSSs), diminished hippocampal volume, and presence of abnormal cavum septum pellucidum (CSP) were found in Vietnam combat veteran twins with PTSD and their "high-risk," unexposed cotwins compared to Vietnam combat veteran twins without PTSD and their "low-risk," unexposed cotwins. These results support the conclusion that the latter abnormalities represent antecedent, familial vulnerability factors for developing chronic PTSD upon exposure to a traumatic event.

Neurocognitive function in monozygotic twins discordant for combat exposure: relationship to posttraumatic stress disorder.

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.

Effects of beta blockade, PTSD diagnosis, and explicit threat on the extinction and retention of an aversively conditioned response.

An aversively conditioned SC response was assessed in 18 males meeting DSM-IV criteria for chronic posttraumatic stress disorder (PTSD) and 10 trauma-exposed males who never developed PTSD. Effects of beta blockade on acquisition and retention of a conditioned response (CR) were examined by administering propranolol HCl before acquisition or following extinction trials. Retention of the CR was assessed 1 week following acquisition under conditions of non-threat and threat. Conditioned stimuli were colored circles and the unconditioned stimulus (UCS) was a "highly annoying" electrical stimulus. The propranolol failed to produce any measurable effects on acquisition or retention of the CR and there was no evidence of increased conditionability in individuals diagnosed with PTSD. One week following acquisition, the differential CR to the reinforced stimulus was evident only in the threat condition. This suggests that belief in the presence of a threat is necessary and sufficient for activating a previously established CR.

Subtle neurologic compromise as a vulnerability factor for combat-related posttraumatic stress disorder: results of a twin study.

CONTEXT: Previous studies have demonstrated subtle neurologic dysfunction in chronic posttraumatic stress disorder (PTSD) manifest as increased neurologic soft signs (NSSs). The origin of this dysfunction is undetermined. OBJECTIVE: To resolve competing origins of increased NSSs in PTSD, namely, preexisting vulnerability factor vs acquired PTSD sign. DESIGN: Case-control study of identical twins. SETTING: A Veterans Affairs and academic medical center (ambulatory). PARTICIPANTS: A convenience sample of male Vietnam veteran twins with (n = 25) and without (n = 24) PTSD and their combat-unexposed identical (monozygotic) co-twins. INTERVENTIONS: Neurologic examination for 45 NSSs. MAIN OUTCOME MEASURE: Average scores for 45 NSSs, each scored on an ordinal scale from 0 to 3, masked to diagnosis and combat exposure status. RESULTS: There was a significant between-pair main effect of PTSD diagnosis (as determined in the combat-exposed twin) on average NSS score in the absence of a significant combat exposure main effect or diagnosis x exposure interaction. Combat veterans with PTSD had significantly higher NSS scores than combat veterans without PTSD. The "high-risk," unexposed co-twins of the former also had significantly higher NSS scores than the "low-risk," unexposed co-twins of the latter. This result could not be explained by age, number of potentially traumatic lifetime noncombat events, alcoholism, or the presence of a comorbid affective or anxiety disorder. The average NSS score in unexposed co-twins was not significantly associated with combat severity in combat-exposed twins. CONCLUSIONS: These results replicate previous findings of increased NSSs in Vietnam combat veterans with PTSD. Furthermore, results from their combat-unexposed identical co-twins support the conclusion that subtle neurologic dysfunction in PTSD is not acquired along with the trauma or PTSD but rather represents an antecedent familial vulnerability factor for developing chronic PTSD on exposure to a traumatic event.

Cavum septum pellucidum in monozygotic twins discordant for combat exposure: relationship to posttraumatic stress disorder.

BACKGROUND: Abnormally large cavum septum pellucidum has been reported in posttraumatic stress disorder; however, the origin of this association is uncertain. METHODS: We utilized magnetic resonance imaging to measure cavum septum pellucidum in pairs of identical twins discordant for combat exposure in Vietnam. RESULTS: Presence of abnormal cavum septum pellucidum was significantly correlated between exposed and unexposed twins, indicating that it is partially determined by heredity and/or shared environment. There was a greater proportion of cavum septum pellucidum in combat-exposed twins with posttraumatic stress disorder and their noncombat-exposed co-twins. CONCLUSIONS: The presence of abnormally large cavum septum pellucidum is a familial vulnerability factor for posttraumatic stress disorder.

Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma.

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.