"Prevailing neurobiological models of PTSD focus on the interaction between ventromedial prefrontal cortex (vmPFC), amygdala, and hippocampus4,5. The role of the amygdala in fear and anxiety is well documented6, as is the role of hippocampus in episodic memory7. vmPFC projects directly to amygdala8,9, and is thought to provide inhibitory input that regulates emotion10. PTSD patients have reduced hippocampus and vmPFC volumes4,5,11. When exposed to reminders of traumatic events, PTSD patients exhibit diminished hemodynamic responses in vmPFC12-14, but exaggerated hemodynamic responses in amygdala5,15-17. Taken together, these data suggest that PTSD is associated with overactivation of the amygdala due to a lack of inhibitory control by vmPFC, as well as deficient hippocampal function. However, imaging data cannot determine whether any of these neuroanatomical findings reflect an underlying cause of the disorder (such as a preexisting risk factor for the development of PTSD or trauma-induced neuropathology that engenders PTSD symptoms), or a secondary effect of the disorder (such as an artifact of primary dysfunction in other brain areas or the neural response to the experience of PTSD symptoms). Lesion studies could, in principle, elucidate the causal contribution of vmPFC, amygdala, and hippocampus by determining if damage to these brain areas changes the likelihood of developing PTSD. However, in an illness such as PTSD that is not amenable to animal lesion studies, this requires the standardized clinical evaluation of a large group of people who suffered the unlikely coincidence of a localizable focal brain lesion as well as emotionally traumatic events. In addition, the lesions would need to adequately sample various areas of the brain, including vmPFC, amygdala, and hippocampus. Remarkably, we have this unique resource available in the Vietnam Head Injury Study (VHIS).

The VHIS (Phase 3) includes 193 Vietnam veterans with lesions distributed throughout the brain (as a result of penetrating head injuries sustained during combat) and 52 veterans with combat exposure but no brain injury. We evaluated each of these 245 individuals for PTSD using the Structured Clinical Interview for DSM-IV-TR Axis I disorders, Non-Patient edition (SCID-N/P)18. A psychiatrist trained to administer the SCID-N/P performed the assessment between April 2003 and November 2006. We classified veterans as either having developed PTSD at some point in their lifetime (PTSD-positive) or having never developed PTSD (PTSD-negative). To identify the neural substrates of PTSD, we employed two complementary analyses: 1) an exploratory approach in which we grouped brain-injured veterans according to PTSD diagnosis (positive or negative) and then compared the distributions of lesions between groups, and 2) a hypothesis-driven approach in which we grouped veterans based on lesion location (involvement of vmPFC, amygdala, or neither) and then compared the prevalence of PTSD between groups."

In summary, veterans with vmPFC or amygdala damage were significantly less likely to develop PTSD than veterans with damage to other parts of the brain, or veterans with no brain damage. Particularly striking was the complete absence of a lifetime diagnosis of PTSD among veterans with amygdala damage, which could not be attributed to damage to surrounding temporal lobe regions, including hippocampus.