The lesion method is a unique and powerful means of determining the importance of a particular brain area for a particular function. The lesion method refers to an approach whereby a focal area of brain damage is associated with the development of a defect in some aspect of cognition or behavior, and then an inference is made that the damaged brain region is a critical part of the neural substrate for the impaired function. That is, unlike functional imaging data, lesion data reveal causality—damage to a particular brain area causes a change
in a particular function. In principle, lesion studies could elucidate the causal contribution of vmPFC and amygdala to PTSD 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 the vmPFC and amygdala. This unique resource is in fact available in the Vietnam Head Injury Study (VHIS) (Koenigs and others 2008b
; Raymont and others 2008
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. During the last several years, each of these 245 individuals has been evaluated for PTSD using the Structured Clinical Interview for DSM-IV-TR Axis I disorders, Non-Patient edition (SCID-N/P) (First 2002
). In addition, all brain-injured VHIS veterans have undergone a CT scan, allowing the accurate determination of lesion location. Thus each veteran could be classified as either having developed PTSD at some point in their lifetime (PTSD-positive) or having never developed PTSD (PTSD-negative). In a recent study of these VHIS patients (Koenigs and others 2008b
), we sought to test the two main predictions of the conventional mPFC-amygdala model of PTSD pathogenesis. Specifically, if PTSD symptomotology is caused by amygdala hyperactivity due to defective inhibition by vmPFC, then veterans with amygdala damage will have a lower-than-normal likelihood of developing PTSD, whereas veterans with vmPFC damage (but intact amygdala) will have a greater-than-normal likelihood of developing PTSD.
PTSD prevalence following vmPFC or amygdala damage
To test these hypotheses directly, we divided the VHIS participants into four groups based on lesion location: 1) significant damage to vmPFC in either hemisphere (vmPFC lesion group; n=40; ), 2) damage to amygdala in either hemisphere (amygdala lesion group; n=15; ), 3) damage not involving vmPFC or amygdala (non-vmPFC /non-amygdala lesion group; n=133), and 4) no brain damage (non-brain damaged group; n=52). Brain-injured groups did not significantly differ from each other on basic demographic variables (age, race, sex, and education) nor did they differ in combat exposure, tour duration, or intellectual decline following brain injury, thereby ruling out a host of variables as potential explanations for differences in PTSD occurrence among the groups of brain-injured veterans.
Figure 4 The color indicates the number of veterans in the vmPFC group (n=40) with damage to a given voxel. The greatest lesion overlap (red) occurred in the anterior vmPFC bilaterally. Top row, sagittal views of the vmPFC group lesion overlap. The left hemisphere (more ...)
Figure 5 The color indicates the number of veterans with damage to a given voxel. Top row, coronal views of a healthy adult brain. Slices are arranged with the anterior-most slice on the left (y=14; y=8; y=2; y=-4; respectively). Middle row, coronal views of the (more ...)
The prevalence of PTSD in the non-brain damaged group (48%) and the non-vmPFC/non-amygdala lesion group (40%) was similar to published estimates of PTSD prevalence among Vietnam veterans exposed to intense combat (Dohrenwend and others 2006
). Remarkably, none of the veterans in the amygdala lesion group (0%) developed PTSD. To rule out the possibility that the absence of PTSD in the amygdala group was due to accompanying damage in anterior temporal cortex or medial temporal lobe structures, rather than damage to the amygdala per se, we selected from the non-vmPFC/non-amygdala group those veterans who had anterior temporal and/or medial temporal lobe damage, but no amygdala damage (n=28) (“temporal lobe comparison group”, ). The PTSD prevalence among these veterans (32%) was significantly greater than the amygdala group, but not significantly different than the non-brain damaged group or the rest of non-vmPFC/non-amygdala group. These data confirm the prediction that the amygdala damage would result in a lower-than-normal likelihood of developing PTSD, and thereby support the hypothesis that amygdala hyperactivity plays a causal role in the pathophysiology of PTSD.
With regard to the other predicted result, we did not find that the prevalence of PTSD in the vmPFC lesion group was greater-than-normal. To the contrary, PTSD prevalence in the vmPFC lesion group (18%) was significantly lower than that of the non-brain damaged and the non-vmPFC/non-amygdala lesion comparison groups. The markedly low levels of PTSD among veterans vmPFC damage calls into question the veracity of a model in which defective vmPFC-mediated inhibition is the basis of the amygdala hyperactivity in PTSD. If this were the case, then vmPFC damage would presumably diminish the inhibition of the amygdala, resulting in greater susceptibility to PTSD.