To our knowledge, this is one of the few studies to examine, within a single model, the contribution of childhood and adult trauma exposure, and PTSS to alterations in brain circuitry that have been associated with PTSD. We tested this circuitry using a dynamic faces task, which requires implicit emotion regulation and attentional processing of emotional cues. We focused on angry and happy emotional distractors in our analyses, with the prediction that angry faces are potent threat cues and would specifically elicit differences associated with childhood maltreatment, combat exposure, and PTSS. Both emotion conditions elicited activation of the vmPFC and amygdala, suggesting engagement of circuitry underlying the detection of emotional cues and implicit regulation of emotional responses.
In the angry, but not happy trials, PTSS (CAPS scores) were positively correlated with insula and hippocampus activation, and a small cluster in BA10. PTSS also correlated with amygdala activation in earlier angry blocks. Combat exposure and childhood maltreatment scores positively correlated with activation of adjacent areas of the anterior dACC. Dissociative symptoms, in contrast, negatively correlated with dACC activation.
Increased dACC activation has been observed in studies of PTSD, including studies of fear conditioning and extinction, emotional interference, and resting (Shin & Liberzon 2010
). The dACC subserves the appraisal and expression of fear and anxiety, as well as conflict adaptation (Phillips et al. 2008
; Etkin et al. 2011
; Shackman et al. 2011
). The dACC shows strong connectivity with the amygdala and is the likely homologue of the rat prelimbic cortex (PL) (Milad et al. 2006
; Etkin et al. 2011
). Deactivation, stimulation, and neuronal recording studies of the rat PL suggest that this region promotes the expression of fear responses, e.g. (Vidal-Gonzalez et al. 2006
; Quirk & Mueller 2008
; Burgos-Robles et al. 2009
; Sierra-Mercado et al. 2011
). As such, heightened activity in this structure could underlie, in part, the hypervigilance (heightened threat appraisal) and generalized fear responses associated with PTSS. A study of Vietnam veteran twin pairs revealed increased dACC activation in both the twin with PTSD and their non-PTSD co-twin, suggesting that increased dACC activation is a familial risk factor for developing PTSD (Shin et al. 2009
). Our results suggest that one important familial risk factor may be childhood maltreatment exposure, which would be expected to be a common risk among siblings. Our findings further suggest that both childhood maltreatment and adult combat exposure independently correlate with dACC activation to threat. Clinically, both childhood maltreatment and combat exposure scores were significantly correlated with PTSS. Thus, trauma-associated dACC activation could represent one putative mechanism for the development of PTSS, by creating vulnerability at the brain level. A recent study in rats revealed that chronic stress exposure resulted in a failure to decrease prelimbic firing during fear extinction recall (Wilber et al. 2011
). In humans, a longitudinal study of combat veterans revealed that perceived threat during combat may lead to a lasting, reduced negative coupling between the dACC and amygdala, even in the absence of PTSD (van Wingen et al. 2011b
). In this context, our findings suggest that both childhood and adult trauma exposure may sensitize the dACC, which may promote the appraisal of threat and the expression of fear responses through its connections with the amygdala. PTSS could then emerge from this vulnerability with additional changes in brain circuitry as described below.
Consistent with studies of PTSD, our results demonstrate that PTSS are positively correlated with insula, amygdala, and hippocampus activation to threat stimuli. Furthermore, these associations were specific to PTSS, and not attributable to childhood maltreatment or combat exposure. Increased insula and amygdala activation have been relatively common findings in studies of PTSD, with hippocampal activation being more variable (Shin & Liberzon 2010
). While our study is associational only, we speculate that altered activation in these areas could result from greater dACC activation related to trauma exposure. The dACC is known to have strong connections with both the amygdala and insula (Shackman et al. 2011
). Sensitization of the dACC could, at least in vulnerable individuals, then lead to greater activation of the insula and amygdala-hippocampus complex, promoting anxiety and fear responses typical of PTSD. This would presumably occur in concert with vmPFC hypoactivation, though we did not detect associations with the vmPFC in our study (see below for discussion). Clearly, more longitudinal studies in traumatized populations, beginning in childhood, will be needed to examine these possibilities.
PTSS were also positively associated with dorsomedial PFC (BA10) activation in our study. This area has been implicated in the suppression of emotional responses, and in selecting choices or actions based on the affective value of an outcome (Phillips et al. 2008
; Grabenhorst & Rolls 2011
). In this context, increased BA10 activation may reflect a greater effort required in the presence of PTSS to suppress emotional responses and choose correct responses. Given the lack of differences in reaction times or accuracy, this could reflect a compensatory mechanism.
Our study did not reveal any significant correlations between trauma exposure or PTSS and vmPFC activation. While vmPFC hypoactivation is commonly reported in studies of PTSD, some studies have found no differences between PTSD and control subjects (Francati et al. 2007
; Etkin & Wager 2007
). There are several possible reasons for the lack of vmPFC associations in this study. First, though our study included subjects with a wide range of PTSS, we may not have had sufficiently high CAPS scores to detect an association within the vmPFC. When considering only subjects with PTSD, their past month CAPS scores were lower (average 53) than other studies of PTSD. Subjects were also younger than in most studies, with fewer comorbidities, and less chronicity of PTSD. Thus it is possible that vmPFC differences, which have also been shown to correlate with PTSD symptom severity (Shin & Liberzon 2010
), are only more evident with more severe and chronic PTSD. Second, it is possible that alterations in vmPFC may have been present shortly after the end of deployment but have since normalized. Further longitudinal studies will be needed to test these possibilities.
Of note, we found that dissociative symptoms were negatively correlated with dACC activation in the threat, but not positive, emotion trials. Reduced dACC activation related to dissociative symptoms could reflect reduced appraisal and expression of fear and anxiety at the neural level (Lanius et al. 2010
). It should be noted, however, that dissociative symptoms in this sample were quite low, with all but three individuals with DES scores less than 15. Thus comparisons to studies of dissociative subtypes of PTSD are limited.
There are several limitations to the current study. First, these findings are cross-sectional and correlational only and cannot be used to infer causation. It is thus difficult to tease out whether observed changes represent preexisting vulnerabilities, state-related changes, or compensatory changes. Second, these findings may not generalize to other populations (particularly women given the all-male sample), trauma types, or to individuals with more severe PTSD as discussed above. Third, while subjects were free of any current alcohol or substance abuse, this study did not have measures of cumulative, lifelong alcohol use which could affect the current results. However, the PTSD and non-PTSD subjects had similar frequencies of past alcohol abuse/dependence, which makes it less likely that this potential confound systematically influenced the results. Finally, this study enrolled a relatively small number of subjects and would merit replication with a larger sample.
In conclusion, our findings suggest that dorsal ACC activation observed in prior studies of PTSD may be attributable to childhood and adult trauma exposure. In contrast, insula, amygdala, and hippocampal activation may be specifically associated with the PTSD syndrome. The specificity of these results to threat, and not positive stimuli, is consistent with abnormalities in threat processing associated with PTSD. Taken together, the results of the current study begin to suggest putative mechanisms by which childhood and adult trauma exposure may create a vulnerable brain substrate for the development of PTSS, which itself may emerge with additional changes in limbic circuitry.