A Role for the Human Dorsal Anterior Cingulate Cortex in Fear Expression, 2007

Source

Dorsal ACC is involved in conditional fear response.

Discussion

We found that dACC thickness was positively correlated with conditioned fear responses to the CS􏰀, as indexed by SCR. In a separate cohort of subjects, dACC functional activation increased to the CS􏰀 relative to the CS􏰁 during fear conditioning, and dACC activity was positively correlated with differential SCR. The convergence of structural and functional correlates of condi- tioned fear responding in the dACC reported herein is remark- able, considering that these two data sets were obtained from separate cohorts. Although the presentation of the CS􏰁 and the US did not induce significant activation in the dACC, the SCRs induced by these two stimuli were positively correlated with the variance in dACC activation during these two conditions. This suggests that the dACC might be involved in the expression of fear responses in general. In a finding consistent with this view, Vogt et al. (25) suggested that fear is associated with activation specifically in this region of the ACC. Indeed, rodent studies support the involvement of a homologous region, the prelimbic cortex, in the expression of conditioned fear (7,8,11,13).

An alternate interpretation of the present data is that the correlations observed between dACC and SCR might reflect a role of the dACC in detecting salience (i.e., the importance of the stimulus being presented). The data presented herein cannot rule out this possibility. However, presentation of the CS􏰁 and the US were also arousing, especially during the early conditioning trials. Yet, we did not observe a significant dACC response to either the CS􏰁 or US, which argues against this possibility. Also, SCR induced after the presentation of the context was not correlated with dACC activity. Nonetheless, further studies are needed to more fully delineate the involvement of the dACC in fear expression.

A role for the dACC in the generation of autonomic responses has been previously reported (26). Electrical stimulation of the dACC induces SCRs (27), whereas lesions of this brain region attenuate SCRs (28). Previous neuroimaging studies have re- ported positive correlations between activation in sub-regions of the ACC (including dACC) and changes in autonomic responses including SCR during high arousal states (reviewed in 29). Non-specific SCRs have been found to be positively correlated with dACC activation during aversive fear conditioning (21). These studies suggest a link between dACC and SCR in general.

Other neuroimaging studies, however, have failed to find corre- lations between resting state or spontaneous fluctuations of SCR and dACC activation (30–32). Furthermore, frontal lesions in humans, including dACC lesions, do not affect resting or orient- ing SCRs (33). In the present study, the absence of a significant correlation between dACC activation and SCR to the context alone indicates that dACC activation is not associated with changes in SCR under all circumstances.

The location of the dACC region that we found to be correlated with fear expression approximates the target of ante- rior cingulotomy (34,35), an ablative neurosurgical treatment for patients with treatment-refractory mood and anxiety disorders (see Figure 1E). Up to 40% of patients with severe obsessive compulsive disorder (OCD) who had previously failed to re- spond to medications and behavioral therapy show marked improvement in OCD symptoms after cingulotomy (Figure 1F) (36). Patients receiving brief intra-operative electrical stimulation of the dACC report feelings of intense fear, whereas ablation of this brain region significantly reduces anxiety symptoms (37). The data obtained herein further suggest that the dACC could be a potential target for future anti-anxiety therapies. Whereas enhancement of function within ventromedial PFC has been proposed as a means for suppressing amygdala responses and facilitating extinction recall (3,23,38 – 41), neutralizing dACC function might be an effective complementary strategy for ame- liorating anxiety.