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

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
Biological Psychiatry (Impact Factor: 10.25). 12/2007; 62(10):1191-4. DOI: 10.1016/j.biopsych.2007.04.032
Source: PubMed

ABSTRACT Rodent studies implicate the prelimbic (PL) region of the medial prefrontal cortex in the expression of conditioned fear. Human studies suggest that the dorsal anterior cingulate cortex (dACC) plays a role similar to PL in mediating or modulating fear responses. This study examined the role of dACC during fear conditioning in healthy humans with magnetic resonance imaging (MRI).
Novel analyses were conducted on data from two cohorts that had previously undergone scanning to study fear extinction. Structural and functional brain data were acquired with MRI; the functional MRI (fMRI) component employed an event-related design. Skin conductance response (SCR) was the index of conditioned responses.
We found that: 1) cortical thickness within dACC is positively correlated with SCR during conditioning; 2) dACC is activated by a conditioned fear stimulus; and 3) this activation is positively correlated with differential SCR. Moreover, the dACC region implicated in this research corresponds to the target of anterior cingulotomy, an ablative surgical treatment for patients with mood and anxiety disorders.
Convergent structural, functional, and lesion findings from separate groups of subjects suggest that dACC mediates or modulates fear expression in humans. Collectively, these data implicate this territory as a potential target for future anti-anxiety therapies.

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Available from: Scott P Orr, Aug 16, 2015
    • "For example, during extinction recall in the context associated with extinction learning, activity in both the vmPFC and hippocampus correlated positively with the degree of psychophysiologically expressed extinction recall, and activities in the vmPFC and hippocampus were significantly correlated with each other (Milad, Wright, et al., 2007). Milad et al. (2007) suggested that contextual information, resulting from differentiation of the conditioning and extinction contexts, was represented by such hippocampal activity. Kalisch et al. (2006) also reported correlated activation of hippocampus and vmPFC during extinction recall when the CSϩ was presented in the extinction context but not in the conditioning context. "
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    Psychological Bulletin 04/2015; 141(4). DOI:10.1037/bul0000014 · 14.39 Impact Factor
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    • "The current neurocircuitry model of fear extinction (Milad and Quirk 2012) implies a dual cortical control of limbic activity with opposing modulatory roles for the two subparts of the PFC: The IL inhibits amygdalar CE fear output via projections to the intercalated cells thereby mediating extinction, while the PL with its excitatory projections to the BLA is directly involved in the expression of learned fear. Although it is difficult to define homologous areas between rodents and humans, the vmPFC, including the subgenual anterior cingulate cortex and the medial orbitofrontal cortex, has been proposed as homologs to the rodent IL (Ongur and Price 2000), while numerous findings support the idea that the dorsal anterior cingulate cortex (dACC) is the human homolog of the rodent PL (Milad et al. 2007a). Although our study confirms the structural basis of vmPFC involvement in extinction learning in humans , we found no significant association between fear acquisition capacity and the thickness of the dACC or any other cortical area. "
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    ABSTRACT: The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear.
    Brain Structure and Function 02/2015; DOI:10.1007/s00429-015-1013-z · 4.57 Impact Factor
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    • "Neuroimaging work in humans is largely consistent with these findings. During extinction learning, vmPFC activity increases (Phelps et al., 2004) and correlates with the magnitude of later extinction retention (Milad et al., 2007). The vmPFC is also active during extinction retrieval (Phelps et al., 2004; Kalisch et al., 2006) and the volume of cortical tissue in this region has been shown to be positively associated with the magnitude of extinction retrieval (Hartley et al., 2011), confirming an important role across species for this region in the successful retrieval of extinction training. "
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