Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions

Abstract

Functional imaging studies of cued fear conditioning in humans have mostly confirmed findings in animals, but it is unclear whether the brain mechanisms that underlie contextual fear conditioning in animals are also preserved in humans. We investigated this issue using functional magnetic resonance imaging and virtual reality contexts. Subjects underwent differential context conditioning in which they were repeatedly exposed to two contexts (CXT+ and CXT-) in semirandom order, with contexts counterbalanced across participants. An unsignaled footshock was consistently paired with the CXT+, and no shock was ever delivered in the CXT-. Evidence for context conditioning was established using skin conductance and anxiety ratings. Consistent with animal models centrally implicating the hippocampus and amygdala in a network supporting context conditioning, CXT+ compared with CXT- significantly activated right anterior hippocampus and bilateral amygdala. In addition, context conditioning was associated with activation in posterior orbitofrontal cortex, medial dorsal thalamus, anterior insula, subgenual anterior cingulate, and parahippocampal, inferior frontal, and parietal cortices. Structural equation modeling was used to assess interactions among the core brain regions mediating context conditioning. The derived model indicated that medial amygdala was the source of key efferent and afferent connections including input from orbitofrontal cortex. These results provide evidence that similar brain mechanisms may underlie contextual fear conditioning across species.

Figure 1.

Contextual fear conditioning paradigm and pictures of the contexts. A, Example of one run in the context conditioning paradigm. During each of three runs, each context (CXT+ and CXT−) was presented four times in semirandom order. An unsignaled shock was consistently paired with the CXT+ and no shock was ever delivered during the CXT−. During each context presentation, which lasted 28 s, subjects underwent a tour of the virtual environment. This was followed by a period of rest during which subjects viewed a static outdoors scene. B, Pictures of the VR contexts (color omitted). Pictures are still frames extracted from the house and airport VR environments depicting sample views of each context.

Figure 2.

Successful acquisition of contextual fear. SCR to the onset of the CXT+ and CXT− and SCL in CXT+ and CXT− during acquisition of contextual fear. The larger SCR and SCL to the CXT+ compared with the CXT− indicates successful contextual fear conditioning. Error bars reflect within-subject SE.

Figure 3.

Context conditioning network for CXT+ versus CXT− and key peristimulus time courses for the hemodynamic response. The brackets indicate coordinates of peak activation. Images are in neurological format (right = right). All activations are overlaid on a mean structural image from the group aligned to the EPI data. Thresholded at corrected p < 0.05. Error bars reflect SE. aINS, Anterior insula; PHC, parahippocampal cortex; OFC, orbitofrontal; sACC, subgenual anterior cingulate; THA, thalamus.

Figure 4.

ROI analyses. A, Group activation maps and peak coordinates for two clusters within the left amygdala, one more lateral and the other more medial, and right anterior hippocampus for CXT+ versus CXT− shown overlaid on axial, coronal, and sagittal slices. B, Peristimulus time courses showing greater activation to the CXT+ than the CXT− early in the context followed by rapid attenuation across time. Thresholded at corrected p < 0.05. Error bars reflect SE.

Figure 5.

Path diagram showing “optimal” model of effective connectivity within the specified context conditioning network. The optimal model included 19 paths; path coefficients accompany each path.