Amygdala Adaptation and Temporal Dynamics of the Salience Network in Conditioned Fear: A Single-Trial fMRI Study.

Research in rodents has established the role of the amygdaloid complex in defensive responses to conditioned threat. In human imaging studies, however, activation of the amygdala by conditioned threat cues is often not observed. One hypothesis states that this finding reflects adaptation of amygdaloid responses over time. We tested this hypothesis by estimating single-trial neural responses over a large number of conditioning trials. Functional MRI (fMRI) was recorded from 18 participants during classical differential fear conditioning: Participants viewed oriented grayscale grating stimuli (45° or 135°) presented centrally in random order. In the acquisition block, one grating (the CS+) was paired with a noxious noise, the unconditioned stimulus (US), on 25% of trials. The other grating, denoted CS-, was never paired with the US. Consistent with previous reports, BOLD in dorsal anterior cingulate cortex (dACC) and insula, but not the amygdala, was heightened when viewing CS+ stimuli that were not paired with US compared to CS- stimuli. Trial-by-trial analysis showed that over the course of acquisition, activity in the amygdala attenuated. Interestingly, activity in the dACC and insula also declined. Representational similarity analysis (RSA) corroborated these results, indicating that the voxel patterns evoked by CS+ and CS- in these brain regions became less distinguishable over time. Together, the present findings support the hypothesis that the lack of BOLD differences in the amygdaloid complex in many studies of classical conditioning is due to adaptation, and the adaptation effects may reflect changes in large-scale networks mediating aversive conditioning, particularly the salience network.