Rewarded Extinction Increases Amygdalar Connectivity and Stabilizes Long-Term Memory Traces in the vmPFC

Abstract

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study with both female and male participants, we compared counterconditioning (CC; a form of rewarded-extinction) to standard extinction at recent (24 h) and remote (approximately one month) retrieval tests. Relative to standard extinction, rewarded extinction diminished 24-h relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ventral striatum, whereas the retrieval of standard-extinction memories was associated with connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). One month later, the retrieval of both standard-extinction and rewarded-extinction was associated with amygdala-vmPFC connectivity. However, only rewarded extinction created a stable memory trace in the vmPFC, identified through overlapping multivariate patterns of fMRI activity from extinction to 24-h and one-month retrieval. These findings provide new evidence that reward may generate a more stable and enduring memory trace of attenuated threat in humans.SIGNIFICANCE STATEMENT Prevalent treatments for pathologic fear and anxiety are based on the principles of Pavlovian extinction. Unfortunately, extinction forms weak memories that only temporarily inhibit the retrieval of threat associations. Thus, to increase the translational relevance of extinction research, it is critical to investigate whether extinction can be augmented to form a more enduring memory, especially after long intervals. Here, we used a multiday fMRI paradigm in humans to compare the short-term and long-term neurobehavioral effects of aversive-to-appetitive counterconditioning (CC), a form of augmented extinction. Our results provide novel evidence that including an appetitive stimulus during extinction can reduce short-term threat relapse and stabilize the memory trace of extinction in the ventromedial prefrontal cortex (vmPFC), for at least one month after learning.

Keywords: amygdala; fMRI; fear extinction; reward; striatum; vmPFC.

Figure 1.

Experimental design and behavioral results. A, Participants underwent threat acquisition with category exemplars of animals or tools (CS+s) paired with a shock on a partial reinforcement schedule, and a third category, food (CS–), never paired with shock. Conditioning was followed by the extinction phase, in which the shock was omitted following CS+EXT trials (counterbalanced, tools or animals, in this example tools), and CC, in which the shock was replaced by a positive picture at the end of each CS+CC trial (animals or tools, respectively, in this example animals). Subjects returned 24 h and approximately one month later, and new CSs from the same categories, were presented in the absence of any shocks or positive pictures. B, Shock expectancy results confirmed successful acquisition and extinction of threat expectancy. Twenty-four hours after day 1, shock expectancy toward the CS+EXT category significantly increased from the end of extinction to early renewal. Shock expectancy toward the CS+s remained even at the approximately one-month follow-up. C, Conditioned SCRs replicated prior findings (Keller and Dunsmoor, 2020), there were no differences between CS+s during acquisition or extinction, but 24 h later, SCRs were higher for the CS+EXT category as compared with the CS– category, and there were no differences between the CS+CC category and the CS– category. One month later, there was no renewal of conditioned SCRs toward the CS+s. Colored borders are for illustrative purposed only. The rainbow, which represents the positive pictures, and the lightning bolt, which represents an electrical shock, depict the outcome following a given CS type. For example, following CS+CC trials during extinction, there is a positive picture. Error bars indicate the 95% confidence interval of the mean; ***p < 0.001, **p < 0.01, *p < 0.05.

Figure 2.

CC was associated with reduced activity in threat ROIs during extinction, and enhanced amygdala activation during 24-h renewal. A, A whole-brain contrast of CS+EXT > CS+CC during the extinction phase, identified at Z > 3.1, cluster corrected at p < 0.05, revealed activity in regions traditionally associated with threat appraisal and expression (e.g., periaqueductal gray, dACC, insula and thalamus). B, A whole-brain contrast of CS+CC > CS+EXT during the 24-h renewal phase, identified at p < 0.001 uncorrected for multiple comparisons, revealed a cluster in the left amygdala. C, Parameter estimates extracted from a priori regions associated with threat (periaqueductal gray, dACC, insula, and thalamus), during the last half of extinction, revealed significantly lower activity for CS+CC stimuli in comparison to both CS+EXT and CS– stimuli. The rainbow, which represents the positive pictures, depict the outcome following CS+CC stimuli; ***p < 0.001, **p < 0.01, *p < 0.05.

Figure 3.

Functional connectivity during recent and remote renewal tests in two a priori pathways. A, Functional connectivity using the BLA as a seed region and the NAc as a target region, was enhanced for CS+CC stimuli during 24-h renewal, but was not different between CS types at approximately one-month renewal. B, Functional connectivity using the vmPFC as a seed region and the CeM as a target region, was enhanced for CS+EXT, in comparison to CS+CC stimuli during 24-h renewal. At approximately one month, connectivity for CS+CC stimuli significantly increased and was not different from CS+EXT stimuli. At this remote time point, both CS+s were associated with a greater functional vmPFC→CeM connection than CS– stimuli; ***p < 0.001, **p < 0.01, *p < 0.05.

Figure 4.

Stimuli that underwent CC were associated with a heightened pattern of similarity in the vmPFC. A, Pattern similarity from encoding to recent renewal (extinction→24-h retrieval) in the vmPFC was enhanced for the CS+CC category in comparison to both the CS+EXT and CS– categories. B, Pattern similarity from encoding to remote renewal (extinction→ approximately one-month renewal) in the vmPFC was enhanced for the CS+CC category in comparison to the CS– category. C, Pattern similarity from recent to remote renewal (extinction→24-h renewal) in the vmPFC was marginally enhanced for the CS+CC category in comparison to the CS– category; ***p < 0.001, **p < 0.01, *p < 0.05.