Active Avoidance: Neural Mechanisms and Attenuation of Pavlovian Conditioned Responding

Abstract

Patients with anxiety disorders often experience a relapse in symptoms after exposure therapy. Similarly, threat responses acquired during Pavlovian threat conditioning often return after extinction learning. Accordingly, there is a need for alternative methods to persistently reduce threat responding. Studies in rodents have suggested that exercising behavioral control over an aversive stimulus can persistently diminish threat responses, and that these effects are mediated by the amygdala, ventromedial prefrontal cortex, and striatum. In this fMRI study, we attempted to translate these findings to humans. Subjects first underwent threat conditioning. We then contrasted two forms of safety learning: active avoidance, in which participants could prevent the shock through an action, and yoked extinction, with shock presentation matched to the active condition, but without instrumental control. The following day, we assessed subjects' threat responses (measured by skin conductance) to the conditioned stimuli without shock. Subjects next underwent threat conditioning with novel stimuli. Yoked extinction subjects showed an increase in conditioned response to stimuli from the previous day, but the active avoidance group did not. Additionally, active avoidance subjects showed reduced conditioned responding during novel threat conditioning, but the extinction group did not. We observed between-group differences in striatal BOLD responses to shock omission in Avoidance/Extinction. These findings suggest a differential role for the striatum in human active avoidance versus extinction learning, and indicate that active avoidance may be more effective than extinction in persistently diminishing threat responses.SIGNIFICANCE STATEMENT Extinguished threat responses often reemerge with time, highlighting the importance of identifying more enduring means of attenuation. We compared the effects of active avoidance learning and yoked extinction on threat responses in humans and contrasted the neural circuitry engaged by these two processes. Subjects who learned to prevent a shock through an action maintained low threat responses after safety learning and showed attenuated threat conditioning with novel stimuli, in contrast to those who underwent yoked extinction. The results suggest that experiences of active control over threat engage the striatum and promote a shift from expression of innate defensive responses toward more adaptive behavioral responses to threatening stimuli.

Keywords: active avoidance; anxiety; coping; instrumental learning; resilience; threat conditioning.

Figure 1.

Design. In the Acquisition phase, subjects saw a CS⁺ face that sometimes coterminated with shock, and a CS⁻ face that was not paired with shock. In Avoidance/Extinction, Master subjects were able to prevent the shock on CS⁺ trials by moving the circle to the opposite “chamber” from which it started. Yoke subjects each were paired to a Master subject. Yoke subjects received identical CS and shock exposure as their Master subjects, and they performed a motor control task. On the subsequent day, subjects saw the CSs in the Retrieval phase, but they were not shocked. Novel Acquisition was identical to initial Acquisition, but subjects saw a new pair of CS⁺ and CS⁻ stimuli.

Figure 2.

Skin conductance results. A, Skin conductance data are plotted in two-trial blocks. B, Average conditioned responses (CS⁺ − CS⁻ skin conductance responses) during each phase of the experiment. CR, conditioned response. Error bars show SEM.

Figure 3.

Spontaneous Recovery Indices and Novel Acquisition Index. A, Spontaneous Recovery Index, as measured by the average conditioned response across all Retrieval trials minus the average conditioned response across all Avoidance/Extinction trials. The two-sample t test p value is equivalent to that of the CS type × group × phase (Avoidance/Extinction vs Retrieval) ANOVA interaction. B, Spontaneous Recovery Index, as measured by the average conditioned response from the first two trials of Retrieval minus the average conditioned response from the last two trials of Avoidance/Extinction. C, Novel Acquisition Index, the conditioned response during Novel Acquisition minus the conditioned response during Initial Acquisition. The two-sample t test p value is equivalent to that of the CS type × group × phase (Acquisition vs Novel Acquisition) ANOVA interaction. Error bars show SEM.

Figure 4.

CS⁺ versus CS⁻ BOLD responses during Acquisition, across the whole group (N = 56). FWE corrected, using nonparametric clusterwise correction for comparisons across the whole brain, with a cluster-forming threshold of t = 3, clusterwise p < 0.05, two-tailed. Colored pixels represent the clusterwise corrected p values.

Figure 5.

BOLD responses in late Avoidance/Extinction during CS⁺ versus CS⁻ presentation. N = 27 in each group. Uncorrected threshold of p = 0.001, one-tailed, 10 voxels. Image is masked by regions of interest (in this slice, vmPFC). M, Masters; Y, Yokes.

Figure 6.

BOLD responses in late Avoidance/Extinction, CS⁺ versus CS⁻ offset. N = 27 in each group. FWE corrected, using nonparametric clusterwise correction for comparisons across voxels in regions of interest, with a cluster-forming threshold of t = 3, clusterwise p ≤ 0.05, one-tailed. Image is masked by regions of interest (in this slice, bilateral caudate, putamen, accumbens). Colored pixels represent the clusterwise SVC p values. M, Masters; Y, Yokes; SV, small volume.