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. 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.

Renewal of fear and avoidance in humans to escalating threat: Implications for translational research on anxiety disorders

“…It is also plausible that SCR insensitivity to escalating threats during renewal testing occurred because avoidance prevented losses. Comparable fear reductions have been reported in human functional neuroimaging studies in which there are significant decreases in prefrontal and limbic activation in regions associated with fear expression during avoidance learning (Boeke, Moscarello, LeDoux, Phelps, & Hartley, 2017), sustained avoidance responding (Schlund, Hudgins, Magee, & Dymond, 2013), and successful compared to unsuccessful avoidance (Schlund, Brewer, Richman, Magee, & Dymond, 2015). These findings also parallel those reported in research on the controllability of aversive stimuli (Seligman, Maier, & Solomon, 1971).…”

Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man

“…Both strategies can be maladaptive if used excessively or in a fashion in which the individual has no control; however, there is evidence to suggest that active avoidance strategies can dampen responses to subsequent stressors 60 . For example, a recent human study with a clever yoked-subject design showed a decreased skin conductance response in non-psychiatric control participants who were given access to an active avoidance strategy to prevent electrical shock compared with those who were not 61 . This decreased skin conductance was observed both for subsequent presentations of the extinguished conditioned stimulus and for presentation of a novel conditioned stimulus.…”

Human extinction learning is accelerated by an angiotensin antagonist via ventromedial prefrontal cortex and its connections with basolateral amygdala

“…After initial quality assessment of the data the primary hypotheses were evaluated in n = 30 LT-and n = 29 PLC-treated subjects (exclusion according to recommendations from ref. 27 , details provided in Methods). Treatment groups did not differ in pre-and post-treatment self-reported affective state or cardiovascular activity and were unaware of whether they had received LT or PLC (Table 1).…”

“…refs. 27,28 ) ( Supplementary Figure 2). Importantly, two-sample t-tests did not reveal between-group activation differences during this stage arguing against confounding effects of pre-treatment differences in threat acquisition.…”