Opposing roles for amygdala and vmPFC in the return of appetitive conditioned responses in humans

Claudia Ebrahimi,Stefan P Koch,Charlotte Pietrock,Thomas Fydrich,Florian Schlagenhauf,Andreas Heinz

doi:10.1038/s41398-019-0482-x

Abstract

Learning accounts of addiction and obesity emphasize the persistent power of Pavlovian reward cues to trigger craving and increase relapse risk. While extinction can reduce conditioned responding, Pavlovian relapse phenomena—the return of conditioned responding following successful extinction—challenge the long-term success of extinction-based treatments. Translational laboratory models of Pavlovian relapse could therefore represent a valuable tool to investigate the mechanisms mediating relapse, although so far human research has mostly focused on return of fear phenomena. To this end we developed an appetitive conditioning paradigm with liquid food rewards in combination with a 3-day design to investigate the return of appetitive Pavlovian responses and the involved neural structures in healthy subjects. Pavlovian conditioning (day 1) was assessed in 62 participants, and a subsample (n = 33) further completed extinction (day 2) and a reinstatement test (day 3). Conditioned responding was assessed on explicit (pleasantness ratings) and implicit measures (reaction time, skin conductance, heart rate, startle response) and reinstatement effects were further evaluated using fMRI. We observed a return of conditioned responding during the reinstatement test, evident by enhanced skin conductance responses, accompanied by enhanced BOLD responses in the amygdala. On an individual level, psychophysiological reinstatement intensity was significantly anticorrelated with ventromedial prefrontal cortex (vmPFC) activation, and marginally anticorrelated with enhanced amygdala-vmPFC connectivity during late reinstatement. Our results extend evidence from return of fear phenomena to the appetitive domain, and highlight the role of the vmPFC and its functional connection with the amygdala in regulating appetitive Pavlovian relapse.

Highlights

Learning about environmental cues that signal desirable outcomes constitutes an important mechanism to flexibly adapt behavior and foster survival
unconditioned stimulus (US) pleasantness The perceived pleasantness of the chosen juice/smoothie was high throughout conditioning (M (SD) = 32.32(13.60); Fig. 2a) and before the reinstatement test (M (SD) = 32.61 (15.68)), and remained unchanged over sessions
Contingency awareness Reward contingencies for CS+ were rated significantly higher than for CS− after conditioning, indicating overall contingency knowledge across subjects that varied to different degrees (M (SD)diff = 30.40(31.58), t(61) = 7.58, p < .001, range: −18.84 to 99.34; Fig. 2a, see Supplementary Material for further details), suggesting that uninstructed conditioning in addition to our cover story allowed for variability regarding explicit learning

Summary

Introduction

Learning about environmental cues that signal desirable outcomes constitutes an important mechanism to flexibly adapt behavior and foster survival. Learning theories of addiction and obesity emphasize the persistent power of Pavlovian reward cues (conditioned stimuli, CS+)—a beer brand label in the super market or the smell of a freshly-baked cake—to trigger the desire for the associated drug/food (unconditioned stimulus, US), drive habits, and increase the risk of relapse long after abstinence[1,2,3,4]. Extinction—repeatedly presenting a CS+ without the US—reduces conditioned responding[5], it does not “erase” the original cue-reward association, but induces new, highly context-dependent inhibitory learning[6]. Several Pavlovian relapse phenomena—a return of conditioned responding towards the extinguished CS+—. Anxiety research experimentally investigates return of fear following extinction on multiple response systems, including psychophysiological measures (skin conductance, fear-potentiated startle) and neuroimaging[13,14,15]. Experimental research on appetitive Pavlovian conditioning and relapse in humans is still in its infancy[16,17,18]. This research gap has been explained by difficulties to find universally-rewarding USs and a lack of established measures sensitive to appetitive responses[19,20,21]

Objectives

Methods

Results

Discussion

Conclusion