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

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.

Pupil dilation as an implicit measure of appetitive Pavlovian learning

“…No conditioning effect was observed in the SCR or acoustic startle responses (EBR, PAR). Previous studies showed both significant SCR effects during appetitive conditioning (Andreatta & Pauli, ; Ebrahimi et al, ; Klucken et al, , , ; Tapia León et al, ), as well as no significant differential response to the conditioned CS (Ebrahimi et al, ; Klucken et al, ; Stussi et al, ; van den Akker et al, ). Our nonsignificant finding may result from insufficient statistical power (especially due to the exclusion of eight participants from the SCR analysis) or habituation effects (i.e., a decrement in response amplitude with repeated CS presentation), which particularly afflicts experiments with a longer duration as used in our study (Leuchs et al, ; Lonsdorf et al, ).…”

“…The three possible pairings of CS and outcome (CS+ reinforced, CS+ unreinforced, and CS− trials) appeared equally often in the first and second half of the experiment (Klucken et al, ). Additionally, the following criteria were applied to the trial sequences: There were never more than three consecutive trials of the same condition, cues were never displayed for more than three successive trials on the same side of the fixation cross, and there was a balanced succession of CS+ and CS− trials following a trial with US delivery (Ebrahimi et al, , ).…”

“…Regarding the first, it is difficult to determine a US whose rewarding properties or subjective pleasantness is inter‐individually equivalent. So far, a variety of both primary and secondary stimuli have been used for appetitive reinforcement, for example, food (Andreatta & Pauli, ; Blechert, Testa, Georgii, Klimesch, & Wilhelm, ; van den Akker et al, ; Wardle, Lopez‐Gamundi, & Flagel, ), drink (Ebrahimi et al, ; O'Doherty, Buchanan, Seymour, & Dolan, ; O'Doherty, Dayan, Friston, Critchley, & Dolan, ; Pauli et al, ; Prévost, McNamee, Jessup, Bossaerts, & O’Doherty, ), odor (Gottfried, O'Doherty, & Dolan, ; Hermann, Ziegler, Birbaumer, & Flor, ; Stussi, Delplanque, Corai, Pourtois, & Sander, ), attractive faces (Bray & O'Doherty, ), erotic images (Klucken et al, , , ; Klucken, Wehrum‐Osinsky, Schweckendiek, Kruse, & Stark, ), and money (Austin & Duka, ; Delgado, Gillis, & Phelps, ; Ebrahimi et al, ; Tapia León, Kruse, Stalder, Stark, & Klucken, ). Although there exists a certain overlap, primary and secondary rewards are processed in distinct neural systems (Sescousse, Caldú, Segura, & Dreher, ).…”

“…Psychophysiological measures similarly often present inconsistent results. Electrodermal activity, which is a common learning index used in aversive conditioning paradigms (Lonsdorf et al, ; Ney et al, ), has shown both an enhanced skin conductance response (SCR; Andreatta & Pauli, ; Ebrahimi et al, ; Klucken et al, , , ; Tapia León et al, ), as well as no differential response (Klucken et al, ; Stussi et al, ; van den Akker et al, ) to the reward‐associated stimulus and appears to be dependent on task context (van den Akker et al, ). Heart period response (HPR) has seldom been examined in an appetitive context and has not yielded a conclusive differential effect (Hermann, Ziegler, Birbaumer, & Flor, ; Wardle et al, ).…”

“…Both SCR and HPR are characterized by long response latencies and durations, which unfortunately prolong the experiment’s duration (Lonsdorf et al, ; Sjouwerman & Lonsdorf, ). In contrast, acoustic startle responses (eyeblink reflex, EBR; Andreatta & Pauli, ; Ebrahimi et al, ; Hermann et al, ; Stussi et al, ; Wardle et al, ) and the vestigial postauricular microreflex (PAR; Aaron & Benning, ; Ebrahimi et al, ; Sandt, Sloan, & Johnson, ; Stussi et al, ) have short reaction latencies; however, their inherent aversive quality limits their utility in the appetitive conditioning domain, where they are confined to being post‐hoc measures.…”