This is a revised R21 (PA-03-107) application originally reviewed by the NPAS study section in June 2005 and October 2006. Using an event-related reward conditioning functional magnetic resonance imaging (fMRI) task, we propose to study the neurocognitive substrates underlying reward devaluation (through extinction) and relapse in drug addiction. In this task, three phases distinguish between conditioning, extinction, and extinction retention of monetary conditioned stimuli (CS). We hypothesize that compared to control subjects (N=25), recovering cocaine addicted individuals (N=80) are impaired in the ability to retain information about reductions in the value of monetary reward conditioned cues as indexed by skin conductance responses (SCR), value or intensity ratings, and ventromedial prefrontal cortical (vmPFC) signal changes to a previously rewarded target CS (CS+Tgt) compared to a still rewarded non-target CS (CS+nTgt) or a never rewarded CS (CS-). We further predict that a restricted differential in the psychophysiological, self-rating, or neuronal responses to the CS+Tgt vs. the CS+nTgt, specifically during the extinction retention and not initial extinction testing, would be predictive of relapse (assessed by a variety of qualitative and quantitative measures) at six-months follow-up. The innovation and novelty of this proposal lie in the use of fMRI to identify subregions of the PFC to predict susceptibility to relapse in recovering drug addicted individuals. Furthermore, while extinction paradigms have primarily been used in fear related disorders with fear inducing stimuli, we suggest implementing similar paradigms using appetitive stimuli in disorders characterized by compromised reward processing. Our underlying assumption is that appetitive cues are as emotionally salient and thus difficult to extinguish to the drug addicted individual as fear stimuli are to the post-traumatic stress disorder patient. The current proposal will therefore advance our understanding of the core affective learning mechanisms that may predict longer-term relapse in cocaine addicted individuals. Major changes since the previous application include: 1) clarifications in response to specific concerns raised by the reviewers (e.g., strength of experimental manipulation, effects of chronic cocaine use/craving, other confounding factors, ROI definitions, recruitment);2) modification of our event-related paradigm to closely follow the classical conditioning task for fMRI developed by our consultant (E. Phelps);3) addition of SCR recordings (conducted simultaneously with fMRI) as an objective measure of response;and 4) a newly established collaboration with director of an inpatient treatment facility (R. Sinha) to double the number of addicted individuals recruited for relapse prediction.
