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Background and aims Individuals with methamphetamine dependence ( MD) exhibit dysfunction in brain regions involved in goal maintenance and reward processing when compared with healthy individuals. We examined whether these characteristics also reflect relapse vulnerability within a sample of MD patients. Design Longitudinal, with functional magnetic resonance imaging ( fMRI) and clinical interview data collected at baseline and relapse status collected at 1-year follow-up interview. Setting Keck Imaging Center, University of California San Diego, USA. Participants MD patients ( n = 60) enrolled into an in-patient drug treatment program at baseline. MD participants remaining abstinent at 1-year follow-up (abstinent MD group; n = 42) were compared with MD participants who relapsed within this period (relapsed MD group; n = 18). Measurements Behavioral and neural responses to a reinforcement learning (paper-scissors-rock) paradigm recorded during an fMRI session at time of treatment. Findings The relapsed MD group exhibited greater bilateral inferior frontal gyrus ( IFG) and right striatal activation than the abstinent MD group during the learning of reward contingencies ( Cohen's d range: 0.60-0.83). In contrast, the relapsed MD group displayed lower bilateral striatum, bilateral insula, left IFG and left anterior cingulate activation than the abstinent MD group ( Cohen's d range: 0.90-1.23) in response to winning, tying and losing feedback. Conclusions Methamphetamine-dependent individuals who achieve abstinence and then relapse show greater inferior frontal gyrus activation during learning, and relatively attenuated striatal, insular and frontal activation in response to feedback, compared with methamphetamine-dependent people who remain abstinent. [ABSTRACT FROM AUTHOR]