Predicting individual incubation of opioid craving by whole-brain functional connectivity

A high risk of relapse triggered by craving during abstinence remains a main challenge in opioid addiction treatment. Multiple brain regions have been implicated in opioid craving, but the brain-wide neural mechanisms underlying this process remain poorly understood. Using resting-state fMRI and connectome-based predictive modeling, we identified a whole-brain connectome that predicted the time-dependent increases (incubation) in oxycodone craving in individual rats after voluntary abstinence induced by exposure to an electric barrier. Incubation of oxycodone craving was operationally defined as the increase in non-reinforced lever pressing during relapse tests from early (day 1) to late (day 15) abstinence (incubation score). We found that changes in whole-brain functional connectivity during abstinence, but not during oxycodone self-administration, predicted the incubation score. Greater decreases in functional connectivity were associated with higher incubation scores. The predictive connectome involved complex interactions across multiple brain systems, including frontal-striatal, frontal-insula, insula-striatal, and hippocampal and sensorimotor circuits. To test causality of the predictive connectome, we examined the effect of pharmacological inactivation of dorsomedial striatum (DMS), which significantly decreased oxycodone seeking after electric barrier-induced abstinence. DMS inactivation increased connectivity strength within the predictive connectome, supporting a causal role of this connectome in incubation of oxycodone craving. The predictive connectome did not predict food-reward seeking after electric barrier-induced abstinence, indicating specificity to oxycodone craving. Our findings identify a brain-wide connectome marker that predicts individual differences in the incubation of opioid craving and provide potential targets for developing personalized interventions and monitoring therapeutic outcomes in opioid addiction treatment. Significance statementRelapse driven by craving remains a central challenge in treating opioid addiction. Using resting-state fMRI and connectome-based predictive modeling, we identified a whole-brain connectivity pattern that predicted incubation of oxycodone craving after voluntary abstinence in rats. Connectivity changes during abstinence predicted the magnitude of incubation, measured by increased oxycodone seeking from early to late abstinence. The predictive connectome involved interactions among cortical, basal ganglia, insular, hippocampal and sensorimotor systems. Pharmacological inactivation of the dorsomedial striatum modulated connectivity strength within this network, demonstrating a causal role of the connectome in incubation of craving. These findings identify a brain-wide marker of incubation of opioid craving and provide a translational framework for developing targeted interventions and monitoring therapeutic outcomes in opioid addiction treatment.