Cortical and Subcortical Signatures of Incentive Salience Attribution in Tobacco Use Disorder

Relapse is a defining feature of substance use disorders, yet relapse risk varies widely across individuals. This variability has been linked to individual differences in incentive salience attribution to drug-related cues. We used fMRI to identify cortical and subcortical circuits underlying individual differences in incentive salience attribution among people with tobacco use disorder. Fifty daily cigarette users viewed pleasant, unpleasant, cigarette-related and neutral images during task-based fMRI and completed a resting-state scan. We extracted per-condition BOLD activity from a functionally defined extended visual region (Emotional > Neutral) and applied k-means clustering (k = 2) to derive neuroaffective profiles. Whole-brain voxelwise tests assessed Group × Content (cigarette vs. pleasant) effects. We compared groups' resting-state connectivity at the network level and for subcortical-cortical pairs. Individuals were clustered based on neuroaffective reactivity to drug-related and pleasant stimuli: The C > P profile showed larger BOLD responses to cigarette cues than to pleasant stimuli, whereas the P > C profile showed the opposite pattern. Whole-brain analyses showed significant Group × Content interactions that mirrored these profiles across left dorsolateral and medial prefrontal cortices and amygdala-hippocampal regions. At rest, individuals in the C > P profile showed weaker within-network connectivity of the frontoparietal control network (FPCN) and, in exploratory analyses, reduced FPCN-nucleus accumbens coupling. By replicating and extending prior psychophysiological work, this study identifies neuroaffective profiles that reflect the variation in incentive salience attribution central to neurobehavioral models of relapse. These findings provide convergent neurobiological markers that characterize distinct motivational pathways in substance use disorders.