Brain reactivity to nicotine cues mediates the link between resting-state connectivity and cue-induced craving in individuals who smoke or vape nicotine.

Individual differences in brain intrinsic functional connectivity (FC) and reactivity to nicotine cues are linked to variability in clinical outcomes in nicotine dependence. However, the relative contributions and potential interdependencies of these brain imaging-derived phenotypes in the context of craving and nicotine dependence are unclear. Moreover, it is unknown whether these relationships differ in individuals who smoke versus vape nicotine. To investigate these questions, eighty-six individuals who use nicotine daily (n = 67 smoking, n = 19 vaping) completed either a smoking or vaping cue-reactivity task and a resting-state scan during functional magnetic resonance imaging (fMRI). Validating the efficacy of the smoking and vaping tasks, both cohorts displayed robust reactivity to nicotine versus neutral cues in the default mode network (DMN) and the anterior insula (AI), a primary node of the salience network (SN), which did not habituate over time. In the smoking and vaping groups, lower prefrontal reactivity to nicotine versus neutral cues and greater resting-state FC between nodes of the SN and DMN were associated with higher cue-induced craving. Moreover, we found that the former partially mediated the latter, suggesting a mechanism in which high resting SN-DMN connectivity increases craving susceptibility partly via a constraining effect on regulatory prefrontal reactivity to cues. These relationships were not impacted by group, suggesting that links between brain function and craving are similar regardless of smoking or vaping nicotine.