Despite these limitations, the present findings point to a novel pathophysiological mechanism underlying nicotine withdrawal symptoms that promote smoking relapse. These data move beyond the concept of a dysregulated DMN to suggest that the ability of the SN to toggle (or perhaps rapidly oscillate) between the ECN and the DMN, along with the ability to disengage from DMN activity, may be critical in cognitive alterations that underlie nicotine addiction. Because successful quitting requires top-down executive cognitive control over smoking urges, exploration of the relationship of the RAI to quitting success in a longitudinal cohort study would be important. On validation, the RAI could serve as a clinical bio-marker to identify smokers who are most likely to respond to a particular treatment. For example, evidence that antidepressant treatment normalizes altered resting-state DMN connectivity among patients with dysthymia46 suggests that smokers who exhibit abstinence-induced reductions in the RAI may benefit from the antidepressant bupropion hydrochloride for smoking cessation. With additional validation in other cohorts, the RAI could also be a potential biomarker for screening novel treatments for smoking cessation.51
