Association of nicotine addiction and nicotine's actions with separate cingulate cortex functional circuits

Context: Understanding the mechanisms underlying nicotine addiction to develop more effective treatment is a public health priority. Research consistently shows that nicotine transiently improves multiple cognitive functions. However, using nicotine replacement to treat nicotine addiction yields generally inconsistent results. Although this dichotomy is well known, the reasons are unclear. Imaging studies showed that nicotine challenges almost always involve the cingulate cortex, suggesting that this locus may be a key region associated with nicotine addiction and its treatment. Objective: To identify cingulate functional circuits that are associated with the severity of nicotine addiction and study how nicotine affects them by means of regionspecific resting-state functional magnetic resonance imaging. Design: Double-blind, placebo-controlled study. Setting: Outpatient clinics. Participants: Nineteen healthy smokers. Intervention: Single-dose (21- or 35-mg) nicotine patch. Main Outcome Measures: Correlation of nicotine addiction severity and cingulate resting-state functional connectivity, and effects of short-term nicotine administration on connectivity strength. Results: Clearly separated pathways that correlated with nicotine addiction vs nicotine's action were found. The severity of nicotine addiction was associated with the strength of dorsal anterior cingulate cortex (dACC)- striatal circuits, which were not modified by nicotine patch administration. In contrast, short-term nicotine administration enhanced cingulate-neocortical functional connectivity patterns, which may play a role in nicotine's cognition-enhancing properties. Conclusions: Resting-state dACC-striatum functional connectivity may serve as a circuit-level biomarker for nicotine addiction, and the development of new therapeutic agents aiming to enhance the dACC-striatum functional pathways may be effective for nicotine addiction treatment.