Comparing neuromodulation targets to reduce cigarette craving and withdrawal: A randomized clinical trial

Importance: Cigarette smoking remains the leading preventable cause of death worldwide, leading to development of new therapeutics, such as repetitive transcranial magnetic stimulation (rTMS). Objective: To optimize treatment, we compared three TMS targets to evaluate the effects on cigarette craving and withdrawal, and on within- and between-network connectivity of the default mode, salience, and executive control networks. Design: Data were collected using a repeated-measures, crossover trial. Investigators were not blinded, nor were participants, who were aware of the location of the stimulating magnet but not which locations were designated as the control and experimental sites. Setting: Data were collected in a neuromodulation clinic within an academic medical center. Participants: Participants were men and women (44%) aged 21-45 (M = 33.3 years), who met DSM-5 criteria for tobacco use disorder and endorsed daily smoking for at least one year. Interventions: TMS was delivered to three neuroanatomical targets: dorsolateral prefrontal cortex (dlPFC), superior frontal gyrus (SFG), and posterior parietal cortex (PPC). Area v5 of the visual cortex served as an active control site. Participants were scanned with resting-state fMRI and completed behavioral assessments before and after TMS. Main Outcomes and Measures: Self-reports of craving, withdrawal, and negative affect were obtained, and resting-state functional connectivity of three canonical networks (executive control, default mode, and salience networks) was measured. Results: Seventy-two participants completed at least one data collection session, and 57 completed all 4, yielding 61, 60, 62, and 66 complete stimulation sessions to the dlPFC, SFG, PPC, and v5, respectively. Stimulation to the SFG significantly reduced craving (95% CI, 0.0476-7.9559) and withdrawal (95% CI, 0.9225-8.1063) more than control stimulation. Effect sizes were larger in men (up D = 0.59) than in women (up to D =0.30). Neither PPC nor control site stimulation significant effects on craving, withdrawal, or negative affect. Functional connectivity analyses revealed that SFG stimulation did not produce significant changes to the networks examined, whereas dlPFC stimulation led to increased connectivity between somatomotor, default mode, and dorsal attention networks. Conclusions and Relevance: The SFG appears to be a viable target for smoking-cessation treatment, especially for men, with possible advantages over dlPFC.