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 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 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 the 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 produced 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.

Question What is the most promising cortical target for TMS treatment of tobacco use disorder for men and women?

Findings In a randomized crossover trial, stimulation to the superior frontal gyrus relieved craving and withdrawal the most.

Meaning The superior frontal gyrus is a promising neuromodulation target for smoking cessation. Men and women may respond differently to this intervention.

Andrew Leuchter has received research support from the NIH, the Department of Defense, MagVenture, and NeurOptics. He has served as a consultant to eFovea, Options MD, Kernel, Inc., and ElMindA.

NCT03827265

This work was supported by K99/R00DA045749 (Transcranial Magnetic Stimulation and Tobacco Use Disorder: A Network-Level Approach with Attention to Sex as a Biological Variable) and the Friends of Semel Award to NP.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRB of the University of California, Los Angeles gave ethical approval for this work.

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All data produced in the present study are available upon reasonable request to the authors.