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

Cigarette smoking remains the leading preventable cause of death, emphasizing the need for new therapeutics, such as repetitive transcranial magnetic stimulation (TMS). We tested the hypothesis that TMS to three targets would reduce cigarette craving and withdrawal by modulating connectivity within and between three canonical networks in a randomized clinical trial (ClinicalTrials.gov: NCT03827265). Participants (N = 72; DSM-5 tobacco use disorder, ≥1 year of daily smoking) received one session of TMS to hubs of canonical resting-state networks: the dorsolateral prefrontal cortex (dlPFC), superior frontal gyrus (SFG), posterior parietal cortex (PPC), and area v5 (control). Self-reports (craving, withdrawal, and negative affect) and resting-state functional connectivity were measured before and after stimulation. SFG stimulation significantly reduced craving (95% CI, 0.0476-7.9559) and withdrawal (95% CI, 0.9225-8.1063) versus control, with larger effects in men (D = 0.59) than in women (D = 0.30). SFG stimulation did not change network connectivity, whereas dlPFC stimulation increased somatomotor, default mode, and dorsal attention network connectivity. No severe or unexpected treatment-related adverse events occurred. These findings suggest that SFG shows promise as a target for smoking-cessation treatment, especially for men. Further trials are warranted to confirm efficacy and develop imaging biomarkers for precision neuromodulation.