DLPFC rTMS is more effective than sham or orbitofrontal stimulation for smoking cessation and alters frontal brain activity: A double-blind, sham-controlled randomized clinical trial

Repetitive transcranial magnetic stimulation (rTMS) shows promise for smoking cessation, but its neural mechanisms remain unclear. It is unknown whether rTMS reduces smoking by enhancing executive control or suppressing reward-related brain activity. This study aimed to address this gap by comparing excitatory and inhibitory rTMS targeting distinct cortical circuits implicated in tobacco use disorder (TUD). In a double-blind, sham-controlled design, treatment-seeking individuals with TUD were randomized to 15 sessions of personalized, fMRI-guided, E-field–dosed rTMS: (1) sham rTMS, (2) excitatory 10 Hz rTMS over the left dorsolateral prefrontal cortex (L-DLPFC; 3,000 pulses/session), or (3) inhibitory 1 Hz rTMS over the left medial orbitofrontal cortex (L-mOFC; 900 pulses/session). fMRI scans were conducted pre- and post- 15 sessions of rTMS. Primary outcomes were reductions in cigarettes per day (CPD) and changes in blood-oxygen-level–dependent (BOLD) activity. Thirty-five of 46 participants completed the study (sham = 9; 10 Hz L-DLPFC = 12; 1 Hz L-mOFC = 14). The 10 Hz L-DLPFC group showed a significantly greater CPD reduction than 1 Hz L-mOFC and sham (–11.14 vs. –4.92 and –6.43, respectively; p < 0.0001, partial η 2 = 0.135). rTMS to the L-DLPFC also increased prefrontal activity and decreased orbitofrontal activity (p < 0.05), with the degrees of CPD reduction correlating with enhanced activation in L-DLPFC (p<0.05). Enhancing executive control via 10 Hz rTMS over the L-DLPFC was more effective for smoking reduction than suppressing reward circuitry with 1 Hz rTMS over the L-mOFC. Findings suggest that strengthening prefrontal regulation of reward processing is a key mechanism by which rTMS promotes smoking cessation. clinicaltrials.gov Identifier: NCT 04903028 • Multiple sessions of daily MRI-guided rTMS to the left DLPFC aided smoking cessation. • 10 Hz DLPFC for three weeks is superior to 1 Hz mOFC and sham treatment. • 3-week daily 10 Hz rTMS over the left DLPFC increased prefrontal cortex activity and decreased medial frontal cortex activity.