SUMMARY/ABSTRACT Smoking cessation is difficult, despite the demonstrated efficacy of several pharmacotherapeutic agents and cognitive behavioral therapies. This may be due to imbalanced neuronal circuits, including elevated functional connectivity in the drive-reward circuit (medial orbital frontal cortex [mOFC] to nucleus accumbens [NAc]) and decreased functional connectivity in the executive control circuit (dorsolateral prefrontal cortex[ DLPFC] to NAc). Repetitive transcranial magnetic stimulation (rTMS) is a new class of therapeutics that has already displayed remarkable potential for producing novel, non-pharmacological interventions for neuropsychiatric disorders. Previous studies have reported that rTMS decreased cue craving, reduced cigarette consumption, and increased smoking quit rate in tobacco use disorders(TUDs). However, the treatment parameters and exact mechanism for rTMS increasing smoking quit rate need further refinement. The goal of this UG3/UH3 application is to develop a circuit-based precision rTMS therapy for smoking cessation further. In the 2-year UG3 phase, we will recruit 45 TUDs. Participants will undergo a baseline cue-exposure fMRI and a resisting-to smoke fMRI session. Participants will be randomized into three groups: 1) Sham rTMS over the left mOFC or the left DLPFC. 2) Active, inhibitory low-frequency rTMS (LF-rTMS) over the left mOFC (1 Hz, 900 pulses, E- field modeling, 15 minutes, smoking cue exposure fMRI-guided target). Or 3) Active, high-frequency rTMS (HF- rTMS) over the left DLPFC (10 Hz, 3000 pulses, E-field modeling,15 minutes, resisting-to-smoke fMRI guided target). Fifteen sessions of rTMS will be completed over three weeks, after which we will acquire fMRI scans. Go/No-Go: To move on the UH3 phase, the UG3 must demonstrate (1) daily 1-Hz TMS over the left mOFC shows a different clinical effect in the reduction of cigarette consumption by 3 or more cigarette per day, compared to daily 10-Hz over the left DLPFC (2) compared to sham, one of the active site/frequency combinations shows relative clinical improvement (reduces cigarette consumption by 5 cigarettes per day) and significant brain connectivity changes (p < 0.05) (decreases the connection between NAc and mOFC, and increases the connection between DLPFC and NAc). In the 3-year UH3 phase, we will test the therapeutic effects of 4 weeks of active rTMS (1 Hz rTMS over the left mOFC or 10 Hz over the left DLPFC by the UG3 phase) vs sham rTMS in 64 TUDs and follow participant outcomes for 4 months post-treatment. We will also test the imbalanced function of drive-reward and executive control before and after 4 weeks of treatments to compare the imbalanced function between groups.

PROJECT NARRATIVE Cigarette smoking is a significant public health concern. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive form of brain stimulation that has already displayed remarkable potential for producing novel, non-pharmacological interventions for neuropsychiatric disorders. Here we will develop a brain circuit-based precision rTMS therapy for smoking cessation.