Determinants of Repetitive Transcranial Magnetic Stimulation Efficacy in Tobacco Use Disorder: A Pre-Registered Study

Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising treatment for tobacco use disorder (TUD). Although at a group level, active stimulation outperforms sham, at an individual level, variability exists in clinical response. The behavioral and neurobiological factors that differentiate those who respond to rTMS from those who do not remain unclear. To explore individual factors that influence acute responses to rTMS, N = 60 human participants received one session of rTMS to the dorsolateral prefrontal cortex (DLPFC) and to a control region (visual cortex; V5) in a randomized order. They completed behavioral assessments and neuroimaging before and after rTMS sessions. Hypotheses involving behavioral and neuroimaging predictors of response were pre-registered prior to completion of data collection. rTMS to the DLPFC led to significant reductions in self-reported cigarette craving compared with rTMS to a control brain region (p = 0.0006) and participants were classified as n = 38 responders and n = 22 nonresponders. Responders used significantly more cigarettes per day (M = 11.441) compared to nonresponders (M = 7.952), reported higher levels of cigarette craving (d = 1.059), and more severe nicotine withdrawal (d = 0.803) prior to rTMS. Neuroimaging analyses based on preregistered hypotheses indicated that DLPFC-frontoparietal and insula whole-brain functional connectivity did not differ significantly between responders and nonresponders. However, exploratory analyses revealed that responders had reduced pre-rTMS functional connectivity between the insula and nucleus accumbens, precuneus, and occipital pole. These findings suggest that response to rTMS for TUD is associated with greater baseline cigarette consumption, craving, and withdrawal, in addition to distinct functional connectivity patterns related to salience, reward, and self-referential processes, providing candidate behavioral and neural markers for personalized rTMS interventions for TUD.