A novel therapeutic application of closed-loop neuromodulation of the brain reward system in nicotine use disorder

PROJECT SUMMARY/ABSTRACT Decades of animal models have taught us that addiction is, indeed, a disorder of dysregulated neural circuits. However, there are currently no circuit-based biomarkers or treatments for human patients. Transcranial magnetic stimulation (TMS) has the potential to radically transform how substance use disorders (SUDs) are treated. Presently, multiple sessions of 10-Hz repetitive TMS (rTMS) passively applied over the left dorsal lateral prefrontal cortex (DLPFC) for 20 to 30 min (2000–3000 pulses) has recently been adopted for the treatment of nicotine use disorder (NUD), particularly reducing craving and cigarette consumption. It has been suggested that the observed modulation of the mesocorticolimbic reward circuitry by 10-Hz prefrontal rTMS might mediate the therapeutic effects of TMS in NUD and other substance-related disorders. However, in clinical practices, a half- hour TMS therapy 5 days a week could take weeks to be fully effective, and its therapeutic efficacy remains limited and varies greatly across individuals. Thus, the primary goal of this proposal is to develop a faster and more concentrated TMS protocol that may reduce the treatment time length and increase its clinical efficiency by more precisely identifying and actively targeting the reward circuitry and proximal functions. Building on recent advances in combining TMS with EEG, which allow TMS protocols to be directly controlled by the EEG signal (closed-loop modulation), we aim to test a novel close-loop TMS intervention capable of real-time tracking and modulation of distinct episodes of reward-related midcingulate cortex (MCC) activity in nicotine-dependent individuals. This approach potentially offers bidirectional treatments that are spatially, temporally, and cognitively precise. Our lab and others have identified oscillatory EEG signals in the theta band over frontal sites (frontal midline theta, FMT) that accompany dopaminergic reward prediction errors, and that are altered in NUD and other substance use disorders. Since the phase of oscillations in the EEG can reflect local processing, the timing of TMS pulses to precise periods during these rhythms should have direct neural, behavioral, and computational effects, and thereby improved clinical outcomes. Thus, we have developed a novel closed-loop system capable of tracking these theta oscillations in real-time and using that information to control delivery of TMS. This proposal seeks to test the neural, computational, behavioral efficacy of these protocols for modulating MCC reward function (Aim 1), and then test whether precisely triggering TMS synchronized with the peak or trough of FMT oscillations would temporarily reduce the subjective craving triggered by exposure to smoking cues in nicotine- dependent adult smokers (Aim 2). This project is innovative because it enables the possibility to instantaneously probe the MCC neural response pattern and to deliver TMS manipulations as they occur during reward-directed behavior. The proposed research is significant, because the scientific knowledge will provide best practices to choose stimulation parameters that will advance the treatment for particular neurocognitive processes involved in both NUD and other substance-related disorders.