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.
