ABSTRACT Background: Converging lines of evidence suggest that neuromodulation of the neural circuits underlying methamphetamine use disorder (MUD) and subsequent relapse may be an innovative next step in improving treatment outcomes. Emerging research supports the salience network (SN) as a promising target to accomplish these goals. Deep transcranial magnetic stimulation (dTMS) is one type of neuromodulation technique that allows for deeper stimulation of cortical neurons, thus reaching core nodes of the SN like the insula. Objective: The aim of this 2-phase proposal is to assess: 1) whether the H4 coil protocol is effective at engaging the AIns core node of the SN, 2) does this coil and protocol engage the neural target better than a sham condition, and 3) does stimulation of this core node have downstream effects on behavior (i.e., relapse risk). Methods/Design: In the UG3 phase, we will enroll 30 treatment-seeking participants with MUD into a mechanistic trial to determine whether this treatment site and protocol effectively modifies the desired neural target and reduced relapse rates. Participants will receive 30 sessions of 10Hz dTMS to the insula and PFC using the H4 coil. Participants will receive 3 dTMS treatments per day for 10 days totaling 30 treatment sessions. Participants will complete neuroimaging assessments at baseline, after 50% of treatment sessions, post-treatment and 1 month after treatment. In order to advance to the UH3 phase, we will require that dTMS increases activation (of at least a medium effect size) to the respective neural target AND result in reduced relapse rates relative to treatment as usual. If the UG3 milestone criteria are met, in the UH3 phase we will enroll an additional 60 adults with MUD into a 2-arm randomized, double-blind, sham-controlled mechanistic trial to confirm target engagement relative to sham, assess the impact of the protocol on methamphetamine use behaviors, and determine moderators of treatment response. Specific Aims: For the UG3 (Study 1), we aim to demonstrate feasibility, tolerability and target engagement (neural and behavioral improvements). If milestone criteria are met, in the UH3 phase (Study 2), we aim to 1. Confirm target engagement in a 2-arm randomized, double blind, sham-controlled trial. 2. Examine the relationship between target engagement to a more refined measure of use behaviors (i.e., % days abstinent). 3. Determine predictors of treatment outcomes. Impact: The proposed research will elucidate mechanisms of brain and behavior change, accelerate the development of new, device-based, treatment options and will be the basis for developing a large-scale, dose-varying, clinical trial to test new treatment strategies for MUD.

PROJECT NARRATIVE Converging lines of research support the utilization of deep transcranial magnetic stimulation (dTMS) as a novel, non-pharmacologic approach to improving treatment outcomes for those with methamphetamine use disorder (MUD) by modulating neural circuits related to relapse. The results of this study will be used to determine whether the proposed dTMS protocol has an effect on neural target engagement and subsequent use behaviors (% days abstinent). These data will set the foundation for increasing the clinical indications of dTMS to be used as an innovative, new treatment option for individuals with MUD.