PROJECT SUMMARY/ABSTRACT Substance use disorders (SUDs) are associated with reward-related abnormalities of the anterior midcingulate cortex (MCC), a brain region strongly implicated in goal-directed decision-making. Our recent findings show the reward positivity, an electrophysiological signal believed to index sensitivity of the MCC to rewards, to be abnormal in SUDs: People who abuse substances produce a blunted reward positivity to monetary rewards, but following an overnight period of drug abstinence, the size of the reward positivity is enhanced by drug-related rewards. This maladaptive process is thought to bias the MCC action-selection mechanism to favor behaviors that ultimately converge on drug use. Importantly, we provided compelling evidence that an FDA approved treatment for depression, 10-Hz transcranial magnetic stimulation (TMS) to the prefrontal cortex, can recover the reward function of the MCC in problematic substance users, and further, reverse the magnitude of the reward bias between monetary and drug-related rewards in abstained smokers. These important findings suggest that (i) the reward positivity is a highly sensitive biomarker of SUD severity and treatment efficacy and (ii) modulating MCC with TMS may correct the aberrant reward processes that sustain SUDs. However, given the limitations and variability of conventional TMS methods used to target the MCC, the optimal TMS protocol for MCC modulation is currently unknown. We therefore propose to use a cutting-edge technology called robot-assisted image-guided TMS (Ri-TMS) to identify the optimal TMS protocol aimed to restore the reward function of the MCC in SUDs with the highest level of precision. In the UG3 phase, we will establish the optimal Ri-TMS parameters needed to maximize excitatory effects on reward-related MCC electrophysiology in dependent smokers and healthy controls. In Study 1, we will utilize powerful quantitative neuroimaging methods to construct stimulation targets based on prefrontal structure, function, and connectivity with MCC, and test the targets efficacy to modulate the reward positivity, decision-making performance, and craving scores in abstained smokers (Aim 1). In Aim 2, we will evaluate the efficacy of various pulse protocols to enhance and suppress the reward positivity to monetary and cigarette rewards, respectively, in abstained smokers. The targeting protocol achieving our Go criteria and with the largest effect size across these aims will advance to the UH3 phase. In Aim 3, we will apply our candidate Ri-TMS protocol to enhance the reward positivity to monetary rewards and suppress the reward positivity to drug-related rewards in abstinent smokers. We will also assess the protocols impact on decision-making and craving scores. In Aim 4, we will assess the long-term effects of the Ri-TMS across multiple Ri-TMS sessions on reward positivity, decision-making, and smoking behavior (craving, abstinence, and cigarette valuation). Our long-term goal is to provide treatment programs with a more relevant neurocognitive treatment option, which may increase substance users' success in treatment, maintaining abstinence, as well as achieving broader life goals.

Project Narrative Reward‐related neural dysfunction is known to accompany chronic substance abuse and may put substance users at higher risk of treatment dropout and drug relapse. Using a combination robotics, neuroimaging, and non-invasive brain stimulation methods, the proposed research seeks to develop new brain-based interventions aimed to correct the aberrant reward processes that sustain substance use disorders. Providing current treatment programs with a highly effective brain-based intervention may increase substance users' success in treatment, and thereby help reduce the major burden substance use disorders places on the US healthcare system.