Project Summary/Abstract Stress-exposure may lead to negative physical and psychological responses. Stress can be especially problematic for people trying to recover from opioid use disorder (OUD) because it impairs executive function (EF) and increases craving and likelihood of relapse. The applicant’s Sponsor (Dr. Greenwald) demonstrated that pharmacological stress increases drug-seeking behavior; however, the mechanisms by which stress impacts behavior are not fully understood. Moreover, there are no FDA-approved medications to reduce effects of stress on cognitive function and current OUD treatments do not effectively address stress. The goals of this training project are to train the applicant in neurobiological mechanisms involved in substance use disorders (SUDs) while developing skills in repetitive transcranial magnetic stimulation (rTMS) and EEG techniques. These goals will be accomplished by expanding the Sponsor’s work to determine the roles of the dorsolateral prefrontal cortex (dlPFC) and medial prefrontal cortex (mPFC) in modulating stress-induced drug-seeking, and to investigate how modulation of these targets alters stress-induced cognitive and affective functions. Neuromodulation with rTMS is a promising tool for developing a deeper understanding of mechanisms relating stress to drug-related outcomes. The Competing Neurobehavioral Decisions System theory posits that persons with SUDs may have hyperactive limbic reward circuitry and hypoactive executive control circuitry; this theory supports using rTMS to target limbic reward (via mPFC) or executive control (via dlPFC) circuitry to modulate drug seeking. Using a mixed design, we will examine the effects of pharmacological stressor (54mg yohimbine + 20mg hydrocortisone) vs. placebo (within subject) in conjunction with either 10Hz dlPFC vs. sham rTMS (group 1) or 1Hz mPFC vs. sham rTMS (group 2) in participants with OUD. Overall hypothesis: Excitation of EF circuitry via dlPFC rTMS or inhibition of limbic circuitry via mPFC rTMS will attenuate stress-induced executive dysfunction (Aim 1) or emotional dysregulation (Aim 2), respectively, relative to sham. rTMS of either target will attenuate stress-induced opioid-seeking (Aim 3). The experimental design, rigorous and reproducible methods, and innovative hypotheses are based on scientific literature and strong preliminary and published data from the Sponsor’s lab. Significance: This project will systematically advance understanding of neurobiological mechanisms of stress-reactivity and drug use in OUD, forming the foundation for future programmatic inquiry. Potential future research would evaluate: (1) the role of stimulating other brain structures to reduce stress response; (2) use of brain imaging and other biomarkers to further explore mechanisms in response to these interventions; and (3) effects of multiple rTMS sessions on modulating longer-term patterns of drug use. The applicant has assembled a strong mentorship team who alr...