PROJECT SUMMARY The addiction epidemic continues to ravage the nation despite the scientific efforts of researchers and the funding resources provided at state and government levels. Overdose deaths this year, most of which involved opioids, were the highest in recorded history. While medication for opioid use disorder (MOUD) has been effective in improving outcomes, approximately 50% of those seeking treatment subsequently relapse on opioids and/or other substances. Further complicating matters, the prevalence of substance use disorders (SUDs) co-occurring with OUD, many of which do not yet have effective medication treatments available (e.g., methamphetamine), suggests that this epidemic extends well beyond opioids. As such, new treatment modalities are urgently needed to address the addiction epidemic plaguing our communities. Various forms of neuromodulation have demonstrated promising results as a potential adjunctive treatment to the standard level of care for SUD; however, these forms of neuromodulation are not without their limitations. Noninvasive forms are unable to precisely target subcortical structures integral to the addiction/reward circuitry, such as the nucleus accumbens (NAc), while those capable of targeting these regions require an invasive surgery with accompanying potential complications and burden. Low Intensity Focused Ultrasound (LIFU), circumvents these limitations, demonstrating the capability to precisely target subcortical structures without requiring an invasive surgical procedure or device implantation. Our team recently completed a pilot study investigating LIFU in eight individuals with OUD which demonstrated that LIFU targeting the NAc, was safe and well-tolerated. Participants who received a “therapeutic” LIFU dose (90-100W; n=6) also evidenced substantial decreases in craving acutely during LIFU sonication and suggestion of prolonged reductions throughout post-LIFU Day 90 follow-up. The overarching goal of the current application is to enroll a new cohort of 5 participants with OUD for purposes of replicating and expanding the findings demonstrated in the six previously enrolled participants who received the “therapeutic” LIFU dose (resulting in a dataset with a cumulative sample of 11 participants). Co-primary outcomes include safety and cue-induced craving at the post-LIFU Day 7 endpoint with secondary endpoints extending through the post-LIFU Day 90 follow-up. Secondary/exploratory outcomes include the evaluation of NAc LIFU on substance use, functional connectivity (assessed via fMRI), emotional symptoms, cognitive functioning, and treatment engagement. We hypothesize that LIFU applied to the NAc will be safe and well- tolerated and will modulate the brain networks associated with reward and addiction, thereby reducing opioid and other substance craving and improving outcomes in individuals with OUD. An important outcome of this proposal is the generation of new information regarding the impact of LIFU as a treatment for OUD. These data will be used to develop future grant proposals to investigate, refine, and establish LIFU treatment for OUD to address this emergent health crisis that continues to grow at alarming rates.

PROJECT NARRATIVE Novel treatments for opioid use disorder are critically needed as the addiction epidemic continues to ravage the nation; overdose deaths this year were the highest ever recorded. Neuromodulation has demonstrated promising results as a potential adjunctive treatment to the standard level of addiction care. Given the high rate of relapse to opioids and other substances following treatment, this proposal seeks to expand treatment options for patients with opioid use disorder by evaluating a novel, non-pharmacological treatment – Low Intensity Focused Ultrasound – targeting the center of the reward neurocircuitry (the Nucleus Accumbens).