Project Summary and Narrative Many mental health and neurological diseases have significant affective components of their disease and/or significant comorbidities with affective disorders, such that treating the affective component of the disease is beneficial for treating the whole disease process. In the parent award of this proposal, ultrasonic uncaging of ketamine will be applied to the anterior cingulate cortex of patients with chronic pain to treat the affective component of this disorder – to modulate how severe the patient experiences pain, less so modulating whether they experience pain in the first place. This same strategy could in principle be applied to other neuropsychiatric disorders that have a strong affective component. In particular opioid use disorder (OUD) is a significant cause of morbidity and mortality worldwide with a strong affective component. Traditional treatments like buprenorphine or methadone often fail to address the mood disturbances associated with OUD, leading to high relapse rates. Specifically, the withdrawal/abstinence period of OUD is associated with a negative affective state, dubbed ‘hyperkatifeia,’ that predisposes to relapse later. Like in the chronic pain application, ketamine uncaging targeted to a critical brain region could treat the affective component of substance use disorders, including OUD, to break the cycle of binge, withdrawal, and relapse that defines the disorder. In this training period, the candidate will explore the use of ultrasonic ketamine uncaging to modulate affective behaviors in rodent models of chronic pain as well as of OUD. This activity will better define the protocols for ultrasonic ketamine uncaging to be used in the clinical trial phase of the parent award, guide interpretation of the clinical and physiologic data in that clinical trial phase, and generate data to suggest further applications of ketamine uncaging, and the use of ultrasonic uncaging more broadly to treat affective disorders and the affective component of neuropsychiatric disease. During the preclinical phase of the parent award, the candidate will gain training in in vivo application of therapeutic ultrasound, neurobehavioral assay development and implementation, quantitative video behavioral analysis, functional ultrasound imaging, and neuroscientific data analysis. For the clinical phase of the parent award it is anticipated that the candidate will stay with the investigatory group, with or without a successful extension of this funding, to gain training in the clinical use of therapeutic ultrasound and neuropsychological trial implementation.