ABSTRACT. Cocaine use disorder (CUD) is highly debilitating and common, but without established treatments. Individuals with CUD show elevated activity to cocaine cues in the ventral striatum (VS), a key region in the prefrontal cortex-striatal reward network (RNet) supporting reward valuation, other RNet regions, and the dorsal anterior cortex-insula salience network (SN). This pattern of elevated activity is positively associated with craving and years of cocaine use. Carefully-monitored studies show that transcranial focused ultrasound (tFUS) is a safe intervention that has the advantage over other neuromodulation techniques of being able to target deep subcortical structures, such as the VS. tFUS is thus a promising intervention for CUD, and other neurological and psychiatric disorders characterized by abnormally elevated subcortical activity. Yet, no studies have determined whether the VS can be modulated by tFUS. We propose a proof-of-concept study targeting the VS with tFUS, as a promising way to develop new device-based interventions for individuals with CUD, in accord with PAR-20-279. Our first goal is to determine that VS engagement by tFUS is possible (UG3 phase) in 25 healthy volunteers (aged 18-45 years; VS tFUS [and same hemisphere sham] laterality counterbalanced across participants). We will use a reward task that reliably activates the VS to reward prediction error (PE), the difference between the expected and actual reward, in healthy individuals, where greater VS activity to reward PE is associated with higher levels of impulsive decision-making, a behavioral trait predisposing to substance use disorders. Greater VS activity to reward PE in healthy individuals is thus a neural marker of substance use disorder risk, as well as a target for tFUS. We will then (UH3 phase) perform a sham-controlled trial to determine the effects of VS tFUS on neural responses to cocaine cues and cocaine craving in 40 individuals with CUD. In UG3, we aim: 1. To determine in healthy individuals target engagement of the VS by tFUS, and the duration and tolerability of the intervention. We will measure: a) how VS tFUS vs. sham tFUS impacts VS activity and VS- RNet and VS-SN functional connectivity (FC) to reward PE with fMRI; and b) if it has lingering effects on neural network measures, and adverse effects. tFUS positioning and delivery will be guided by neuronavigation and individualized simulation of the US field of stimulation; 2. To finalize all regulatory approvals for UH3, including protocol approval by the University of Pittsburgh Institutional Review Board, and an Investigational Device Exemption by the FDA, for tFUS use in individuals with CUD. In UH3, we aim: 3. To determine the effects of VS vs. sham tFUS on neural responses to cocaine cues and cocaine craving in individuals with CUD. We will measure: a) how VS tFUS vs. sham tFUS affects VS activity and VS- RNet and SN FC to cocaine cues; and b) if these neural changes are associated with c...