ABSTRACT Cocaine use disorder (CUD) is a chronic relapsing disorder with significant burden to society costing more than $85 billion per year globally and there is no US Food and Drug Administration-approved intervention. There is a critical need to develop effective new treatment strategies. One rapidly emerging potential therapeutic is neuromodulation using low-intensity focused ultrasound (LIFU). The enormous potential of LIFU stems from the ability to focus ultrasound through the intact skull to a millimeter-sized focal spot size anywhere in the brain. This makes it a powerful alternative to both invasive neurosurgical procedures and other noninvasive brain stimulation techniques that have limited spatial resolution and can only reach superficial areas of the brain. One promising target to treat cocaine use disorder (CUD) is the dorsal anterior insular cortex (dAI). Unfortunately, the dAI lies deep within the lateral sulcus covered by the overlying opercula of the temporal lobe and is not accessible with conventional noninvasive neuromodulatory techniques. As such, LIFU provides a potentially transformative methods to non-invasively modulate the dAI to reduce cocaine craving and addiction. The dAI is a critical brain region which is activated in the response to drug cue exposure and its extent of activation is positively correlated with self-reported craving in human studies. In small animal models, reversible inactivation of dorsal anterior insula reduces cocaine seeking, decreases relapse after voluntary abstinence and decreases cue-induced and context-induced reinstatement of cocaine seeking. Remarkably, humans with damage to the insula were able to stop smoking easily and without experiencing cravings or relapse. In addition, the dAI is part of the salience network (SN). The SN is implicated in the direction of attention toward important stimuli and integration of top- down appraisal and bottom-up visceral and sensory information. Models posit the dAI first assesses the emotional value of incoming stimuli before transmitting the information to other nodes to plan and initiate future goal directed actions. In addiction this network is dysfunctional leading to a disproportionate saliency and sensitivity to drug related cues that biases decision making to use and ultimately abuse. To advance LIFU as a potential therapeutic for the treatment of CUD, in the UG3 phase of this proposal we will first test the safety and tolerability of the intervention and examine how selective inhibition of dAI reduces its activity to affect cue-induced craving. Develop. Upon successful completion of the UG3 phase, the UH3 phase will build upon these findings by examining the effect of dose and the duration of effect as well as how LIFU to dAI affects whole-brain network dynamics as how this affects craving for cocaine. The application of this information will provide a fundamental break-through in understanding how ultrasound energy can be rationally deployed to produce predictable clinical effects and act as a catalyst for the widespread clinical adoption of this technology for the treatment of CUD as well as other forms of substance use disorder.

NARRATIVE Cocaine use is on the rise with cocaine-induced deaths increasing by about 27% per year, on average, from 2013 through 2018, with no FDA approved pharmacotherapy. Low-intensity focused ultrasound (LIFU) is an innovative method of non-surgical brain modulation that can be focused anywhere in the brain with precise targeting to alter brain activity and potentially repair dysfunctional brain circuits involved in cocaine use disorder (CUD). This project will examine how ultrasound directed to a small but critical brain region implicated in CUD can affect brain activity to reduce craving for cocaine.