Towards treatment for the complex patient: investigations of low-intensity focused ultrasound.

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Opioid use disorder with co-morbid chronic pain and anxiety (OCpA) is a clinical triad associated with the highest risk of opiate overdose deaths. Co-occurrence of these three disorders amplifies symptoms of each and results in poorer treatment outcomes. There are shared neurobiological substrates for these disorders such as reward processing and stress response. The anterior insula (AI) is a brain region involved in these processes as well as in clinical disorder of pain, addiction, and anxiety. The AI is upregulated in pain, addiction and anxiety disorders and is therefore a potential therapeutic target for neuromodulation. Low-intensity focused ultrasound (LIFU) is a noninvasive method to inhibit cortical and deep brain regions. LIFU can reach deep brain regions such as the AI with spatial specificity, unlike traditional noninvasive neuromodulation methods which lack spatial specificity and depth penetration. LIFU can selectively target the insula and its subregions and provides a potentially transformative method to reduce symptoms of pain, opiate craving, and anxiety in a complex patient population such as OCpA. In the UG3 phase of this study, we will administer one session of inhibitory LIFU to the AI in individuals with OCpA [opiate use disorder, chronic back pain, and anxiety disorders (generalized anxiety disorder, post-traumatic stress disorder, or social anxiety disorder)]. The aim of this phase of the study is to establish that LIFU vs sham LIFU to AI is safe and well tolerated as measured by adverse events, clinical evaluation and repeated structural brain magnetic resonance imaging scans. We will also gather preliminary data on the effect of LIFU to AI on opiate cue-induced craving and laboratory measures of central sensitization(CS) which occurs with pain chronicity such as temporal summation of pain and conditioned pain modulation. In the second phase of this project (UH3), we will examine the efficacy, in a larger sample of individuals with OCpA, of repeated LIFU delivery on measures of pain and opiate cue-induced craving, anxiety symptoms, interoception and autonomic reactivity as these outcomes are dysregulated in OCpA and are mediated by the AI. LIFU will be delivered for 10 minutes each hour for 4 hours on a single day. We hypothesize that repeated sessions of LIFU will reduce measures of CS, opiate cue-induced craving, state anxiety symptoms, increase heart rate variability and normalize measures of interoception. We will examine the durability and effect of 1 vs 2 sessions of repeated LIFU on these outcome measures. Repeated sessions of other forms of neuromodulation result in increased magnitude and longer lasting effects. We hypothesize that 2 sessions vs 1 of repeated LIFU will result in greater magnitude of change in the outcome measures. Lastly, we will examine the safety and tolerability of repeated LIFU sessions. There is a need for improved treatments for complex patients such as OCpA beyond combining treatments for each disorder. LIFU provides an ability to transiently and selectively inhibit AI to determine its causal role in OCpA symptoms which then may lead to improved treatments for this clinical triad which is associated with poor treatment outcomes.