Low Intensity Focused Ultrasound for Tobacco Use Disorder: High Resolution Targeting of the Human Insula

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Tobacco use disorder (TUD) remains the leading cause of preventable death in the world. Rates of cigarette smoking are higher and cessation rates are lower in the veteran population in the United States compared to the nonveteran population. Noninvasive neuromodulation holds promise as a therapeutic approach to TUD. Low-intensity focused ultrasound (LIFU) is a noninvasive method to inhibit cortical and deep brain regions. LIFU can reach deep brain regions and has spatial specificity. For smoking, one promising target to treat TUD is the dorsal anterior insular cortex (dAI), a brain structure whose function is linked to the desire to smoke. The insula 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. Remarkably, humans with damage to the insula were able to stop smoking easily and without experiencing cravings or relapse. LIFU can selectively target the dAI and provides a potentially transformative method to reduce nicotine craving and addiction. We will assess the safety and tolerability of LIFU to dAI in individuals with TUD. LIFU looks to have a similar safety profile to other non-invasive methods though there is limited data for its use in clinical populations and no data in substance use disorder. It is the purpose of this aim to produce a definitive multi- modal dataset demonstrating that LIFU as a safe non-invasive treatment option. To do so, we will use anatomical magnetic resonance imaging, neurological assessment, and patient query to assess the safety and tolerability of LIFU. We will also explore smoking behavior 24 hours post LIFU to the dAI compared to that delivered to the anatomic control site, the somatosensory cortex (S1) to determine whether there is a short- term effect of 1 session of LIFU to dAI on smoking behavior. We will also inhibit the dAI with LIFU to determine whether there is a causal role for the dAI in smoking cue induced craving and neural response in order to understand the mechanism of cue induced craving in TUD which is a clinically important behavior which has been associated with the severity of nicotine addiction. We propose to examine the effects of LIFU to left dAI fMRI blood level oxygen dependent (BOLD) activity and craving in response to smoking cue exposure. To achieve this, we will measure the effect of LIFU on 1) dAI compared to S1 blood-oxygen-level-dependent (BOLD) activation in response to smoking (compared to neutral) cue exposure and 2) cue-induced craving in individuals with TUD. We also plan to examine how LIFU to left dAI compared to S1 affects the temporal dynamics of large-scale networks implicated in addiction. We will examine resting state functional connectivity in the salience network (dAI- dorsal anterior cingulate (dACC). We hypothesize that LIFU will reduce SN connectivity and this reduction will be significantly correlated with the reduction in cue-induced craving. Treatments for TUD have limited efficacy. There is a need in the veteran population for safe-effective treatments for TUD. Selective inhibition of the dAI reduces craving, use and relapse in addiction animal models and lesion of the insula dramatically abolishes use and craving of cigarette smoking in humans. LIFU provides an ability to transiently and selectively inhibit this critical brain area to determine its causal role in TUD which then may lead to approved treatments for TUD that could also be applied to other substance use disorders.