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

烟草使用障碍(TUD)仍然是世界上可预防的死亡的主要原因。吸烟率 与美国退伍军人相比，美国退伍军人的吸烟率更高，戒烟率更低 非退伍军人群体。无创神经调节有望成为治疗TUD的一种方法。 低强度聚焦超声(LIFU)是一种非侵入性的方法，可以抑制大脑皮质和深部区域。 利福可以触及脑深部区域，并具有空间特异性。对于吸烟，治疗TUD的一个有希望的靶点 是背侧前岛叶皮质(DAI)，这是一种大脑结构，其功能与吸烟的欲望有关。这个 脑岛是大脑的一个关键区域，在对药物线索暴露的反应中被激活，其程度 在人类研究中，激活与自我报告的渴望呈正相关。值得注意的是，人类 对脑岛造成损害的患者能够轻松戒烟，而不会有烟瘾或复发。利福可以 选择性地针对DAI，并提供了一种潜在的变革性方法来减少对尼古丁的渴望和 上瘾。我们将评估利福对DAI的安全性和耐受性。利福看起来有一个 与其他非侵入性方法的安全性相似，但用于临床的数据有限 而且没有药物使用障碍方面的数据。这一目标的目的是产生一个明确的多- 模式数据集证明利福是一种安全的非侵入性治疗选择。为此，我们将使用 解剖磁共振成像、神经学评估和患者查询，以评估安全性和 利福的耐受性。我们还将调查24小时后的吸烟行为，并将其与利福至达赖进行比较 传送到解剖控制点，即躯体感觉皮质(S1)，以确定是否存在短- 利福至达赖1次疗程对吸烟行为的影响。我们还会用利福来抑制达人的决定 DAI在吸烟线索诱导的渴求和神经反应中是否有因果作用 了解线索诱导TUD渴求的机制，这是一种临床上重要的行为， 与尼古丁成瘾的严重程度有关。我们建议考察理府对左黛族的影响 功能磁共振成像的血液水平氧依赖(BOLD)活动和对吸烟线索暴露的渴望反应。至 要做到这一点，我们将测量利福对1)DAI的影响，并与S1血氧水平依赖的比较 (BOLD)对吸烟反应的激活(与中性)线索暴露和2)线索诱导的渴望 患有TUD的个体。我们还计划研究Lifu to Left DAI与S1相比如何影响时间 与成瘾有关的大规模网络的动态。我们将检查休眠状态的功能连接 在突起网络(DAI-背侧前扣带核(DACC)。我们假设利福将降低SN 连通性和这种减少将与线索诱导的渴望的减少显著相关。 治疗TUD的疗效有限。在退伍军人群体中需要安全有效的 治疗TUD。选择性抑制DAI可减少成瘾动物的渴求、使用和复发 脑岛的模型和损伤极大地消除了人类吸烟的使用和渴望。利福 提供一种暂时和选择性地抑制这一关键大脑区域的能力，以确定其在TUD中的因果作用 这可能会导致TUD的批准治疗，也可以应用于其他物质的使用 精神错乱。

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.