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死亡的主要原因。香烟价格 吸烟率较高，戒烟率较低，在美国退伍军人人口相比， 非退伍军人群体。无创神经调节有望成为TUD的治疗方法。 低强度聚焦超声（LIFU）是一种非侵入性的方法，以抑制皮层和深部脑区。 LIFU可以到达脑深部区域，并具有空间特异性。对于吸烟，一个有希望的治疗TUD的靶点 背侧前岛叶皮层（dAI），这是一种功能与吸烟欲望有关的大脑结构。的 海马是一个关键的脑区，在对药物线索暴露及其程度的反应中被激活。 在人类研究中，激活与自我报告的渴望正相关。值得注意的是， 吸烟者能够很容易地戒烟，而不会有烟瘾或复发。LIFU可以 选择性地靶向dAI，并提供了一种潜在的变革性方法来减少尼古丁渴望， 成瘾我们将在TUD患者中评估LIFU对dAI的安全性和耐受性。LIFU看起来有一个 与其他非侵入性方法相似的安全性，尽管其临床使用数据有限 没有关于物质使用障碍的数据。这一目标的目的是产生一个明确的多- 模态数据集证明LIFU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、神经系统评估和患者询问，以评估安全性和 LIFU的耐受性。我们还将探索LIFU后24小时至dAI的吸烟行为， 传递到解剖控制部位，体感皮层（S1），以确定是否有短- 1个疗程LIFU至dAI对吸烟行为的远期影响。我们还将用LIFU抑制dAI，以确定 是否有一个因果关系的作用，dAI在吸烟线索诱导的渴望和神经反应，以 了解TUD中线索诱导渴望的机制，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。我们建议检查LIFU对左DAI的影响 fMRI血液水平氧依赖（BOLD）活动和渴望响应吸烟线索暴露。到 为了实现这一点，我们将测量LIFU对1）与S1血氧水平依赖性相比dAI的影响 （BOLD）激活响应吸烟（与中性相比）线索暴露和2）线索诱导的渴望， 个人TUD我们还计划研究LIFU与S1相比如何影响左dAI的颞叶 与成瘾有关的大规模网络的动态。我们将研究静息状态下的功能连接 在显著性网络中（dAI-背侧前扣带（dACC））。我们假设LIFU会降低SN 连接性，并且这种减少将与线索诱导的渴望的减少显著相关。 TUD的治疗效果有限。退伍军人群体需要安全有效的 治疗TUD。选择性抑制dAI减少成瘾动物的渴望、使用和复发 模型和病变的研究显著地消除了人类对吸烟的使用和渴望。立夫 提供了一种暂时性和选择性抑制这一关键脑区的能力，以确定其在TUD中的因果作用 这可能会导致批准治疗TUD，也可以应用于其他物质的使用 紊乱

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.