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

低强度聚焦超声治疗烟草使用障碍：人类脑岛的高分辨率靶向

• 批准号: 10481949
• 负责人: MARY LEE
• 金额: --
• 依托单位: U.S. DEPT/VETS AFFAIRS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481949
• 关键词: Adult; Affect; Anatomy; Animal Model; Anterior; Area; Behavior; Behavioral; Brain; Brain region; Cigarette Smoker; Clinical; Clinical assessments; Cues; Data; Dorsal; Emotional; Exposure to; Focused Ultrasound; Functional Magnetic Resonance Imaging; Hour; Human; Individual; Insula of Reil; Lateral; Lead; Left; Lesion; Link; Magnetic Resonance Imaging; Measures; Methods; Neurologic; Neurosurgical Procedures; Nicotine Dependence; Patient Self-Report; Patients; Pharmaceutical Preparations; Physiological; Population; Relapse; Resolution; Rest; Role; Safety; Severities; Site; Smoke; Smoker; Smoking; Smoking Behavior; Somatosensory Cortex; Specificity; Spottings; Stimulus; Structure; Substance Use Disorder; Techniques; Temporal Lobe; Testing; Therapeutic; Tobacco Use Disorder; Transcranial magnetic stimulation; United States; United States Food and Drug Administration; addiction; blood oxygen level dependent; cigarette craving; cigarette smoking; cost; cranium; craving; effective therapy; experience; military veteran; millimeter; multimodal data; neuroregulation; nicotine craving; noninvasive brain stimulation; preventable death; relating to nervous system; response; smoking cessation; smoking cue; stem

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.

烟草使用障碍（TUD）仍然是世界可预防死亡的主要原因。香烟的速度 吸烟较高，与美国退伍军人人口相比，退伍军人人口较低 非退伍军人人口。非侵入性神经调节是一种对TUD的治疗方法的希望。 低强度聚焦超声（LIFU）是抑制皮质和深脑区域的无创方法。 Lifu可以到达深度大脑区域并具有空间特异性。为了吸烟，一个有希望的目标治疗tud 是背前岛状皮质（DAI），它是一种大脑结构，其功能与吸烟的渴望有关。这 绝缘是一个关键的大脑区域，在对药物提示暴露的反应中被激活 激活与人类研究中的自我报告的渴望呈正相关。值得注意的是，人类与 对岛屿的损害能够轻松停止吸烟，而不会感到渴望或复发。 Lifu可以 有选择地针对DAI，并提供了一种潜在的变革性方法来减少尼古丁的渴望和 瘾。我们将评估TUD患者中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概况，尽管在临床中使用的数据有限 种群，没有药物使用障碍的数据。这是该目标的目的 模态数据集证明了LIFU是一种安全的非侵入性治疗选项​​。为此，我们将使用 解剖磁共振成像，神经系统评估和患者查询以评估安全性和 Lifu的耐受性。与此相比 交付到解剖控制部位，体感皮质（S1），以确定是否有短暂 1次LIFU对DAI的期限影响对吸烟行为。我们还将用Lifu抑制DAI以确定 DAI在吸烟提示中是否有因果作用引起的渴望和神经反应 了解提示在TUD中引起的提示的机制，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对离开DAI的影响 fMRI血液水平氧气依赖性（粗体）活性和对吸烟提示暴露的渴望。到 实现这一目标，我们将测量LIFU对1）DAI的效果，而S1血氧级依赖性依赖性 （大胆）激活吸烟（与中性的）提示暴露和2）提示引起的渴望 有TUD的人。我们还计划检查Lifu与S1相比如何离开DAI会影响时间 大规模网络的动态与成瘾有关。我们将检查静止状态功能连接 在显着网络中 连通性和这种降低将与提示引起的渴望的减少显着相关。 TUD治疗的功效有限。资深人口需要安全有效 TUD治疗。选择性抑制DAI减少了成瘾动物中的渴望，使用和复发 岛岛的模型和病变极大地消除了人类吸烟的使用和渴望。 lifu 提供了瞬时和选择性地抑制这个关键大脑区域以确定其因果关系在TUD中的作用的能力 然后可能导致批准的TUD处理，也可以应用于其他物质使用 疾病。