Low-intensity focused ultrasound for cocaine use disorder: High resolution targeting of the human insula

低强度聚焦超声治疗可卡因使用障碍：人类脑岛的高分辨率靶向

• 批准号: 10669693
• 负责人: NASSIMA AIT-DAOUD
• 金额: $ 59.48万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669693
• 关键词: Abstinence; Addictive Behavior; Adoption; Affect; Anatomy; Animal Model; Anterior; Area; Behavioral; Brain; Brain region; Cessation of life; Chronic; Clinical; Cocaine; Cocaine Dependence; Cocaine use disorder; Cues; Data; Decision Making; Disease; Dorsal; Dose; Emotional; FDA approved; Focused Ultrasound; Future; Goals; Human; Individual; Insula of Reil; Intervention; Lateral; Lesion; Longevity; Magnetic Resonance Imaging; Maintenance; Measures; Methods; Modeling; Neurologic; Neurosurgical Procedures; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Population; Predisposition; Relapse; Resolution; Safety; Sensory; Societies; Spottings; Stimulus; Substance Use Disorder; Techniques; Technology; Temporal Lobe; Therapeutic; Therapeutic Effect; Treatment Efficacy; Ultrasonic Therapy; United States Food and Drug Administration; Visceral; addiction; blood oxygen level dependent; brain dysfunction; catalyst; clinical effect; cocaine craving; cocaine cue; cocaine exposure; cocaine seeking; cocaine use; cost; cranium; craving; cue reactivity; directed attention; experience; improved; innovation; millimeter; multimodal data; neurobehavioral; neuroregulation; noninvasive brain stimulation; novel therapeutic intervention; repaired; response; safety assessment; safety testing; smoking cessation; stem; transmission process; ultrasound

ABSTRACT Cocaine use disorder (CUD) is a chronic relapsing disorder with significant burden to society costing more than $85 billion per year globally and there is no US Food and Drug Administration-approved intervention. There is a critical need to develop effective new treatment strategies. One rapidly emerging potential therapeutic is neuromodulation using low-intensity focused ultrasound (LIFU). The enormous potential of LIFU stems from the ability to focus ultrasound through the intact skull to a millimeter-sized focal spot size anywhere in the brain. This makes it a powerful alternative to both invasive neurosurgical procedures and other noninvasive brain stimulation techniques that have limited spatial resolution and can only reach superficial areas of the brain. One promising target to treat cocaine use disorder (CUD) is the dorsal anterior insular cortex (dAI). Unfortunately, the dAI lies deep within the lateral sulcus covered by the overlying opercula of the temporal lobe and is not accessible with conventional noninvasive neuromodulatory techniques. As such, LIFU provides a potentially transformative methods to non-invasively modulate the dAI to reduce cocaine craving and addiction. The dAI 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. In small animal models, reversible inactivation of dorsal anterior insula reduces cocaine seeking, decreases relapse after voluntary abstinence and decreases cue-induced and context-induced reinstatement of cocaine seeking. Remarkably, humans with damage to the insula were able to stop smoking easily and without experiencing cravings or relapse. In addition, the dAI is part of the salience network (SN). The SN is implicated in the direction of attention toward important stimuli and integration of top- down appraisal and bottom-up visceral and sensory information. Models posit the dAI first assesses the emotional value of incoming stimuli before transmitting the information to other nodes to plan and initiate future goal directed actions. In addiction this network is dysfunctional leading to a disproportionate saliency and sensitivity to drug related cues that biases decision making to use and ultimately abuse. To advance LIFU as a potential therapeutic for the treatment of CUD, in the UG3 phase of this proposal we will first test the safety and tolerability of the intervention and examine how selective inhibition of dAI reduces its activity to affect cue-induced craving. Develop. Upon successful completion of the UG3 phase, the UH3 phase will build upon these findings by examining the effect of dose and the duration of effect as well as how LIFU to dAI affects whole-brain network dynamics as how this affects craving for cocaine. The application of this information will provide a fundamental break-through in understanding how ultrasound energy can be rationally deployed to produce predictable clinical effects and act as a catalyst for the widespread clinical adoption of this technology for the treatment of CUD as well as other forms of substance use disorder.

摘要 可卡因使用障碍(CUD)是一种慢性复发性障碍，对社会造成重大负担，花费超过 全球每年850亿美元，而且没有美国食品和药物管理局批准的干预措施。有一个 迫切需要制定有效的新治疗策略。一种迅速崛起的潜在治疗方法是 使用低强度聚焦超声(LIFU)进行神经调节。礼福的巨大潜力源于 能够通过完整的头骨将超声波聚焦到大脑中任何位置的毫米大小的焦点。这 使其成为侵入性神经外科手术和其他非侵入性脑刺激的有力替代方案 空间分辨率有限，只能触及大脑表面区域的技术。一件有希望的事 治疗可卡因使用障碍(CUD)的靶点是背侧前岛叶皮质(DAI)。不幸的是，傣族人撒谎了 位于外侧沟的深处，由上覆的颞叶盖覆盖，不能通过 传统的非侵入性神经调节技术。因此，利福提供了一种潜在的变革性 方法对DAI进行无创性调节，减少对可卡因的渴求和依赖。傣族是一个批判性的大脑 药物线索反应中被激活的区域与其激活程度呈正相关 在人体研究中有自我报告的渴望。在小动物模型中，背侧前部可逆性失活 脑岛减少寻求可卡因，减少自愿戒断后的复发，并减少线索诱导的和 上下文诱导的可卡因寻求的恢复。值得注意的是，脑岛受损的人类能够 轻松戒烟，不要有烟瘾或故态复萌。此外，DAI是突出的一部分 网络(SN)。SN在注意重要刺激的方向和顶端整合的方向上被牵连。 自下而上的评价和自下而上的内脏和感觉信息。模型假设戴相龙首先评估 在将信息传输到其他节点以计划和发起未来之前，输入刺激的情感价值 目标导向的行动。在上瘾时，这种网络功能失调，导致不成比例的突出和 对与药物有关的线索的敏感性，这些线索使决策偏向于使用并最终滥用。 为了促进利福作为治疗慢性阻塞性肺疾病的潜在疗法，在本提案的UG3阶段，我们将 首先测试干预的安全性和耐受性，并检查选择性抑制DAI如何降低其 影响线索诱导的渴望的活动。发展。在UG3阶段成功完成后，UH3阶段 将在这些发现的基础上，通过检查剂量的影响和作用的持续时间，以及利福如何 DAI影响全脑网络动态，就像这如何影响对可卡因的渴望一样。这一点的应用 信息将为理解超声能量如何合理利用提供一个根本性的突破 部署以产生可预测的临床效果，并作为催化剂广泛应用于临床 治疗CUD以及其他形式的物质使用障碍的技术。