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

摘要 滥用障碍（CUD）是一种慢性复发性疾病，对社会造成重大负担， 全球每年850亿美元，美国食品和药物管理局没有批准干预。有一个 迫切需要开发有效的新治疗策略。一种迅速出现的潜在治疗方法是 使用低强度聚焦超声（LIFU）进行神经调节。LIFU的巨大潜力源于 能够通过完整的颅骨将超声波聚焦到大脑中任何地方的毫米大小的焦点。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 这些技术具有有限的空间分辨率，只能到达大脑的表面区域。一个有希望 治疗可卡因使用障碍（CUD）的靶点是背侧前岛皮质（dAI）。不幸的是，检察官撒谎了 在外侧沟的深处，由颞叶的覆盖盖覆盖， 传统的非侵入性神经调节技术。因此，LIFU提供了潜在的变革性 非侵入性调节dAI以减少可卡因渴望和成瘾的方法。DAI是一个批判性的大脑 在对药物线索暴露的反应中被激活的区域及其激活程度正相关 在人类研究中自我报告的渴望。在小动物模型中， 减少可卡因寻求，减少自愿戒烟后的复发，并减少线索诱导和 情境诱发的可卡因寻求复发值得注意的是，大脑受损的人能够 戒烟容易，没有经历渴望或复发。此外，dAI是显著性的一部分， 网络（SN）。SN与注意力朝向重要刺激的方向和顶部- 向下的评价和自下而上的内脏和感官信息。DAI模型首先评估 在将信息传输到其他节点以计划和启动未来之前，输入刺激的情感价值 目标导向的行动。在成瘾中，这个网络功能失调，导致不成比例的突出， 对药物相关线索的敏感性使决策偏向使用并最终滥用。 为了推进LIFU作为治疗CUD的潜在治疗方法，在本提案的UG 3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 活动来影响线索诱导的渴望。开发.在成功完成UG 3阶段后，UH 3阶段 将通过检查剂量效应和效应持续时间以及LIFU如何 dAI影响全脑网络动力学，就像它如何影响对可卡因的渴望一样。适用本 信息将提供一个根本性的突破，了解如何超声能量可以合理地 部署以产生可预测的临床效果，并作为广泛临床采用的催化剂， 治疗CUD以及其他形式的物质使用障碍的技术。

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.