Translating an MR-guided focused ultrasound system for first-in-human precision neuromodulation of pain circuits

将 MR 引导聚焦超声系统用于人体首个疼痛回路精确神经调节

• 批准号: 10805159
• 负责人: Charles F Caskey
• 金额: $ 436.43万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10805159
• 关键词: Acceleration; Acoustics; Autopsy; Behavior; Brain; Brain region; Cephalic; Chronic; Clinical; Clinical Management; Clinical Trials; Data; Development; Device Safety; Devices; Disease; Electrodes; Engineering; Ensure; Essential Tremor; Evaluation; Experimental Models; Exposure to; Feedback; Focused Ultrasound; Focused Ultrasound Therapy; Frequencies; Functional Magnetic Resonance Imaging; Funding; Future; Goals; Hand; Hand functions; Helping to End Addiction Long-term; Histology; Human; In Situ; Laboratories; Location; Magnetic Resonance; Magnetic Resonance Imaging; Marketing; Medical; Methods; Modeling; Monitor; Movement Disorders; Neurosciences; Nociception; Pain; Pain management; Patient-Focused Outcomes; Patients; Perception; Phase; Physicians; Physiologic pulse; Preclinical Testing; Procedures; Radiation; Refractory; Research Personnel; Safety; Scanning; Schedule; Structure; Support System; System; Systems Integration; Technology; Testing; Thalamic Nuclei; Time; Transducers; Translating; Translations; Treatment Protocols; Visualization; Work; blood oxygen level dependent; chronic pain; chronic pain management; clinical application; clinical pain; clinical translation; cranium; design; design and construction; experience; feasibility trial; first-in-human; follow-up; image guided; improved; in vivo; indexing; information processing; interdisciplinary approach; meetings; millimeter; neural; neuroregulation; next generation; nonhuman primate; novel; pain patient; pain relief; post stroke pain; pre-clinical; programs; research clinical testing; safety and feasibility; safety assessment; skills; tool; ultrasound

This proposal responds to PAR-21-315 Blueprint MedTech Translator and aims to translate a next-generation noninvasive neuromodulation system that supports a device-based strategy for non-addictive pain treatments. Specifically, we have developed an integrated magnetic resonance (MR) image-guided focused ultrasound (MRgFUS) stimulation system for targeted and high precision modulation of deep brain regions with real-time targeting feedback and functional monitoring by fMRI. Although there are several devices available on the market to treat pain, their efficacy is limited by imprecise targeting resulting from insufficient mechanistic data about “device-able” targets, and from lack of feedback of effects to modulate the therapy. Reversible FUS stimulation under MRI guidance (MRgFUS) combines the dual neuromodulation capacity of low frequency focal ultrasound with simultaneous monitoring of neuromodulation in action using fMRI. MRgFUS overcomes the limitations of existing pain-treatment devices and has great potential to improve patient outcomes through FUS and MRI technologies that enable targeting and control. Our group has developed an MRgFUS system for non-human primate (NHP) use and successfully modulated neural activity in the brain regions responsible for nociceptive information processing validated by fMRI. As part of previously funded work, we have scaled the device to function with a human skull, and here we propose to translate this early-stage technology into a new non-addictive pain therapy. We have designed the human device to use FUS to stimulate pain targets (thalamic nuclei, ACC, and PAG/PVG) that are currently used in clinical pain treatments with the ability to validate the location of stimulation and to monitor brain activity using blood oxygenation level dependent fMRI. Our experimental plan navigates barriers to deploying FUS, including 1) optimizing MR-based methods to visualize the ultrasound beam with high precision while using safe ultrasound exposure to the brain, 2) assessing device safety in non-human primates, and 3) obtaining regulatory approval for use of the proposed device for a first-in-human trial of high precision MRgFUS in patients with medically-refractory essential tremor and intractable chronic central post-stroke pain. The UG3-phase is designed to prepare the device for human use and has quantitative go/no-go milestones for establishing safe use of high precision MRgFUS in humans with regulatory approval. Successful completion of the UG3 milestones will place this groundbreaking technology into the hands of treating physicians and lead to the first clinical trial of high precision MRgFUS neuromodulation in patients with movement disorders and chronic pain. The proposed work will deliver a system that overcomes technical barriers in transcranial ultrasound and is ready for pilot clinical trials in various pain management applications.

该建议对PAR-21-315蓝图MedTech翻译人员做出了反应，并旨在翻译下一代非侵入性神经调节系统，该系统支持基于设备的非添加性疼痛治疗的策略。具体而言，我们已经开发了一个集成的磁共振（MR）图像引导聚焦超声（MRGFUS）模拟系统，用于对深脑区域的靶向和高精度调节，并通过fMRI实时靶向反馈和功能监测。尽管市场上有几种可用于治疗疼痛的设备，但由于对“可设备”靶标的机械数据不足以及缺乏对疗法的影响的反馈，其有效性受到抑制靶向的限制。在MRI引导下（MRGFU）下的可逆FUS模拟结合了低频局灶性超声的双重神经调节能力和使用fMRI在作用中对神经调节进行的简单监测。 MRGFU克服了现有疼痛治疗设备的局限性，并具有通过FUS和MRI技术改善患者预后的巨大潜力，这些技术能够实现靶向和控制。我们的小组开发了一种用于非人类灵长类动物（NHP）使用的MRGFUS系统，并在负责由fMRI验证的负责伤害性信息处理的大脑区域中成功调节了神经活动。作为先前资助的工作的一部分，我们已经扩展了该设备以使用人类头骨运作，在这里，我们建议将这种早期技术转化为一种新的非成瘾性疼痛疗法。我们已经设计了人体装置来使用FUS刺激疼痛靶标（丘脑核，ACC和PAG/PVG），这些疼痛靶标在临床疼痛处理中使用，具有验证刺激位置并使用依赖于血液氧合水平的FIMRI验证脑活动的能力。我们的实验计划在部署FUS的障碍中导航障碍，包括1）优化基于MR的方法，以高精度可视化超声波梁，同时使用安全的超声接触大脑，2）评估非人类隐私的设备安全性，3）3）获得调节性的批准，以在拟议的设备中使用高精度的MERGFUS杂物及其在高精度中，并在中间的杂物中使用，并在中间进行了杂物，并获得了高精度。冲程后疼痛。 UG3期旨在为人类使用准备该设备，并具有定量的GO/NO-GO里程碑，以确保在监管批准的人类中安全使用高精度MRGFU。成功完成UG3里程碑将使这项开创性的技术掌握在治疗医生的手中，并导致在运动障碍和慢性疼痛患者中进行高精度MRGFUS神经调节的首次临床试验。拟议的工作将提供一个克服经颅超声技术障碍的系统，并准备在各种疼痛管理应用中进行试验临床试验。