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.

该提案响应了PAR-21-315 Blueprint MedTech Translator，旨在翻译下一代无创神经调节系统，该系统支持基于设备的非成瘾性疼痛治疗策略。具体来说，我们已经开发了一种集成的磁共振（MR）图像引导聚焦超声（MRgFUS）刺激系统，用于通过fMRI实时靶向反馈和功能监测对深部脑区进行靶向和高精度调制。尽管市场上有几种可用于治疗疼痛的装置，但它们的疗效受到不精确的靶向的限制，这是由于关于“可装置”靶点的机械数据不足以及缺乏调节治疗的效果反馈造成的。MRI引导下的可逆FUS刺激（MRgFUS）结合了低频局灶超声的双重神经调节能力，同时使用fMRI监测神经调节的作用。MRgFUS克服了现有疼痛治疗设备的局限性，并具有很大的潜力，通过FUS和MRI技术，使目标和控制，以改善患者的结果。我们的小组已经开发出一种用于非人类灵长类动物（NHP）的MRgFUS系统，并成功地调制了负责fMRI验证的伤害性信息处理的大脑区域的神经活动。作为先前资助的工作的一部分，我们已经将该设备扩展到人类头骨的功能，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。我们设计了人体装置，使用FUS刺激疼痛靶点（丘脑核、ACC和PAG/PVG），这些靶点目前用于临床疼痛治疗，能够验证刺激的位置，并使用血氧水平依赖性fMRI监测大脑活动。我们的实验计划克服了部署FUS的障碍，包括1）优化基于MR的方法，以高精度可视化超声波束，同时使用安全的超声波暴露于大脑，2）评估非人类灵长类动物中的器械安全性，以及3）获得监管机构批准，将所提出的设备用于在患有医学疾病的患者中进行高精度MRgFUS的首次人体试验，顽固性特发性震颤和顽固性慢性中枢性卒中后疼痛。UG 3阶段旨在准备供人类使用的器械，并具有定量的通过/不通过里程碑，以确定高精度MRgFUS在人体中的安全使用，并获得监管批准。UG 3里程碑的成功完成将把这项突破性的技术交给治疗医生，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点临床试验。