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

该提案响应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脑深部区域进行靶向和高精度调制。虽然市场上有几种治疗疼痛的装置，但由于“可装置”靶点的机制数据不足，以及缺乏调节治疗的效果反馈，它们的疗效受到限制。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和fMRI同时监测作用中的神经调节。MRgFUS克服了现有疼痛治疗设备的局限性，通过FUS和MRI技术实现靶向和控制，具有改善患者预后的巨大潜力。我们的团队已经开发了一种用于非人灵长类动物（NHP）的MRgFUS系统，并成功地调节了负责伤害性信息处理的大脑区域的神经活动。作为先前资助工作的一部分，我们已经将该设备扩展到与人类头骨一起工作，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治疗方法。我们设计了一种人体装置，使用FUS来刺激目前用于临床疼痛治疗的疼痛靶点（丘脑核、ACC和PAG/PVG），能够验证刺激的位置，并使用依赖血氧水平的功能磁共振成像来监测大脑活动。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，在使用安全超声暴露于大脑的同时高精度地可视化超声束，2)评估设备在非人类灵长类动物中的安全性，以及3)获得监管机构批准，将拟议的设备用于医学难治性特发性震颤和难治性慢性中枢性卒中后疼痛患者的高精度MRgFUS的首次人体试验。ug3阶段旨在为人类使用的设备做准备，并具有定量的go/no-go里程碑，以建立高精度MRgFUS在人类中的安全使用，并获得监管部门的批准。UG3里程碑的成功完成将使这项突破性技术进入治疗医生的手中，并导致高精度MRgFUS神经调节在运动障碍和慢性疼痛患者中的首次临床试验。这项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。

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.