Development of an MRgFUS system for precision-targeted neuromodulation of pain circuits with simultaneous functional MRI

开发 MRgFUS 系统，通过同步功能 MRI 对疼痛回路进行精确靶向神经调节

• 批准号: 9932739
• 负责人: Charles F Caskey
• 金额: $ 361.46万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9932739
• 关键词: Ablation; Acoustics; Address; Autopsy; BRAIN initiative; Brain; Brain region; Clinical; Clinical Trials; Computer software; Data; Deep Brain Stimulation; Development; Device or Instrument Development; Devices; Documentation; Dose; Echo-Planar Imaging; Electrophysiology (science); Engineering; Enhancement Technology; Environment; Feedback; Focused Ultrasound; Frequencies; Functional Magnetic Resonance Imaging; Funding; Goals; Gold; Government; Grant; Head; Histology; Human; Image; Individual; Laboratories; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Measurement; Microelectrodes; Modeling; Monitor; Neuronavigation; Neurosciences; Neurosurgeon; Nociception; Pain; Pain management; Patient-Focused Outcomes; Physicians; Practice Management; Procedures; Protocols documentation; RF coil; Radiation; Radio; Regulatory Pathway; Research Personnel; Resolution; Safety; Somatosensory Cortex; Structure; Support System; System; Technology; Temperature; Testing; Thalamic Nuclei; Time; Translating; Ultrasonic Transducer; Ultrasonography; Validation; base; blood oxygen level dependent; clinical pain; design; dosimetry; experience; image guided; improved; in vivo; innovation; neuroimaging; neuroregulation; next generation; nociceptive response; nonhuman primate; real time monitoring; relating to nervous system; safety testing; scale up; sound; tool; treatment planning; virtual

This proposal responds to RFA-EB-18-003 HEAL initiative: Translational Development of Devices to Treat Pain, and aims to develop a next-generation noninvasive neuromodulation system that supports a device- based strategy for non-addictive pain treatments. Specifically, we will build an integrated magnetic resonance (MR) image-guided focused ultrasound (MRgFUS) stimulation system for targeted and high precision modulation of pain regions and circuits. 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 the “device-able” targets, and from lack of feedback of effects to modulate the therapy (as stated in the RFA). 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 somatosensory cortex as observed by fMRI. Here we propose to improve and translate this early-stage technology into new non-addictive pain treatments by developing and integrating innovative FUS and MRI technologies and scaling up the NHP system to humans. We will use the nociceptive pain system of the NHP as our test model since NHP brains closely resemble the human brain in function and structure. The goals will be to overcome the substantial technological challenges required to accurately and reliably stimulate identified regions of cortex, and to navigate precisely under MR guidance to three specific pain targets (thalamic nuclei, ACC, and PAG/PVG) that are currently used in clinical pain treatments, and to subsequently monitor the responses of the nociceptive pain circuits using a functional MRI (fMRI) readout. We will focus on the challenges of targeting focused ultrasound beams safely within the head with high resolution and accuracy, of providing real-time feedback of the amplitude and distribution of the modulating sound fields at sub-thermal doses, and of rapid imaging of FUS action on the activity of pain regions and circuits based on blood oxygenation level dependent (BOLD) signatures and gold-standard microelectrode electrophysiology. We will develop engineering solutions for neuronavigation and dosimetry that are critical for the clinical deployment of FUS neuromodulation. The three partnering laboratories will address the following Aims: (Aim 1) Development of focused ultrasound technology for neuromodulation in humans. (Aim 2) Development of MRI Technology for neuromodulation. (Aim 3) Validation of MRgFUS neuromodulation of brain pain regions in NHPs. By the end of the project, we will have a fully developed and validated MRIgFUS system that is ready for pilot clinical trials in various pain management applications.

本提案响应RFA-EB-18-003 HEAL倡议：治疗器械的转化开发 疼痛，并旨在开发下一代无创神经调节系统，支持一种设备- 基于非成瘾性疼痛治疗的策略。具体来说，我们将建立一个集成的磁共振 (MR)用于靶向和高精度的图像引导聚焦超声（MRgFUS）刺激系统 疼痛区域和回路的调节。虽然市场上有几种设备可以治疗 疼痛，它们的疗效受到不精确的靶向限制，这是由于关于疼痛的机制数据不足造成的。 “可器械”靶点的影响，以及缺乏调节治疗的效果反馈（如RFA中所述）。 MRI引导下的可逆FUS刺激（MRgFUS）结合了 低频聚焦超声，同时使用功能磁共振成像监测神经调节作用。 MRgFUS克服了现有疼痛治疗设备的局限性，并且具有很大的改进潜力。 通过FUS和MRI技术实现靶向和控制，我们集团 开发了一种用于非人类灵长类动物（NHP）的MRgFUS系统，并成功调节了神经活动 在躯体感觉皮层的功能磁共振成像观察。在这里，我们建议改进和翻译这一早期阶段， 通过开发和整合创新的FUS和MRI技术， 技术和扩大NHP系统到人类。我们将使用NHP的伤害性疼痛系统 作为我们的测试模型，因为NHP大脑在功能和结构上与人脑非常相似。这些目标将 克服准确可靠地刺激识别所需的重大技术挑战 皮层区域，并在MR引导下精确导航到三个特定的疼痛目标（丘脑核， ACC和PAG/PVG），并随后监测其在临床疼痛治疗中的应用。 使用功能性磁共振成像（fMRI）读出伤害性疼痛回路的反应。重点抓好 以高分辨率和准确度在头部内安全地瞄准聚焦超声波束的挑战， 提供亚热条件下调制声场的幅度和分布的实时反馈， 剂量，以及FUS对疼痛区域和基于血液的回路活动的快速成像 氧合水平依赖性（BOLD）信号和金标准微电极电生理学。我们将 开发神经导航和剂量测定的工程解决方案，这对临床部署至关重要。 FUS神经调节。这三个实验室将致力于实现以下目标：（目标1）发展 聚焦超声波技术在人类神经调节中的应用。(Aim 2）MRI技术的发展 神经调节(Aim 3）NHP中脑疼痛区域的MRgFUS神经调节的验证。年底前 在该项目中，我们将拥有一个完全开发和验证的MRIgFUS系统，已准备好进行试点临床试验 各种疼痛管理应用。