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.

对RFA-EB-18-003治疗计划的这种提议回应：设备的转化开发以治疗 疼痛，旨在开发下一代无创神经调节系统，该系统支持设备 基于非成瘾性疼痛治疗的策略。具体而言，我们将建立一个集成的磁共振 （MR）图像引导聚焦超声（MRGFUS）模拟系统，用于靶向和高精度 调节疼痛区域和电路。尽管市场上有几种可用的设备可以治疗 疼痛，他们的效率受到侵犯的限制。 “可设备”的目标，以及缺乏对疗法的影响的反馈（如RFA中所述）。 MRI指导下的可逆FUS刺激（MRGFU）结合了双重神经调节能力 低频局灶性超声检查使用fMRI对神经调节进行简单监测。 MRGFU克服了现有疼痛处理设备的局限性，并具有改进的巨大潜力 通过FUS和MRI技术实现靶向和控制的FUS和MRI技术。我们的小组有 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 如fMRI所观察到的体感皮质。在这里，我们建议改进和翻译这个早期 通过开发和整合创新的FUS和MRI，将技术进入新的非成瘾性疼痛治疗 技术并将NHP系统扩展到人类。我们将使用NHP的伤害感受性疼痛系统 作为我们的测试模型，因为NHP大脑在功能和结构上非常类似于人脑。目标将 要克服准确，可靠刺激所需的重大技术挑战 皮质区域，并在MR指导下准确导航至三个特定的疼痛靶标（丘脑核， 当前用于临床疼痛治疗的ACC和PAG/PVG），然后监测 使用功能性MRI（fMRI）读数的伤害性疼痛回路的反应。我们将专注于 以高分辨率和准确性安全地瞄准集中的超声梁的挑战， 提供在亚热的放大器的实时反馈和调制声场的分布 剂量，以及基于血液的疼痛区域和电路活动的毒杆作用快速成像 氧合水平依赖性（粗体）特征和金色标准的微电极电生理学。我们将 开发工程解决方案针对神经元活动和剂量测定，这对于临床部署至关重要 FUS神经调节。三个合作实验室将解决以下目标：（目标1）开发 专注于人类神经调节的超声技术。 （目标2）开发MRI技术 神经调节。 （AIM 3）验证NHP中脑疼痛区域的MRGFU神经调节。到结束 该项目，我们将拥有一个完全开发和验证的MRIGFUS系统，该系统已准备好用于试点临床试验 各种疼痛管理应用。