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

该提案响应了RFA-EB-18-003 Hear倡议：治疗设备的翻译开发 Pain，目标是开发下一代非侵入性神经调节系统，支持一种设备- 基于非成瘾疼痛治疗的策略。具体地说，我们将构建一个集成的磁共振 用于靶向和高精度的(MR)图像引导聚焦超声(MRgFUS)刺激系统 痛觉区域和神经回路的调制。尽管市场上有几种设备可以治疗 疼痛，其疗效受到靶向不精确的限制，这是由于缺乏关于 “设备可用”靶点，以及缺乏效果反馈以调整治疗(如RFA中所述)。 磁共振引导下的可逆性FUS刺激(MRgFUS)结合了 使用功能磁共振成像同时监测神经调节作用的低频聚焦超声。 MRgFUS克服了现有疼痛治疗设备的局限性，具有很大的改进潜力 通过FUS和MRI技术实现靶向和控制的患者结果。我们的团队已经 开发了一种用于非人灵长类(NHP)的MRgFUS系统，并成功地调节了神经活动 功能磁共振成像观察到的躯体感觉皮质。在这里，我们建议改进和翻译这一早期阶段 通过开发和集成创新的FUS和MRI，将技术应用于新的非成瘾性疼痛治疗 技术，并将NHP系统扩大到人类。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类大脑非常相似。目标将会是 是为了克服准确和可靠地刺激已确定的 并在磁共振引导下精确导航到三个特定的疼痛目标(丘脑核团， ACC和PAG/PVG)，以监测目前用于临床疼痛治疗的 使用功能磁共振(FMRI)读数对伤害性痛觉环路的反应。我们将重点关注 以高分辨率和精确度在头部安全地瞄准聚焦的超声波束的挑战， 在亚热区提供调制声场的幅度和分布的实时反馈 剂量，以及FUS对基于血液的痛区和回路活动的快速成像 氧水平依赖(BOLD)信号和金标准微电极电生理学。我们会 开发对临床部署至关重要的神经导航和剂量学工程解决方案 FUS神经调节。三个合作实验室将实现以下目标：(目标1)发展 聚焦超声技术在人类神经调节中的应用。(目标2)磁共振成像技术的发展 神经调节。(目的3)对NHP中脑痛区的MRgFUS神经调节进行验证。到年底的时候 在这个项目中，我们将拥有一个完全开发和验证的MRIgFUS系统，准备在 各种疼痛管理应用程序。

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.