Focused Ultrasound Neuromodulation of Dorsal Root Ganglion for Noninvasive Mitigation of Low Back Pain

项目摘要 该项目的目标是开发一种完全非侵入性的、精确的和持久的治疗方案 背部疼痛，据估计，每年直接医疗支出为300亿美元。慢性LBP是 通常是诊断和管理挑战，因为有多个潜在的疼痛来源，生物力学 和炎症机制。阿片类药物等全身止痛药的失败往往是由于它们的 偏离目标的毒性、耐受性的发展和滥用的可能性。介入性疼痛程序提供靶点 特异性，但缺乏长期疗效，并与程序风险有关。了解 这种治疗的幕上效应可能是开发有效治疗模式的重要组成部分。 聚焦超声(FUS)是一种风险较低、完全非侵入性的方式，能够提供 磁作用下小组织区域(背根神经节[DRG])的空间受限声能 磁共振成像引导神经调节治疗轴性下腰痛。 这项研究的中心目标是演示FUS对DRG的神经调节作用以减少神经 传导，它可以用来减弱痛感。在第一个目标中，我们将建立 检测神经炎模型和正常人疼痛变化的电生理学标准数据 进行脑电和体感诱发电位检测。在第二个目标中，我们将演示FUS 猪背根神经节的神经调节：(A)探索导致背根神经节的超声参数 在神经刺激期间由SEPS评估的神经调节以及(B)评估 非侵入性FUS神经调节在猪神经炎模型和对照中的应用 行为评估，专门测试表示脊柱上痛感的行为。在第三节 目的，我们将设计和建造一种针对LBP的MRgFUS设备，用于快速翻译为 通过使用监管标准对DRG神经调节的FUS超声进行充分表征， 构建MRI射频线圈和换能器支架，以允许在人体内靶向DRG，以及 对样机进行图像和声学质量评估。 这项探索性研究将演示1)在DRG上使用FUS来中断和调节神经传导， 2)使用体感诱发电位监测脑变化和独特的行为评估 3)FUS DRG神经调节的安全性；4)a) 人类使用的原型。重要的是，与侵入性神经调节相比，FUS神经调节相关的低风险 程序，将导致快速的临床翻译。 我们认为FUS是一种非侵入性的治疗慢性下腰痛的神经调节方式，并有 有可能取代目前的侵入性或系统性有害的治疗方式。通过证明 FUS的神经调节可以通过皮质监测和行为评估改变疼痛感知， 最终目标是开发一种完全非侵入性的系统来治疗下腰痛并调整 根据皮质反应进行实时治疗。与神经调节相关的风险越低， 与更具侵入性的程序相比，将导致快速翻译为人类。

Project Summary The goal of this project is to develop a completely non-invasive, precise and durable treatment option for low back pain, which is estimated to cost $30 billion in direct health care expenditures annually. Chronic LBP is often a diagnostic and management challenge due to multiple potential pain sources with both biomechanical and inflammatory mechanisms. The failure of systemic analgesic drugs, such as opioids, is often due to their off-target toxicity, development of tolerance, and abuse potential. Interventional pain procedures provide target specificity but lack long-term efficacy and are associated with procedural risks. Understanding the supratentorial effects of such treatments may be an important part of developing effective treatment modalities. Focused ultrasound (FUS) is a lower risk, completely non-invasive modality that enables the delivery of spatially-confined acoustic energy to a small tissue region (dorsal root ganglion [DRG]) under magnetic resonance (MR) imaging guidance to treat axial low back pain by neuromodulation. The central goal of this study is to demonstrate neuromodulation of the DRG with FUS to decrease nerve conduction, which can be used to attenuate pain sensation. In the first Aim, we will establish electrophysiologic normative data for detecting changes in pain in neuritis models and normals measured by EEG and somatosensory evoked potentials. In the second Aim, we will demonstrate FUS neuromodulation of the DRG in pigs by (a) exploring FUS sonication parameters that results in DRG neuromodulation as assessed by SEPs during nerve stimulation and (b) evaluating the safety and efficacy of non-invasive FUS neuromodulation in neuritis pig model and controls by performing longitudinal unique behavioral assessments, which specifically test behaviors indicative of supraspinal pain sensation. In the third Aim, we will design and construct an LBP-specific MRgFUS device for rapid translation to patients with back pain by fully characterizing FUS sonications for DRG neuromodulation using regulatory standards, constructing an MRI radiofrequency coil and transducer mount to allow targeting of the DRG in humans, and evaluating the prototype for image and sonication quality. This exploratory study will demonstrate 1) using FUS on the DRG to interrupt and modulate nerve conduction, 2) using somatosensory evoked potentials to monitor brain changes and unique behavioral assessments in a pig model after modulating the effect of pain stimuli, 3) the safety of FUS DRG neuromodulation, and 4) a prototype for human use. Importantly, the low risk associated with FUS neuromodulation, compared to invasive procedures, will result in rapid clinical translation. We propose that FUS is a noninvasive modality to treat chronic low back pain with neuromodulation and has the potential to replace current invasive or systemically detrimental treatment modalities. By demonstrating that neuromodulation with FUS can alter pain perception with cortical monitoring and with behavioral assessments, with the ultimate goal of developing a completely non-invasive system to treat low back pain and adjust the treatment in real-time depending on the cortical response. The lower risk associated with neuromodulation, compared to more invasive procedures, will result in fast translation to humans.