Biophysical and Neural Basis of Focused Ultrasound Stimulation

聚焦超声刺激的生物物理和神经基础

• 批准号: 10415733
• 负责人: Charles F Caskey
• 金额: $ 268.93万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415733
• 关键词: Acoustics; Area; Autopsy; BRAIN initiative; Behavior; Behavioral; Bilateral; Biological Models; Biology; Biophysical Process; Biophysics; Brain; Brain region; Disease; Distant; Dose; Electrodes; Electrophysiology (science); Environment; Experimental Models; Feedback; Focused Ultrasound; Focused Ultrasound Therapy; Frequencies; Functional Magnetic Resonance Imaging; Funding; Future; Goals; Hand functions; Histology; Human; Image; Individual; Interneurons; Investigational Therapies; Knowledge; Laboratories; Link; Location; Macaca; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Measurement; Measures; Methods; Modeling; Monitor; Monkeys; Neurons; Neurosciences; Outcome Measure; Output; Pharmacology; Physical Stimulation; Physiologic pulse; Primates; Procedures; Radiation; Research; Research Personnel; Rest; Safety; Signal Transduction; Site; Structure; System; Tactile; Techniques; Technology; Testing; Therapeutic Intervention; Time; Translations; Work; behavior change; deep learning; dosimetry; excitatory neuron; experience; falls; hand grasp; hemodynamics; image guided; improved; inhibitory neuron; millimeter; neural stimulation; neuroimaging; neuromechanism; neuronal circuitry; neuroregulation; neurotransmission; neurovascular coupling; nonhuman primate; optogenetics; pressure; putamen; relating to nervous system; response; sensorimotor system; side effect; somatosensory; spatiotemporal; tactile stimulation; ultrasound

This proposal responds to BRAIN Initiative RFA-NS-20-006 and aims to elucidate the neural and biophysical mechanisms of noninvasive focused ultrasound (FUS) neuromodulation. FUS overcomes shortcomings of other neuromodulation methods and can noninvasively stimulate millimeter-scale regions in any part of the brain including deep brain structures. We seek to understand how different doses and spatiotemporal applications of FUS interact with the brain at cellular, circuit, and behavioral level. When used in conjunction with MRI, the FUS beam can be precisely localized while network-level effects can be observed with BOLD fMRI. In the past few years, through BRAIN Initiative funded projects, we have developed an integrated MRI guided FUS system (MRgFUS) with image-guidance and MRI capabilities required to place the beam accurately in the brain and map its location using magnetic resonance acoustic radiation force imaging (MR- ARFI). Using this system, we have demonstrated that FUS exerts bidirectional (excitatory and inhibitory) and state dependent neuromodulation of the nonhuman primate (NHP) sensorimotor system. FUS directly excites somatosensory area 3a/3b neurons at resting state but suppresses activated neurons when they are engaged in processing tactile inputs and elicits activation in downstream off-target brain regions. Here, we seek to investigate the mechanisms underlying FUS neuromodulation by evaluating neural signals at multiple scales using multiunit array electrodes and functional MRI during FUS neuromodulation over a parameter space chosen to test the influence of pulse duration, pulse repetition frequency, and amplitude. The planned studies will use optogenetics and pharmacological manipulations to test the hypothesis that increasing repetition frequency independent from other parameters preferentially drives specific groups of neurons. Studies varying amplitude will assess a hypothesis derived from our recent observation that FUS at moderate pressures elicits stronger inhibitory effects than high pressures. We will map invasive electrophysiological measurements to non-invasive measurements of neural activity (e.g. BOLD fMRI) that can be used in humans. Safety will be assessed with imaging, deep learning analysis of hand grasping behavior, and post-mortem assessment, providing important information for the ongoing translation of FUS neuromodulation. Our proposed studies will elucidate mechanisms underlying FUS neuromodulation over a broad parameter space in experimental models that span the individual neurons through whole brain networks and connect these multi scale electrophysiological and functional MRI observations made at the cellular, local microcircuit, and global levels to behavior changes in a NHP model system. Thus, our approach is closely aligned with the goals of this RFA and will further our knowledge of FUS neuromodulation, a fast-growing non-invasive method for dissecting circuits in the mammalian brain that offers the potential for therapeutic interventions to diseases involving abnormality in regional and network functions.

该提案响应 BRAIN Initiative RFA-NS-20-006，旨在阐明无创聚焦超声 (FUS) 神经调节的神经和生物物理机制。 FUS克服了其他神经调节方法的缺点，可以无创地刺激大脑任何部位的毫米级区域，包括大脑深部结构。我们试图了解 FUS 的不同剂量和时空应用如何在细胞、回路和行为水平上与大脑相互作用。与 MRI 结合使用时，可以精确定位 FUS 光束，同时可以使用 BOLD fMRI 观察网络级效应。在过去的几年中，通过 BRAIN Initiative 资助的项目，我们开发了一种集成 MRI 引导 FUS 系统 (MRgFUS)，具有图像引导和 MRI 功能，可将光束准确地放置在大脑中并使用磁共振声辐射力成像 (MR-ARFI) 绘制其位置。使用该系统，我们证明了 FUS 对非人灵长类动物 (NHP) 感觉运动系统发挥双向（兴奋性和抑制性）和状态依赖性神经调节作用。 FUS 在静息状态下直接兴奋体感区 3a/3b 神经元，但在处理触觉输入时抑制激活的神经元，并引发下游脱靶大脑区域的激活。在这里，我们试图通过在 FUS 神经调节期间使用多单元阵列电极和功能 MRI 在选择用于测试脉冲持续时间、脉冲重复频率和幅度影响的参数空间上评估多个尺度的神经信号来研究 FUS 神经调节的机制。计划中的研究将使用光遗传学和药理学操作来检验这样的假设：独立于其他参数增加重复频率优先驱动特定的神经元组。不同幅度的研究将评估我们最近观察得出的假设，即中等压力下的 FUS 会比高压下产生更强的抑制作用。我们将把侵入性电生理测量映射到可用于人类的非侵入性神经活动测量（例如 BOLD fMRI）。安全性将通过成像、手部抓取行为的深度学习分析和尸检评估来评估，为 FUS 神经调节的持续转化提供重要信息。我们提出的研究将阐明实验模型中广泛参数空间上 FUS 神经调节的机制，这些模型跨越单个神经元到整个大脑网络，并将在细胞、局部微电路和全局水平上进行的多尺度电生理和功能 MRI 观察与 NHP 模型系统中的行为变化联系起来。因此，我们的方法与本次 RFA 的目标密切相关，并将进一步加深我们对 FUS 神经调节的了解，FUS 神经调节是一种快速发展的非侵入性方法，用于解剖哺乳动物大脑中的回路，为涉及区域和网络功能异常的疾病提供了治疗干预的潜力。