Biophysical and Neural Basis of Focused Ultrasound Stimulation

该建议响应了脑计划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，可以非侵入性地刺激大脑任何部分的毫米级区域，包括大脑深层结构。我们试图了解不同剂量和时空应用的FUS如何在细胞、电路和行为水平上与大脑相互作用。当与MRI结合使用时，FUS波束可以精确定位，而BOLD fMRI可以观察到网络级效应。在过去的几年里，通过大脑倡议资助的项目，我们开发了一个集成的MRI引导FUS系统(MRgFUS)，它具有图像引导和MRI能力，需要将波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。利用该系统，我们证明了FUS对非人类灵长类(NHP)感觉运动系统的双向(兴奋和抑制)和状态依赖的神经调节作用。FUS在静息状态直接兴奋体感3a/3b区神经元，但在它们参与处理触觉输入时抑制激活的神经元，并在下游非靶区引起激活。在这里，我们试图通过使用多单元阵列电极和功能磁共振在多个尺度上评估FUS神经调节过程中的神经信号来研究FUS神经调节的机制，所选择的参数空间用于测试脉冲持续时间、脉冲重复频率和幅度的影响。计划中的研究将使用光遗传学和药理学操作来测试这一假设，即独立于其他参数的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到的一个假说，即中等压力下的FUS比高压下产生更强的抑制效应。我们将把侵入性电生理测量映射到可用于人类的神经活动的非侵入性测量(例如BOLD fMRI)。安全性将通过成像、握手行为的深度学习分析和尸检评估进行评估，为正在进行的FUS神经调节的翻译提供重要信息。我们建议的研究将在跨越单个神经元通过全脑网络的实验模型中阐明FUS神经调节的潜在机制，并将这些在细胞、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电路，为涉及区域和网络功能异常的疾病的治疗干预提供了可能性。

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.