Neurostimulation by Ultrasound: Physical, Biophysical and Neural Mechanisms

描述（由申请人提供）：本项目的目标是了解超声波（US）对神经活动的影响。超声可以改变体外神经元的动作电位活动， 而不会损伤神经组织这种现象可以应用于基础和临床神经科学的强大新工具，对与精神和神经疾病有关的公共卫生问题产生广泛影响。为了指导和加速这些新工具的开发，我们的研究将深入了解美国神经刺激的物理，生物物理和神经机制。 我们的方法是独一无二的，它将技术开发与从单细胞到整个动物的复杂程度的US神经刺激机制研究相结合。我们先前的和初步的结果表明，美国辐射力引起组织位移，导致细胞膜应变，从而通过离子通道活性或神经递质胞吐的变化影响神经活动。我们将研究这一假设相结合，美国神经刺激与脑电图记录和辐射力成像在大鼠中，光学位移测量和多电极记录在蝾螈和大鼠视网膜在体外和体内，和电生理测量的离子通道活性和胞吐在单个HEK和PC 12细胞。我们还将测试与超声的其他两种物理效应（空化和加热）相关的替代假设。为了将这些机制与辐射力区分开来，我们将研究US神经刺激对频率和强度的依赖性。为了促进这些实验，我们将开发和实施新的US设备，使US能够以多焦点和微米级分辨率应用。 美国神经刺激可能对公共卫生产生重大影响。脑刺激疗法用于治疗帕金森病、肌张力障碍和癫痫，并对许多其他疾病有希望。与依赖于侵入性植入电极或具有有限的空间分辨率和深度穿透（例如，经颅磁刺激），超声提供了空间分辨率、深度穿透和非侵入性的理想组合。US神经刺激也可以在假体装置中实施;例如，刺激视网膜回路以恢复视力。此外，美国神经刺激有望成为基础神经科学中非常有用的研究工具，因此与所有公共卫生关注的精神和神经疾病相关。然而，所有这些结果都取决于安全应用US神经刺激的能力以及良好控制的可预测结果。实现这一目标需要我们的多学科研究项目将提供的美国神经刺激的详细机制的理解。

DESCRIPTION (provided by applicant): The goal of this project is to understand the effects of ultrasound (US) on neural activity. US can modify action potential activity in neurons in vitro and in vivo without damaging neural tissue. This phenomenon can be applied in powerful new tools for basic and clinical neuroscience, with broad impact on public health issues related to mental and neurological disorders. To guide and hasten the development of these new tools, our research will provide insight into the physical, biophysical and neural mechanisms underlying US neurostimulation. Our approach is unique in combining technology development with mechanistic studies of US neurostimulation at levels of complexity ranging from the single cell to the whole animal. Our prior and preliminary results suggest that US radiation force causes tissue displacement, resulting in cell membrane strain and thereby affecting neural activity through changes in ion channel activity or neurotransmitter exocytosis. We will investigate this hypothesis by combining US neurostimulation with EEG recording and radiation force imaging in rats, optical displacement measurements and multielectrode recording in the salamander and rat retina in vitro and in vivo, and electrophysiological measurements of ion channel activity and exocytosis in single HEK and PC12 cells. We will also test alternative hypotheses related to two other physical effects of US, cavitation and heating. To distinguish these mechanisms from radiation force we will examine the dependence of US neurostimulation on frequency and intensity. To facilitate these experiments, we will develop and implement new US devices, allowing US to be applied with multifocal and micron-scale resolution. US neurostimulation is likely to have significant impact on public health. Brain stimulation therapies are used to treat Parkinson's disease, dystonia, and epilepsy and hold promise for many others. Compared to current brain stimulation techniques that rely on invasive implanted electrodes or have limited spatial resolution and depth penetration (e.g., transcranial magnetic stimulation), US offers an ideal combination of spatial resolution, depth penetration, and non-invasiveness. US neurostimlation can also be implemented in prosthetic devices; for example, to stimulate retinal circuitry to restore vision. In addition, US neurostimulation promises to become an enormously useful research tool in basic neuroscience, and is therefore relevant to all mental and neurological disorders of public health concern. However, all of these outcomes depend on the ability to apply US neurostimulation safely and with well-controlled, predictable results. Achieving this goal requires a detailed mechanistic understanding of US neurostimulation that our multidisciplinary research project will provide.