The mechanistic basis of non-invasive deep brain stimulation by ultrasound

描述（由申请人提供）：脑刺激疗法目前用于治疗几种类型的神经系统疾病（帕金森病、肌张力障碍、癫痫），并有望治疗许多其他疾病（例如阿尔茨海默病、焦虑症、精神分裂症和中风）。目前脑刺激的临床应用涉及植入电极（受植入的侵入性限制）或经颅磁刺激（受其空间分辨率和深度穿透限制）。最近，研究表明，聚焦超声（一种能够深入大脑的非侵入性技术）可以激活电压门控钠通道（Nav通道），从而增加体内小鼠运动皮层中动作电位放电的速率。这些发现表明，聚焦超声可以克服目前脑刺激疗法的局限性，从而扩大脑刺激的有用性，并彻底改变神经系统疾病的治疗。然而，聚焦超声刺激大脑活动的机制尚不清楚，导致这项技术发展的关键瓶颈。超声波激活产生大脑活动的离子通道的机械基础的知识将彻底改变超声波作为神经刺激工具的发展。为了实现这样一个机制的理解，超声波与膜和离子通道的相互作用将使用几个精心控制的实验系统进行研究：纯脂质双层，脂质双层与模型离子通道（短杆菌肽），和脂质双层与Nav通道。模型系统的使用将使我们能够确定理想地激活离子通道的超声参数，同时最大限度地减少对膜或膜蛋白的不良影响，这在完整大脑的复杂环境中将是一项棘手的任务。初步实验表明，没有蛋白质的模型膜表现出强大的电响应超声刺激，并导致我们假设：（1）超声辐射压力微妙地扭曲脂质双层结构;（2）这些扭曲改变膜蛋白的功能状态之间的平衡，通过蛋白质双层相互作用;和（3）这些相互作用是由蛋白质和双层之间的疏水性错配介导的。拟议的实验将测试这些假设，使用电生理记录和光学干涉测量在三个实验系统。研究结果将为开发聚焦超声作为实验和治疗性脑深部刺激的非侵入性工具提供一个重要的定量框架。 公共卫生相关性：聚焦超声是一种很有前途的新技术，可用于刺激大脑活动，并有可能为许多神经系统疾病提供革命性的新疗法。然而，聚焦超声刺激大脑活动的机制尚不清楚，导致这项技术发展的关键瓶颈。这项研究将为聚焦超声如何刺激大脑活动提供必要的机制理解。

DESCRIPTION (provided by applicant): Brain stimulation therapies are currently used to treat several types of neurological disorders (Parkinson's disease, dystonia, eplilepsy) and hold promise for treatment of many others (Alzheimer's, anxiety, schizophrenia, and stroke, for example). Current clinical applications of brain stimulation involve either implanted electrodes (which is limited by the invasive nature of the implantation) or transcranial magnetic stimulation (limited by its spatial resolution and depth penetration). Recently, it was shown that focused ultrasound (a non-invasive technology capable of deep brain penetration) can activate voltage-gated sodium channels (Nav channels) and consequently increase the rate of action potential firing in the mouse motor cortex in vivo. These findings indicate that focused ultrasound could overcome the limitations of current brain stimulation therapies, thereby expanding the usefulness of brain stimulation and revolutionizing treatment of neurological disorders. However, the mechanisms by which focused ultrasound stimulates brain activity are not understood, causing a critical bottleneck in development of this technology. Knowledge of the mechanistic basis by which ultrasound activates the ion channels that generate brain activity will revolutionize the development of ultrasound as a tool for neurostimulation. To achieve such a mechanistic understanding, the interaction of ultrasound with membranes and ion channels will be studied using several carefully-controlled experimental systems: pure lipid bilayers, lipids bilayers with a model ion channel (gramicidin), and lipid bilayers with Nav channels. The use of model systems will allow us to determine the ultrasound parameters that ideally activate ion channels while minimizing undesired effects on membranes or membrane proteins, which would be an intractable task in the complex environment of an intact brain. Preliminary experiments reveal that model membranes devoid of proteins exhibit a robust electrical response to ultrasound stimulation and lead us to hypothesize that (1) ultrasonic radiation pressure subtly distorts lipid bilayer structure; (2) these distortions alter the equilibrium between functional states of membrane proteins through protein-bilayer interactions; and (3) these interactions are mediated by hydrophobic mismatch between protein and bilayer. The proposed experiments will test these hypotheses using electrophysiological recording and optical interferometry measurements in the three experimental systems. The results will provide a crucial and quantitative framework for developing focused ultrasound as a non-invasive tool for experimental and therapeutic deep brain stimulation. PUBLIC HEALTH RELEVANCE: Focused ultrasound is a promising new technology that can be used to stimulate brain activity and has the potential to provide revolutionary new therapies for numerous neurological disorders. However, the mechanisms by which focused ultrasound stimulates brain activity are not understood, causing a critical bottleneck in development of this technology. This research will provide the necessary mechanistic understanding of how focused ultrasound stimulates brain activity.