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（例如阿尔茨海默氏症、焦虑症、精神分裂症和中风）。目前脑刺激的临床应用包括植入电极（受植入侵入性的限制）或经颅磁刺激（受其空间分辨率和深度穿透的限制）。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），从而增加小鼠体内运动皮层的动作电位放电率。这些发现表明，聚焦超声可以克服当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，这导致了这项技术发展的关键瓶颈。了解超声波激活离子通道产生大脑活动的机制基础，将彻底改变超声波作为神经刺激工具的发展。为了获得这样的机制理解，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：纯脂质双分子层，脂质双分子层与模型离子通道（gramicidin），脂质双分子层与Nav通道。模型系统的使用将使我们能够确定理想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是一项棘手的任务。初步实验表明，缺乏蛋白质的模型膜对超声刺激表现出强大的电响应，并使我们假设：(1)超声辐射压力微妙地扭曲了脂质双层结构；(2)这些扭曲通过蛋白质-双层相互作用改变了膜蛋白功能状态之间的平衡；(3)这些相互作用是由蛋白与双分子层之间的疏水失配介导的。所提出的实验将在三个实验系统中使用电生理记录和光学干涉测量来测试这些假设。研究结果将为聚焦超声作为实验和治疗深部脑刺激的非侵入性工具的发展提供一个关键的定量框架。

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.