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

描述(申请人提供)：脑刺激疗法目前被用于治疗几种类型的神经疾病(帕金森氏病、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(受植入的侵袭性限制)或经颅磁刺激(受其空间分辨率和深度穿透的限制)。最近有研究表明，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质动作电位的放电频率。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，并使神经疾病的治疗发生革命性变化。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。了解超声波激活产生大脑活动的离子通道的机制基础，将彻底改变超声波作为神经刺激工具的发展。为了从机理上理解超声与膜和离子通道的相互作用，我们将使用几个精心控制的实验系统来研究超声与膜和离子通道的相互作用：纯脂双分子膜、具有模型离子通道(Granicidin)的脂类双分子膜和具有Nav通道的脂双分子膜。使用模型系统将使我们能够确定理想地激活离子通道的超声参数，同时将对膜或膜蛋白的不良影响降至最低，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，不含蛋白质的模型膜对超声刺激表现出很强的电学响应，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质功能状态之间的平衡；以及(3)这些相互作用是由蛋白质和双层之间的疏水失配所介导的。拟议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验证这些假设。这一结果将为发展聚焦超声作为实验性和治疗性脑深部刺激的非侵入性工具提供重要的量化框架。

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.