Dissecting human brain circuits in vivo using ultrasonic neuromodulation

使用超声波神经调制在体内解剖人脑回路

• 批准号: 8828517
• 负责人: Mikhail Shapiro
• 金额: $ 47.19万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-26 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828517
• 关键词: Acoustics; Address; Affect; Animal Model; Animals; Area; Behavior; Behavioral; Biological Models; Biophysical Process; Brain; Brain Diseases; Brain imaging; Caliber; Cell Culture Techniques; Cells; Cellular Structures; Clinical; Clinical Research; Collaborations; Complex; Decision Making; Deep Brain Stimulation; Dependence; Development; Diagnosis; Dissection; Dreams; Electric Stimulation; Electroencephalography; Electromagnetics; Engineering; Epilepsy; Focused Ultrasound Therapy; Foundations; Frequencies; Functional Magnetic Resonance Imaging; Human; Image; In Vitro; Intractable Epilepsy; Learning; Lesion; Link; Lipid Bilayers; Macaca; Maps; Measurement; Measures; Mechanics; Mental Depression; Methods; Modality; Modeling; Molecular Structure; Nature; Nervous system structure; Neurons; Neurosciences; Oocytes; Operative Surgical Procedures; Parkinson Disease; Patients; Pattern; Performance; Physics; Physiologic pulse; Prefrontal Cortex; Preparation; Primates; Process; Recording of previous events; Research; Resolution; Rest; Risk; Rodent; Safety; Signal Transduction; Source; Spatial Distribution; Staging; Structure; Symptoms; Task Performances; Techniques; Technology; Testing; Transcranial magnetic stimulation; Ultrasonic Therapy; Ultrasonics; Ultrasonography; Work; base; bioimaging; candidate identification; frontal eye fields; hemodynamics; human subject; imaging modality; in vivo; innovation; insight; multidisciplinary; neuroregulation; new technology; non-invasive imaging; public health relevance; relating to nervous system; research study; response; sensory discrimination; spatiotemporal; tool

 DESCRIPTION (provided by applicant): A dream of neuroscience is to be able to non-invasively modulate any given region of the human brain with high spatial resolution. This would open new horizons for understanding human brain function and connectivity, and create completely new options for the non-invasive treatment of brain diseases such as intractable epilepsy, depression, and Parkinson's disease. Current non-invasive brain stimulation methods such as transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) can be applied only to superficial cortical areas, with crude 1 cm-scale resolution, limits placed upon these techniques by fundamental physics. Ultrasonic neuromodulation, the use of ultrasound as an energy modality to affect the activity of the brain, could overcome these limitations and thereby transform both basic and clinical human neuroscience. In fact, the engineering challenge of non-invasively focusing ultrasound to mm-sized regions, either shallow or deep in the brain, has been solved: clinical studies have already demonstrated the feasibility of making focal (~ 3 mm diameter) brain lesions in subcortical regions through transcranial high intensity ultrasound. Furthermore, recent human studies have documented enhanced sensory discrimination following relatively mild ultrasound stimulation. These two findings suggest that ultrasonic neuromodulation has the potential to serve as a game-changing new tool for functional dissection of the human brain, and development of non-invasive therapies for human brain disorders. However, we believe three major questions need to be addressed before ultrasound can be used as an effective and safe tool for modulating human brain activity: (1) What are the basic biophysical mechanisms through which ultrasound acts to affect neural activity? (2) What are the optimal ultrasound parameters for maximally modulating neural activity in the primate brain? (3) How does ultrasound targeted to specific brain areas affect the spatiotemporal pattern of activity across the entire brain to causally modify behavior? We will address these three fundamental questions through a systematic effort spanning in vitro preparations, rodents, macaques, and human subjects. First, we will elucidate the endogenous mechanisms by which ultrasound produces changes in neural activity through biophysical experiments in oocytes, purified lipid bilayers, and cell cultures (Shapiro). Second, we will identify the optimal parameters for eliciting ultrasonic neuromodulation in the macaque, the closest animal model of the human brain, through EEG, fMRI, and single-unit recordings (Tsao). Finally, following initial macaque studies, we will test the effects of ultrasound stimulation on te human brain, both spatially through fMRI (O'Doherty) and temporally through EEG (Makeig), examining effects both during rest and during performance of decision-making tasks. The innovations this project will provide are exactly those called for by RFA-MH-14-217: "development of breakthrough technology to measure brain processes that were formerly inaccessible to imaging, including...local and micro-circuits in the nervous system and mechanisms linking single cell or circuit activity to hemodynamic or macro-electromagnetic signals." Ultimately it's the combination of local circuit perturbation with non-invasive imaging that will give us the greatest insights into brain function. The pairing of focal ultrasound with fMRI/EEG has potential to reveal human brain circuits with unprecedented spatial resolution and create a new bridge for linking circuit activity to non -invasively measured brain signals. Our approach is only possible through intense collaboration among a unique multidisciplinary team working across model systems, and prepares the necessary experimental foundations to test whether ultrasound is the answer to the long -held dream for a technique to focally stimulate any part of the human brain at will.

 描述（由适用提供）：神经科学的梦想是能够以高空间分辨率对人脑的任何给定区域进行非侵入性调节。这将为理解人脑功能和连通性的新视野开放，并为无创脑疾病（例如顽固性癫痫，抑郁症和帕金森氏病）提供全新的选择。当前的非侵入性大脑刺激方法，例如thranaile磁刺激（TMS）和经颅电模拟（TES），只能应用于浅表皮质区域，并具有粗略的1 cm尺度分辨率，基本物理学对这些技术施加的限制。超声神经调节（将超声用作能量方式影响大脑活性）可能会克服这些局限性，从而改变基本和临床人类神经科学。实际上，已经解决了非侵入性将超声集中到MM大小区域的工程挑战，无论是大脑中的浅或深度区域：临床研究已经证明，通过经颅高强度超声超声波化，在皮层区域中使局灶性（〜3 mm直径）脑损伤的可行性。此外，最近的人类研究表明，相对轻度的超声刺激后，感觉歧视增强。这两个发现表明，超声神经调节有可能作为改变人类脑功能解剖的新工具，并开发针对人脑疾病的非侵入性疗法。但是，我们认为，在将超声用作调节人脑活动的有效且安全的工具之前，需要解决三个主要问题：（1）超声可以影响神经活动的基本生物物理机制是什么？ （2）在隐私大脑中最大程度地调节神经活动的最佳超声参数是什么？ （3）针对特定大脑区域的超声波如何影响整个大脑活动的空间时间模式以改变行为？我们将通过跨越体外制剂，啮齿动物，猕猴和人类受试者的系统努力来解决这三个基本问题。首先，我们将通过卵母细胞，纯化的脂质双层和细胞培养物（Shapiro）中的生物物理实验来阐明超声通过生物物理实验产生神经活动的变化。其次，我们将通过EEG，fMRI和单单元记录（TSAO）确定在猕猴中引起超声神经调节的最佳参数。最后，经过最初的猕猴研究，我们将通过fMRI（O'Doherty）和通过EEG（Makeig）临时测试超声刺激对人脑的影响，并在决策任务执行过程中检查效果。该项目将提供的创新正是RFA-MH-14-217所要求的：“突破性技术的开发以测量以前对成像无法访问的大脑过程，包括...神经系统中的局部和微电路以及将单细胞或电路活动与血液动力学或宏观电子或宏观电动磁性信号联系起来的机制。”最终，正是局部电路扰动与非侵入性成像的结合将使我们对大脑功能有最大的见解。局灶性超声与fMRI/EEG的配对有潜力揭示人脑回路具有前所未有的空间分辨率，并创建了一个新的桥梁，以将电路活性与非不创测量的脑信号联系起来。只有通过在跨模型系统工作的独特多学科团队之间进行激烈的合作，我们的方法才有可能，并准备了必要的实验基础，以测试超声是否是长期实现的梦想的答案，该技术是一种技术，以侧重刺激人类大脑的任何部分。