Dissecting human brain circuits in vivo using ultrasonic neuromodulation

 描述(申请人提供)：神经科学的梦想是能够以高空间分辨率非侵入性地调节人脑的任何给定区域。这将为了解人类大脑的功能和连通性开辟新的视野，并为顽固性癫痫、抑郁症和帕金森病等脑部疾病的非侵入性治疗创造全新的选择。目前的非侵入性脑刺激方法，如经颅磁刺激(TMS)和经颅电刺激(TES)，只能应用于皮质浅层，分辨率为1厘米，这是基础物理学对这些技术的限制。超声神经调节，即利用超声波作为一种能量方式来影响大脑的活动，可以克服这些限制，从而改变基础和临床人类神经科学。事实上，将超声非侵入性聚焦到大脑浅层或深层的毫米级区域的工程挑战已经解决：临床研究已经证明了通过经颅高强度超声在皮质下区域制造局灶性(直径约3毫米)脑损伤的可行性。此外，最近的人体研究证明，在相对温和的超声波刺激后，感觉辨别能力会增强。这两个发现表明，超声波神经调节有可能成为改变游戏规则的新工具，用于人脑功能解剖和开发人脑疾病的非侵入性治疗。然而，我们认为，在超声被用作一种有效和安全的调节人类大脑活动的工具之前，需要解决三个主要问题：(1)超声波影响神经活动的基本生物物理机制是什么？(2)最大限度地调节灵长类动物大脑中的神经活动的最佳超声参数是什么？(3)针对特定脑区的超声波如何影响整个大脑的活动的时空模式，从而因果地改变行为？我们将通过一个跨越体外制剂、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，我们将通过在卵母细胞、纯化的脂质双层和细胞培养中的生物物理实验来阐明超声波引起神经活动变化的内源性机制(夏皮罗)。其次，我们将通过EEG、fMRI和单单位记录(TSAO)来确定在猕猴--最接近人脑的动物模型--中诱发超声神经调节的最佳参数。最后，在初步的猕猴研究之后，我们将通过fMRI(O‘Doherty)和EEG(Makeig)在空间和时间上测试超声波刺激对人脑的影响，检查休息和执行决策任务时的影响。该项目将提供的创新正是RFA-MH-14-217所要求的：“开发突破性技术，以测量以前无法进行成像的大脑过程，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流动力学或宏观电磁信号联系起来的机制。”最终，局部电路扰动和非侵入性成像的结合将给我们对大脑功能的最大洞察。聚焦超声与fMRI/EEG的结合具有以前所未有的空间分辨率揭示人类大脑回路的潜力，并创建了一座将回路活动与非侵入性测量的大脑信号联系起来的新桥梁。我们的方法只有通过一个跨模型系统工作的独特的多学科团队的密切合作才有可能，并准备必要的实验基础，以测试超声波是否是对一种可以随意集中刺激人脑任何部分的技术的长期梦想的答案。

 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.