Dissecting human brain circuits in vivo using ultrasonic neuromodulation

 描述（由申请人提供）：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。这将为理解人类大脑功能和连通性开辟新的视野，并为难治性癫痫、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），只能应用于表层皮层区域，具有粗糙的1厘米级分辨率，基础物理学对这些技术的限制。超声波神经调节，使用超声波作为能量模态来影响大脑的活动，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，无创聚焦超声到毫米大小区域的工程挑战，无论是浅的还是深的大脑，已经得到解决：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 mm）脑损伤的可行性。此外，最近的人类研究已经记录了相对温和的超声刺激后增强的感觉辨别力。这两项研究结果表明，超声神经调节有可能成为改变游戏规则的新工具，用于人类大脑的功能解剖，以及开发人类大脑疾病的非侵入性疗法。然而，我们认为，在超声波作为一种有效和安全的工具用于调节人脑活动之前，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时空模式，从而因果地改变行为？ 我们将解决这三个基本问题，通过系统的努力跨越体外制剂，啮齿动物，猕猴和人类的主题。首先，我们将阐明的内源性机制，超声产生的变化，通过生物物理实验在卵母细胞，纯化的脂质双层，细胞培养（Shapiro）的神经活动。其次，我们将通过EEG、fMRI和单单位记录（Tsao）确定在猕猴（最接近人脑的动物模型）中引发超声神经调制的最佳参数。最后，在最初的猕猴研究之后，我们将测试超声波刺激对人类大脑的影响，无论是空间上通过功能磁共振成像（O 'Doherty）还是时间上通过脑电图（Makeig），检查休息期间和决策任务执行期间的影响。该项目将提供的创新正是RFA-MH-14-217所要求的：“开发突破性技术来测量以前无法成像的大脑过程，包括......神经系统中的局部和微回路以及将单细胞或回路活动与血液动力学或宏观电磁信号联系起来的机制。“最终，局部电路扰动与非侵入性成像的结合将使我们对大脑功能有最深入的了解。聚焦超声与功能磁共振成像/脑电图的配对有可能以前所未有的空间分辨率揭示人类大脑回路，并为将回路活动与非侵入性测量的大脑信号联系起来建立一座新的桥梁。我们的方法只有通过一个独特的跨模型系统的多学科团队之间的密切合作才有可能，并准备必要的实验基础来测试超声是否是长期以来梦想的答案，即一种技术可以随意局部刺激人脑的任何部分。

 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.