High density chronic optogenetic interface for primate brains

灵长类大脑的高密度慢性光遗传学接口

• 批准号: 10706899
• 负责人: Alessandra Angelucci
• 金额: $ 49.64万
• 依托单位: BLACKROCK MICROSYSTEMS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706899
• 关键词: Acceleration; Acute; Address; Anesthesia procedures; Animals; Area; BRAIN initiative; Behavioral; Biological Models; Brain; Brain Diseases; Cerebral cortex; Chronic; Color; Coupled; Development; Device Designs; Devices; Electrodes; Electronics; Electrophysiology (science); Encapsulated; Engineering; Environment; Epilepsy; Failure; Foundations; Functional disorder; Funding; Future; Gene Expression; Generations; Geometry; Goals; Human; Immediate-Early Genes; Investigation; Learning; Light; Link; Macaca; Measurable; Medical; Methods; Morphologic artifacts; Names; Neurologic; Neurons; Neurophysiology - biologic function; Neurosciences; Optics; Output; Pattern; Penetration; Performance; Periodicals; Phase; Physiologic pulse; Population; Primates; Printing; Process; Schizophrenia; Shapes; Side; Signal Transduction; Site; Small Business Technology Transfer Research; Surface; Target Populations; Technology; Temperature; Testing; Therapeutic Intervention; United States National Institutes of Health; Universities; Update; Utah; Validation; Visual Cortex; Work; autism spectrum disorder; cell type; density; design; ex vivo imaging; experimental study; fabrication; implantation; improved; in vivo; in vivo evaluation; layered ceramics; manufacture; nervous system disorder; neural; neural circuit; neural patterning; neuroregulation; new technology; nonhuman primate; novel; operation; optogenetics; performance tests; process optimization; prosthesis control; response; sensor; spatiotemporal; tool

PROJECT SUMMARY Understanding the function of neural circuits in the cerebral cortex of the non-human primate (NHP), the model system closest to human, is crucial to understanding normal cortical function and the circuit-level basis of human brain disorders. Optogenetics has become a powerful tool for studying neural circuit function, but challenges remain in its application to NHPs. Large volume manipulations are essential in the large NHP brain in order to observe measurable electrophysiological or behavioral effects and understand the encoding of information across multiple brain areas. Under previous NIH BRAIN Initiative funding, an interdisciplinary team led by the University of Utah has developed and tested in vivo the Utah Optrode Array (UOA). This is a 10x10 array of penetrating transparent light guides, bonded to a µLED array, for large-volume, spatiotemporally patterned optogenetic modulation of neural circuits in large brains. In vivo testing of the UOA in NHP visual cortex demonstrated that the device allows for selective activation of deep cortical layers, as well as for both focal and large-scale photostimulation by simply varying the number of simultaneously activated µLEDs and/or their light irradiance These results establish the UOA as a powerful tool for studying local and large-volume targeted neuronal populations in large brains. Led by Blackrock Neurotech, the goal of this STTR is to transition the UOA into a commercializable device by combing the best features of its current ‘LED Stim’ optogenetic surface stimulation array with the UOA. Thus, the goal of Phase I is to engineer the first iteration of this new device, termed ‘OA2’ for development purposes: Aim 1: Integration of blue stimulation array, in which redesign, fabrication, and integration of the two-level stimulation device will be performed using independent 10×10 and 9×9 arrays of blue µLEDs for deep-layer and surface stimulation, respectively. Aim 2: Device encapsulation and packaging, in which robust encapsulation processes will be developed and tested, suitable for acute in vivo use. Aim 3: Development of matrix driver, in which a new driver and firmware will be developed in order to independently control the deep and surface stimulation arrays for spatially-multiplexed operation. The project includes a Go-NoGo to phase II paradigm which requires >90% of the stimulation sites to remain active >2.8 mW/mm2 following acute soak testing with 50% simultaneous operation at 10% duty cycle, artifact-free. Phase II will consist of four Aims: Aim 4: Device optimization for multi-color stimulation, in which the active µLED component will be modified to facilitate placement and hard encapsulation of µLEDs onto the topside of the device, allowing multi-color stimulation at each deep/surface site. Both single and two-color devices will be produced in Phase II. Aim 5: Device encapsulation and packaging, will build upon the work of Aim 2 to include hard encapsulation of the active components of the device in order to increase device in vivo reliability. Processes will be developed and tested suitable for chronic in vivo use. Aim 6: Development of dual-color matrix driver, in which the matrix driver will be updated to bipolar drive signals to enable multiplexed control of two µLEDs per stimulation site. Aim 7: In vivo testing in NHP, in which both acute and chronic testing of the OA2 device will be performed in macaque for periods up to 6 months.

项目摘要 了解非人类灵长类动物（NHP）大脑皮层中神经回路的功能， 最接近人类的神经系统，对于理解正常的大脑皮层功能和人类的电路水平基础至关重要。 大脑紊乱光遗传学已成为研究神经回路功能的有力工具，但挑战 它仍然适用于NHP。大容量操作在大NHP脑中是必不可少的，以便 观察可测量的电生理或行为效应，并了解信息的编码， 多个脑区在之前的NIH BRAIN计划资助下，由美国国家卫生研究院领导的跨学科团队 犹他州大学开发并在体内测试了犹他州光电极阵列（UOA）。这是一个10 x10的数组， 穿透透明光导，粘合到µLED阵列，用于大体积时空图案化 大大脑神经回路的光遗传学调节。NHP视皮层中UOA的体内测试 表明该装置允许选择性激活深层皮质层，以及局灶性和 通过简单地改变同时激活的µ LED的数量和/或它们的光， 这些结果确立了UOA作为研究局部和大体积靶向的强有力的工具 大脑中的神经元群体。在Blackrock Neurotech的领导下，该STTR的目标是将UOA 通过结合其当前“LED Stim”光遗传表面的最佳功能， 刺激阵列与UOA。因此，第一阶段的目标是设计这种新设备的第一次迭代， 出于开发目的称为“OA 2”：目标1：蓝色刺激阵列的集成，其中重新设计， 将使用独立的10×10和 分别用于深层和表面刺激的9×9蓝色µ LED阵列。目标2：器件封装和 包装，其中将开发和测试耐用的封装工艺，适用于急性体内使用。 目标3：开发矩阵驱动程序，其中将开发新的驱动程序和固件，以便 独立地控制深部和表面刺激阵列以进行空间多路复用操作。项目 包括Go-NoGo到阶段II范例，其需要>90%的刺激部位保持活性>2.8 在10%占空比下50%同时运行的急性浸泡测试后的mW/mm 2，无伪影。相 II将包括四个目标：目标4：多色刺激的设备优化，其中有源µLED 组件将进行修改，以便于将µ LED放置和硬封装到 设备，允许在每个深/表面部位进行多色刺激。单色和双色设备都将 在第二阶段生产。目标5：设备封装和包装，将建立在目标2的工作，包括 硬封装器件的活性成分，以增加器件的体内可靠性。过程 将开发和测试适合长期体内使用。目标6：双色矩阵驱动器的开发 该矩阵驱动器将更新为双极性驱动信号，以实现每 刺激部位。目标7：NHP体内试验，其中将对OA 2器械进行急性和慢性试验 在猕猴中进行长达6个月的试验。