Smart Dura: A Functional Large-scale, High-Density Optoelectric Dura for Non-Human Primates

智能硬脑膜：用于非人类灵长类动物的功能性大型高密度光电硬脑膜

• 批准号: 10238757
• 负责人: Maysamreza Chamanzar
• 金额: $ 39.2万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10238757
• 关键词: Address; Adhesions; Advanced Development; Animal Model; Animals; Area; Behavior; Behavioral; Brain; Calcium; Cephalic; Chronic; Communication; Complex; Coupled; Deposition; Development; Device or Instrument Development; Dura Mater; Electrocorticogram; Electrodes; Electronics; Electrophysiology (science); Engineering; Equilibrium; Equine mule; Fiber; Future; Head; Human; Hybrids; Image; Implant; Investigation; Light; Macaca; Mechanics; Microfabrication; Modeling; Monitor; Monkeys; Morphologic artifacts; Mus; Neuronal Plasticity; Neurons; Opsin; Optical Coherence Tomography; Optics; Pattern; Performance; Process; Public Health; Publishing; Reporting; Resolution; Site; Source; Stroke; Structure; Surface; System; Techniques; Technology; Testing; Time; Translating; Virus; awake; base; biocompatible polymer; biomaterial compatibility; cell type; density; design; experimental study; flexibility; imaging modality; indium tin oxide; insight; interest; lithography; millisecond; multi-photon; multimodal data; nervous system disorder; neural circuit; neural network; neurophysiology; nonhuman primate; novel; novel therapeutic intervention; optical fiber; optogenetics; parylene C; polydimethylsiloxane; pressure; prevent; relating to nervous system; stroke recovery; success; temporal measurement; tool; tool development

Project Summary Optogenetics is a powerful tool for relating brain function to behavior because it enables cell- type specific manipulation of neurons with millisecond temporal precision and artifact-free neural recordings. Such capabilities are particularly needed in studies using non-human primates (NHPs), where sophisticated behavioral techniques are commonly employed but neurophysiological tools have lagged those used in other model species. While the use of optogenetics in NHPs has grown rapidly in recent years, the full power of the technique requires the ability to perform large-scale, bi-directional study of neural circuits. Systems to achieve this have become widely used in other animal models, particularly mice, while there have been limited systems implemented in NHPs. In this proposal, a large-scale, high-density, and stable optoelectric neural interface (smart dura) for large brains will be developed and validated in macaques, for the first time. This novel interface enables simultaneous electrical recording from 4096 electrodes and optical stimulation in 4096 sites over about 5 cm2 of cortex, which is more than two orders of magnitude higher than the state-of-the-art technology. As opposed to existing surface electrocorticography (ECoG) electrode arrays, the proposed neural interface is in the form of an artificial dura that monolithically embeds electrical recording and optical stimulation functionalities such that it can permanently replace the native dura as a chronic, seamless neural interface, while maintaining the natural cranial pressure. Therefore, this novel design combines the best of passive/static artificial dura windows and functional surface electrode arrays in one unified platform. The proposed smart dura enables long-term recording, provides new opportunities for creating sophisticated closed-loop stimulation and recording paradigms, and advances the development of new stimulation-based therapies. The smart dura can be implanted as a stable port into large brains and consists of high-density recording electrodes as well as optical micro light sources all embedded in a hybrid biocompatible polymer platform. In this project, a novel fabrication process will be designed to implement the proposed large-scale (5 cm2) smart dura in two stages of: i) Fabricating high-density transparent electrical smart dura for electrophysiology recording and external optical access (transparent electric dura: transparent e- dura), enabled by high resolution interconnects (300 nm features). ii) The optoelectric dura (oe- dura) consisting of high-density recording electrodes and embedded micro light emitting diodes (µLEDs). In each stage of the device development, the neural interface will be tested in two hemispheres of two monkeys, with large optogenetic expression of activating opsin (ChR2) in sensorimotor cortex via electrophysiology recording, behavior, and imaging. The proposed smart dura will greatly enhance the opportunities for closed-loop optogenetic experiments in macaques, which can serve as a powerful tool for understanding brain function and for developing novel therapeutic interventions that can be translated to humans. After successful demonstration of the smart dura in this proposal, the results can be extended in future to i) develop even larger interfaces that cover the whole brain for translational use ii) integrate recording, stimulation, processing, communication and power-transfer electronics into the smart dura to enable tetherless chronic neural interfacing with freely-moving subjects.

项目概要 光遗传学是将大脑功能与行为联系起来的强大工具，因为它能够使细胞 具有毫秒时间精度和无伪影的神经元的类型特定操作 录音。在使用非人类灵长类动物的研究中尤其需要这种能力 （NHP），通常采用复杂的行为技术，但 神经生理学工具落后于其他模型物种中使用的工具。虽然使用 近年来，NHP 中的光遗传学发展迅速，该技术的全部功能需要 对神经回路进行大规模、双向研究的能力。实现这一目标的系统 已广泛应用于其他动物模型，特别是小鼠，但目前的研究还很有限 NHP 中实施的系统。在该方案中，大规模、高密度、稳定的 用于大大脑的光电神经接口（智能硬脑膜）将在 猕猴，第一次。这种新颖的接口可以同时进行电子记录 4096 个电极和 4096 个部位的光刺激，覆盖约 5 cm2 的皮层，这比 比最先进的技术高出两个数量级。与现有的 表面皮层电图（ECoG）电极阵列，所提出的神经接口的形式 整体嵌入电记录和光刺激的人造硬脑膜 其功能使其可以永久取代天然硬脑膜作为慢性、无缝神经 界面，同时保持自然颅压。因此，这种新颖的设计结合了 最好的被动/静态人工硬脑膜窗和功能表面电极阵列合二为一 统一平台。所提出的智能硬脑膜能够实现长期记录，提供新的 创建复杂的闭环刺激和记录范例的机会，以及 促进新的基于刺激的疗法的开发。智能硬脑膜可植入 作为进入大大脑的稳定端口，由高密度记录电极以及 光学微光源全部嵌入混合生物相容性聚合物平台中。在这个 项目中，将设计一种新颖的制造工艺来实现拟议的大规模（5 cm2) 智能硬脑膜分两个阶段： i) 制造高密度透明电智能硬脑膜 电生理学记录和外部光学访问（透明电硬脑膜：透明e- dura），通过高分辨率互连（300 nm 功能）实现。 ii) 光电硬脑膜 (oe- Dura）由高密度记录电极和嵌入式微型发光二极管组成 （μLED）。在设备开发的每个阶段，神经接口将分两次进行测试 两只猴子的半球，激活视蛋白（ChR2）的大量光遗传学表达 感觉运动皮层通过电生理学记录、行为和成像。拟议的智能 硬脑膜将大大增加猕猴闭环光遗传学实验的机会， 它可以作为理解大脑功能和开发新颖的强大工具 可以转化为人类的治疗干预措施。演示成功后 该提案中的智能硬脑膜，其结果可以在未来扩展至 i) 开发更大 覆盖整个大脑以供翻译使用的接口 ii) 集成记录、刺激、 将处理、通信和电力传输电子设备集成到智能硬脑膜中，以实现 与自由移动的受试者进行无绳慢性神经接口。