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

项目摘要 光遗传学是将大脑功能与行为联系起来的强大工具，因为它使细胞- 具有毫秒时间精度和无伪影神经的神经元类型特定操作 录音。这种能力在使用非人类灵长类动物的研究中尤其需要 (NHP)，其中通常使用复杂的行为技术，但 神经生理学工具落后于其他模式物种使用的工具。虽然使用的是 近几年来，NHP的光遗传学发展迅速，这项技术的全部威力需要 对神经回路进行大规模、双向研究的能力。实现这一点的系统 已被广泛应用于其他动物模型，特别是小鼠，而目前 在卫生保健计划中实施的系统。在这一建议中，一个大规模、高密度、稳定的 用于大型大脑的光电神经接口(智能硬脑膜)将于#年开发和验证 猕猴，这是第一次。这一新颖的接口允许同时从 4096个电极和4096个部位的光刺激超过约5平方厘米的皮质，这是更多 比最先进的技术高出两个数量级。与现有的 表面皮层脑电(ECoG)电极阵列，所提出的神经接口的形式为 单片嵌入电记录和光刺激的人造硬脑膜 它可以永久取代天然硬脑膜，成为一种慢性、无缝的神经 界面，同时保持自然的颅压。因此，这种新颖的设计结合了 无源/静态人工硬脑膜窗与功能性表面电极阵列的最佳结合 统一平台。拟议的智能硬盘能够实现长期记录，提供新的 创造复杂的闭环刺激和记录范例的机会，以及 促进以刺激为基础的新疗法的发展。智能硬脑膜可以植入 作为进入大型大脑的稳定端口，由高密度记录电极以及 光学微光源全部嵌入混合生物兼容聚合物平台。在这 项目，将设计一种新的制造工艺来实施拟议的大规模(5 Cm2)智能硬脑膜分为两个阶段：i)制造高密度透明电智能硬脑膜，用于 电生理记录和外部光学通道(透明电硬脑膜：透明e- DURA)，由高分辨率互连(300纳米特征)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，神经接口将分两个阶段进行测试 激活视蛋白(ChR2)在两个猴大脑半球的大量光遗传表达 通过电生理学记录、行为和成像的感觉运动皮质。建议的SMART 杜拉将极大地增加在猕猴身上进行闭环光遗传实验的机会， 它可以作为了解大脑功能和开发小说的有力工具 可转化为人类的治疗性干预措施。在成功演示了 智能硬脑膜在本方案中，成果可以推广到未来i)发展得更大 覆盖整个大脑以供翻译使用的接口II)集成了记录、刺激、 处理、通信和将电子设备传输到智能硬脑膜中，以实现 与自由活动的受试者的无绳慢性神经接口。

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.