EAGER: Real-Time: Free-Floating Wireless Implantable Optical Stimulators for Untethered Optogenetics

光遗传学是利用光门离子通道或泵来通过光脉冲刺激或抑制遗传靶向神经元的瞬时活动，已经证明它在理解大脑功能和行为背后的神经元电路机制方面具有巨大的潜力，并最终为治疗许多神经和精神疾病提供治疗方法。尽管光遗传学工具在过去十年中发展迅速，但系链光学设备在实验动物中造成了重大限制，在潜在的临床应用中更是如此。这项拟议的研究将通过开发一种分布式、无线(无绳系和无电池)、可植入的光刺激器体系结构来解决系留光遗传学系统中的根本挑战，该体系结构更节能、更安全、更实用于临床应用。该项目的成功完成将产生一个新的神经接口工具，显著扩展快速增长的光遗传学领域的用途，该领域已成为脑科学研究、基因治疗和各种神经疾病新药开发的前沿。此外，该项目将培训研究生进行多学科研究，并通过综合推广活动扩大K-12科学、技术、工程和数学(STEM)教育，包括美国国家科学基金会赞助的密歇根州立大学教师研究经验(RET)计划。拟议的无线光遗传学刺激器将集成一个毫米大小的对二甲苯涂层系统片上(SoC)，带有嵌入式接收线圈、表面贴装存储电容器和微型发光二极管(MicroLED)，以选择性地刺激目标神经组织。研究人员将利用以下技术解决向神经组织输送无线电能的低效问题：1)四线圈遥测链路，包括一个可植入高品质因数谐振器，以增强无线功率耦合效率；2)一个内置反射镜，用于反射microLED的背面照明，以提高光吞吐量；以及3)SoC的开关电容刺激(SCS)结构，用于直接从感应链路对一系列存储电容器阵列充电，并定期将它们放电到microLED，而无需加载感应链路。单个无线刺激器能够以高时空分辨率对目标神经元进行局部光刺激，而一组这样的植入物能够以最小的侵入性和运动限制轻松访问大规模神经元电路。建议的设备还为光遗传学转化为行为动物研究和临床应用提供了一个明显更安全和更实用的解决方案。消除拴系的慢性物理创伤可以有效地将组织损伤降至最低，并使高效稳定的慢性无线光刺激成为可能。此外，分布式硬膜外植入策略允许对皮质中任何所需区域进行选择性刺激。这一新的范例将为神经科学界提供前所未有的灵活性，在丰富的、不受限制的环境中进行无限的实验，而不需要小动物受试者携带笨重的电池四处走动。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Optogenetics, the use of light-gated ion channels or pumps to excite or inhibit the transient activity of genetically targeted neurons by pulses of light, has proved its enormous potential for understanding neuronal circuit mechanisms underlying brain functions and behavior, and ultimately, for providing therapeutics to treat numerous neurological and psychiatric disorders. Despite the rapid development of optogenetics tools over the past decade, tethered optical devices pose significant limitations in experimental animals and even more so in potential clinical applications. This proposed research will address fundamental challenges in tethered optogenetics systems, by developing a distributed, wireless (untethered and battery-less), implantable optical stimulator architecture that is more power efficient, significantly safer, and more practical for translation to clinical applications. The successful completion of the project will yield a new neural interface tool to significantly expand the utility of the rapidly growing field of optogenetics, which has become the frontier in brain science research, gene therapy, and new drug discovery for a variety of neural diseases. In addition, the project will train graduate students in multidisciplinary research and broaden K-12 education in Science, Technology, Engineering, and Mathematics (STEM) through integrated outreach activities, including the NSF sponsored Research Experiences for Teachers (RET) Program at Michigan State University.The proposed wireless optogenetics stimulator will integrate a mm-sized, Parylene-coated system-on-a-chip (SoC) with an embedded receiver coil, surface-mount storage capacitors, and microscale light-emitting diodes (microLEDs) to selectively stimulate the target neural tissue. Researchers will tackle inefficiencies in wireless power delivery to the neural tissue using: 1) a four-coil telemetry link including an implantable high quality factor resonator to enhance wireless power coupling efficiency; 2) a built-in mirror to reflect backside illumination of microLED for improving light throughput; and 3) a switched-capacitor stimulation (SCS) structure of the SoC to directly charge an array of storage capacitors from the inductive link and periodically discharge them into a microLED without loading the inductive link. A single wireless stimulator enables localized optical stimulation of targeted neurons with high spatiotemporal resolution, while a cluster of such implants enables easy access to large-scale neuronal circuits with minimal invasiveness and movement restriction. The proposed device also enables a significantly safer and more practical solution for potential translation of optogenetics into behaving animal research and clinical applications. Removing the chronic physical trauma of tethering can effectively minimize tissue damage and enable efficient and stable chronic wireless optical stimulation. Moreover, the distributed, epidural implantation strategy permits selective stimulation of any desired area in the cortex. This new paradigm will offer neuroscience community an unprecedented level of flexibility with unlimited experiment duration in an enriched, untethered environment, without requiring small animal subjects to carry bulky batteries around.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.