A Wireless Implanted Device for Brain Monitoring in Support of Addiction Research

描述（由申请人提供）：在这个前沿的基础研究奖（CEBRA）提案中，电气工程师/计算机科学家（PI Mohseni）和神经生物学家/分析化学家（PI Garris）将合作开发一种超小型可植入设备，用于无线神经监测和刺激清醒的动物。该装置将通过扩展碳纤维微电极（CFM）上的快速扫描循环伏安法（FSCV）的最新创新，推进药物成瘾生物学机制的研究。由于在微米大小的探针上具有亚秒时间分辨率的化学选择性记录，CFM的FSCV被认为是最先进的神经递质监测技术。在过去的十年中，在CFM中将FSCV应用于流动大鼠，研究阶段性多巴胺能传递在目标导向行为中的作用，特别是在可卡因强化方面，以及在同一探针上结合化学和电测量来量化脑多巴胺动力学的突触后效应，已经取得了很大的进展。通过在CFM上扩展FSCV已经很有吸引力的分析属性，我们坚信这里提出的设备符合CEBRA计划的标准。建议的发展包括：(1)用数字遥测链路取代硬连线连接；(2)用片上组件替换外部刺激发生器；(3)显著减小整体尺寸、重量和功耗；(4)支持多个独立配置通道，用于FSCV、电生理和组合测量。总的来说，这些进展解决了与目前使用“大型”头戴式设备以及将动物拴在设备上有关的问题，这些设备可能会改变行为，成为噪声源，并妨碍在较小但有价值的动物模型（如转基因小鼠）中进行测量。此外，多个数据通道提供了结合两种强大的神经监测技术的诱人前景，CFM的FSCV和多电极阵列单单元记录，以在综合水平上评估药物相关行为的复杂电路水平控制。三个具体目标是：(1)使用标准互补金属氧化物半导体技术中的大规模集成技术，开发一种16通道设备，支持伏安法，电生理学和组合测量以及电刺激；(2)在多个层面对该装置进行测试和表征，包括台式工程评估、流动注射分析体外校准、麻醉和清醒大鼠；(3)在两个试点应用中展示该设备的功能，在高剂量精神兴奋剂安非他明给药期间，在清醒的大鼠中FSCV测量多巴胺，以及在转基因小鼠模型中长期植入微丝束进行单单元记录。通过开发首个支持化学和电传感和电刺激的无线集成电路，CEBRA提案将解决CFM中FSCV现有仪器的关键限制，并推进这项已经强大的神经监测技术。公共卫生相关性：该项目将开发一种小型无线设备，支持化学和电记录以及对小型实验动物大脑的电刺激。该装置将促进药物成瘾神经机制的基础科学研究。

DESCRIPTION (provided by applicant): In this Cutting-Edge Basic Research Award (CEBRA) proposal, an electrical engineer/computer scientist (PI Mohseni) and a neurobiologist/analytical chemist (PI Garris) will collaborate to develop an ultra-small, implantable device for wireless neural monitoring and stimulation in awake animals. This device will advance the investigation of biologic mechanisms of drug addiction by extending recent innovations in fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM). By virtue of chemically selective recording with sub-second temporal resolution at a micron-sized probe, FSCV at a CFM is recognized as state-of-the-art for neurotransmitter monitoring. In the last decade, great strides have been made applying FSCV at a CFM to ambulatory rats for studying the role of phasic dopaminergic transmission in goal-directed behaviors, particularly with regard to cocaine reinforcement, and combining chemical and electrical measurements at the same probe for quantifying postsynaptic effects of brain dopamine dynamics. By extending the already attractive analytical attributes of FSCV at a CFM on several fronts, we firmly believe that the device proposed here meets criteria for the CEBRA program. Proposed developments include: (1) replacing the hardwired connection with a digital telemetry link; (2) replacing the external stimulus generator with an on-chip component; (3) significantly reducing overall dimensions, weight, and power consumption; (4) supporting multiple, independently configurable channels for FSCV, electrophysiology, and combined measurements. Collectively, these advances address concerns related to the current use of "large" head-mounted devices as well as tethering animals to equipment, which may alter behavior, act as a noise source, and preclude measurements in smaller, but valuable animal models such as transgenic mice. Moreover, multiple data channels afford the enticing prospect of marrying two powerful technologies for neural monitoring, FSCV at a CFM and multielectrode array single-unit recording, to assess complex circuit-level control of drug-related behavior on an integrative level. The three specific aims are to: (1) using very-large-scale-integration techniques in standard complementary-metal-oxide-semiconductor technology, develop a 16-channel device supporting voltammetry, electrophysiology, and combined measurements, as well as electrical stimulation; (2) test and characterize the device on several levels, including benchtop engineering assessment, in vitro calibration with flow injection analysis, and anesthetized and awake rats; (3) showcase device features in two pilot applications, FSCV dopamine measurements in the awake rat during high-dose administration of the psychostimulant amphetamine and single-unit recording with microwire bundles chronically implanted in a transgenic mouse model. By developing the first wireless integrated circuit supporting chemical and electrical sensing and electrical stimulation, this CEBRA proposal will address key limitations of existing instrumentation for FSCV at a CFM and advance this already powerful neural monitoring technique. PUBLIC HEALTH RELEVANCE: This project will develop a miniaturized wireless device supporting chemical and electrical recording as well as electrical stimulation in the brain of small laboratory animals. This device will advance basic science research investigating neural mechanisms of drug addiction.