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

描述(由申请人提供)：在这份尖端基础研究奖(CEBRA)提案中，一位电气工程师/计算机科学家(Pi Mohseni)和一位神经生物学家/分析化学家(Pi Garris)将合作开发一种超小型植入式设备，用于清醒动物的无线神经监测和刺激。该装置将在碳纤维微电极(CFM)上扩展快速扫描循环伏安法(FSCV)的最新创新，从而推动药物成瘾生物机制的研究。由于在微米大小的探头上具有亚秒级时间分辨率的化学选择性记录，CFM上的FSCV被认为是神经递质监测的最先进技术。在过去的十年里，在CFM将FSCV应用于可移动的大鼠，以研究多巴胺能相性传递在目标定向行为中的作用，特别是在可卡因强化方面，并在同一探针上结合化学和电学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的几个方面扩展已经很有吸引力的FSCV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)用片上组件取代外部刺激发生器；(3)显著降低整体尺寸、重量和功耗；(4)支持FSCV、电生理和组合测量的多个可独立配置的通道。总而言之，这些进展解决了与当前使用“大型”头盔设备以及将动物拴在设备上有关的担忧，这些设备可能会改变行为，充当噪声源，并排除在较小但有价值的动物模型(如转基因小鼠)中进行测量的可能性。此外，多个数据通道提供了将两种强大的神经监测技术--CFM上的FSCV和多电极阵列单单元记录--结合在一起的诱人前景，以在综合水平上评估复杂的电路级别的药物相关行为控制。这三个具体目标是：(1)利用标准互补金属氧化物半导体技术中的超大规模集成技术，开发支持伏安法、电生理学、联合测量以及电刺激的16通道设备；(2)在多个层面上测试和表征该设备，包括台式工程评估、流动注射分析的体外校准以及麻醉和苏醒的大鼠；(3)展示两个试点应用中的设备特征：高剂量精神刺激剂苯丙胺对清醒大鼠的FSCV多巴胺测量，以及长期植入转基因小鼠模型的微线束的单单位记录。通过开发第一个支持化学和电气传感以及电刺激的无线集成电路，CEBRA的这项提案将解决CFM中现有FSCV仪器的关键限制，并促进这一已经强大的神经监测技术的发展。与公共卫生相关：该项目将开发一种微型无线设备，支持在小型实验动物的大脑中进行化学和电记录以及电刺激。该装置将推进研究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.