Neurochemical Pattern Generation with Smart Electrical Stimulation

描述（由申请人提供）：利用智能电刺激生成神经化学模式 Pedram Mohseni1 和 Paul A. Garris2 1 凯斯西储大学 2 伊利诺伊州立大学 在这项小型研究补助金（父 R03）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) 将合作开发下一代无线神经化学传感集成电路 (IC)，方法是将化学模式生成的附加功能与电刺激。 实时化学微传感器在研究大脑功能和病理学方面具有广阔的前景。 它们的定义分析特征是通过识别释放的神经递质来询问单个神经元类型的活动的能力。 也许迄今为止这种测量方式最具有里程碑意义的成就是在碳纤维微电极（CFM）上使用快速扫描循环伏安法（FSCV）在目标导向行为期间通过植入大脑的微米级探针以亚秒时间分辨率进行多巴胺监测。 支持这一突破性技术的无线 IC 也取得了长足的进步。 将神经化学模式生成添加到现有的仅传感 IC 中，极大地扩展了化学传感 IC 的实用性，最终为未来的闭环设备奠定了基础。 我们认为，将被动化学测量扩展到高精度、动态化学控制领域符合R03新研究技术的发展范围。 该提案的两个具体目标是：(1) 开发一种在 CFM 上支持 FSCV 的神经化学传感 IC，具有用于神经化学模式生成的集成电刺激功能； (2) 测试并表征 IC。 工程创新在于，无论何时通过外部触发器激活刺激器，IC 架构都将精确同步伏安法和刺激电流生成的时序，以避免时间重叠，并最大限度地减少刺激伪影干扰 FSCV 记录的可能性。 除了台式工程评估之外，还将使用不同的神经化学模式作为模板，通过流动注射分析进行体外功能测试，并使用麻醉大鼠进行体内功能测试。 概念创新是传递函数驱动的神经化学模式生成，以及随后由刺激传感 IC 验证生成轮廓的保真度。 在这项工作中选择多巴胺作为测试分析物是非常明智的。 多巴胺涉及重要的大脑功能和使人衰弱的神经病理学，适合 FSCV 检测，是使用微传感器研究最多的神经递质，并且具有适合基于时间和幅度的模式生成的完善的传递函数。 可转移到其他神经递质、微传感器策略和应用，我们强调所提出的 IC 的通用性，作为超出这些多巴胺开发测试的更广泛的设备。 因此，从长远来看，所提出的 IC 将为神经生物学工具包提供创新和强大的补充，用于研究行为和疾病症状的神经基础，并且可以通过提供最终为许多人类神经病理学开发新的神经调节设备的框架来具有额外的临床意义。

DESCRIPTION (provided by applicant): Neurochemical Pattern Generation with Smart Electrical Stimulation Pedram Mohseni1 and Paul A. Garris2 1 Case Western Reserve University 2 Illinois State University In this Small Research Grant (Parent R03) proposal, an electrical engineer/computer scientist (PI Mohseni) and a neurobiologist/analytical chemist (PI Garris) will collaborate to develop the next generation of wireless neurochemical sensing integrated circuits (ICs) by incorporating the additional functionality of chemical pattern generation with electrical stimulation. Real-time chemical microsensors hold great promise for investigating brain function and pathology. Their defining analytical characteristic is the capability to interrogate the activity of a single neuron type, by virtue of identifying the released neurotransmitter. Perhaps the most monumental achievement to date with this measurement modality is dopamine monitoring with subsecond temporal resolution at a brain-implanted, micron-sized probe during goal-directed behavior using fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM). Great strides have also been made in wireless ICs supporting this ground-breaking technology. Adding neurochemical pattern generation to extant sensing- only ICs substantively expands the utility of chemical sensing ICs, ultimately laying foundational work for future closed-loop devices. We submit that extending passive chemical measurements to the realm of high-precision, dynamic chemical control is consistent with the R03 scope of development of new research technology. The two specific aims of this proposal are to: (1) develop a neurochemical sensing IC supporting FSCV at a CFM with integrated electrical stimulation capability for neurochemical pattern generation; (2) test and characterize the IC. The engineering innovation is that IC architecture will precisely synchronize the timing of voltammetry and stimulus current generation to avoid temporal overlap and minimize the possibility of stimulus artifacts interfering with FSCV recordings, whenever the stimulator is activated via an external trigger. In addition to benchtop engineering assessment, functionality will be tested in vitro with flow injection analysis and in vivo with anesthetized rats, using diverse neurochemical patterns as templates. The conceptual innovation is transfer function-driven neurochemical pattern generation and subsequent verification of the fidelity of the generated profile by the stimulating-sensing IC. Selection of dopamine as the test analyte in this work is very judicious. Involved in important brain functions and debilitating neuropathologies, dopamine is amenable to FSCV detection, is the most studied neurotransmitter using microsensors, and has well-established transfer functions suitable for time- and amplitude-based pattern generation. Transferable to other neurotransmitters, microsensor strategies, and applications, we emphasize the general versatility of the proposed IC as a more wide-ranging device beyond these development tests with dopamine. Thus, in the long term, the proposed IC will provide an innovative and powerful addition to the neurobiology toolkit for investigating the neural underpinnings of behavior and disease symptoms, and could have additional clinical bearing by providing the framework for ultimately developing new neuromodulation devices for many human neuropathologies.