Neurochemical Pattern Generation with Smart Electrical Stimulation

描述(申请人提供)：智能电刺激的神经化学模式生成Pedram Mohseni1和Paul A.Garris2 1案例西部储备大学2伊利诺伊州立大学在这项小型研究拨款(家长R03)提案中，一名电气工程师/计算机科学家(Pi Mohseni)和一名神经生物学家/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相结合。实时化学微传感器在研究大脑功能和病理方面有很大的前景。它们的决定性分析特征是通过识别释放的神经递质来询问单一神经元类型的活动的能力。也许迄今为止这种测量方式最不朽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)在目标定向行为期间在大脑植入的微米大小的探头上以亚秒级的时间分辨率监测多巴胺。支持这一突破性技术的无线IC也取得了长足的进步。在现有的纯传感IC的基础上增加神经化学模式的产生，实质上扩展了化学传感IC的用途，最终为未来的闭环器件奠定了基础。我们认为，将被动化学测量扩展到高精度、动态化学控制的领域与R03新研究技术的开发范围是一致的。这项建议的两个具体目标是：(1)开发一种支持CFM中FSCV的神经化学传感IC，具有集成的用于神经化学模式生成的电刺激能力；(2)测试和表征该IC。工程上的创新之处在于，每当刺激器通过外部触发器激活时，IC架构将精确同步伏安法和刺激电流产生的时间，以避免时间重叠，并将刺激伪影干扰FSCV记录的可能性降至最低。除了桌面工程评估外，还将使用流动注射分析在体外测试功能，并使用不同的神经化学模式作为模板在体内测试麻醉大鼠。概念上的创新是传递函数驱动的神经化学模式生成，并随后由刺激传感IC验证所生成的轮廓的保真度。在这项工作中选择多巴胺作为测试分析物是非常明智的。多巴胺参与重要的大脑功能和衰弱的神经病理，可用于FSCV检测，是使用微型传感器研究最多的神经递质，具有成熟的传递函数，适合于基于时间和幅度的模式生成。可以移植到其他神经递质、微传感器策略和应用中，我们强调建议的IC作为一种更广泛的设备的通用通用性，而不是这些多巴胺的开发测试。因此，从长远来看，拟议的IC将为研究行为和疾病症状的神经基础提供一个创新和强大的神经生物学工具包，并可能通过提供最终为许多人类神经病理开发新的神经调节设备的框架而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.