Neurochemical Pattern Generation with Smart Electrical Stimulation

描述（由申请人提供）：基于智能电刺激的神经化学模式生成Pedram mohseni和Paul A. garris1 Case西储大学2伊利诺伊州立大学在这项小型研究资助（家长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），将化学模式生成的附加功能与电刺激结合起来。实时化学微传感器在研究脑功能和病理方面具有很大的前景。他们定义的分析特征是能够通过识别释放的神经递质来询问单一神经元类型的活动。也许迄今为止，这种测量方式最具里程碑意义的成就是在目标导向行为过程中，利用碳纤维微电极（CFM）上的快速扫描循环伏安法（FSCV），在大脑植入的微米级探针上进行亚秒级时间分辨率的多巴胺监测。支持这项突破性技术的无线集成电路也取得了巨大的进步。将神经化学模式生成添加到现有的仅感测ic中，极大地扩展了化学感测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、动态化学控制领域，符合新研究技术发展的R03范围。本提案的两个具体目标是：(1)开发一种支持FSCV的神经化学传感IC，具有集成电刺激能力，用于神经化学模式生成；(2)测试和表征IC。工程创新之处在于，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，并最大限度地减少刺激工件干扰FSCV记录的可能性，无论何时通过外部触发器激活刺激器。除了台式工程评估外，还将使用多种神经化学模式作为模板，在体外通过流动注射分析和麻醉大鼠体内进行功能测试。概念上的创新是传递函数驱动的神经化学模式生成，并随后通过刺激感应IC验证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。多巴胺参与重要的脑功能和衰弱性神经病变，可用于FSCV检测，是使用微传感器研究最多的神经递质，并且具有完善的传递函数，适用于基于时间和振幅的模式生成。可转移到其他神经递质，微传感器策略和应用中，我们强调所提出的IC的通用性，作为一个更广泛的设备，超出了这些与多巴胺的开发测试。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，并可能通过为最终开发用于许多人类神经病理的新神经调节装置提供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.