A New Device for Electrical & Chemical Modulation of Pathological Neural Activity

描述（由申请人提供）：本研究的目的是由麻省理工学院的化学工程师、材料工程师和神经科学家组成的团队开发一种用于治疗焦虑和情绪障碍的组合微套管和脑深部电刺激装置。焦虑和情绪障碍是困扰数百万美国人的常见和使人衰弱的疾病。新出现的想法是，这些疾病实际上根源于神经回路活动的中断，而不是任何一个区域的缺陷。包括口服和静脉内施用治疗剂的当前治疗在空间上和时间上都太粗糙，不能适当地减弱跨神经回路的动态活动。我们的目标是开发一种可植入的微套管装置，该装置能够同时输注多种治疗剂，以及电刺激和真实的时间化学传感。该设备将以微创的方式进行微制造，但足够耐用，可以扩展到非人类灵长类动物使用。精确的解剖靶向和不同的刺激（电和化学）能力的结合应该提高我们以适当的动力学调节特定神经回路活动的能力。这项提案以及组建的研究团队结合了微制造、材料工程、化学、生物学和神经科学的各个领域。我们的具体目标总结如下：1）设计神经调节治疗剂的故障安全递送。这一目标将确保准确和可重复地输送所需剂量。2)评价通过金属沉积和化学功能化改善器械结构完整性和生物相容性的方法。神经刺激电极已被证明由于神经胶质增生而在长时间植入后丧失功能。我们提出的研究将开发一种通过延缓神经胶质增生来延长装置功能的方法。3)将外围组件（储药器、泵和管路）优化为适合长期植入的独立装置。这将增加拟议器械的实用性，并代表临床使用的重要一步。4)通过申报器械提供刺激（电刺激和化学刺激），在焦虑和情绪障碍的动物（非人类灵长类动物）模型中展示行为变化。5)证明行为变化是通过所提出的器械调节神经回路活动的结果。我们的目的是，证明该设备在体内的故障安全功能，并通过精确的时空控制研究其改善焦虑和情绪障碍行为的能力。在最后一步中，我们计划通过病理活动的真实的时间感测来开发基于反馈的设备激活。这代表了临床使用的重要一步，其中致焦虑刺激通常是未知的和不可预测的。

DESCRIPTION (provided by applicant): The purpose of this study is for a team of chemical engineers, materials engineers and neuroscientists at MIT to develop a combined micro-cannula and deep brain electrical stimulation device for the treatment of anxiety and mood disorders. Anxiety and mood disorders are common and debilitating disorders that afflict millions of Americans. The emerging thought is that these disorders are actually rooted in disruptions in activity across neural circuits, as opposed to defects in any one region. Current treatments comprising oral and i.v. administration of therapeutics are too coarse, both spatially and temporally, to appropriately attenuate the dynamic activity across neural circuits. Our goal is to develop an implantable micro-cannula device that is capable of simultaneous infusion of multiple therapeutics, as well as electrical stimulation and real time chemical sensing. This device will be micro-fabricated in such a way as to be minimally invasive, yet durable enough to be scaled to non-human primate use. The combination of precise anatomical targeting and diverse stimulatory (electrical & chemical) capabilities should improve our ability to modulate activity across specific neural circuits with the appropriate kinetics. This proposal, and the assembled research team, combines the varied fields of micro-fabrication, materials engineering, chemistry, biology and neuroscience. Our specific goals are summarized as follows: 1) Design for failsafe delivery of neuro-modulatory therapeutics. This aim will ensure that the desired doses are delivered accurately and reproducibly. 2) Evaluate methods of improving the structural integrity and biocompatibility of the device via metal deposition and chemical functionalization. Neuro-stimulatory electrodes have been shown to lose function over prolonged periods of implantation due to gliosis. Our proposed studies will develop a method for prolonging device function by retarding gliosis. 3) Refine the peripheral components (reservoir, pump and tubing) to be a stand-alone unit suitable for chronic implantation. This will increase the utility of the proposed device, as well as represent an important step towards clinical usage. 4) Demonstrate behavior change in animal (non-human primate) models of anxiety and mood disorders by delivering stimulation (electrical & chemical) via the proposed device. 5) Demonstrate that the behavioral change is a result of modulating neural circuit activity by the proposed device. Our aim is to, demonstrate the failsafe function of the device in vivo and investigate its capability to ameliorate anxiety and mood disorder based behaviors via precise spatiotemporal control. In a final step we plan to develop feedback based activation of the device by real time sensing of pathological activity. This represents an important step towards clinical usage where anxiogenic stimuli are frequently unknown and un-predictable.