Massively parallel microwire arrays for deep brain stimulation

项目摘要： 基底神经节脑深部电刺激（DBS）是一种行之有效的治疗各种运动 帕金森氏病（PD）和特发性震颤。此外，它也是一种新兴疗法 几种精神和神经疾病，包括癫痫，严重抑郁症和强迫症- 强迫症（OCD）。尽管它在临床上取得了成功，但对神经系统的理解有限。 DBS背后的机制典型的DBS系统包括一个脉冲发生器，用于输送刺激 脉冲通过植入的金属电极。DBS可能通过几种方式发挥治疗作用 不同的机制包括：（1）直接调节靶核的神经放电;（2）激活邻近的核团;（3）激活靶核团的神经放电 神经元轴突;（3）通过激活逆向和顺向影响通过长距离投射轴突 动作电位因为当前DBS电极激发大量神经组织，所以难以将其与神经刺激器连接。 精确地确定这些靶点和机制中的哪一个负责DBS的治疗效果。 因此，开发下一代DBS技术是至关重要的，该技术能够选择性地靶向不同的 神经结构的群体，理想地具有单神经元和单轴突纤维精度。此外， 有利于开发大规模并行DBS电极阵列（10，000+电极），以输送不同的 可以针对治疗功效优化的活动的时空模式。最近的方法 材料科学和工程的进步现在使这样的设备成为可能。该提案描述了一个 一种基于集束化高密度大规模并行单细胞单轴突水平刺激装置 微丝（BMW）：数万根外径小于30微米的玻璃包金属丝。的 这种方法将是革命性的神经生理学，允许突破性的实验，无论是在运动 疾病和神经回路行为的基本理解。在此，我们建议：（1）发展和 表征BMW刺激阵列并证明其在急性脑切片和体内的功效。2)到 将BMW阵列与现代半导体技术相结合，展示了 市售的微显示器芯片能够将图案化的刺激电流注入通过 宝马我们将在脑切片和体内验证性能，以测试不同的电模式是否 刺激可靠地在脑切片和体内产生相应的活动模式。在一起，这 该提案将把神经科学和工程学结合在一起，以创造最高密度的电生理学 刺激接口，并通过组合提供原理证明演示 微导丝刺激、双光子功能成像和经典电生理学方法。这些 微线阵列将是一个强大的工具，它不仅可以为运动提供实质性的临床益处， 疾病，如PD，但也提供了DBS的机制见解。 1

Project Summary: Deep brain stimulation (DBS) of basal ganglia is a well-established therapy for a variety of movement disorders, such as Parkinson's disease (PD) and essential tremor. In addition, it is also an emerging therapy for several psychiatric and neurological conditions, including epilepsy, major depression and obsessive- compulsive disorder (OCD). Despite its clinical success, there is a limited understanding of the neural mechanism behind DBS. Typical DBS system consists of a pulse generator, which deliveries the stimulation pulses via an implanted metal electrode. It is possible that DBS exerts is therapeutic effect through several different mechanisms including: (1) directly regulating neural firing at target nucleus; (2) activating nearby neuronal axons; (3) influencing passing long-range projection axons by activating antidromic and orthodromic action potentials. Because current DBS electrodes excite a large volume of neural tissue, it has been difficult to precisely determine which of these targets and mechanisms are responsible for the therapeutic effects of DBS. It is therefore critical to develop next generation DBS technology that enables selective targeting of different populations of neural structures, ideally with single neuron and single axon fiber precision. In addition, it would be beneficial to develop massively parallel DBS electrode arrays (10,000+ electrodes) to delivery different spatiotemporal patterns of activity that can be optimized for therapeutic efficacy. Recent methodological advances in material science and engineering now make such a device possible. This proposal describes a high-density, massively parallel single cell and single axon level stimulation device based on bundled microwires (BMWs): tens of thousands of metal-in-glass wires of less than 30 micrometers outer diameter. The approach will be revolutionary for neurophysiology, allowing break-through experiments both in movement disorders and fundamental understanding of neural circuit behavior. Here we propose: 1) To develop and characterize a BMW stimulation array and demonstrate its efficacy in acute brain slices and in vivo. 2) To couple the BMW array with modern semiconductor technology, demonstrating that driver circuit of a commercially available micro-display chip is capable of injecting patterned stimulation current through the BMW. We will validate the performance in brain slices and in vivo to test if different patterns of electrical stimulation reliably generate corresponding activity patterns in the brain slice and in vivo. Together, this proposal will bring neuroscience and engineering together to create the highest density electrophysiological stimulation interface ever made, and provide proof of principle demonstrations through the combined approaches of microwire stimulation, 2-photon functional imaging and classical electrophysiology. These microwire arrays would be a powerful tool, which would not only offer substantial clinical benefits for movement disorders, such as PD, but also provide mechanistic insights for DBS.   1