Bioactive Microelectrode for Chronic Single Neuron Recording In-vivo

描述（由申请人提供）：在1999年，我们报道了一个重要的脑机接口（BMI）的工作演示，其中来自大鼠感觉运动皮质区域的多个单个神经元的记录被用来直接控制一只手臂来获取水奖励（Chapin, Moxon et al., 1999）。最近对脊髓损伤患者的研究表明，来自多个单一神经元的记录可以被患者用来控制电脑屏幕上的光标。有希望的是，有一天将有可能使用这些来自神经元的控制信号来重新激活患者自己的四肢。然而，长时间记录大量单个神经元的能力受到阻碍，因为要么电极本身失效，要么微电极周围组织的免疫反应产生神经胶质疤痕，阻止了单个神经元的记录。虽然合适的绝缘材料在很大程度上解决了电极失效的问题，但对于微电极插入的免疫反应，其对神经元记录的影响，以及最重要的如何减少这种影响，我们所知甚少。我们工作的长期目标是开发一种具有生物活性的、多位点的、单神经元记录电极，它可以在大鼠身上记录至少一个神经元的100%的记录位点，并在灵长类动物身上记录10年以上。这项提议的目的是确定干预策略，当这些策略结合在一起时，将允许在大鼠中进行一年的高质量单神经元记录。我们的中心假设是，由于胶质瘢痕的形成是由于两种不同的机制：电极插入对神经元的机械损伤和对异物（即微电极）的持续免疫反应，因此需要多种干预措施来确保单个神经元的长期记录。这一提议的基本原理是，如果这两种导致神经胶质疤痕的机制都得到改善，那么就有可能记录更多、更长时间的单个神经元，并具有更好的信噪比。我们使用免疫组织化学和电生理学来评估不同干预措施对胶质瘢痕形成和神经元活动的影响。我们已经为开展这项研究做好了充分的准备，因为我们有以下方面的经验：1)BMI电生理记录；2)电极开发，开发了一种基于陶瓷的多位点微电极记录装置（CBMSE阵列），与硅基微电极相比，具有优越的强度和绝缘性能；3)利用免疫组化方法研究损伤对神经元组织的影响；4)研究神经细胞损伤的机制及修复剂对神经元存活的影响。通过长期植入的微电极阵列来完善长时间记录单个神经元的能力，主要有三个动机：1)更好地了解神经元功能，2)开发新的脑机接口设备和传感器，3)神经机器人的临床应用。虽然已经证明，长期植入的微电极可以用作脑机接口的神经接口，用于治疗瘫痪和残疾患者，如果神经接口可以增强，使神经元记录可以持续数十年，那么最大的潜在效益就可以实现。然而，在短期内，即使微电极记录能力的适度改进也将增强我们理解神经元如何编码运动命令的能力，可塑性在这些电路中的作用，最重要的是，这些电路在大脑中如何在疾病或损伤后被修改。

DESCRIPTION (provided by applicant): In 1999 we reported an important demonstration of a working brain-machine interface (BMI), in which recordings from multiple, single neurons in sensorimotor cortical areas of rats were used to directly control an arm to retrieve a water reward (Chapin, Moxon et al., 1999). Recent studies in humans with spinal cord injury have shown that recording from multiple, single neurons can be used by the patient to control the cursor on a computer screen. The promise is that one day it will be possible to use these control signals from neurons to re-activate the patient's own limbs. However, the ability to record from large populations of single neurons for long periods of time has been hampered because either the electrode itself fails or the immunological response of the tissue surrounding the microelectrode produces a glial scar, preventing single-neuron recording. While appropriate insulating materials have largely solved the problem of electrode failure, much less is known about the immunological response to insertion of a microelectrode, its effect on neuronal recordings and, of greatest importance, how it can be reduced. The long-term goal of our work is to develop a bioactive, multisite, single neuron recording electrode that can record at least one single neuron from 100% of the recording sites for more than one year in rat and ten years in primates. The objective of this proposal is to identify intervention strategies that, when combined, will allow high quality, single neuron recordings for one year in the rat. It is our central hypothesis that because the development of a glial scar is due to two separate mechanisms: mechanical damage to neurons due to electrode insertion and sustained immunological response to the foreign body (i.e., the microelectrode), multiple interventions are necessary to ensure long-term recordings of single neurons. The rationale for this proposal is that if both of these mechanisms that contribute to the glial scar are ameliorated, then it will be possible to record more single neurons, longer, with better signal-to-noise. We use immunohistochemistry and electrophysiology to assess the effect of different interventions on the formation of a glial scar and neuronal activity. We are well prepared to undertake this research because we have experience in 1) electrophysiological recordings for BMI, 2) electrode development, having developed a ceramic-based, multi-site microelectrode recording device (CBMSE array), with superior strength and insulating properties compared to silicon based microelectrodes, 3) immunohistochemical methods to study the effects of injury on neuronal tissue and 4) the study of the mechanisms of neural cell injury and the effects of repair agents on neuronal survival. There are three primary motivations for perfecting the ability to record single neurons for long periods of time from chronically implanted arrays of microelectrodes: 1) to better understand neuronal function, 2) to develop novel brain-machine interface devices and sensors and 3) for clinical applications in neurorobotics. While it has been demonstrated that chronically implanted microelectrodes can be used as the neural interface in a brain machine interface for the treatment of paralyzed and disabled patients, if the neural interface could be enhanced such that the neuronal recordings can be sustained for decades, then the maximum potential benefit can be realized. However, in the short term, even moderate improvements in the recording capabilities of microelectrodes will enhance our ability to understand how ensembles of neurons code for motor commands, the role of plasticity in these circuits and most importantly how these circuits in the brain are modified after disease or injury.