Bioactive Microelectrode for Chronic Single Neuron Recording In-vivo

描述(申请人提供)：1999年，我们报告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一神经元的记录被用来直接控制一只手臂来取回水奖励(Chapin，Moxon等人，1999)。最近对患有脊髓损伤的人类的研究表明，患者可以使用来自多个单一神经元的记录来控制计算机屏幕上的光标。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肢体。然而，长时间记录大量单个神经元的能力受到了阻碍，因为要么是电极本身失效，要么是微电极周围组织的免疫反应产生了神经胶质疤痕，阻止了单个神经元的记录。虽然适当的绝缘材料在很大程度上解决了电极失效的问题，但人们对插入微电极的免疫反应、它对神经元记录的影响以及最重要的是如何减少它的了解要少得多。我们工作的长期目标是开发一种生物活性的、多部位的单神经元记录电极，它可以记录至少一个来自100%记录部位的单个神经元，在大鼠身上记录一年以上，在灵长类动物中记录十年。这项建议的目标是确定干预策略，当组合在一起时，将允许在大鼠中进行一年的高质量的单个神经元记录。我们的中心假设是，由于胶质瘢痕的形成是由两种不同的机制引起的：电极插入对神经元的机械性损伤和对异物(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，如果这两种导致胶质瘢痕的机制都得到改善，那么就有可能记录到更多的单个神经元，更长的时间，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性的影响。我们已经为开展这项研究做好了充分的准备，因为我们在1)BMI的电生理记录方面拥有经验，2)电极开发，已经开发出陶瓷基多点微电极记录设备(CBMSE阵列)，与硅基微电极相比，具有更好的强度和绝缘性能，3)研究损伤对神经元组织的影响的免疫组织化学方法，4)神经细胞损伤机制和修复剂对神经元存活的影响的研究。完善从长期植入的微电极阵列中长时间记录单个神经元的能力主要有三个动机：1)更好地了解神经元的功能，2)开发新型的脑机接口设备和传感器，3)临床应用于神经机器人。虽然已经证明，长期植入的微电极可以用作治疗瘫痪和残疾患者的脑机接口中的神经接口，但如果神经接口能够得到增强，使得神经元记录可以持续数十年，那么就可以实现最大的潜在好处。然而，在短期内，即使微电极记录能力的适度改善也将增强我们理解神经元集合如何编码运动指令的能力，可塑性在这些回路中的作用，以及最重要的是，大脑中的这些回路在疾病或损伤后是如何修改的。

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.