Physiology of Vestibular Compensation

项目摘要 这项研究计划的动机有两个目标。首先，我们试图了解神经机制， 大脑适应前庭（内耳平衡）输入的变化。其次，我们寻求进步 前庭假体/植入物的开发，这是一种高度创新的治疗方法， 改善前庭功能丧失后视力不平衡和不稳定残疾人生活质量 感觉。仅在美国，就有大约15万成年人患有眩晕和站立不稳 年，由于急性单侧前庭功能丧失，而约65，000患有慢性失衡， 视力不稳定，典型的严重的双侧感觉丧失，尽管现有的治疗仍未能解决。 前庭神经输入的突然、永久性丧失会导致平衡失调， 前庭-眼反射（VOR）和由于前庭-脊髓反射的破坏引起的姿势不稳定。这些 症状通常伴随着令人印象深刻但不完全的恢复。在上一个财政年度，我们 在确定介导这些重要的神经元的通路中的补偿动力学方面取得了很大的进展， 反射此外，我们还确定了这些通路如何对多通道的激活做出急性反应。 前庭假体（MVP）。在拟议的研究计划中，我们将建立在这一坚实的基础上， 通过三个协同目标取得进展。针对目标1的实验将确定中央前庭如何 神经元适应恒定假体刺激的开始，随后的刺激停止， 运动调制刺激。我们预测，适应主要涉及两个方面之一的变化 平行的路径，减少传入放电同步性和/或增加一致的前庭外 自我运动提示将进一步改善反应。目标2实验将研究中枢神经元如何处理 在自然行为过程中的假体前庭输入，例如聚散、主动注视转移和VOR抑制， 这些都需要编码非前庭感觉和传出神经的神经元信号的特定整合 命令.这些实验将使我们的研究超越反射途径，并提供两种系统 和神经元水平的洞察如何中枢神经系统（CNS）优化性能在复杂的 日常生活中的典型行为。针对目标3的实验将表征中枢前庭神经元 在旨在降低VOR的新型训练模式中适应自然和假体刺激 不对称结合起来，这些在警觉的非人灵长类动物中的研究将增强对CNS如何 适应前庭输入的变化;推进潜在的革命性治疗方法的发展， 内耳功能;并阐明如何在细胞水平上学习的神经元机制， 用于优化因前庭感觉丧失而残疾的个体的恢复。

Project Summary This research program is motivated by two goals. First, we seek to understand the neural mechanisms by which the brain adapts to changes in vestibular (inner ear balance) input. Second, we seek to advance development of a vestibular prosthesis/implant, a highly innovative treatment approach with potential to improve quality of life for individuals disabled by disequilibrium and unsteady vision after loss of vestibular sensation. In the United States alone, about 150,000 adults suffer disabling vertigo and unsteadiness each year due to acute unilateral loss of vestibular function, while about 65,000 suffer chronic imbalance and unsteady vision typical of severe bilateral sensory loss that fails to resolve despite existing treatments. Sudden, permanent loss of vestibular nerve input causes disequilibrium, visual blurring due to disruption of the vestibulo-ocular reflex (VOR), and postural instability due to disruption of vestibulo-spinal reflexes. These symptoms are usually followed by impressive but incomplete recovery. During the previous funding period, we made excellent progress toward defining the dynamics of compensation in pathways that mediate these vital reflexes. In addition, we established how these pathways respond acutely to activation of a multichannel vestibular prosthesis (MVP). In the proposed research program, we will build upon this solid foundation of progress through 3 synergistic aims. Experiments addressing Aim 1 will determine how central vestibular neurons adapt to the onset of constant prosthetic stimulation, to subsequent cessation of stimulation, and to motion-modulated stimulation. We predict that adaptation predominantly involves changes in one of two parallel paths, and that reduction of afferent discharge synchrony and/or addition of congruent extra-vestibular self-motion cues will further improve responses. Aim 2 experiments will examine how central neurons process prosthetic vestibular input during natural behaviors such as vergence, active gaze shifts and VOR suppression, which all require context-specific integration of neuronal signals encoding non-vestibular senses and efferent commands. These experiments will extend our investigation beyond reflex pathways and provide both systems and neuronal-level insight into how the central nervous system (CNS) optimizes performance during complex behaviors typical of daily life. Experiments addressing Aim 3 will characterize central vestibular neuron adaptation to natural and prosthetic stimulation during a novel training paradigm designed to reduce VOR asymmetry. Combined, these studies in alert nonhuman primates will enhance understanding of how the CNS adapts to changes in vestibular input; advance development of a potentially revolutionary treatment for loss of inner ear function; and clarify how neuronal mechanisms that underlie learning at a cellular level can be leveraged to optimize recovery of individuals disabled by loss of vestibular sensation.