Physiology of Vestibular Compensation

项目摘要 这项研究计划有两个目标。首先，我们试图通过以下方式来理解神经机制 大脑适应前庭(内耳平衡)输入的变化。第二，我们努力推进 开发前庭假体/植入物，一种高度创新的治疗方法，具有潜在的 改善前庭失明后视力不平衡和不稳定致残患者的生活质量 轰动一时。仅在美国，就有大约15万成年人分别患有致残眩晕和身体不稳 一年内由于急性单侧前庭功能丧失，而约65,000人患有慢性失衡和 视力不稳是严重的双侧感觉丧失的典型表现，尽管现有的治疗方法仍不能解决。 前庭神经输入的突然、永久性丧失会导致平衡失调、视觉模糊 前庭-眼反射(VOR)，以及由于前庭-脊髓反射中断而导致的姿势不稳。这些 症状之后通常是令人印象深刻但不完全的恢复。在上一个资助期内，我们 在确定补偿动态方面取得了很大进展，这些路径调节这些至关重要的 条件反射。此外，我们还建立了这些通路如何对多通道的激活做出敏锐的反应 前庭假体(MVP)。在建议的研究计划中，我们将建立在这个坚实的基础上 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 神经元适应持续假体刺激的开始，随后刺激的停止，以及 运动调制刺激。我们预测，适应主要涉及以下两种变化中的一种 平行通路，以及传入放电同步性降低和/或增加一致的前庭外 自动提示将进一步改善反应。Aim 2实验将研究中枢神经元如何处理 假体前庭输入在自然行为期间，如收敛、主动凝视转移和VOR抑制， 所有这些都需要对编码非前庭感觉和传出的神经元信号进行特定于上下文的整合 命令。这些实验将把我们的研究扩展到反射通路之外，并提供这两个系统 以及神经元水平的洞察，了解中枢神经系统(CNS)如何在复杂的 日常生活中的典型行为。针对目标3的实验将描述中央前庭神经元 在旨在减少VOR的新训练范例中对自然和假体刺激的适应 不对称。综合起来，这些对警觉的非人类灵长类动物的研究将加强对中枢神经系统如何 适应前庭输入的变化；推动开发一种潜在的革命性治疗方法 内耳功能；并阐明在细胞水平上学习的神经机制是如何 用于优化因前庭感觉丧失而致残的人的康复。

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.