Cochlear Synaptopathy: Prevalence, Diagnosis and Functional Consequences

总体项目摘要 对噪声引起的和年龄相关的听力损失的动物研究的见解表明， 内耳中脆弱的部分是毛细胞和感觉神经元之间的突触连接。 这种原发性耳蜗神经变性（CND）不会提高阈值，因此，它可以广泛分布于 耳毛细胞群完整，可以“隐藏”在正常的听力图后面。这可能有助于 在嘈杂的环境中理解语音的困难，可能是产生 耳鸣和听觉过敏。CND也可能是广泛的，甚至更严重，在获得性的情况下， 感觉神经性听力损失（SNHL），其中存在毛细胞损伤和阈值升高。因此，它可能是一个 主要贡献者之间的听觉表现的人，具有相同的知名差异 明显听力损失的听力模式。 我们的研究中心旨在将这些范式转变的想法从动物模型带到人类受试者身上。 基于许多研究线索的综合，我们设计了一套生理，心理物理和 我们认为对耳蜗功能和听力的行为测定在诊断CND方面最有效， 了解其对阈上听力的影响。在项目1中，我们将电生理测试应用于 暴露于噪声或耳毒性药物的动物，并验证其在预测潜在CND中的实用性， 行为方法来评估CND在产生耳鸣和听觉过敏中的作用。在项目2中，我们 研究SNHL受试者的人类尸检材料，以直接评估CND的患病率和模式 并评估其在损害单词识别分数中的作用以及作为耳鸣的危险因素。在 项目3，我们研究SNHL患者，以描述CND的影响，从“自下而上”推断 外周听觉功能的电生理测量，在困难听力中的单词识别 研究耳鸣和听觉过敏的发病机制，探讨CND在耳鸣和听觉过敏中的作用。在项目4中，我们 进一步研究相同的主题，探索CND对中枢通路神经过度活跃的影响，以及其 “自上而下”的影响，对声音的高反应，占主导地位的耳鸣的临床负担， 听觉过敏 在我们的研究中心，我们利用P50机制，将联合收割机的研究视角从听觉 神经科学和听力学在SNHL的最障碍方面的协调研究。进展 了解CND的影响以及如何有效地诊断它，越来越重要， 毛细胞和耳蜗神经元再生疗法的进展从实验室走向临床试验。

Overall Project Summary Insights from animal studies of noise-induced and age-related hearing loss suggest that the most vulnerable elements in the inner ear are the synaptic connections between hair cells and sensory neurons. This primary cochlear neural degeneration (CND) does not elevate thresholds, thus, it can be widespread in ears with intact hair cell populations and can “hide” behind a normal audiogram. It likely contributes to difficulties understanding speech in a noisy environment and may be an instigating factor in the generation of tinnitus and hyperacusis. CND may also be widespread, and even more severe, in cases of acquired sensorineural hearing loss (SNHL) where there is hair cell damage and threshold elevation. Thus, it may be a major contributor to the well-known differences in auditory performance among people with identical audiometric patterns of overt hearing loss. Our Research Center aims to take these paradigm-shifting ideas from animal models to human subjects. Based on the synthesis of many research threads, we have devised a set of physiological, psychophysical and behavioral assays of cochlear function and hearing that we believe are most powerful in diagnosing CND and understanding its effects on suprathreshold hearing. In Project 1, we apply electrophysiological tests to animals exposed to noise or ototoxic drugs and validate their utility in predicting the underlying CND and apply behavioral approaches to assess the role of CND in generating tinnitus and hyperacusis. In Project 2, we study human autopsy material from subjects with SNHL to directly assess the prevalence and patterns of CND in humans and to evaluate its role in compromising word-recognition scores and as a risk factor for tinnitus. In Project 3, we study patients with SNHL to characterize the effects of CND, as inferred from “bottom-up” electrophysiological measures of peripheral auditory function, on word identification in difficult listening environments and to probe the role of CND in the generation of tinnitus and hyperacusis. In Project 4, we further study the same subjects, probing the effects of CND on neural hyperactivity in central pathways, and its “top-down” effects on the hyper-reactivity to sound that dominates the clinical burden of tinnitus and hyperacusis. In our Research Center, we leverage the P50 mechanism to combine research perspectives from auditory neuroscience and audiology in a coordinated study of the most handicapping aspects of SNHL. Progress in understanding the effects of CND and how to effectively diagnose it, are of increasing importance as the progress in regenerative therapies for hair cells and cochlear neurons move from laboratories to clinical trials.