Cochlear Synaptopathy: Prevalence, Diagnosis and Functional Consequences

耳蜗突触病：患病率、诊断和功能性后果

• 批准号: 10641746
• 负责人: Sharon G Kujawa
• 金额: $ 268.43万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-02 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641746
• 关键词: Acceleration; Acoustic Nerve; Acoustics; Afferent Neurons; Aging; Aminoglycosides; Animal Model; Animals; Audiology; Auditory; Autopsy; Behavioral; Behavioral Assay; Bilateral; Biological Assay; Biological Markers; Brain; Cells; Cisplatin; Clinical; Clinical Trials; Clinical Trials Design; Cochlea; Databases; Denervation; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disinhibition; Drug Exposure; Ear; Electrophysiology (science); Elements; Environment; Etiology; Exposure to; Frequencies; Generations; Hair Cells; Hearing; Hearing Tests; Hearing problem; Human; Hyperactivity; Hyperacusis; Individual; Injury; Inner Hair Cells; Laboratories; Labyrinth; Life Style; Loudness Perception; Maps; Measurement; Measures; Mediation; Meniere' s Disease; Mus; Nerve; Nerve Degeneration; Nerve Fibers; Neurons; Neurophysiology - biologic function; Neurosciences; Noise; Noise-Induced Hearing Loss; Outer Hair Cells; Pathway interactions; Patients; Pattern; Perceptual Disorders; Performance; Peripheral; Persons; Pharmaceutical Preparations; Physiological; Population; Presbycusis; Prevalence; Psychophysics; Public Health; Recording of previous events; Records; Research; Risk Factors; Role; Sensorineural Hearing Loss; Sensory; Specialized Center; Speech; Speech Discrimination; Statistical Models; Study Subject; Synapses; Testing; Tinnitus; Work; behavioral study; cell injury; clinical application; cochlear synaptopathy; collaborative approach; design; diagnostic biomarker; diagnostic strategy; diagnostic value; handicapping condition; hearing impairment; human subject; insight; nerve damage; neural; noise exposure; normal aging; ototoxicity; public health relevance; regenerative therapy; sound; speech in noise; speech recognition; statistics

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.

项目总体概要 对噪音引起的和与年龄相关的听力损失的动物研究的见解表明，最 内耳中的脆弱因素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，它可以广泛存在于 耳朵具有完整的毛细胞群，可以“隐藏”在正常听力图后面。它可能有助于 在嘈杂的环境中理解语音存在困难，并且可能是产生 耳鸣和听觉过敏。 CND 也可能广泛存在，并且在获得性感染的情况下甚至更为严重 感音神经性听力损失 (SNHL)，其中存在毛细胞损伤和阈值升高。因此，它可能是一个 众所周知，具有相同特征的人之间听觉表现存在差异的主要原因 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转移到人类受试者身上。 基于许多研究线索的综合，我们设计了一套生理学、心理物理和 我们认为，耳蜗功能和听力的行为分析对于诊断 CND 最为有效 了解其对超阈听力的影响。在项目1中，我们应用电生理测试 暴露于噪音或耳毒性药物的动物并验证其在预测潜在 CND 方面的效用并应用 行为方法来评估 CND 在产生耳鸣和听力过敏中的作用。在项目2中，我们 研究 SNHL 受试者的人体尸检材料，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方面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“自下而上”推断出 CND 的影响特征 周围听觉功能的电生理测量，在困难听力中的单词识别 环境并探讨 CND 在耳鸣和听觉过敏产生中的作用。在项目4中，我们 进一步研究同一对象，探讨 CND 对中枢通路神经亢进的影响及其作用 对声音过度反应的“自上而下”影响主导了耳鸣和耳鸣的临床负担 听觉过敏。 在我们的研究中心，我们利用P50机制来结合听觉的研究视角 神经科学和听力学对 SNHL 最不利方面进行协调研究。进展情况 了解 CND 的影响以及如何有效诊断它变得越来越重要 毛细胞和耳蜗神经元再生疗法的进展已从实验室转向临床试验。

项目成果

Age-related stereocilia pathology in the human cochlea.

人类耳蜗中与年龄相关的静纤毛病理学。

• DOI: 10.1016/j.heares.2022.108551
• 发表时间: 2022
• 期刊: Hearing research
• 影响因子: 2.8
• 作者: Wu,Pei-Zhe;Liberman,MCharles
• 通讯作者: Liberman,MCharles

Noise-Induced Hearing Loss in Gerbil: Round Window Assays of Synapse Loss.

• DOI: 10.3389/fncel.2021.699978
• 发表时间: 2021
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Jeffers PWC;Bourien J;Diuba A;Puel JL;Kujawa SG
• 通讯作者: Kujawa SG

Predicting Atrophy of the Cochlear Stria Vascularis from the Shape of the Threshold Audiogram.

从阈值听力图的形状预测耳蜗血管纹的萎缩。

• DOI: 10.1523/jneurosci.1138-23.2023
• 发表时间: 2023
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Kaur,Charanjeet;Wu,Pei-Zhe;O'Malley,JenniferT;Liberman,MCharles
• 通讯作者: Liberman,MCharles

Middle Ear Muscle Reflex and Word Recognition in "Normal-Hearing" Adults: Evidence for Cochlear Synaptopathy?

• DOI: 10.1097/aud.0000000000000804
• 发表时间: 2020-01-01
• 期刊: EAR AND HEARING
• 影响因子: 3.7
• 作者: Mepani, Anita M.;Kirk, Sarah A.;Maison, Stephane F.
• 通讯作者: Maison, Stephane F.

Fluctuations in Subjective Tinnitus Ratings Over Time: Implications for Clinical Research.

主观耳鸣评级随时间的波动：对临床研究的影响。

• DOI: 10.1097/mao.0000000000002759
• 发表时间: 2020-10
• 期刊: Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology
• 作者: Chen JX;Whitton JP;Parthasarathy A;Hancock KE;Polley DB
• 通讯作者: Polley DB