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: 10222641
• 负责人: Sharon G Kujawa
• 金额: $ 236.19万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222641
• 关键词: Acoustic Nerve; Address; Affect; Afferent Neurons; Aging; Aminoglycoside Antibiotics; Animal Model; Animal Testing; Animals; Auditory; Autopsy; Biological Markers; Brain; Brain Stem; Cell Death; Cell Therapy; Cells; Cisplatin; Clinical Trials Design; Cochlea; Complement; Consensus; Coupled; Diagnosis; Diagnostic; Diffuse; Disease; Drug Exposure; Ear; Elderly; Electrophysiology (science); Elements; Environment; Etiology; Exposure to; Frequencies; Functional disorder; Generations; Gerbils; Hair Cells; Hearing; Hearing Tests; Histopathology; Human; Hyperacusis; Immersion; Impairment; Inner Hair Cells; Intervention; Labyrinth; Measures; Midbrain structure; Modeling; Mus; Music; Nerve; Nerve Degeneration; Neurites; Neurons; Noise; Outer Hair Cells; Patients; Pattern; Performance; Peripheral; Physiological; Pilot Projects; Population; Presbycusis; Prevalence; Psychophysics; Public Health; Reporting; Research; Risk; Sampling; Sensorineural Hearing Loss; Sensory; Signal Transduction; Speech; Structure; Synapses; Temporal bone structure; Testing; Therapeutic; Tinnitus; Training; Work; base; cell injury; cellular development; chemotherapy; clinically relevant; cochlear synaptopathy; diagnostic biomarker; drug testing; hearing impairment; hidden hearing loss; human subject; improved; insight; nerve damage; neurotrophic factor; normal aging; normal hearing; ototoxicity; ototoxin; public health relevance; relating to nervous system; sound; speech in noise; spiral ganglion; success; synaptogenesis; therapy design; university student; young adult

Overall Project Summary New 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 neural degeneration, also called cochlear synaptopathy, does not elevate thresholds. Thus, it can be widespread in ears with intact hair cell populations and normal audiograms, where it has been called “hidden” hearing loss. It likely contributes to difficulties understanding speech in a noisy environment and may be an instigating factor in the generation of tinnitus and hyperacusis. Cochlear synaptopathy may also be widespread in acquired sensorineural hearing loss of other etiologies and degrees of hair cell damage. 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 from the study of overt and hidden hearing loss, we have devised a set of physiological, electrophysiological and psychophysical tests of hearing and cochlear function that we believe are most powerful in the diagnosis and understanding of cochlear synaptopathy in human subjects. In Project 1, we apply this test battery to gerbils exposed to noise or ototoxic drugs and test their diagnostic power by directly measuring the underlying cochlear histopathology in cases of overt or hidden hearing loss. In Project 2, we use immunostaining to directly assess the prevalence of cochlear synaptopathy in human temporal bones from subjects with overt or hidden hearing loss with a range of etiologies. In Project 3, we study hidden hearing loss in college students by applying the test battery to subjects with normal audiograms but a broad range of reported and measured sound exposures. In Project 4, we assess older adults with overt hearing loss by applying the tests to a subject pool with carefully matched down-sloping audiograms and by characterizing training-based improvements in speech-in-noise performance as reflected at different peripheral, brainstem, midbrain and cortical levels. Our preliminary studies of young adults show clear signs of hidden hearing loss in a group with repeated exposure to high-level music, suggesting the importance of this phenomenon to the public health. The success of neurotrophin-based approaches to the treatment of cochlear synaptopathy in animal models suggests that therapies may be on the horizon. Thus, the need for better understanding of the prevalence, diagnosis and functional consequences of cochlear synaptopathy is clear.

总体项目摘要 动物研究对噪声引起的和年龄有关的听力损失的新见解表明 内耳中最脆弱的元素是毛细胞和感觉之间的突触连接 神经元。这种主要的神经元变性，也称为人工耳蜗突触病，不升高 阈值。那就可以在耳朵中宽度宽度，具有完整的毛细胞群体和正常的听力图， 它被称为“隐藏”听力损失。这可能有助于难以理解演讲 在噪声环境中，可能是耳鸣和超苏斯的产生的刺激因素。 耳蜗突触病在获得其他的感官听力损失中也可能是广泛的 病因和毛细胞损伤程度。那可能是众所周知的主要贡献者 具有“公开”听力的听力模式的人的听觉表现差异 损失。 我们的研究中心旨在将这些范式转移的想法从动物模型转移到人类 主题。基于从公开和隐藏听力的研究中综合许多研究线程的综合 损失，我们设计了一组听力的物理，电生理和心理物理测试 我们认为在对人工耳蜗的诊断和理解中最强大的人工耳蜗功能 人类受试者的突触病。在项目1中，我们将此测试电池应用于暴露于噪声或 耳毒性药物并通过直接测量潜在的耳蜗测试其诊断能力 在明显或隐藏听力损失的情况下，组织病理学。在项目2中，我们使用免疫染色直接 评估来自具有公开或公开或 隐藏的听力损失具有一系列病因。在项目3中，我们研究大学中隐藏的听力损失 学生通过将测试电池应用于正常听力图的受试者，但报告了广泛的报告 并测量的声音曝光。在项目4中，我们评估了老年人的公开听力损失 将测试应用于具有仔细匹配的倾斜听力图的主题池，并通过 表征基于培训的改进语音表演的表现，如不同 周围，​​脑干，中脑和皮质水平。 我们对年轻人的初步研究表明，与 反复接触高级音乐，这表明这种现象对公众的重要性 健康。基于神经营养的方法在治疗耳蜗突触病中的成功 动物模型表明疗法可能即将到来。那，需要更好地理解 人工耳蜗病的患病率，诊断和功能后果是明显的。