Biomarkers of cochlear synaptopathy and their relation to suprathreshold hearing disorders in humans with sensorineural hearing loss

耳蜗突触病的生物标志物及其与感音神经性听力损失人类阈上听力障碍的关系

• 批准号: 10641773
• 负责人: Stéphane Maison
• 金额: $ 57.82万
• 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/10641773
• 关键词: Accounting; Acoustic Nerve; Adult; Affective; Animal Model; Animals; Auditory; Auditory system; Behavioral; Biological Assay; Biological Markers; Brain Stem; Cell Death; Cell physiology; Central Nervous System; Characteristics; Chronic; Cochlea; Development; Diagnosis; Disease; Electrocochleographies; Environment; Frequencies; Future; Grant; Hair Cells; Hearing; Hearing Aids; Hearing Tests; Hearing problem; Histopathology; Human; Hyperactivity; Hyperacusis; Hypersensitivity; Impairment; Inner Hair Cells; Labyrinth; Light; Location; Loudness; Maintenance; Maps; Measures; Medial; Meniere' s Disease; Nerve Degeneration; Nerve Fibers; Neurologic Symptoms; Noise; Outcome; Outcome Measure; Outer Hair Cells; Participant; Patient Recruitments; Patients; Pattern; Performance; Peripheral; Physiological; Population; Presbycusis; Prevalence; Psychoacoustics; Psychophysics; Questionnaires; Reflex action; Regression Analysis; Reporting; Research; Residual state; Role; Secondary to; Sensorineural Hearing Loss; Sensory; Series; Severities; Speech; Speech Intelligibility; Statistical Models; Subjective Tinnitus; Synapses; Temporal bone structure; Testing; Therapeutic; Time; Tinnitus; Traction; Vertigo; Visual; analog; auditory processing; biomarker identification; candidate identification; cellular pathology; cochlear synaptopathy; cognitive function; ear muscle; hearing impairment; middle ear; neural; normal aging; normal hearing; otoacoustic emission; outcome prediction; public health relevance; repaired; response; sex; sound; therapy design

Project 3 Summary – Abstract Difficulty understanding speech in noisy backgrounds, reduced sound-level tolerance and tinnitus are the most common complaints associated with noise- and age-related hearing loss. Parsing the sensory vs. neural contributions to these impairments gained new traction from animal studies showing that hair cell death (and the threshold shift it produces) is often preceded by loss of hair cell synapses with auditory nerve fibers. This cochlear neural degeneration (CND) degrades auditory processing and may contribute to difficulties understanding speech, especially in noisy environments, but has little effect on thresholds in quiet until it becomes extreme. CND could also be a major contributor to the genesis of tinnitus and hyperacusis, via an induction of central-gain adjustment secondary to the loss of auditory input to the central nervous system. Over the last grant period, we showed correlations between inferred measures of CND and word- recognition performance in difficult listening environments among normal-hearing listeners. Over the next five years, we broaden our focus to include those with threshold shifts. In Aim 1 we study high-tone hearing-loss, because temporal bone studies show that CND will be worse, despite normal thresholds in the speech- frequency region. In Aim 2 we study the flat hearing loss in late-stage Ménière's, because CND may be particularly severe in this disorder. In both, we test the correlation of the word-score outcomes with a battery of physiological measures chosen to probe the early stages of auditory processing, i.e. distortion product otoacoustic emissions and high-frequency audiometry to evaluate OHC function, threshold-in-noise tests and pitch-masking tasks to identify cochlear dead regions, and electrocochleography (including stacked ABRs), envelope-following responses to rectangular envelopes and middle-ear-muscle reflexes to probe for CND and assess its severity as a function of cochlear location. A medial olivocochlear reflex assay will evaluate the potential for hyperresponsivity of brainstem circuits. In Aim 3, we test if CND is a major elicitor of tinnitus and hyperacusis by assessing the relationships between our physiological estimates of CND, word-identification tasks, and several psychophysical measures of tinnitus and sound level tolerance. In concert with Project 4, which will further examine the same subjects, we will directly probe the relation between estimated CND and central manifestations of neural hyperactivity, perceptual hypersensitivity and behavioral hyperreactivity. The successful completion of these Aims will determine if, and to what extent, markers consistent with CND are associated with the speech intelligibility deficits observed in patients with SNHL and will clarify the association between biomarkers of peripheral neural deficits with psychophysical measures of tinnitus and sound-level intolerance. Given progress in the repair of noise-induced cochlear neural degeneration in animal models, reliable markers of CND in humans are needed to identify candidates for future therapeutics and to track the efficacy of any treatments designed to rebuild a damaged inner ear.

项目 3 总结 – 摘要 在嘈杂的背景下难以理解语音、声级耐受力降低和耳鸣是 与噪声和年龄相关的听力损失相关的最常见的投诉。解析感觉与神经性听力损失。 动物研究表明，毛细胞死亡（和 它产生的阈值偏移）通常先于听觉神经纤维的毛细胞突触丧失。 耳蜗神经变性 (CND) 会降低听觉处理能力并可能导致困难 理解语音，尤其是在嘈杂的环境中，但对安静的阈值影响很小，直到它 CND 变得极端也可能是耳鸣和听觉过敏的主要原因。 继发于中枢神经系统听觉输入损失的中枢增益调整的诱导。 在上一个资助期间，我们展示了 CND 的推断测量值和单词之间的相关性 在接下来的五年内，听力正常的听众在困难的聆听环境中的识别性能。 多年来，我们扩大了关注范围，将那些有阈值变化的人纳入其中。在目标 1 中，我们研究高音听力损失， 因为颞骨研究表明 CND 会更糟，尽管言语阈值正常 - 在目标 2 中，我们研究晚期梅尼埃病的平坦听力损失，因为 CND 可能是 在这两种疾病中，我们都测试了单词分数结果与一系列的相关性。 选择用于探测听觉处理早期阶段的生理测量，即失真产物 耳声发射和高频测听，以评估 OHC 功能、噪声阈值测试和 用于识别耳蜗死区的音调掩蔽任务和耳蜗电图（包括堆叠的 ABR）， 对矩形包络的包络跟踪反应和中耳肌肉反射以探测 CND 和 评估其严重程度与耳蜗位置的关系。内侧橄榄耳蜗反射测定将评估其严重程度。 在目标 3 中，我们测试 CND 是否是耳鸣的主要诱发因素。 通过评估我们对 CND 的生理估计、单词识别之间的关系来评估听觉过敏 任务，以及耳鸣和声级耐受性的几种心理物理测量 与项目 4 相一致， 这将进一步检查相同的主题，我们将直接探讨估计的 CND 和 神经过度活跃、知觉过度敏感和行为过度反应的中心表现。 这些目标的成功完成将决定标记是否以及在多大程度上与 CND 与 SNHL 患者中观察到的言语清晰度缺陷相关，并将阐明 周围神经缺陷的生物标志物与耳鸣的心理物理测量之间的关联 声级不耐受在修复动物噪声引起的耳蜗神经变性方面取得了进展。 模型、人类 CND 的可靠标记物需要确定未来治疗的候选者并 跟踪旨在重建受损内耳的任何治疗的效果。