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摘要-摘要 在嘈杂的背景下难以理解语音，降低声级耐受性和耳鸣是 最常见的投诉与噪音和年龄相关的听力损失。解析感官与神经 动物研究表明，毛细胞死亡（和 其产生的阈值偏移）通常在与听觉神经纤维的毛细胞突触丧失之前。这 耳蜗神经变性（CND）降低了听觉处理能力， 理解语音，特别是在嘈杂的环境中，但在安静的情况下， 变得极端。CND也可能是耳鸣和听觉过敏发生的主要原因，通过一个 中枢增益调节的诱导继发于中枢神经系统的听觉输入的损失。 在上一个资助期，我们显示了CND和单词的推断测量之间的相关性- 正常听力的听众在困难的听力环境中的识别性能。在未来五 多年来，我们扩大了我们的重点，包括那些门槛变化。在目标1中，我们研究了高音听力损失， 因为颞骨研究表明，尽管语言阈值正常，但CND会更糟- 频域在目标2中，我们研究了晚期梅尼埃的平坦听力损失，因为CND可能是 在这种疾病中尤为严重。在这两种情况下，我们测试了单词分数结果与一组 选择生理测量来探测听觉处理的早期阶段，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 音高掩蔽任务，以确定耳蜗死区，耳蜗电描记术（包括堆叠ABR）， 对矩形包络的跟随性反应和中耳肌反射以探测CND， 评估其严重程度作为耳蜗位置的函数。内侧橄榄耳蜗反射测定将评估 潜在的脑干回路高反应性。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， 任务，以及耳鸣和声级耐受性的几种心理物理测量。与Project 4合作， 这将进一步研究相同的主题，我们将直接探讨估计的CND和 中枢表现为神经活动过度、知觉超敏和行为反应过度。 这些目标的成功实现将决定标志是否以及在多大程度上符合 CND与SNHL患者中观察到的言语清晰度缺陷相关， 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， 声音水平的不容忍。噪声性耳蜗神经退行性变的动物修复研究进展 在人类CND模型中，需要可靠的CND标记物来鉴定未来治疗的候选者， 跟踪任何旨在重建受损内耳的治疗方法的效果。