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

项目3摘要-摘要 在嘈杂的背景下理解语言的困难、对声级的耐受性降低和耳鸣是 最常见的主诉与噪音和年龄相关的听力损失有关。分析感官与神经 动物研究表明，毛细胞死亡(和 其产生的阈值漂移)通常在毛细胞与听神经纤维的突触丢失之前。这 耳蜗神经退行性变(CND)会降低听觉处理能力，并可能造成困难 理解语音，尤其是在嘈杂的环境中，但在安静的环境中对阈值几乎没有影响，直到 变得极端。CND也可能是耳鸣和听力亢进的主要因素，通过 中枢增益调节的诱导，继发于中枢神经系统的听觉输入丧失。 在过去的授权期内，我们显示了CND的推断测量与单词- 听力正常的听者在困难听力环境中的再认表现。在接下来的五年里 几年来，我们扩大了我们的重点，将那些门槛变化的人包括在内。在目标1中，我们研究高音听力损失， 因为颞骨研究表明，尽管演讲中的正常阈值，CND将会更糟- 频率区域。在目标2中，我们研究了晚期梅尼埃病的扁平性听力损失，因为CND可能是 在这种疾病中尤为严重。在这两种测试中，我们都使用一组测试结果来测试单词得分结果的相关性 选择生理指标来探索听觉加工的早期阶段，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 用于识别耳蜗死区的音调掩蔽任务，以及耳蜗术(包括堆叠的ABR)， 矩形包膜和中耳肌肉反射的包络跟随反应探测CND和 评估其严重程度作为耳蜗位置的函数。内侧橄榄耳蜗肌反射测试将评估 脑干回路的高响应性潜力。在目标3中，我们测试CND是否是耳鸣和耳鸣的主要诱因 通过评估我们对CND的生理估计与单词识别之间的关系来实现听力亢进 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协调一致， 这将进一步考察相同的主题，我们将直接探索估计的CND与 神经多动、知觉高敏感和行为高反应的中枢表现。 这些目标的成功实现将决定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有关，并将澄清 周围神经功能缺失的生物标志物与耳鸣和耳鸣的心理物理指标的关系 声音级别的不容忍。噪声诱导的动物耳蜗神经退行性变修复研究进展 模型，人类CND的可靠标记物，需要用来确定未来治疗的候选者和 追踪任何旨在修复受损内耳的治疗方法的疗效。

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.