Effects of Age-related Cochlear Synaptopathy on Speech-in-noise Intelligibility: A Cross-species Approach

年龄相关的耳蜗突触病对噪声中语音清晰度的影响：跨物种方法

• 批准号: 10579924
• 负责人: Aravindakshan Parthasarathy
• 金额: $ 18.93万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579924
• 关键词: ATPase inhibitory protein; Acceleration; Acoustic Nerve; Address; Adult; Affect; Age; Age Years; Aging; Anatomy; Animal Experimentation; Animal Model; Animals; Auditory; Auditory Threshold; Autopsy; Behavioral; Biological Markers; Birth; Clinic; Clinical; Cochlea; Code; Communication; Complex; Cues; Data; Development; Diagnostic; Diagnostic tests; Dose; Elderly; Electrophysiology (science); Exhibits; Frequencies; Future; Gerbils; Goals; Hearing; Hearing Tests; Hearing problem; Histologic; Human; Impaired cognition; Individual; Infusion procedures; Inner Hair Cells; Intervention; Labyrinth; Life; Link; Measurement; Measures; Methods; Nerve; Nerve Fibers; Ouabain; Patients; Performance; Peripheral; Phase; Presbycusis; Quality of life; Research; Rodent Model; Role; Specimen; Speech; Speech Intelligibility; Speech Perception; Stimulus; Structure; Synapses; Temporal bone structure; Testing; Therapeutic Intervention; Translations; age effect; age related; auditory pathway; cochlear synaptopathy; comorbidity; design; efficacy testing; experience; experimental study; hearing impairment; hearing range; help-seeking behavior; hidden hearing loss; human model; indexing; innovation; juvenile animal; middle age; neural; normal hearing; novel diagnostics; preclinical study; programs; response; response biomarker; speech in noise; translational approach

Project Summary Age-related hearing loss is exceedingly common, with an estimated 60% of individuals over 70 years of age having hearing loss significant enough to interfere with communication and affect quality of life. However, increasing evidence suggests that the overt loss of hearing thresholds alone fails to capture real-world hearing difficulties experienced by older adults. One hitherto undiagnosed cause of hearing deficits could be the progressive loss of synapses between the inner hair cell and the auditory nerve with age, termed cochlear synaptopathy. Cochlear synaptopathy is thought to affect speech intelligibility under complex listening conditions, yet it goes undetected by the threshold audiogram, remaining ‘hidden’. While the functional consequences of cochlear synaptopathy are still unclear, emerging evidence suggests that it is associated with deficits in representation of timing cues in the auditory periphery. This may differentially affect the encoding of rapid stimulus temporal fine structure (sTFS) cues in speech, which are critical for listening in noisy conditions. Establishing the effects of cochlear synaptopathy on decreased speech-in-noise intelligibility cannot be accomplished in a single species. Perceptual deficits observed in humans cannot be attributed directly to cochlear synaptopathy, because anatomical synaptopathy is only verifiable in post-mortem specimens. Rodent models offer the means to directly measure cochlear synaptic integrity but are limited in their potential to serve as models of human speech perception under real-world settings. This proposal addresses these translational challenges by integrating research in humans and animal models, with non-invasive electrophysiological responses measured under near identical conditions in both humans and animal models acting as the translational bridge. Experiments in Aim 1 will use a battery of behavioral and electrophysiological methods in humans to test the hypothesis that degradations in speech-in-noise intelligibility with age are accompanied by altered neural coding of sTFS cues. In Aim 2, the role of age-related cochlear synaptopathy in degraded sTFS processing will be studied in an animal model whose hearing range is sensitive to human speech frequencies, using the electrophysiological biomarkers of sTFS processing validated in humans. Aim 3 will isolate contributions of cochlear synaptopathy to the neural coding of sTFS cues from possible confounding age-related effects by inducing graded synaptopathy in young animals and evaluating the same electrophysiological and immunohistological markers used in Aim 2. The completion of this project has the potential to result in a single biomarker that links cochlear synaptopathy to deficits in speech-in-noise intelligibility. The project will further establish an integrated research pipeline that can accelerate the translation of pre-clinical studies to early human trials for future biomarkers or interventional therapies. Finally, the data obtained here will form the basis for future studies that will follow this translational approach to explore the interactions between age-related cochlear synaptopathy, peripheral threshold sensitivity, and compensatory plasticity in the central auditory pathway.

项目摘要 与听力损失相关的听力损失非常常见，估计有60%的70岁以上的人 听力损失严重到足以干扰交流并影响生活质量的年龄。然而，在这方面， 越来越多的证据表明，听力阈值的明显损失本身无法捕捉真实世界的听力 老年人遇到的困难。一个迄今未被诊断的听力缺陷的原因可能是 随着年龄的增长，内毛细胞和听神经之间的突触逐渐丧失，称为耳蜗 突触病在复杂的听音条件下，耳蜗突触病被认为会影响语言清晰度， 然而它却未被阈值听力图检测到，保持“隐藏”。虽然功能性后果 耳蜗突触病仍然不清楚，新出现的证据表明，它与缺陷有关， 听觉周边的时间线索的表征。这可能会不同程度地影响快速 语音中的刺激时间精细结构（sTFS）线索，这对于在噪声条件下进行听力至关重要。 建立耳蜗突触病对噪声中语音清晰度降低的影响， 在单一物种中完成。在人类中观察到的知觉缺陷不能直接归因于 耳蜗突触病，因为解剖学上的突触病只能在死后的标本中证实。啮齿动物 模型提供了直接测量耳蜗突触完整性的方法，但其服务潜力有限 作为人类在真实世界环境下的语音感知模型。该提案涉及这些翻译 通过将人类和动物模型的研究与非侵入性电生理学相结合， 在几乎相同的条件下在人类和动物模型中测量的反应， 平移桥目标1中的实验将使用一系列行为和电生理学方法， 人类测试的假设，在语音噪声可懂度随着年龄的下降是伴随着 改变了sTFS信号的神经编码在目标2中，年龄相关性耳蜗突触病在降低sTFS中的作用 将在听觉范围对人类语音频率敏感的动物模型中研究处理， 使用在人类中验证的sTFS处理的电生理学生物标志物。目标3将隔离 耳蜗突触病对来自可能的年龄相关混淆的sTFS线索的神经编码的贡献 通过在年轻动物中诱导分级突触病并评估相同的电生理和 Aim 2中使用的免疫组织学标记物。该项目的完成有可能产生一个单一的 将耳蜗突触病与噪声中语音清晰度缺陷联系起来的生物标志物。该项目将进一步 建立一个综合的研究管道，可以加速临床前研究向早期人类的转化。 用于未来生物标志物或介入治疗的试验。最后，这里获得的数据将成为未来的基础。 将遵循这种转化方法来探索年龄相关耳蜗之间的相互作用的研究 突触病、外周阈值敏感性和中枢听觉通路的代偿可塑性。