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: 10360725
• 负责人: Aravindakshan Parthasarathy
• 金额: $ 19.12万
• 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/10360725
• 关键词: ATPase inhibitory protein; 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; Cognitive; Communication; Complex; Cues; Data; Development; Diagnostic; Diagnostic tests; Dose; Elderly; Electrophysiology (science); Exhibits; Frequencies; Future; Gerbils; Goals; Hearing; Hearing Tests; Hearing problem; Histologic; Human; Individual; Infusion procedures; Inner Hair Cells; Intervention; Labyrinth; Lead; 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; Testing; Therapeutic Intervention; Translations; age effect; age related; auditory pathway; base; 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; normal hearing; novel diagnostics; preclinical study; programs; relating to nervous system; 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 与年龄相关的听力损失非常普遍，估计有60％的人在70年以上 听力损失的年龄足够大，可以干扰沟通并影响生活质量。然而， 越来越多的证据表明，仅听证阈值的明显丧失就无法捕捉真实的听力 老年人的困难经历。一个迄今未诊断出听力不足的原因可能是 随着年龄的增长，内部毛细胞和听觉神经之间的突触逐渐逐渐丧失，称为人工耳蜗 突触病。人工耳蜗突触病被认为会影响复杂聆听条件下的语音清晰度， 然而，它没有被阈值听力图所检测到，仍然是“隐藏”。而功能后果 人工耳蜗突触病仍不清楚，新兴的证据表明，它与缺陷有关 听觉外围的定时提示表示。这可能会不同地影响快速的编码 语音中的刺激临时精细结构（STFS）线索，这对于在噪声条件下倾听至关重要。 建立人工耳蜗突触病对改善语音智能智能的影响不能是 在一个物种中完成。感知定义在人类中观察到的定义不能直接归因于 人工耳蜗突触病，因为解剖突触病仅在验尸标本中可验证。啮齿动物 模型提供了直接测量人工耳蜗突触完整性的手段，但其服务的潜力受到限制 作为现实世界中人类言语感知的模型。该提议解决了这些翻译 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来挑战 在人类和动物模型中，在几乎相同条件下测得的反应 翻译桥。 AIM 1中的实验将使用一系列的行为和电生理方法 人类检验以下假设，即随着年龄的降解，毫无疑问的语音可理解性是由年龄的 STFS提示的神经编码改变了。在AIM 2中，与年龄相关的人工耳蜗突触病在降解的STF中的作用 处理将在一个动物模型中进行研究，该模型的听力范围对人的语音频率敏感， 使用在人类中验证的STFS处理的电生理生物标志物。 AIM 3将隔离 人工耳蜗突触病对可能的混杂相关的STF提示的神经编码的贡献 诱导分级突触病在幼小动物中的作用，并评估相同的电生理学和 AIM 2中使用的免疫组织学标志物。该项目的完成有可能导致一个单一 将人工耳蜗突触性疾病与语音中的智能定义的生物标志物。该项目将进一步 建立一个综合研究管道，可以加速临床前研究向早期人类的翻译 未来生物标志物或介入疗法的试验。最后，这里获得的数据将构成未来的基础 将遵循这种翻译方法的研究，以探索与年龄相关的耳蜗之间的相互作用 中央听觉途径中的突触病，外周阈值灵敏度和代偿性可塑性。