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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要与年龄相关的听力损失非常常见，估计 70 岁以上的人中 60% 然而，听力损失严重到足以干扰沟通并影响生活质量的年龄。越来越多的证据表明，仅听力阈值的明显丧失并不能捕捉真实世界的听力老年人所经历的困难之一可能是迄今为止尚未确诊的听力缺陷原因。随着年龄的增长，内毛细胞和听觉神经之间的突触逐渐丧失，称为耳蜗耳蜗突触病被认为会影响复杂听力条件下的言语清晰度，但它并没有被阈值听力图检测到，仍然处于“隐藏”状态。耳蜗突触病仍不清楚，新出现的证据表明它与耳蜗突触缺陷有关听觉外围的时间线索的表示可能会不同地影响快速的编码。语音中的刺激时间精细结构（sTFS）线索，这对于在嘈杂条件下聆听至关重要。无法确定耳蜗突触病对噪声中言语清晰度下降的影响在人类中观察到的感知缺陷不能直接归因于单一物种的实现。耳蜗突触病，因为解剖学突触病只能在啮齿类动物的尸检标本中得到证实。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现实世界环境下人类语音感知的模型，该提案解决了这些翻译问题。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应对挑战在人类和动物模型中在几乎相同的条件下测量的反应目标 1 中的实验将使用一系列行为学和电生理学方法。人类测试这样一个假设：随着年龄的增长，噪声中的语音清晰度会下降 sTFS 线索的神经编码改变在目标 2 中，年龄相关的耳蜗突触病在 sTFS 退化中的作用。将在听力范围对人类语音频率敏感的动物模型中研究处理，使用在人体中验证的 sTFS 处理的电生理生物标志物，Aim 3 将进行分离。耳蜗突触病对 sTFS 线索神经编码的贡献可能与年龄相关通过在幼年动物中诱导分级突触病并评估相同的电生理和目标 2 中使用的免疫组织学标记。该项目的完成有可能产生单一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推进。建立综合研究管道，加速临床前研究向早期人类的转化最后，这里获得的数据将构成未来的基础。研究将遵循这种转化方法来探索与年龄相关的耳蜗之间的相互作用突触病、外周阈值敏感性和中枢听觉通路的代偿可塑性。