Individualized Profiles of Sensorineural Hearing Loss from Non-Invasive Biomarkers of Peripheral Pathology

摘要 听力图是临床听力评估的基石，但言语知觉的个体差异， 特别是在嘈杂的环境中，不能仅用可听度来解释。听力阈值正常的人 经常抱怨在噪声中理解语音的困难，以及患有感觉神经性听力损失(SNHL)的听众 在语音感知方面表现出显著的可变性，即使在听觉恢复的情况下也是如此。SNHL和SNHL动物模型的建立 颞骨组织学提示听力图遗漏的周围性病理可能解释了部分原因。 差异。外毛细胞(OHC)功能障碍可提高听力阈值，而内毛细胞(IHC)和听觉 神经(AN)功能障碍可能隐藏在听力图中，尽管它们对声音的神经编码有影响。 然而，特定的耳蜗病的存在及其对知觉的相对贡献不能 直接在人体上测试。取而代之的是，使用了非侵入性的病理生物标志物。尽管诊断学已经 是为识别听力正常的人的隐藏病理而开发的，单个指标不太可能 当SNHL是由外周功能障碍组合引起的时，就足够了。为了解决这一差距，我们使用 一系列非侵入性诊断工具，以确定单个受试者的生物标记物概况并评估其 不同程度的OHC和OHC与耳蜗解剖及噪声中言语知觉的关系 非OHC功能障碍。这项建议测试了我们的中心假设，即从 对OHC和非OHC病理敏感的生物标记物的集成显著提高了对 仅通过听力图就能听到阈值以上的听力。使用跨物种方法，三个协同特定 AIMS验证了我们的假设。首先，我们评估了两种不同类型的龙猫模型的生物标志物分布的差异。 SNHL亚型、仅OHC听力损失和复杂SNHL(例如，OHC、IHC和An的组合 功能障碍)，以衡量当它们与OHC功能障碍共存时非OHC病理的影响。第二, 我们测量患有SNHL的人类的生理生物标记物特征，并测试它们是否能更好地预测语音 比听力图更能理解人。第三，使用我们的协调生理测试电池作为连接 物种，我们对患有复杂疾病的人类的潜在耳蜗病的病理分布进行预测。 SNHL基于我们已知接触过的龙猫的组织学。无论我们的假设是否得到支持，还是 被驳斥的是，这个跨物种的数据集将促进我们对日常生活中重要因素的理解 并建立一个量化框架，以制定更详细的诊断档案。更大 识别SNHL多因素生理基础的诊断精度将支持 听力保健和治疗的个性化，特别是针对听力损失的药物干预。 此外，通过完成这些目标而接受的数量、跨物种和专业培训 补充了我在听力学方面的临床训练，并将是我作为一名翻译听力师职业生涯的基础 神经学家。

ABSTRACT The audiogram is the cornerstone of clinical hearing assessment, but individual differences in speech perception, especially in noisy environments, cannot be explained by audibility alone. People with normal hearing thresholds often complain of difficulty understanding speech-in-noise, and listeners with sensorineural hearing loss (SNHL) show significant variability in speech perception, even when audibility is restored. Animal models of SNHL and temporal bone histology suggest that peripheral pathology missed by the audiogram may explain some of this variance. Outer hair cell (OHC) dysfunction elevates hearing thresholds, but inner hair cell (IHC) and auditory nerve (AN) dysfunction may be hidden from the audiogram despite their impact on neural encoding of sound. The presence of specific cochlear pathologies and their relative contribution to perception, however, cannot be directly tested in humans. Instead, non-invasive biomarkers of pathology are used. Though diagnostics have been developed for identifying hidden pathologies in people with normal hearing, an individual metric is unlikely to be enough when SNHL results from a combination of peripheral dysfunctions. To address this gap, we use a battery of non-invasive diagnostic tools to determine a biomarker profile for individual subjects and assess its relationship to cochlear anatomy and speech-in-noise perception when there are varying degrees of OHC and non-OHC dysfunctions. This proposal tests our central hypothesis that identifying subtypes of SNHL from integration of biomarkers sensitive to both OHC and non-OHC pathologies significantly improves prediction of suprathreshold hearing over the audiogram alone. Using a cross-species approach, three synergistic specific aims test our hypothesis. First, we assess the differences in biomarker profiles of two chinchilla models of distinct SNHL subtypes, OHC-only hearing loss and complex SNHL (e.g., a combination of OHC, IHC, and AN dysfunction), to measure the effect of non-OHC pathologies when they co-occur with OHC dysfunction. Second, we measure physiological biomarker profiles in humans with SNHL and test whether they better predict speech understanding than the audiogram. Third, using our coordinated physiological test battery as a link between species, we make predictions about the underlying cochlear pathology distributions in humans with complex SNHL based on our histology from chinchillas with known exposures. Whether our hypotheses are supported or refuted, this cross-species dataset will advance our understanding of the factors important for everyday communication and establish a quantitative framework for developing more detailed diagnostic profiles. Greater diagnostic precision that recognizes the multifactorial physiological underpinnings of SNHL will support personalization of hearing healthcare and treatment, especially pharmaceutical interventions for hearing loss. Additionally, the quantitative, cross-species, and professional training received through completion of these aims complements my clinical training in audiology and will be foundational to my career as a translational auditory neuroscientist.