Place and Time Processing of Pitch in the Context of Cochlear Dysfunction

摘要： 15%的美国成年人发生感音神经性听力损失，目前的治疗方案通常是在指导下进行的 有限而陈旧的诊断方法。并不是所有类型的感音神经性耳聋在生理和心理上都是相同的 当前听觉研究的主要重点是在精确的听觉诊断领域进行创新和 治疗。了解耳蜗神经或听神经损伤的特定模式如何可变地损害 对不同声音特征的感知对于改善听力受损患者的治疗至关重要。这个 听觉研究的历史使人们对听觉的解剖成分如何 外周，即内毛细胞(IHCs)、外毛细胞(OHCs)和耳蜗突触共同发挥作用 转换、放大和编码简单的声音。然而，在我们的知识中存在着相当大的差距 这些外围组件负责维持更复杂的听觉现象的保真度 和感知力。音高，给定音的“高”或“低”，是一个复杂的例子。 心理声学现象。音调提示被用来听和谱曲，以及处理元音、识别 说话者，并传达情感。没有完整的音调感知，谈话就变得没有感情，就像一首交响乐 变成了刺耳的声音。虽然已经对音调进行了广泛的感性研究，但我们对潜在的 音调的神经生理学在很大程度上仍然是假设的。三种音高理论试图解释音高 根据我们听觉系统(地点)的声调组织进行编码，存在于 神经放电模式(时间)，或这些模式的组合(地点-时间)。我们计划对这些理论进行评估。 预计会不同地改变地点和时间线索的耳蜗病理学背景，从而形成 对音高有更全面的理解。基于文献，我们的中心假设是 时间编码和地点编码都会影响神经编码和基音感知，但对地点编码的影响较大 发挥更强大的作用。我们将使用OHC、IHC、耳蜗突触的动物模型来验证这一假设 研究SNHL对音高相关电生理的影响(目标1)。OHC 损伤主要扰乱位置线索，而IHC和耳蜗突触损伤会改变计时线索。到时候我们会的 将这种动物电生理学与听力正常和听力受损的人类的相同测量方法进行比较， 评估对行为音调辨别的影响(目标2)。最后，我们将开发四个统计量 识别如何通过非侵入性听力分析预测音调编码和感知变化的模型 SNHL的损失和轮廓(AIM 3)。这种跨物种的方法通过测试油井来推动该领域的发展- 在SNHL的背景下建立了音调理论，并通过打开大门更好地识别功能 听力个体差异的后果。总体而言，跨物种设计的拟议工作 将开发我作为内科科学家的潜力，增强我设计转化实验的能力 他们使用理想的神经疾病实验室模型来预测临床相关的结果。

Abstract: Sensorineural hearing loss occurs in 15% of American adults and current treatment protocols are often guided by limited and archaic diagnostics. Not all types of sensorineural hearing loss are identical in physiology and a major priority of current auditory research is to innovate in the space of precision auditory diagnostics and treatments. Understanding how specific patterns of damage to the cochlea or auditory nerve variably impair the perception of different sound features is critical to improve treatments for hearing-impaired individuals. The history of auditory research has led to considerable insight as to how anatomic components of the auditory periphery, namely inner hair cells (IHCs), outer hair cells (OHCs), and the cochlear synapse function together to transduce, amplify, and code simple sounds. However, there exists considerable gaps in our knowledge of how these peripheral components are responsible for maintaining the fidelity of more complex auditory phenomena and perception. Pitch, the perceived “highness” or “lowness” of a given sound, is an example of a complex psychoacoustic phenomenon. Pitch cues are used to listen to and compose music and to process vowels, identify talkers, and convey emotion. Without intact pitch perception, conversation becomes emotionless, a symphony becomes a cacophony. While pitch has been extensively studied perceptually, our knowledge of the underlying neurophysiology of pitch remains mostly hypothetical. Three categories of pitch theories attempt to explain pitch coding in terms of the tonotopic organization of our auditory system (place), the temporal information present in neural firing patterns (time), or a combination of these (place-time). We plan to assess these theories in the context of cochlear pathologies that are expected to differentially alter place and timing cues, hence developing a more comprehensive understanding of pitch. Based on the literature, our central hypothesis is that deficits in time and place coding both affect the neural coding and perception of pitch, but with distorted place coding playing a stronger role. We will test this hypothesis by using animal models of OHC, IHC, cochlear synapse damage, and Distorted Tonotopy to investigate SNHL effects on pitch-related electrophysiology (Aim 1). OHC damage primarily disrupts place cues, while IHC and cochlear synapse damage alter timing cues. We will then compare this animal electrophysiology to identical measures in humans with normal and impaired hearing, evaluating the implications on behavioral pitch discrimination (Aim 2). Finally, we will develop four statistical models to identify how variations in pitch coding and perception are predicted by non-invasive assays of hearing loss and profiles of SNHL (Aim 3). This cross-species approach moves the field forward by testing well- established pitch theories in the context of SNHL and by opening doors to better identifying the functional consequences of individual variations in hearing ability. Overall, the cross-species design of the proposed work will develop my potential as a physician-scientist, strengthening my ability to design translational experiments that use ideal laboratory models of neurological disorders to predict clinically relevant outcomes.