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

摘要： 感音神经性听力损失发生在15%的美国成年人和目前的治疗方案往往是指导 有限而陈旧的诊断方法不同类型的听力损失在生理学和心理学上是不同的。 当前听觉研究的主要优先事项是在精确的听觉诊断领域进行创新， 治疗。了解耳蜗或听神经损伤的特定模式如何损害听觉系统， 对不同声音特征的感知对于改善听力受损个体的治疗至关重要。的 听觉研究的历史已经导致相当多的见解，如何解剖组成部分的听觉 外周，即内毛细胞（IHC）、外毛细胞（OHC）和耳蜗突触一起起作用， 对简单的声音进行解码、放大和编码。然而，在我们如何了解 这些外围成分负责维持更复杂的听觉现象的保真度 和感知。音高，感知到的给定声音的“低”或“低”，是复杂的一个例子。 心理声学现象。音高线索被用来听音乐和作曲，处理元音，识别 说话的人，传达情感。没有完整的音高感知，谈话就变成了没有感情的交响乐 变成了刺耳的声音虽然音高已经被广泛地研究了感知，但我们对潜在音高的了解， 音高的神经生理学仍然主要是假设的。三种音高理论试图解释音高 编码在我们的听觉系统（地点）的音调组织方面，时间信息存在于 神经放电模式（时间），或这些的组合（位置-时间）。我们计划评估这些理论在 耳蜗病理的背景，预计差异改变的地方和时间线索，因此发展 对音高有了更全面的了解根据文献，我们的中心假设是， 时间和地点编码都影响神经编码和音高感知，但地点编码失真 发挥更大的作用。我们将使用OHC、IHC、耳蜗突触的动物模型来验证这一假设。 损伤和扭曲的音调，以研究SNHL对音高相关电生理学的影响（目的1）。OHC 损伤主要破坏位置线索，而IHC和耳蜗突触损伤改变时间线索。然后我们将 将该动物的电生理学与听力正常和受损的人类的相同测量进行比较， 评估对行为音高辨别的影响（目标2）。最后，我们将开发四个统计 模型，以确定如何通过听力的非侵入性测定来预测音高编码和感知的变化 SNHL的损失和轮廓（Aim 3）。这种跨物种的方法通过测试很好地推动了该领域的发展- 在SNHL的背景下建立音高理论，并打开大门，以更好地识别功能 听力能力的个体差异的后果。总的来说，提出了跨物种设计的工作建议 我将开发我作为一名物理学家和科学家的潜力，加强我设计转化实验的能力 使用神经系统疾病的理想实验室模型来预测临床相关结果。

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.