Noise-Induced Cochlear Neuronal Degeneration and Its Perceptual Consequences

描述 该CDA-1提案的目的是为Naomi Bramhall博士提供必要的支持和指导，以便从基础科学研究过渡到噪声性听力损失的临床研究。Bramhall博士以前的研究主要集中在遗传性听力损失和毛细胞再生方面，但作为一名认证的听力学家，她渴望转向临床听力研究。该提案将为Bramhall博士提供从事临床研究所需的工具和经验，并生成将用于申请未来资金（如CDA-2）的数据，将指导她作为临床研究人员走向独立。她的主要导师是道恩·康拉德-马丁博士和M。查尔斯·利伯曼是一位共同导师。 在服兵役期间经常会经历大声的噪音暴露，听力损失是退伍军人中第二常见的与服务有关的残疾。听力损失和言语辨别能力差的人通常很少成功， 助听器的优点在于，放大声音可以提高语音信号的可听度，但不能提高清晰度。强噪声暴露不仅可导致外毛细胞损伤，而且可导致听神经元变性。神经缺失会导致单词识别能力下降（Schuknecht 1994），这可能解释了为什么许多退伍军人的语音识别能力比预期的要差，尤其是在嘈杂的环境中。小鼠在暴露于巨大噪声后的几个月内表现出听觉神经外周末梢的快速退化，随后螺旋神经节神经元的缓慢退化，即使它们的纯音听觉阈值完全恢复（Kujawa和Liberman，2009年）。最易受噪声暴露影响的神经元亚群由低自发率纤维组成（Furman et al. 2013），其具有高灵敏度阈值并对较高强度的声音作出反应。这种神经元损失与听觉脑干反应（ABR）第一波振幅的降低相关。已在人类中证实了I波振幅的与听觉相关的降低（Konrad-Martin et al. 2012），并且与显示听觉神经元随年龄而丧失的颞骨研究一致（Makary et al. 2011），表明听觉神经元存活的这种度量也适用于人类。在此之前，量化听觉神经元存活影响言语理解的程度一直是困难的，由于在测量人类听觉神经元损失的限制，这只能通过死后颞骨研究来完成。 本提案的主要目的是使用电生理学方法1）确定ABR波I振幅降低是否与人类噪声暴露相关，2）检查噪声暴露和波I振幅降低对听觉感知的影响。我们的假设是，噪声暴露将与波I振幅下降，与动物研究一致，这种变化将与降低语音识别在高声音水平，难以理解语音在背景噪声的存在，并降低容忍响亮的声音。开发使用现有临床工具评估听觉神经元存活的能力，并推进我们对神经元损失导致的特定听觉感知缺陷的理解，将有助于指导未来患有听力损失的退伍军人的治疗选择。

DESCRIPTION The purpose of this CDA-1 proposal is to provide Dr. Naomi Bramhall with the support and mentorship necessary to make the transition from basic science research to clinical research of noise-induced hearing loss. Dr. Bramhall's previous research has focused on hereditary hearing loss and hair cell regeneration, but as a certified audiologist, she is eager to shift to clinical hearing research. This proposal will provide Dr. Bramhall with the tools and experience necessary to engage in clinical research and generate data which will be used in applying for future funding such as the CDA-2, will guide her path towards independence as a clinical researcher. Her primary mentor for this proposal is Dr. Dawn Konrad-Martin and Dr. M. Charles Liberman is a co-mentor. Loud noise exposure is routinely experienced during military service and hearing loss is the second most common service-related disability among Veterans. Individuals with hearing loss and poor speech discrimination ability often have little success with hearing aids because amplifying sound improves the audibility, but not the clarity, of the speech signal. Loud noise exposure may result not only in damage to outer hair cells, but also lead to auditory neuronal degeneration. Neural loss can result in decreased word recognition (Schuknecht 1994) and may explain why many Veterans have poorer speech discrimination than would be expected based on their ability to detect tones, particularly in noisy environments. Mice show rapid degeneration of auditory nerve peripheral terminals followed by a slow degeneration of spiral ganglion neurons over a period of several months following loud noise exposure, even when their pure tone auditory thresholds recover completely (Kujawa and Liberman 2009). The subpopulation of neurons most vulnerable to noise exposure consists of the low spontaneous rate fibers (Furman et al. 2013), which have a high sensitivity threshold and respond to higher intensity sounds. This neuronal loss is correlated with a decrease in the amplitude of the first wave of the auditory brainstem response (ABR). Age-related reduction in the amplitude of wave I has been demonstrated in humans (Konrad-Martin et al. 2012) and is consistent with temporal bone studies showing auditory neuronal loss with age (Makary et al. 2011), suggesting this metric of auditory neuronal survival is also applicable to humans. Previously, quantification of the degree to which auditory neuronal survival influences speech understanding has been difficult due to limitations in measuring auditory neuronal loss in humans, which could only be accomplished through post-mortem temporal bone studies. The main objectives of this proposal are to use electrophysiological methods to 1) determine if decreased ABR wave I amplitude is associated with noise exposure in humans and 2) examine the impact of noise exposure and decreased wave I amplitude on auditory perception. Our hypothesis is that noise exposure will be associated with decreased wave I amplitude, consistent with animal studies, and that this change will be correlated with decreased speech recognition at high sound levels, difficulty understanding speech in the presence of background noise, and decreased tolerance to loud sounds. Developing the ability to assess auditory neuronal survival with existing clinical tools and advancing our understanding of the specific auditory perceptual deficits resulting from neuronal loss will help guide future treatment options for Veterans suffering from hearing loss.