Physiological Signatures and Behavioral Correlates of Hidden Hearing Loss

摘要 噪音导致的听力损失影响了2500多万成年人，其中大多数病例被怀疑是 是暴露在环境声音中的结果。重要的是，一些没有明显症状的人类 听力损失在嘈杂的环境中处理语音有极大的困难，但直到最近才有 潜在的解释浮出水面。噪声暴露在导致临时阈值的声压级 移位但无永久性阈值移位会导致无毛细胞的带状突触丢失(突触 听性脑干反应(ABR)波的波幅降低和丢失，I.低自发频率 (LSR)听神经纤维(ANF)似乎特别容易受到这种损失的影响。虽然这些影响是好的 在啮齿动物中进行了描述，但尚不清楚它们是否发生在人类身上。不可能表现出突触作用 直接在人类体内。我们建议通过在人类和 在解剖学和力学上与人类有很大相似之处的动物模型：猕猴。 我们最近开发的猕猴突触模型与已建立的啮齿动物有一些共同的特征 模型，但也揭示了易感性的差异，这可能也存在于其他灵长类动物，如 人类。我们建议在对照猕猴和暴露在噪声中的猕猴(没有和有噪声暴露)中进行平行实验 分别)和听力阈值正常的两组人：对照组和 一群暴露在噪音中的人类。我们的主要假设是噪声暴露引起的突触 损害时间加工，导致生理(Aim1)和行为(AIMS 2)指标的缺陷 阈值以上的刺激处理，这些缺陷将与突触的数量相关， 这将通过在猕猴身上的组织学和ANF记录来证实(目标3)。我们预测生理学上 对涉及LSR光纤的过程进行测量(包括对阈值以上声音和 掩蔽的声音、中耳肌肉反射和从前向掩蔽中恢复)将在受试者中受到损害 相对于正常受试者的突触(目标1)。我们预测，需要时间线索的行为 处理简单刺激(调幅检测、超阈值掩蔽检测、前向检测 掩蔽阈值，以及时间线索对检测噪声中的超阈值音调的贡献) 复杂刺激(噪声中的语音和空间注意任务，以及从掩蔽中释放)将受到损害 在有突触的受试者中(目标2)。突触病变将得到组织学证实，其ANF与 (LSR纤维丢失)直接在猕猴身上验证(目标3)。这些研究的结果将揭示敏感的 经组织学和神经生理学验证的突触病变的生理和行为标记物 在猕猴身上的发现。这些在人类和猕猴身上的平行研究将阐明 突触对听觉知觉的影响。我们协调研究计划的结果将是 用于开发可靠的、临床可行的人类突触的生理和行为指标。

ABSTRACT Noise-induced hearing loss affects more than 25 million adults, with the majority of these cases suspected to be the result of exposure to environmental sounds. Importantly, some humans with no overt indications of hearing loss have extraordinary difficulty processing speech in noisy environments, but only recently has a potential explanation emerged. Noise exposure at sound pressure levels that cause a temporary threshold shift but no permanent threshold shift results in a loss of ribbon synapses (synaptopathy) without any hair cell loss, and a reduction in the amplitude of auditory brainstem response (ABR) Wave I. Low spontaneous rate (LSR) auditory nerve fibers (ANFs) seem particularly susceptible to this loss. While these effects are well described in rodents, it is not clear that they occur in humans. It is impossible to demonstrate synaptopathy directly in humans. We propose to bridge this gap by performing parallel experiments in humans and an animal model that shares great similarity, both anatomically and mechanistically, with humans: macaques. Our recently developed macaque model of synaptopathy shares some features with the established rodent model, but also reveals differences in susceptibility, which may also be present in other primates such as humans. We propose parallel experiments in control and noise-exposed macaques (without and with synaptopathy, respectively) and in two groups of humans with normal hearing thresholds: a control group and a noise-exposed human cohort. Our overarching hypothesis is that synaptopathy caused by noise exposure impairs temporal processing, resulting in deficits in physiological (Aim1) and behavioral (Aims 2) metrics of suprathreshold stimulus processing, and these deficits will be correlated with the amount of synaptopathy, which will be verified by histology and ANF recordings in macaques (Aim 3). We predict that physiological measures of processes that involve LSR fibers (including coding of modulation in suprathreshold sounds and masked sounds, middle ear muscle reflexes, and recovery from forward masking) will be impaired in subjects with synaptopathy relative to normal subjects (Aim 1). We predict that behaviors that require temporal cues to process simple stimuli (detection of amplitude modulation, suprathreshold masked detection, forward masking thresholds, and the contribution of temporal cues to the detection of suprathreshold tones in noise) and complex stimuli (speech-in-noise and spatial-attention tasks, and release from masking) will be impaired in subjects with synaptopathy (Aim 2). The synaptopathy will be histologically verified and its ANF correlates (loss of LSR fibers) verified directly in macaques (Aim 3). The results of these studies will reveal sensitive physiological and behavioral markers of synaptopathy, validated by histological and neurophysiological findings in macaques. These parallel studies in humans and macaques will elucidate the functional consequences of synaptopathy on auditory perception. Results of our coordinated research program will be used to develop reliable, clinically viable physiological and behavioral indicators of human synaptopathy.