Suprathreshold processing and binaural interaction in rhesus macaques with cochlear synaptopathy

耳蜗突触病恒河猴的阈上处理和双耳相互作用

• 批准号: 10386444
• 负责人: Chase Mackey
• 金额: $ 3.13万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386444
• 关键词: Acoustic Nerve; Acoustics; Anatomy; Animals; Audiology; Auditory; Auditory Brainstem Responses; Auditory Threshold; Autopsy; Behavioral; Behavioral Assay; Binaural; Biological Markers; Brain; Chinchilla (genus); Clinic; Clinical; Cochlea; Complex; Data; Deafferentation procedure; Detection; Diagnostic; Diagnostic tests; Discrimination; Environment; Equilibrium; Exhibits; Frequencies; Future; Head; Histology; Human; Impairment; Individual Differences; Inner Hair Cells; Knowledge; Laboratories; Link; Literature; Macaca; Macaca mulatta; Measures; Modeling; Monkeys; Neurons; Noise; Oryctolagus cuniculus; Patients; Performance; Peripheral; Phylogenetic Analysis; Physiological; Population; Primates; Property; Rattus; Reporting; Rodent; Signal Transduction; Speech; Stimulus; Synapses; Task Performances; Testing; Therapeutic; Translations; Work; auditory pathway; base; behavior measurement; binaural hearing; cochlear synaptopathy; expectation; hearing impairment; hidden hearing loss; innovation; neurophysiology; neurotransmission; nonhuman primate; noninvasive diagnosis; normal hearing; relating to nervous system; response; sound; species difference; speech in noise; translational study

ABSTRACT As many as 15% of patients in audiology clinics have normal hearing thresholds, but struggle to understand speech in noise. Understanding speech in noisy environments requires perceptual analysis of suprathreshold sound features, in contrast to audiometric threshold, which is an estimate of the softest sound a listener can detect. These suprathreshold processing deficits that normal hearing patients exhibit cannot be treated currently because their basis in the auditory pathway is not well established. A promising explanation is cochlear synaptopathy, which refers to inner hair cell synapse loss. Synaptopathy leaves thresholds unaffected, but degrades the encoding of suprathreshold sounds as measured by the auditory brainstem response (ABR), and alters excitatory-inhibitory balance in the auditory pathway, which is required for encoding spatial and temporal sound features. Corroborating evidence from the human literature comes in the form of studies showing that normal hearing subjects display substantial individual differences in neurophysiological and behavioral measures of spatial and temporal processing. In particular, the binaural interaction component (BIC) of the ABR is compromised in patients with this profile. Importantly, the BIC may depend on subcortical inhibition, which is compromised by synaptopathy. Despite these compelling links between suprathreshold processing deficits and the neurophysiological effects of synaptopathy, there is no direct evidence that synaptopathy causes perceptual deficits. This is largely because synaptopathy can only be verified via post-mortem cochlear histology, and perceptual measures have rarely been used in animal studies of synaptopathy. Moreover, studies of synaptopathy have only used rodents, which differ from primates in their inhibitory neurotransmission, and perceptual measures of spatial and temporal processing. Such differences could complicate the translation of neurophysiological and behavioral findings into diagnostic and therapeutic innovations. It is for these reasons that we propose using our nonhuman primate model of cochlear synaptopathy to link anatomical, neurophysiological, and perceptual effects of synaptopathy. We propose studying the effects of synaptopathy on temporal and spatial processing to establish synaptopathy's perceptual effects (Aim 1), and linking those effects with a neurophysiological correlate of spatial hearing – the BIC of the ABR (Aim 2). Both temporal and spatial processing will be studied in detection and discrimination paradigms, with the expectation the discrimination tasks will show the largest deficits, and that synaptopathy, and degraded BIC, will correlate with these deficits. These links will provide an explanation of how synaptopathy and its neural consequences can cause deficits in normal hearing subjects, and will form the basis for noninvasive diagnostic tests for synaptopathy in humans.

摘要 在听力学诊所中，多达15%的患者听力正常，但难以理解 噪音中的言语在噪声环境中理解语音需要阈上的知觉分析 声音特征，与听力阈值相反，听力阈值是对听众能听到的最柔和声音的估计 检测。听力正常的患者表现出的这些阈上处理缺陷无法治疗 目前，因为它们在听觉通路中的基础还没有很好地建立。一个有希望的解释是 耳蜗突触病，指的是内毛细胞突触丧失。突触病叶阈值 不受影响，但降低了听觉脑干测量的阈上声音编码 反应（ABR），并改变听觉通路中的兴奋-抑制平衡，这是必要的 编码空间和时间声音特征。来自人类文献的确凿证据来自 一种研究形式，表明正常听力受试者在以下方面显示出实质性的个体差异： 空间和时间处理的神经生理学和行为测量。特别是， 在具有这种特征的患者中，ABR的相互作用成分（BIC）受损。重要的是，BIC可以 依赖于皮层下抑制，而皮层下抑制又受到突触病的影响。尽管有这些令人信服的联系 在阈上加工缺陷和突触病的神经生理学效应之间， 突触病导致知觉缺陷的直接证据这在很大程度上是因为突触病只能 通过死后耳蜗组织学验证，并且在动物研究中很少使用感知测量 突触病此外，突触病的研究只使用啮齿动物，啮齿动物与灵长类动物的不同之处在于， 抑制性神经传递，以及空间和时间处理的感知测量。这种差异 可能会使神经生理学和行为学发现转化为诊断和治疗复杂化， 创新。正是由于这些原因，我们建议使用我们的非人灵长类动物耳蜗模型， 突触病的解剖学、神经生理学和知觉效应之间的联系。我们提出 研究突触病对时间和空间处理的影响，以建立突触病的知觉 影响（目标1），并将这些影响与空间听觉的神经生理学相关性-- ABR（目标2）。时间和空间处理都将在检测和辨别范例中进行研究， 预期辨别任务将显示出最大的缺陷，并且突触病， 降低的BIC，将与这些缺陷相关。这些链接将提供一个解释， 其神经后果可能导致正常听力受试者的缺陷，并将形成基础， 用于人类突触病的非侵入性诊断测试。