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，多达15%的患者听力阈值正常，但难以理解 在嘈杂声中讲话。理解噪声环境中的语音需要对阈值上的知觉分析 声音特征，与听力阈值不同，听力阈值是对听者所能听到的最柔和声音的估计 侦测到。正常听力患者表现出的这些阈值上的加工缺陷是无法治疗的 目前，由于它们在听觉通路中的基础还没有很好地建立起来。一个有希望的解释是 耳蜗性突触，指的是内毛细胞突触丢失。突触疾病留下了阈值 不受影响，但根据听觉脑干的测量，降低了阈值以上声音的编码 反应(ABR)，并改变听觉通路中的兴奋-抑制平衡，这是 对空间和时间声音特征进行编码。来自人类文献的确凿证据来自 研究形式表明，听力正常的受试者在以下方面表现出显著的个体差异 空间和时间加工的神经生理和行为测量。尤其是双耳 在有这种特征的患者中，ABR的相互作用成分(BIC)受损。重要的是，金砖四国可能 依赖皮质下抑制，而皮质下抑制会受到突触的影响。尽管这些令人信服的联系 在阈值以上加工缺陷和突触的神经生理效应之间，没有 突触导致知觉缺陷的直接证据。这在很大程度上是因为突触只能 通过死后耳蜗组织学证实，感知测量很少用于动物研究 神经突触的作用。此外，对突触的研究只使用了啮齿动物，而啮齿动物与灵长类动物的 抑制性神经传递，以及空间和时间加工的知觉测量。这样的差异 可能会使神经生理和行为发现转化为诊断和治疗复杂化 创新。正是出于这些原因，我们建议使用我们的非人灵长类耳蜗动物模型 联结突触的解剖学、神经生理学和知觉效应的突触。我们建议 研究突触对时间和空间加工的影响以建立突触的知觉 效应(目标1)，并将这些效应与空间听觉的神经生理学关联--空间听觉的BIC联系起来 ABR(目标2)。时间和空间处理都将在检测和区分范例中进行研究， 预计辨别任务将显示最大的缺陷，以及突触，以及 退化的BIC，将与这些赤字相关。这些链接将解释突触如何 它的神经后果会导致正常听力受试者的听力障碍，并将形成 人类突触病变的非侵入性诊断测试。