The Middle Ear Muscle Reflex and the Diagnosis of Cochlear Neuropathy

中耳肌肉反射与耳蜗神经病的诊断

• 批准号: 8836191
• 负责人: Michelle Denise Valero
• 金额: $ 5.15万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836191
• 关键词: Acoustic Nerve; Acoustic Stimulation; Acoustics; Address; Affect; Algorithms; Animals; Attenuated; Auditory; Auditory Brainstem Responses; Automobile Driving; Biological Assay; Botulinum Toxins; Cell physiology; Cessation of life; Characteristics; Cholinergic Receptors; Chronic; Clinical; Cochlea; Cochlear Nerve; Contralateral; Curare; Data; Dependence; Diagnosis; Diagnostic; Ear; Exposure to; External auditory canal; Facial nerve structure; Fiber; Frequencies; Glutamate Receptor; Growth; Hair Cells; Head; Hearing; Human; Implant; Injection of therapeutic agent; Inner Hair Cells; Ipsilateral; Knockout Mice; Laboratory Animals; Labyrinth; Lead; Measurement; Measures; Medial; Monitor; Mus; Nerve Fibers; Neuromuscular Junction; Neurons; Neuropathy; Noise; Noise-Induced Hearing Loss; Outer Hair Cells; Pathology; Patients; Phase; Phenotype; Play; Presbycusis; Process; Receptor Cell; Reflex action; Role; Sensorineural Hearing Loss; Speech; Stimulus; Synapses; Synaptic Transmission; Testing; Training; Tubocurarine; Work; acoustic reflex; deafness; design; ear muscle; improved; middle ear; millisecond; mutant; novel strategies; otoacoustic emission; pressure; public health relevance; research clinical testing; research study; ribbon synapse; sound; stapedius muscle; tool

DESCRIPTION (provided by applicant): Auditory neuropathy is a kind of deafness in which cochlear outer hair cells function normally, but the auditory nerve fibers and/or the inner hair cells they innervate are dysfunctional. Clinically, this is identified by normal otoacoustic emissions but an absent or grossly abnormal auditory brainstem response. Some patients with auditory neuropathy have normal hearing thresholds but extreme difficulty understanding speech and hearing in noise. The threshold of the middle-ear muscle reflex (MEMR) is often elevated or immeasurable in these patients, as well. Recent work from the Liberman lab has suggested that observation of normal hearing thresholds with concomitant hearing-in-noise deficits can be explained by the degeneration of a specific subtype of cochlear nerve fibers with low spontaneous rates (SR) and high thresholds. This phenotype can be induced in laboratory animals with overexposure to loud sounds that causes only transient threshold elevation. I have assessed the MEMR in mice by measuring suppression of distortion-product otoacoustic emissions (DPOAEs) by contralateral sound before and after systemic application of curare, which blocks synaptic transmission at neuromuscular junctions. My preliminary data suggest that DPOAE suppression by contralateral sound is dominated by the MEMR, and my data substantiate the hypothesis that low-SR fibers dominate the drive to the MEMR, specifically that provided by the stapedial reflex. Here, I propose to design a test for MEMR measurements in mice that is more similar to that used in humans and subsequently use this test to compare MEMR thresholds, growth functions, and maximum suppression in low-SR neuropathic vs. control mice. This will allow me to more rigorously test the hypothesis that the MEMR is driven by low-SR auditory nerve fibers, and that as such, the MEMR can be used as a sensitive clinical test to identify low-SR cochlear neuropathy. The availability of an early diagnostic tool is of utmost importance: because one role of the MEMR is to protect the inner ear from high-level sound, low-SR cochlear neuropathy can lead to a vicious cycle wherein the ear becomes more damaged as its protective mechanisms deteriorate. Potential treatments for some types of auditory neuropathy are on the horizon, but to treat this pathology, we must first be able to identify it. The experiments in this proposal aim to improve the diagnostic utility of the MEMR in cochlear neuropathy that is specific to low-SR cochlear nerve fibers.

描述（申请人提供）：听神经病是一种耳蜗外毛细胞功能正常，但其支配的听神经纤维和/或其内毛细胞功能障碍的耳聋。临床上，这是通过正常的耳声发射但缺乏或严重异常的听觉脑干反应来识别的。一些患有听神经病变的患者听力阈值正常，但在噪声中理解言语和听力极其困难。这些患者的中耳肌肉反射 (MEMR) 阈值通常也升高或无法测量。利伯曼实验室最近的研究表明，观察到正常听力阈值伴随着噪声听力缺陷可以通过具有低自发率（SR）和高阈值的特定亚型耳蜗神经纤维的退化来解释。这种表型可以在实验动物中过度暴露于大声的声音中诱导，而这种声音只会导致短暂的阈值升高。我通过测量全身应用箭毒前后对侧声音对畸变产物耳声发射 (DPOAE) 的抑制来评估小鼠的 MEMR，箭毒会阻止神经肌肉接头处的突触传递。我的初步数据表明，对侧声音对 DPOAE 的抑制主要由 MEMR 主导，并且我的数据证实了这样的假设：低 SR 纤维主导对 MEMR 的驱动，特别是由镫骨反射提供的驱动。在这里，我建议设计一种与人类使用的更相似的小鼠 MEMR 测量测试，然后使用该测试来比较低 SR 神经病变小鼠与对照小鼠的 MEMR 阈值、生长功能和最大抑制。这将使我能够更严格地测试 MEMR 由低 SR 听觉神经纤维驱动的假设，因此，MEMR 可用作识别低 SR 耳蜗神经病变的敏感临床测试。早期诊断工具的可用性至关重要：因为 MEMR 的作用之一是保护内耳免受高强度声音的影响，低 SR 耳蜗神经病变可能导致恶性循环，其中耳朵因保护性声音而变得更加受损。机制恶化。某些类型的听神经病的潜在治疗方法即将出现，但要治疗这种病理，我们必须首先能够识别它。本提案中的实验旨在提高 MEMR 在低 SR 耳蜗神经纤维特有的耳蜗神经病变中的诊断效用。