Cochlear Implants in Reinnervated Ears

重新神经支配的耳朵中的人工耳蜗

• 批准号: 8277430
• 负责人: YEHOASH RAPHAEL
• 金额: $ 44.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277430
• 关键词: Acoustic Nerve; Animals; Area; Auditory; Auditory Brainstem Responses; Back; Basic Science; Basilar Membrane; Brain-Derived Neurotrophic Factor; Cavia; Cells; Chronic; Clinical; Cochlea; Cochlear Implants; Cochlear implant procedure; Cochlear nucleus; Communication; Data; Detection; Ear; Electric Stimulation; Electrodes; Epithelium; Fiber; Gene Transfer; Genes; Growth; Hair Cells; Hearing; Hearing Impaired Persons; Implanted Electrodes; Labyrinth; Long-Term Effects; Masks; Measurable; Measures; Methods; Modeling; Morphology; NTF3 gene; Natural regeneration; Nerve Fibers; Nerve Regeneration; Neurons; Outcome; Output; Patients; Perception; Peripheral; Positioning Attribute; Procedures; Process; Property; Proteins; Psychophysics; Psychophysiology; Pulse Rates; Resolution; Route; Sensorineural Hearing Loss; Site; Source; Stimulus; Testing; Time; Tissues; Transgenes; Translations; Work; adeno-associated viral vector; clinical practice; hearing impairment; improved; middle ear; neuronal cell body; neurotrophic factor; public health relevance; research study; response; spiral ganglion; tool

DESCRIPTION (provided by applicant): Perception of sound with cochlear implants (CIs) is currently accomplished, in most cases, by stimulating spiral ganglion neuron (SGN) bodies in Rosenthal's canal, since cochleae without hair cells typically lack auditory nerve fibers in the basilar membrane area (BMA). If auditory nerve fibers could be induced to regenerate back into the BMA, stimulation of such fibers could potentially lower the amount of current required for stimulus detection, increase dynamic range, improve temporal response properties and decrease channel interaction, thereby enhancing the perception of CI stimulation. Using recently developed methods, we generated preliminary data demonstrating the feasibility for long-term over-expression of a neurotrophin which targeted to the BMA of deaf ears, leading to robust regrowth of auditory nerve fibers into this tissue. This nerve regeneration was accomplished using non-toxic long-acting adeno- associated viral vectors that delivered into the cochlea using clinically feasible routes. Our proposed experiments will test the global hypothesis that presence of neurotrophins secreted by cells in and around the auditory epithelium will attract and maintain auditory nerve fibers, leading to improvement in measurable parameters of the functional (psychophysical and electrophysiological) responses to CI stimulation. Experiments in Aim 1 will compare the efficiency of BDNF versus NTF3 in attracting neurons to the deaf BMA and characterize the source of the neurons and their position in the tissue. Work in Aim 2 will compare detection threshold levels, dynamic ranges, temporal integration properties, spatial selectivity, and amplitude growth functions using established animal psychophysics procedures and electrically-induced auditory brainstem responses (EABR) in deaf reinnervated cochleae and deaf non-reinnervated cochleae. Aim 3 will determine if auditory nerve fiber regeneration into the BMA improves SGN survival and central connections. Aim 4 will determine how the combined effects of long-term chronic electrical stimulation and neurotrophin over-expression influence SGN cell bodies and projections. These experiments will set the groundwork for clinical methods to induce nerve regeneration that could enhance the outcome of cochlear implant procedures in patients with severe or profound sensorineural hearing loss. PUBLIC HEALTH RELEVANCE: The need to develop methods for inducing, directing and maintaining auditory nerve regeneration has been a critical barrier to the field. Our recent break-through in the application of gene transfer now provides the ability to target cells in the deaf inner ear, and insert genes into these cells for secreting a protein of choice (neurotrophin) leading to stable, long-term nerve regeneration in these ears. Auditory nerve fibers will grow into an area where they will be in close proximity to the cochlear implant electrode. Our proposed studies can, for the first time, test the long-term influence of auditory nerve regeneration on the psychophysical responses to electrical stimulation provided by the cochlear implant. We will further correlate these responses with survival and condition of the neurons and their peripheral and central processes. The outcome of the proposed work may improve communication for thousands of people who have severe or profound hearing impairments and use cochlear implants.

描述（由申请人提供）：目前，在大多数情况下，通过刺激罗森塔尔管中的螺旋神经节神经元（SGN）体来实现人工耳蜗（CI）对声音的感知，因为没有毛细胞的耳蜗通常缺乏基底神经中的听觉神经纤维膜面积（BMA）。如果可以诱导听觉神经纤维再生回 BMA，则刺激此类纤维可能会降低刺激检测所需的电流量、增加动态范围、改善时间响应特性并减少通道相互作用，从而增强 CI 刺激的感知。使用最近开发的方法，我们生成了初步数据，证明针对聋耳 BMA 的神经营养蛋白长期过度表达的可行性，导致听觉神经纤维在该组织中强劲再生。这种神经再生是使用无毒的长效腺相关病毒载体完成的，该载体通过临床上可行的途径递送到耳蜗中。我们提出的实验将检验一个总体假设，即听觉上皮内和周围细胞分泌的神经营养因子的存在会吸引和维持听觉神经纤维，从而改善对 CI 刺激的功能（心理物理和电生理）反应的可测量参数。目标 1 中的实验将比较 BDNF 与 NTF3 在将神经元吸引到聋人 BMA 上的效率，并表征神经元的来源及其在组织中的位置。目标 2 的工作将使用已建立的动物心理物理学程序和耳聋神经再支配耳蜗和耳聋非神经再支配耳蜗中的电诱导听觉脑干反应 (EABR) 来比较检测阈值水平、动态范围、时间积分特性、空间选择性和振幅增长函数。目标 3 将确定听神经纤维再生到 BMA 中是否可以改善 SGN 的存活和中枢连接。目标 4 将确定长期慢性电刺激和神经营养素过度表达的综合影响如何影响 SGN 细胞体和预测。这些实验将为诱导神经再生的临床方法奠定基础，从而提高严重或极重度感音神经性听力损失患者的人工耳蜗植入手术的效果。 公共卫生相关性：开发诱导、指导和维持听觉神经再生的方法的需求一直是该领域的一个关键障碍。我们最近在基因转移应用方面取得的突破现在提供了靶向聋内耳细胞的能力，并将基因插入这些细胞中以分泌选择的蛋白质（神经营养蛋白），从而导致这些细胞稳定、长期的神经再生。耳朵。听觉神经纤维将生长到靠近人工耳蜗电极的区域。我们提出的研究首次可以测试听觉神经再生对人工耳蜗提供的电刺激的心理物理反应的长期影响。我们将进一步将这些反应与神经元及其外周和中枢过程的存活和状况相关联。拟议工作的结果可能会改善数千名患有严重或极重度听力障碍并使用人工耳蜗的人的沟通。