Resolving the Paradox of Hearing Complaints with a Normal Audiogram: Differential Diagnosis and Perceptual Impacts of Cochlear Deafferentation

大约10%有听力问题的退伍军人的听力图临床正常。不幸的是， 这些患者的治疗选择有限，结果多种多样，导致缺乏共识。 关于如何管理这些病人。内毛细胞和传入听觉之间的耳蜗突触丢失 神经纤维可以与正常的听力阈值同时出现，并可能解释这些知觉抱怨。 然而，亚临床外毛细胞(OHC)损害或中枢性听力障碍，如由 创伤性脑损伤，可能会导致类似的问题。治疗结果的可变性可能是由于 潜在损害的异质性，这不能用现有的临床试验来确定 测试。最好的治疗方法可能取决于具体的损伤类型。尽管OHC函数可以是 用耳声发射(OAES)进行评估，目前的听力学测试不能区分 外周去传入和中枢听觉系统受损。然而，有几项生理指标 在动物模型中对去传入敏感。这些包括听性脑干反应(ABR)， 包络跟随反应(EFR)和中耳肌肉反射(MEMR)。我们已出版的和初步的 数据显示，在年轻退伍军人中，ABR、EFR和MEMR测量的幅度降低 报告说，与噪音有限的非退伍军人相比，他们在服兵役期间暴露于高水平的噪音 暴露，与噪声诱导的去传入的动物模型一致。此外，我们的数据表明， 这些测量值的减少与听觉知觉缺陷有关，如耳鸣和耳鸣增加 复杂言语感知过程中的认知负荷(即听力努力)。这项提议的总体目标是 开发一种去传入的临床测试，并确定这种情况的知觉影响。我们的中央 假说是，可以通过比较患者的生理测量来识别失去传入的患者。 那些来自正常样本的患者具有较低的去传入风险和异常患者 测量将有听觉知觉缺陷(耳鸣、听觉亢进和复杂语言困难 感知，包括增加倾听的努力)。我们计划通过追求三个具体目标来检验我们的假设： 1)确定ABR、EFR和MEMR测量的标准范围，根据性别和OHC进行统计调整 功能，可以用来识别可能有明显耳蜗性去传入的患者；2)比较 ABR、EFR和MEMR测量，以区分低和高分组的能力 去传入风险；以及3)描述异常生理测量和 听觉知觉缺陷。这种方法是创新的，因为它1)允许识别去传入 在个别患者中；2)通过耳声发射测量，将OHC功能纳入标准范围；3) 研究识别去传入的测试措施/刺激的最佳组合，包括使用 新的EFR和MEMR测量；以及4)评估复杂语音过程中增加的听力努力 知觉是去传入的可能后果。这项拟议的研究具有重要意义，因为 目前还没有关于去传入的临床测试，而且去传入的知觉后果尚不清楚， 阻止治疗选择的发展。这项研究预计将导致1)确定 生理测试措施和刺激参数，具有规范的范围，我们可以推荐给临床 评估耳蜗区的去传入和2)阐明去传入的知觉影响。临床 诊断传入神经失控的建议将对临床实践产生直接影响，因为 听觉学家来测试去感觉神经。去传入性神经传入联合测量的临床试验 使用耳声发射的OHC功能将有助于外周听觉损伤的鉴别诊断。未来的研究可以 然后专注于针对特定病变周边部位的治疗(例如，基于个性化助听器算法 OHC损伤的程度和去传入或突触修复或再生的药物治疗)。

Approximately 10% of Veterans with hearing complaints have clinically normal audiograms. Unfortunately, treatment options for these patients are limited and the outcomes are variable, resulting in a lack of consensus on how to manage these patients. Loss of the cochlear synapses between inner hair cells and afferent auditory nerve fibers can co-occur with normal hearing thresholds and may account for these perceptual complaints. However, subclinical outer hair cell (OHC) damage or central auditory deficits, such as those arising from traumatic brain injury, could lead to similar problems. The variability in treatment outcomes may be due to the heterogeneous nature of the underlying damage, which cannot be determined using existing clinical tests. The best treatment approach may depend on the specific type of damage. Although OHC function can be assessed with otoacoustic emissions (OAEs), current audiological testing cannot differentiate between peripheral deafferentation and damage to the central auditory system. However, several physiological measures are sensitive to deafferentation in animal models. These include the auditory brainstem response (ABR), the envelope following response (EFR), and the middle ear muscle reflex (MEMR). Our published and preliminary data show that ABR, EFR, and MEMR measurements are reduced in magnitude among young Veterans who report high levels of noise exposure during their military service compared to non-Veterans with limited noise exposure, consistent with animal models of noise-induced deafferentation. In addition, our data indicates that reductions in these measurements are associated with auditory perceptual deficits such as tinnitus and increased cognitive load (i.e., listening effort) during complex speech perception. The overall objective of this proposal is to develop a clinical test for deafferentation and determine the perceptual impacts of this condition. Our central hypothesis is that patients with deafferentation can be identified by comparing their physiological measurements to those from a normative sample with a low risk of deafferentation and that patients with abnormal measurements will have auditory perceptual deficits (tinnitus, hyperacusis, and difficulty with complex speech perception, including increased listening effort). We plan to test our hypothesis by pursuing three specific aims: 1) Identify normative ranges for ABR, EFR, and MEMR measurements, statistically adjusted for sex and OHC function, that can be used to identify patients likely to have significant cochlear deafferentation; 2) Compare ABR, EFR, and MEMR measurements in terms of their ability to differentiate between groups with low vs. high deafferentation risk; and 3) Characterize the relationship between abnormal physiological measurements and auditory perceptual deficits. This approach is innovative because it 1) allows for identification of deafferentation in individual patients; 2) incorporates OHC function, through OAE measurements, into the normative ranges; 3) investigates the best combination of test measures/stimuli for identifying deafferentation, including the use of new EFR and MEMR measurements; and 4) assesses increased listening effort during complex speech perception as a possible consequence of deafferentation. The proposed research is significant because there is currently no clinical test for deafferentation and the perceptual consequences of deafferentation are unclear, preventing the development of treatment options. This study is expected to result in 1) identification of physiological test measures and stimulus parameters, with normative ranges, that we can recommend for clinical assessment of cochlear deafferentation and 2) clarification of the perceptual impacts of deafferentation. Clinical recommendations for diagnosing deafferentation will have immediate impacts on clinical practice by allowing audiologists to test for deafferentation. A clinical test for deafferentation in combination with measurement of OHC function using OAEs will allow for differential diagnosis of peripheral auditory damage. Future research can then focus on treatments for specific peripheral sites of lesion (e.g., individualized hearing aid algorithms based on the degree of OHC damage and deafferentation or drug treatments for synapse repair or regeneration).