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临床听力正常。不幸的是， 这些患者的治疗选择有限，结果也不确定，导致缺乏共识 如何管理这些病人。耳蜗内毛细胞与听觉传入神经突触的缺失 神经纤维可以与正常的听力阈值同时出现，并且可以解释这些感知抱怨。 然而，亚临床外毛细胞（OHC）损伤或中枢听觉缺陷，如由 创伤性脑损伤，可能导致类似的问题。治疗结果的变异性可能是由于 潜在损伤的异质性，无法使用现有的临床 试验.最好的治疗方法可能取决于具体的损伤类型。虽然OHC功能可以 通过耳声发射（OAE）进行评估，目前的听力学测试无法区分 外周神经传入阻滞和中枢听觉系统损伤。然而，一些生理指标 在动物模型中对传入神经阻滞很敏感。这些包括听觉脑干反应（ABR）， 包络跟随反应（EFR）和中耳肌反射（MEMR）。我们已公布的和初步的 数据显示，年轻退伍军人的ABR、EFR和MEMR测量值降低， 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，与噪声诱导的传入神经阻滞的动物模型一致。此外，我们的数据表明， 这些测量值的降低与听觉感知缺陷如耳鸣有关， 认知负荷（即，在复杂的语音感知中的听力努力。本建议的总体目标是 开发一个临床测试的传入神经阻滞，并确定这种情况下的感知影响。我们的中央 一种假设是，可以通过比较他们的生理测量来识别传入神经阻滞的患者 对于那些来自正常样本的低传入神经阻滞风险的患者， 测量将具有听觉感知缺陷（耳鸣、听觉过敏和复杂言语困难 （包括提高听力）。我们计划通过追求三个具体目标来测试我们的假设： 1)确定ABR、EFR和MEMR测量值的正常范围，根据性别和OHC进行统计学调整 功能，可用于识别可能具有显著耳蜗传入阻滞的患者; 2）比较 ABR、EFR和MEMR测量在区分低与高的组之间的能力 传入神经阻滞风险;以及3）表征异常生理测量与 听觉知觉缺陷这种方法是创新的，因为它1）允许识别传入神经阻滞 在个体患者中; 2）通过OAE测量将OHC功能纳入正常范围; 3） 研究用于识别传入神经阻滞的测试措施/刺激的最佳组合，包括使用 新的EFR和MEMR测量;以及4）评估在复杂语音期间增加的听力努力 知觉是传入神经阻滞的可能后果。这项研究意义重大，因为 目前没有对传入神经阻滞的临床测试并且传入神经阻滞的感知结果还不清楚， 阻碍了治疗方案的发展。这项研究预计将导致1）识别 生理测试措施和刺激参数，以及我们可以推荐用于临床的标准范围 耳蜗传入阻滞的评估和2）传入阻滞的感知影响的澄清。临床 诊断传入神经阻滞的建议将对临床实践产生直接影响， 听力学家来测试传入神经阻滞。传入神经阻滞的临床试验结合测量 OHC功能使用耳声发射将允许鉴别诊断外周听觉损伤。未来的研究可以 然后集中于对病变的特定外周部位的治疗（例如，助听器选配 OHC损伤和传入神经阻滞的程度或用于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).