Auditory de-afferentation, a permanent reduction in the number of inner-hair-cells and auditory-nerve synapses due to cochlear damage or synaptopathy, can reliably be quantified using temporal bone histology and immunostaining. However, there is an urgent need for non-invasive markers of synaptopathy to study its perceptual consequences in live humans and to develop effective therapeutic interventions. While animal studies have identified candidate auditory-evoked-potential (AEP) markers for synaptopathy, their interpretation in humans has suffered from translational issues related to neural generator differences, unknown hearing-damage histopathologies or lack of measurement sensitivity. To render AEP-based markers of synaptopathy more sensitive and differential to the synaptopathy aspect of sensorineural hearing loss, we followed a combined computational and experimental approach. Starting from the known characteristics of auditory-nerve physiology, we optimized the stimulus envelope to stimulate the available auditory-nerve population optimally and synchronously to generate strong envelope-following-responses (EFRs). We further used model simulations to explore which stimuli evoked a response that was sensitive to synaptopathy, while being maximally insensitive to possible co-existing outer-hair-cell pathologies. We compared the model-predicted trends to AEPs recorded in younger and older listeners (N=44, 24f) who had normal or impaired audiograms with suspected age-related synaptopathy in the older cohort. We conclude that optimal stimulation paradigms for EFR-based quantification of synaptopathy should have sharply rising envelope shapes, a minimal plateau duration of 1.7-2.1 ms for a 120-Hz modulation rate, and inter-peak intervals which contain near-zero amplitudes. From our recordings, the optimal EFR-evoking stimulus had a rectangular envelope shape with a 25\% duty cycle and a 95\% modulation depth. Older listeners with normal or impaired audiometric thresholds showed significantly reduced EFRs, which were consistent with how (age-induced) synaptopathy affected these responses in the model.

中文翻译：

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在人类耳蜗突触筛查中提高包膜跟随反应的敏感性：刺激包膜的作用

可以使用颞骨组织学和免疫染色可靠地量化听觉脱除情感，永久性减少由于耳蜗损伤或突触引起的内毛细胞和听觉神经突触的数量。然而，迫切需要突触病的非侵入性标记物以研究其在活人中的知觉后果并开发有效的治疗干预措施。虽然动物研究已经确定了突触病的候选听觉诱发电位（AEP）标记物，但它们在人类中的解释却遇到了与神经发生器差异，未知的听力损伤组织病理学或缺乏测量敏感性有关的翻译问题。为了使基于AEP的突触病标记物对感觉神经性听力损失的突触病方面更加敏感和有所区别，我们遵循了计算和实验相结合的方法。从听觉神经生理学的已知特征开始，我们优化了刺激包膜，以最佳且同步地刺激可用的听觉神经种群，从而产生强烈的包膜跟随反应（EFR）。我们进一步使用模型模拟来探索哪种刺激引起对突触病敏感的反应，同时对可能并存的外毛细胞病变最大程度地不敏感。我们将模型预测的趋势与在年龄较大的人群中听力正常或受损的可疑年龄相关性突触病的年轻和老年听众（N = 44、24f）中记录的AEP进行了比较。我们得出结论，基于EFR的突触病量化的最佳刺激范例应具有急剧上升的包络形状，120 Hz调制速率的最小平稳持续时间为1.7-2.1 ms，并且峰间间隔包含接近零的幅度。根据我们的记录，最佳的EFR诱发刺激具有矩形包络形状，占空比为25％，调制深度为95％。听觉阈值正常或受损的老年听众显示EFR明显降低，这与（年龄诱发的）突触病如何影响模型中的这些反应是一致的。