Toward a Biomarker for Spatial Hearing Ability

项目摘要 对人体电活动的非侵入性测量已经使用了一个多世纪来评估 生物功能。例如，心电信号的特征被广泛地用于评估 特定的心脏功能。这是可能的，因为心电波的机制和来源是已知的。 同样，刺激诱发电位通常被用来评估感觉功能。例如，听觉 由声音诱发的脑干反应(ABR)被用来评估一个(单耳)或两个耳的功能 (双耳)耳朵。ABR波形中的不同峰值大致映射到上升中的特定核团或纤维束 听觉通路，可以用来评估这些不同水平的功能。虽然ABR被广泛用于 评估单耳听力，双耳听力评估仍然是一个主要的临床挑战-没有常规 目的：目前已有临床方法对其进行检测。但是，ABR的派生组件，称为 作为双耳交互成分(BIC)，在过去的几十年中已经被证明与双耳相关 听力正常和听力受损的听众的听力，因此代表了一个有希望的目标 双耳功能的量度。最显著的BIC峰，称为DN1，已经被证明是减少的(或 即使没有)在患有双耳听力障碍的人群中，包括经历了 暂时性传导性听力损失或被诊断为中枢听觉处理或孤独症 失调症和老年人。此外，DN1的幅度和潜伏期随双耳提示而有系统地变化， 耳间时间和水平差异，并可以预测听觉刺激的感知偏侧性。尽管 BIC作为生物标志物的前景，在人类中，BIC DN1很小，使用典型的临床方法测量不可靠 方法论。我们认为，更好地了解DN1的脑干来源可能会为为什么它提供线索 是不可靠的测量，也为更可靠的测量方法提供了途径。早先的尝试是 使用药理学和损毁方法解决BIC的回路问题尚无定论。然而， 最近的一些研究表明，脑干的外侧上橄榄(LSO)而不是内侧上橄榄(MSO) 作为一个可能的候选人。然而，这些研究是相关的，因此并不能证明LSO是 BIC。LSO从两只耳朵接收近乎一致的兴奋和抑制输入，这可能 从理论上讲，北汽DN1是基础。由AIM 1组成的实验采用了一种新的光遗传学组合 以及电生理技术，以最终确定产生BIC的大脑区域。基于 根据这些结果，目标2将确定唤起BIC的最佳刺激，目标是减少 BIC测量中的可变性。这些实验将揭示BIC DN1和BIC DN1的神经发生器 通过确定最佳刺激来减少BIC测量中的可变性来源。这些发现 将为未来的人体研究铺平道路，旨在提高BIC作为生物标志物的诊断效用 双耳听力。

Project Summary Non-invasive measurement of electrical activity in the body has been used for over a century to assess biological function. For example, characteristics of the electrocardiogram (ECG) are widely used to assess very specific cardiac functions. This is possible because the mechanisms and sources of ECG waves are known. Similarly, stimulus evoked potentials are routinely used to assess sensory function. For example, auditory brainstem responses (ABRs) evoked by sound are used to assess function of one (monaural) or both (binaural) ears. Distinct peaks in ABR waveforms map roughly to specific nuclei or fiber tracts in the ascending auditory pathway and can be used to assess function at these different levels. While ABRs are widely used to assess monaural hearing, assessment of binaural hearing remains a major clinical challenge - no routine objective clinical measure currently exists to test for it. However, a derived component of the ABR, referred to as the binaural interaction component (BIC), has been shown over the past decades to correlate with binaural hearing capabilities in normal and hearing impaired listeners and thus represents a promising objective measure of binaural function. The most prominent BIC peak, termed DN1, has been shown to be reduced (or even absent) in populations with binaural hearing impairments including children who have experienced temporary conductive hearing loss or been diagnosed with central auditory processing or autism spectrum disorders, and the aged. Moreover, the amplitude and latency of DN1 vary systematically with binaural cues, interaural time and level differences, and can predict perceived laterality of an auditory stimulus. Despite the promise of BIC as a biomarker, in humans BIC DN1 is small and unreliably measured using typical clinical methodology. We posit that a better understanding of the brainstem source of DN1 may provide clues to why it is unreliably measured and also suggest avenues for more reliable measurement methods. Earlier attempts to resolve the circuitry of the BIC using pharmacological and lesioning approaches were inconclusive. However, several recent studies suggest that the lateral (LSO) and not the medial (MSO) superior olive of the brainstem as a likely candidate. However, these studies are correlational and thus do not prove the LSO is the source of the BIC. The LSO receives near-coincident excitatory and inhibitory input from the two ears which could theoretically underlie BIC DN1. The experiments comprising Aim 1 employ a novel combination of optogenetic and electrophysiological techniques to conclusively determine the brain region generating the BIC. Based in part on these results, Aim 2 will determine the optimal stimulus for evoking the BIC, with the goal of reducing variability in BIC measurements. These experiments will reveal the neural generator of the BIC DN1 and reduce sources of variability in BIC measurements by determining the optimal stimuli to elicit it. These findings will pave the way for future human studies designed to improve the diagnostic utility of the BIC as a biomarker for binaural hearing ability.