Toward a Biomarker for Spatial Hearing Ability

项目摘要 世纪以来，身体电活动的非侵入性测量一直用于评估 生物功能。例如，心电图（ECG）的特征被广泛用于评估非常重要的 特殊的心脏功能。这是可能的，因为ECG波的机制和源是已知的。 类似地，刺激诱发电位通常用于评估感觉功能。例如，听觉 由声音诱发的脑干反应（ABR）用于评估一个（单耳）或两个的功能。 （双耳）耳朵。ABR波形中的明显峰大致映射到升支中的特定核团或纤维束 听觉通路，并可用于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，评估双耳听力仍然是一个主要的临床挑战-没有常规 目前存在客观的临床措施来测试它。然而，ABR的衍生成分， 作为双耳交互分量（BIC），在过去的几十年中已经被证明与双耳交互分量（BIC）相关。 听力正常和听力受损的听众，因此代表了一个有前途的目标 双耳功能的测量。最突出的BIC峰，称为DN 1，已经显示出降低（或 甚至不存在）的双耳听力障碍人群，包括儿童谁经历了 暂时性传导性听力损失或被诊断患有中央听觉处理或自闭症谱系 疾病和老年人。此外，DN 1的幅度和潜伏期随双耳线索而系统地变化， 耳间时间和水平差异，并可以预测感知的听觉刺激的偏侧性。尽管 BIC作为生物标志物的前景，在人类中，BIC DN 1很小，并且使用典型的临床 方法论我们认为，更好地了解DN 1的脑干来源可能会提供线索，为什么它会发生在脑干。 是不可靠的测量，也提出了更可靠的测量方法的途径。早些时候， 使用药理学和损伤方法来解决BIC的电路是不确定的。然而，在这方面， 最近的几项研究表明，脑干的外侧（LSO）而不是内侧（MSO）上级橄榄 作为可能的候选人。然而，这些研究是相关的，因此不能证明LSO是 的BIC。LSO接收来自双耳的几乎同时的兴奋性和抑制性输入， 理论上是BIC DN 1的基础。包含Aim 1的实验采用了光遗传学的新组合。 和电生理学技术来最终确定产生BIC的大脑区域。总部设在 在这些结果的基础上，目标2将确定唤起BIC的最佳刺激，目标是减少 BIC测量的可变性。这些实验将揭示BIC DN 1的神经发生器， 通过确定最佳刺激来减少BIC测量中的变异性来源。这些发现 这将为未来的人类研究铺平道路，这些研究旨在提高BIC作为生物标志物的诊断效用。 对于双耳听力能力。

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.