Disinhibition and Hyperexcitability in Human Auditory Cortex

人类听觉皮层的去抑制和过度兴奋

• 批准号: 10432789
• 负责人: Andrew R Dykstra
• 金额: $ 22.07万
• 依托单位: UNIVERSITY OF MIAMI CORAL GABLES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432789
• 关键词: Acoustics; Address; Adoption; Adult; Affect; Age; Age of Onset; Aging; Animal Model; Animals; Attention; Audiology; Auditory; Auditory Brainstem Responses; Auditory area; Auditory system; Behavioral; Cell Nucleus; Clinic; Cognitive; Computer Models; Computing Methodologies; Data; Disinhibition; Electroencephalography; Electrophysiology (science); Environment; Foundations; Functional disorder; Future; Goals; Health; Hearing; Hearing Aids; Hearing Tests; Human; Image; Impaired cognition; Individual; Lead; Link; Magnetic Resonance Spectroscopy; Masks; Measures; Modeling; Neurons; Noise; Performance; Peripheral; Persons; Play; Positioning Attribute; Presbycusis; Proxy; Psychophysics; Rehabilitation therapy; Role; Testing; Visit; Work; age related; auditory pathway; auditory processing; base; behavioral study; biophysical model; candidate identification; cost; design; gamma-Aminobutyric Acid; hearing impairment; in vivo; insight; middle age; multidisciplinary; multimodal neuroimaging; neocortical; neural circuit; neuron loss; neurophysiology; noise perception; novel; physiologic model; prevent; relating to nervous system; response; somatosensory; sound; speech in noise; targeted treatment; therapeutic target

PROJECT SUMMARY / ABSTRACT Only 17% of the 466 million people worldwide who might benefit from hearing aids actually use one, imparting a large national and indeed worldwide cost on hearing and cognitive health. One reason for such low hearing-aid adoption rates is the unclear benefit they provide when listening in noisy environments. Difficulty hearing in noise typically begins in mid-life, often well before the onset of age-related hearing loss as measured by audiometry and is the primary hearing rehabilitation goal of individuals visiting audiology clinics. The contributions of dysfunctional central auditory processing towards the inability to hear in noise have received little attention compared to contributions of peripheral dysfunction. One likely contributor to the reduced ability to hear in noise as we age is loss of neuronal inhibition in the central auditory pathway, particularly auditory cortex (AC). Work in experimental animals has shown that both hearing loss and age, per se, are associated with reduced levels of the inhibitory neural transmitter GABA (gamma aminobutyric acid) in AC and other nuclei of the ascending auditory pathway. Such loss of neuronal inhibition likely has severe consequences for the ability to hear in noise via hyperexcitability of AC neurons. Hyperexcitability, defined as increased spontaneous or evoked firing rates, is hypothesized behaviorally to reduce the listener’s ability to suppress distracting acoustic input and focus on behaviorally relevant sounds. However, despite extensive animal work showing reduced GABA levels in AC, very few studies have directly examined this in humans. Even fewer have examined the role such reduced AC GABA levels might play in decreased hearing-in-noise ability. Here, we directly examine the relationship between age-related loss of inhibition in AC, AC hyperexcitability, and the ability to hear in noise. In Aim 1, we establish that age is indeed associated with reduced levels of GABA in human AC, while controlling for age-related hearing loss (Exps. 1A-1C). In Aim 2, we determine how reduced AC GABA levels manifest behaviorally for speech-in-noise perception (Exp. 2A) and behaviorally and neurophysiologically for detecting non-speech target sounds in noise (Exp. 2B). In Aim 3, we examine whether age-related changes in markers of AC hyperexcitability can be accounted for by loss of GABA at the circuit level through the use of biophysical modeling capable of identifying candidate circuit-level mechanisms. The results of this study will establish a combined imaging, physiological, and modeling framework for understanding the behavioral and neurophysiological consequences of loss of neuronal inhibition in human AC. Planned R01 work will solidify the link between AC GABA loss and difficulty hearing noise and identify candidate circuit-level mechanisms that can be further explored with animal models.

项目概要/摘要 全球 4.66 亿可能受益于助听器的人中，只有 17% 实际使用助听器， 给听力和认知健康带来巨大的国家乃至全世界成本。原因之一是 助听器的采用率如此之低，是因为它们在嘈杂的环境中聆听时所提供的好处并不明确 环境。噪音中的听力困难通常始于中年，通常早在听力障碍发作之前 通过听力测试测量的与年龄相关的听力损失是听力康复的主要目标 访问听力学诊所的个人。中枢听觉处理功能失调的贡献 与在噪音中听不到声音的贡献相比，人们很少关注 外周功能障碍。随着年龄的增长，听力能力下降的一个可能原因是听力损失 中枢听觉通路的神经元抑制，特别是听觉皮层（AC）。工作于 实验动物表明，听力损失和年龄本身都与听力下降有关。 AC 和其他细胞核中抑制性神经递质 GABA（γ 氨基丁酸）的水平 上行听觉通路。这种神经元抑制的丧失可能会对 通过 AC 神经元的过度兴奋而在噪音中听到声音的能力。过度兴奋，定义为增加 自发或诱发的放电率，在行为上被假设为降低听者的能力 抑制分散注意力的声音输入并专注于与行为相关的声音。然而，尽管 大量的动物研究表明 AC 中的 GABA 水平降低，但很少有研究直接检验这一点 在人类中。更少有人研究过这种降低的 AC GABA 水平可能在减少 噪声中的听觉能力。在这里，我们直接检查与年龄相关的抑制丧失之间的关系 在 AC 中，AC 过度兴奋，以及在噪音中听到的能力。在目标 1 中，我们确定年龄确实是 与人类 AC 中 GABA 水平降低相关，同时控制与年龄相关的听力损失（Exps. 1A-1C）。在目标 2 中，我们确定降低的 AC GABA 水平如何在噪声中的语音行为中表现出来 感知（实验 2A）以及行为和神经生理学，用于检测非语音目标声音 噪声（实验 2B）。在目标 3 中，我们研究了 AC 过度兴奋标志物的年龄相关变化是否可以 通过使用生物物理模型，可以通过电路水平上的 GABA 损失来解释 确定候选电路级机制。这项研究的结果将建立一个综合 用于理解行为和行为的成像、生理和建模框架 人类 AC 中神经元抑制丧失的神经生理学后果。计划的 R01 工作将 巩固 AC GABA 损失与听力困难噪声之间的联系，并确定候选电路级 可以通过动物模型进一步探索的机制。