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: 10686290
• 负责人: Andrew R Dykstra
• 金额: $ 18.81万
• 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/10686290
• 关键词: Acoustics; Address; Adoption; Adult; Affect; Age; Age of Onset; Aging; Animal Experiments; 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; Link; Magnetic Resonance Spectroscopy; Measures; Modeling; Neocortex; Neurons; Noise; Perception; Performance; Peripheral; Persons; Physiological; Play; Positioning Attribute; Predisposition; Presbycusis; Proxy; Psychophysics; Qualifying; Rehabilitation therapy; Role; Testing; Visit; Work; age related; auditory pathway; auditory processing; behavior prediction; behavioral study; biophysical model; candidate identification; cost; design; examination questions; gamma-Aminobutyric Acid; hearing impairment; human old age (65+); in vivo; insight; middle age; multidisciplinary; multimodal neuroimaging; neocortical; neural; neural circuit; neuron loss; neurophysiology; noise perception; novel; prevent; 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.

项目摘要 /摘要 在全球4.66亿人中，只有17％可能会从助听器中受益，实际上使用了一个 在听力和认知健康方面赋予了巨大的民族，甚至全世界的成本。一个原因 这样的低听力采用率是他们在嘈杂的聆听时提供的不清楚的好处 环境。在噪音中的困难听力通常是在中年开始的，通常是在开始之前的 与年龄相关的听力损失是通过听力测定法衡量的，是主要的听力康复目标 访问听力学诊所的个人。功能失调的中央听觉处理的贡献 与无法听到的声音相比，几乎没有关注 外围功能障碍。随着年龄的年龄，降低噪音能力的降低的可能是损失 中央听觉途径中的神经元抑制作用，尤其是听觉皮层（AC）。工作 实验动物已经表明，听力损失和年龄均与减少有关 AC和其他核中抑制性神经发射器GABA（伽马氨基丁酸）的水平 上升的听觉路径。这种神经元抑制的丧失可能对 通过AC神经元的过度刺激性听到噪声的能力。过度克服，定义为增加 在行为上假设赞助或诱发的燃料率是为了降低听众的能力 抑制分散注意力的声学输入，并专注于行为相关的声音。但是，需求 广泛的动物工作显示AC中的GABA水平降低，很少有研究直接研究了这一点 在人类中。甚至更少检查了这种降低的AC GABA级别的作用可能在下降 毫无听力的能力。在这里，我们直接检查了与年龄相关的抑制丧失之间的关系 在AC中，AC过度刺激性以及在噪声中听到的能力。在AIM 1中，我们确定年龄确实是 与人类AC中的GABA水平降低有关，同时控制与年龄有关的听力损失（Exps。 1A-1C）。在AIM 2中，我们确定了降低的AC GABA级别如何在行为上表现为语音中的语音 感知（exp。2a）以及行为和神经生理学上用于检测非语音目标的声音 噪声（经验2b）。在AIM 3中，我们检查了与年龄相关的AC过度兴奋性标记的变化是否可以 通过使用能够使用的生物物理建模，可以通过在电路级别丢失GABA来解释 识别候选电路级机制。这项研究的结果将建立一个组合 成像，物理和建模框架，用于理解行为和 人类AC中神经元抑制丧失的神经生理后果。计划的R01工作将 巩固AC GABA损失与难以忍受的听力噪声之间的联系，并识别候选电路级别 可以通过动物模型进一步探索的机制。