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.

项目总结/摘要 在全球4.66亿可能贝内于助听器的人中，只有17%的人实际使用助听器， 在听力和认知健康方面造成了巨大的国家和全球成本。的一个原因 如此低的助听器采用率是他们在嘈杂的环境中收听时提供的不明确的贝内。 环境.噪音中的听力障碍通常始于中年，通常早于老年痴呆症的发作。 通过测听法测量的年龄相关性听力损失，是听力康复的主要目标， 访问听力诊所的个人。中枢听觉处理功能障碍的贡献 在噪音中听不到的问题，与 外周功能障碍随着年龄的增长，我们在噪音中听力下降的一个可能原因是听力损失。 中枢听觉通路，特别是听觉皮层（AC）中的神经元抑制。工作 实验动物已经表明，听力损失和年龄本身都与听力下降有关。 AC和其他核团中抑制性神经递质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对神经元的功能产生严重的后果。 通过AC神经元的过度兴奋性在噪声中听到的能力。过度兴奋，定义为增加 自发或诱发放电率，是假设行为，以减少听者的能力， 抑制分散注意力的声音输入，专注于行为相关的声音。但尽管 大量的动物研究显示AC中GABA水平降低，很少有研究直接研究这一点 在人类身上。甚至更少的人研究了AC GABA水平的降低可能在减少脑缺血中发挥的作用。 噪音中的听觉能力在这里，我们直接研究了与年龄相关的抑制损失之间的关系， 在交流中，交流兴奋过度，以及在噪音中听力的能力。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，我们确定如何降低AC GABA水平表现为噪音中的语音行为 感知（Exp. 2A）和行为和神经生理学上用于检测非语音目标声音， 噪音（Exp. 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 通过使用能够 识别候选电路级机制。这项研究的结果将建立一个综合的 成像，生理和建模框架，用于理解行为和 在人类AC中神经元抑制丧失的神经生理学后果。计划的R 01工作将 巩固交流GABA损失和困难性听力噪声之间的联系，并确定候选电路水平 这些机制可以通过动物模型进一步探索。