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.

项目摘要/摘要 在全球可能受益于助听器的4.66亿人中，只有17%的人真正使用助听器， 在全国乃至全世界范围内给听力和认知健康带来了巨大的成本。其中一个原因是 如此低的助听器使用率是它们在嘈杂环境中收听时所提供的不明确的好处(fit)。 环境。Diffi对噪音的痴迷听力通常在中年开始，通常早在 听力测量测量的年龄相关性听力损失是听力康复的主要目标 去听力学诊所就诊的个人。中枢听觉加工功能障碍的贡献 对于在噪音中听不见的人来说，与他们的贡献相比，很少有人注意到 外周功能障碍。随着我们年龄的增长，在噪音中听力下降的一个可能的因素是 中枢听觉通路的神经元抑制，特别是听觉皮质(AC)。在.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。 抑制性神经递质GABA(γ氨基丁酸)在交感神经节和其他核团的水平 上行听觉通路。这种神经元抑制的丧失可能会对 通过AC神经元的过度兴奋在噪声中听力的能力。过度兴奋，DefiNed AS增加 自发或诱发的fi振铃率，是假设的行为，以降低听者的能力 抑制令人分心的声音输入，专注于与行为相关的声音。然而，尽管 广泛的动物研究表明AC中的GABA水平降低，很少有研究直接检验这一点 在人类身上。甚至更少的人研究了这种降低的AC GABA水平可能在 在噪音中的听力能力。在这里，我们直接考察了与年龄相关的抑制丧失之间的关系 在交流电中，交流电的超兴奋性，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水平降低有关，同时控制与年龄相关的听力损失(实验。 1A-1C)。在目标2中，我们确定了AC GABA水平降低如何在噪声中语音的行为中表现出来 感知(经验以及用于检测非语音目标声音的行为和神经生理学 噪波(经验2B)。在目标3中，我们检查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能够在电路水平上解释GABA的损失 确定候选电路级机制。这项研究的结果将建立一个综合的 成像、生理和建模框架，用于了解行为和 人类AC神经元抑制丧失的神经生理学后果。计划中的R01工作将 巩固交流GABA损失和Diffi严重听力噪声之间的联系，并确定候选电路级 可以用动物模型进一步探索的机制。