Neural Mechanisms Underlying the Auditory Phenotype of Mild Traumatic Brain Injury

轻度创伤性脑损伤听觉表型背后的神经机制

• 批准号: 10295788
• 负责人: Elliott Kozin
• 金额: $ 18.61万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295788
• 关键词: Acute; Address; Anatomy; Animal Model; Area; Auditory; Auditory Psychophysics; Auditory area; Auditory system; Award; Awareness; Behavioral; Biological Markers; Brain; Brain Concussion; Clinical; Coal; Cochlea; Code; Cues; Development; Diagnosis; Diagnostic Procedure; Disease; Dizziness; Electroencephalography; Etiology; Exhibits; Financial compensation; Frequencies; Functional disorder; Future; Genetic Transcription; Goals; Head; Hearing; Hearing Tests; Hearing problem; Histopathology; Human; Hyperactivity; Hyperacusis; Image; Individual; Inferior Colliculus; Injury; Inner Hair Cells; Investigation; Lead; Link; Liquid substance; Literature; Measurement; Measures; Mentors; Mentorship; Messenger RNA; Modality; Modeling; Mus; Neurobiology; Neurons; Neuropathy; Pathology; Pathway interactions; Patient Self-Report; Patient observation; Patients; Phenotype; Physiological; Plant Roots; Psychophysics; Public Health; Reporting; Research; Scalp structure; Scientist; Sensory; Serinus; Severities; Signal Transduction; Source; Speech Intelligibility; Stimulus; Structure; Symptoms; Synapses; System; TBI Patients; Technology; Testing; Time; Tinnitus; Training; Traumatic Brain Injury; United States; Vision; auditory pathway; clinical imaging; common symptom; disability; experience; extracellular; hearing impairment; human subject; insight; mechanical force; mild traumatic brain injury; mouse model; neurobiological mechanism; neuromechanism; neurophysiology; neurosensory; novel strategies; psychosocial; relating to nervous system; research clinical testing; response; sensory system; sound; speech in noise; stimulus processing

PROJECT SUMMARY / ABSTACT Mild traumatic brain injury (mTBI) is a major global public health issue. Following mTBI, individuals commonly report difficulties with hearing quality, tinnitus, hyperacusis, and speech-in-noise intelligibility. In order to understand why patients experience auditory dysfunction after mTBI, new approaches are needed that combine quantitative non-invasive biomarkers in mTBI patients with studies of the underlying neurophysiological and anatomical changes. The overarching hypothesis of the proposal is that many of the neurosensory disorders associated with mTBI share a common root related to a disruption of low-level sensory feature coding. Of all the sensory systems, the auditory system places the highest demand on rapid, high-fidelity temporal coding. We therefore propose that abnormal temporal processing and central gain in the auditory system of mTBI patients and animal models would highlight a neural signature of the auditory behavioral sequalae and may serve as the “canary in the coal mine” for distributed pathophysiology occurring more generally in other brain systems. Thus, the Candidate proposes a mentored training plan to develop non-invasive biomarkers of auditory dysfunction in mTBI subjects and to identify the neurobiological substrates for these deficits in a mouse model of mTBI. The Candidate has assembled a mentorship team that has expertise in a range of relevant areas for the proposal, including psychophysics in human subjects, mTBI mouse models, neurophysiological measures of auditory temporal processing and central gain, and quantitative cochlear histopathology. By integrating complementary levels of analysis through the study of different species it will be possible to generate greater insight into the pathophysiology of mTBI. In Aim 1, the Candidate will use a combination of auditory psychophysical tests and measures of the electroencephalography (EEG) frequency following response to test the hypothesis that mTBI subjects show deficits in coding rapid temporal cues and hyperactivity in sound intensity coding relative to controls. In Aim 2, the Candidate will incorporate a mouse mTBI model to compare EEG recordings against extracellular recordings of local field potentials and single unit spiking from the inferior colliculus (IC) and auditory cortex (ACtx) to test whether: 1) mice exhibit a similar auditory temporal processing and central gain phenotype observed in human subjects, and 2) abnormal temporal processing and coding of sound intensity are more prevalent in the IC or ACtx. In Aim 3, the Candidate will examine sensory and neural pathology in the cochlea of mice that have undergone mTBI, as well as transcriptional changes in Gria2 and Gabra1 mRNA levels in the IC and ACtx. These studies in Aim 3 will address the hypothesis that dysregulation of auditory temporal processing and central gain are linked to cochlear afferent neuropathy and imbalanced markers of excitatory and inhibitory signaling in the central auditory pathway. The K08 award will be a crucial stepping-stone toward the goal of developing into an independent clinician-scientist.

项目概要/摘要 轻度创伤性脑损伤（mTBI）是一个重大的全球公共卫生问题。在mTBI之后，个人通常 报告听力质量、耳鸣、听觉过敏和噪声中语音清晰度方面的困难。为了 了解为什么患者在mTBI后会出现听觉功能障碍，需要新的方法，联合收割机 mTBI患者中的定量非侵入性生物标志物， 解剖学变化该提案的首要假设是，许多神经感觉障碍 与mTBI相关的这些症状共享与低水平感觉特征编码的破坏相关的共同根源。所有 在感觉系统中，听觉系统对快速、高保真的时间编码提出了最高的要求。我们 因此提出mTBI患者听觉系统的异常时间处理和中枢增益 动物模型将突出听觉行为后遗症的神经特征，并可能作为 “煤矿里的金丝雀”，用于在其他脑系统中更普遍发生的分布式病理生理学。因此，在本发明中， 候选人提出了一个指导性的培训计划，以开发听觉功能障碍的非侵入性生物标志物， mTBI受试者，并在mTBI小鼠模型中识别这些缺陷的神经生物学基质。 候选人组建了一个导师团队，该团队在一系列相关领域具有专业知识， 建议，包括人类受试者的心理物理学，mTBI小鼠模型， 听觉时间处理和中枢增益，以及定量耳蜗组织病理学。通过整合 通过对不同物种的研究，互补的分析水平将有可能产生更大的 深入了解mTBI的病理生理学。在目标1中，候选人将结合使用听觉 心理物理测试和测试反应后的脑电图（EEG）频率测量 假设mTBI受试者表现出编码快速时间线索的缺陷和声音强度的过度活跃 相对于控件的编码。在目标2中，候选人将纳入小鼠mTBI模型，以比较EEG 记录与局部场电位的细胞外记录和来自下部的单个单位尖峰 丘（IC）和听觉皮层（ACtx），以测试：1）小鼠是否表现出类似的听觉时间处理 和在人类受试者中观察到的中枢增益表型，以及2）异常的时间处理和编码， 声音强度在IC或ACtx中更普遍。在目标3中，候选人将检查感觉和神经 已经经历mTBI的小鼠的耳蜗中的病理学，以及Gria 2和 IC和ACtx中的Gabra 1 mRNA水平。目标3中的这些研究将解决调节异常 听觉时间处理和中枢增益与耳蜗传入神经病变有关， 中枢听觉通路中兴奋性和抑制性信号的标记物。K 08奖将是一个至关重要的 成为一名独立的临床科学家的垫脚石。