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: 10531215
• 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/10531215
• 关键词: Acute; Address; Anatomy; Animal Model; Anosmia; Area; Auditory; Auditory Psychophysics; Auditory area; Auditory system; Award; Awareness; Behavioral; Biological Markers; Brain; Brain Concussion; Classification; Clinical; Coal; Cochlea; Code; Compensation; Craniocerebral Trauma; Cues; Development; Diagnosis; Diagnostic Procedure; Disease; Dizziness; Electroencephalography; Etiology; Exhibits; Frequencies; Functional disorder; Future; Genetic Transcription; Goals; Hearing; Hearing Tests; Hearing problem; Histopathology; Human; Hyperactivity; Hyperacusis; Imaging technology; Individual; Inferior Colliculus; Injury; Inner Hair Cells; 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; Psychophysics; Public Health; Reporting; Research; Scalp structure; Scientist; Sensory; Serinus; Severities; Signal Transduction; Source; Speech Intelligibility; Stimulus; Structure; Symptoms; Synapses; System; Technology; Testing; Time; Tinnitus; Training; Traumatic Brain Injury; United States; Vision; auditory pathway; clinical imaging; common symptom; comparison control; disability; experience; extracellular; hearing impairment; human subject; insight; mechanical force; mild traumatic brain injury; mouse model; neural; neurobiological mechanism; neuromechanism; neurophysiology; neurosensory; novel strategies; psychosocial; 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) 是继 mTBI 之后的一个重大全球公共卫生问题。 报告听力质量、耳鸣、听力过敏和噪声中语音清晰度方面的困难。 为什么患者在 mTBI 后会出现听觉功能障碍，需要新的方法来结合 通过研究潜在的神经生理学和 mTBI 患者的非侵入性生物标志物 该提案的总体假设是许多神经感觉障碍。 与 mTBI 相关的疾病有一个共同的根源，即低级感觉特征编码的破坏。 与感觉系统相比，听觉系统对快速、高保真时间编码的要求最高。 因此提出 mTBI 患者听觉系统的时间处理和中枢增益异常 动物模型将突出行为行为后遗症的神经特征，并可能作为 “煤矿里的金丝雀”对于分布式病理生理学来说更普遍地发生在其他大脑系统中。 候选人提出了一项指导培训计划，以开发听觉功能障碍的非侵入性生物标志物 mTBI 受试者并确定 mTBI 小鼠模型中这些缺陷的神经生物学基础。 候选人组建了一个导师团队，该团队在一系列相关领域拥有专业知识 提案，包括人类受试者的心理物理学、mTBI 小鼠模型、神经生理学测量 听觉时间处理和中枢增益，以及定量耳蜗组织病理学。 通过对不同物种的研究进行互补水平的分析将有可能产生更大的结果 深入了解 mTBI 的病理生理学 在目标 1 中，考生将结合听觉。 心理物理测试和测试反应后脑电图 (EEG) 频率的测量 假设 mTBI 受试者在编码快速时间线索方面表现出缺陷，并且在声音强度方面表现出过度活跃 在目标 2 中，候选人将结合小鼠 mTBI 模型来比较脑电图。 针对局部场电位的细胞外记录和来自下层的单个单元尖峰的记录 丘 (IC) 和听觉皮层 (ACtx) 来测试是否：1) 小鼠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心增益表型，以及2）异常的时间处理和编码 声音强度在 IC 或 ACtx 中更为普遍 在目标 3 中，考生将检查感觉和神经。 经历过 mTBI 的小鼠耳蜗的病理学，以及 Gria2 和 IC 和 ACtx 中的 Gabra1 mRNA 水平。目标 3 中的这些研究将解决失调的假设。 听觉时间处理和中枢增益的降低与耳蜗传入神经病变和不平衡有关 K08 奖将是一个至关重要的奖项。 迈向发展成为独立临床医生科学家目标的踏脚石。