Supplement to cortical contributions to frequency-following response generation and modulation

摘要：频率跟随反应（FFR）是头皮记录的电生理学反应 “神经音”电位反映了整个大脑中神经系综的锁相活动。 听觉通路FFR提供了阈上言语完整性的神经快照 可以使用最小的电生理设置非侵入性地测量的处理， 已经存在于听力学诊所，具有高的重测信度，并需要最少的受试者 准备.最初的项目，题为“在线调制听觉脑干反应， 语言”，检查了血流储备分数的程度，这被认为是主要反映皮层下 听觉加工，受经验依赖性可塑性的影响。先前的提议 系统地测试了一个预测调谐模型，该模型提出皮层下的听觉处理 在成年人中并不是硬连接的，并且对 由自上而下的预期引导的刺激特征。一个不断发展的观点是， 应该被认为是皮层下和皮层神经元的综合反应。 合奏。迫切需要了解皮质对FFR的贡献，以实现 作为许多临床病症的生物标志物的基本翻译潜力。在这次更新中， 应用中，主要关注点是了解血流储备分数皮质源的特性， 一个机械水平，以及更大的作用，皮质丘调制的影响， 血流储备分数通过使用一个高度互补和跨学科的PI团队，该提案建立在 在第一个供资期内获得的关键科学见解，其明确目标是加速 临床翻译使用跨物种（人类，猕猴，豚鼠），跨水平 （细胞到中尺度），神经计算方法，这个建议系统地解构 皮质在血流储备分数生成和调制中的作用。目标1将测量头皮- 记录了人类患者、猕猴和豚鼠的FFR和颅内皮质活动， 表征皮质锁相极限、层状和频率依赖性以及半球 不对称目标2将测量人类和非人类的头皮记录和颅内FFR 在所有三个物种中使用统一的协议发声。使用表征相似性 分析，以量化跨物种和跨水平的相似性，目标2将检查的影响， FFR的可预测性、类别相关性和受试者唤醒。Aim 3利用了这一点 信息，以建立一个新的计算模型，包括一个核心前馈模块 这是由反馈皮质丘模块调制的。该模型的预测将是 在患有Heschl脑回病变的人类患者中进行了系统验证，并使用化学遗传学 在动物模型中进行可逆性抑制皮质-丘反馈的实验。

ABSTRACT: Frequency-following responses (FFRs) are scalp-recorded electrophysiological ‘neurophonic’ potentials that reflect phase-locked activity from neural ensembles across the auditory pathway. FFRs provide a neural snapshot of the integrity of supra-threshold speech processing that can be measured non-invasively using a minimal electrophysiological set-up that already exists in audiology clinics, has high test-retest reliability, and requires minimal subject preparation. The original project, titled “Online modulation of auditory brainstem responses to speech”, examined the extent to which FFRs, which were thought to primarily reflect subcortical auditory processing, were influenced by experience-dependent plasticity. The previous proposal systematically tested a predictive tuning model that proposed that subcortical auditory processing is not hard-wired in adults, and that there is continuous fine-tuning of the representation of stimulus features guided by top-down expectations. An evolving perspective is that the FFR should be considered an integrated response from both subcortical and cortical neural ensembles. There is a critical need to understand cortical contributions to the FFR to realize the fundamental translational potential as a biomarker for many clinical conditions. In this renewal application, the primary focus is to understand the properties of the cortical source of the FFR at a mechanistic level, as well as the larger role of cortico-collicular modulatory influences on the FFR. Using a highly complementary and cross-disciplinary team of PIs, this proposal builds on key scientific insights gained in the first funding period with the explicit goal of accelerating pre- clinical to clinical translation. Using a cross-species (human, macaque, guinea pigs), cross-level (cells to meso-scale), neurocomputational approach, this proposal systematically deconstructs the role of the cortex in the generation and modulation of the FFR. Aim 1 will measure scalp- recorded FFRs and intracranial cortical activity in human patients, macaques, and guinea pigs to characterize cortical phase-locking limits, laminar and frequency dependence, and hemispheric asymmetry. Aim 2 will measure scalp-recorded and intracranial FFRs to human and non-human vocalizations using a harmonized protocol in all three species. Using representational similarity analyses to quantify cross-species and cross-level similarities, Aim 2 will examine the influence of predictability, category relevance, and subject arousal on the FFRs. Aim 3 leverages this information to build a novel computational model that consists of a core feedforward module that is modulated by a feedback cortico-collicular module. Predictions from this model will be systematically validated in human patients with Heschl’s gyrus lesions, and using chemogenetic experiments to reversibly suppress cortico-collicular feedback in animal models.