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反应。 ‘神经音素’电位，反映了来自神经集合的锁相活动 听觉通路。FFR提供了阈值以上语音完整性的神经快照 可以使用最小的电生理设置进行非侵入性测量的处理 已经存在于听力学诊所，具有很高的重测可靠性，并且需要的科目最少 准备工作。最初的项目名为《听觉脑干反应的在线调制》 ，检查了被认为主要反映皮质下的FFR的程度 听觉加工受经验依赖性可塑性的影响。之前的提案 系统地测试了一种预测调谐模型，该模型提出了皮层下听觉处理 在成人中并不是硬连线的，而且有持续的微调的表征 由自上而下的预期指导的刺激功能。一种不断发展的观点是，FFR 应被认为是皮质下神经和皮质神经的综合反应 合唱团。迫切需要了解皮质对FFR的贡献，以实现 作为许多临床疾病的生物标志物的基本翻译潜力。在这次更新中 应用程序，主要的重点是了解FFR的皮质来源的属性在 一个机械性水平，以及皮质-丘脑调节影响的更大作用 FFR。使用高度互补和跨学科的绩效指标团队，这项建议建立在 在第一个资助期获得的关键科学见解，明确的目标是加快预 临床到临床的翻译。使用跨物种(人、猕猴、豚鼠)、跨级别 (细胞到中尺度)，神经计算方法，这一提议系统地解构 大脑皮层在FFR的产生和调节中的作用。目标一号将测量头皮- 记录的人类患者、猕猴和豚鼠的FFR和颅内皮质活动 表征皮质锁相极限、层流和频率相关性以及半球 不对称。Aim 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协议的发声。使用表象相似性 为了量化跨物种和跨层次的相似性，目标2将检查其影响 FFR上的可预测性、类别相关性和主题唤醒。AIM 3充分利用了这一点 用于建立由核心前馈模块组成的新型计算模型的信息 这是由反馈的皮质-丘脑模块调制的。来自该模型的预测将是 在人类Heschl回病变患者中进行系统验证，并使用化学遗传学 动物模型中可逆性抑制皮质-丘脑反馈的实验。

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.