FX ENTRAIN: Perturbation of neurodynamics underlying sensory hyperarousal and statistical learning in Youth with FXS

联系PI/PD：佩达帕蒂，欧内斯特 项目总结 脆性X综合征(FXS)是一种典型的单基因神经发育障碍(NDD)，其中 大量的多物种翻译研究已经阐明了潜在的分子 病理生理学，以及最近更深入的皮质功能电生理学。到目前为止， 在动物模型中的表型抢救并没有导致人类治疗的突破。中心到 这种差异是对平均群体效应的组成神经动力学的一种很差的理解 人类大脑活动的个体变异性与更高水平的认知症状学有关 和临床表型。我们收集的大量初步数据表明，患有FXS的人 不要对感官听觉的嗡嗡声做出精确的神经反应，而是要有“嘈杂”的声音 非同步伽马活动。此外，阿尔法能量的显著降低表明 丘脑皮质功能，降低从噪声中检测信号的能力和代表潜力 “自下而上”夹带的易处理目标。我们的方法涉及三个科学目标，如果 将确定可能缓解感觉和认知的潜在机制 减损。首先，我们将研究阿尔法和阿尔法的瞬时、非连续特征(神经动力学)。 静息状态脑电中的伽马振荡和模拟患者水平的感觉性听觉啁啾 异质性和构成群体效应(目标1A)。我们还将确定这些小说中的哪些(如果有的话) 利用先前存在的小鼠脑电数据在Fmr1-/-KO中保留特征并代表患者 分组(目标1B)。其次，我们将通过学习神经动力学和电路来扩展到认知 与统计学习(SL)相关的建模，它与 感觉性听觉啁啾(目标2)。第三，我们将使用个性化的闭环阿尔法听觉夹带 (AAE)尝试感觉听觉啁啾和SL任务的神经特征的正常化(AIM 3)。目标1和目标2的研究结果将提供关键数据，以优化AAE的闭环系统参数 作为一个“自下而上”的神经探头，通过 丘脑皮质驱动力的微扰。确定这些变化背后的机制将是 有较高的临床影响，特别是加强早期干预，改变智力轨迹 没有确定的治疗方法的发展。

Contact PI/PD: Pedapati, Ernest PROJECT SUMMARY Fragile X Syndrome (FXS) is an exemplar monogenetic neurodevelopmental disorder (NDD) where a tremendous body of multi-species translational research has elucidated the underlying molecular pathophysiology, and more recently, in-depth electrophysiology of cortical function. Thus far, phenotypic rescue in animal models has not resulted in treatment breakthroughs in humans. Central to this discrepancy is a poor understanding of the constituent neurodynamics of averaged group effects and individual variability in human brain activity as related to higher-level cognitive symptomatology and clinical phenotype. Our large collection of preliminary data demonstrates that individuals with FXS do not mount precise neural responses to the sensory auditory chirp and, instead, have “noisy” asynchronous gamma activity. Furthermore, a marked reduction in alpha power suggests altered thalamocortical function, reducing the ability to detect signal from noise and representing potential tractable targets for “bottom-up” entrainment. Our approach involves three scientific aims, which, if addressed, would ascertain underlying mechanisms that may alleviate sensory and cognitive impairments. First, we will study transient, non-continuous features (neurodynamics) of alpha and gamma oscillations in resting-state EEG and sensory auditory chirp that model patient-level heterogeneity and constitute group effects (Aim 1A). We will also identify what, if any, of these novel features are conserved in the Fmr1-/- KO using preexisting murine EEG data and represent patient subgroups (Aim 1B). Second, we will extend into cognition by studying neurodynamics and circuit modeling associated with statistical learning (SL), which shares similar neural mechanisms to the sensory auditory chirp (Aim 2). Third, we will use individualized closed-loop alpha auditory entrainment (AAE) to attempt the normalization of neural signatures of the sensory auditory chirp and SL tasks (Aim 3). Aim 1 and 2 findings will provide critical data to optimize closed-loop parameters of AAE to serve as a “bottom-up” neural probe to understand the mechanics of disorder-relevant circuit activity through perturbation of thalamocortical drive. Ascertaining the mechanisms underlying these alterations would have a high clinical impact, especially to enhance early intervention to alter the trajectory of intellectual development in which no definitive treatments are available.