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

FX ENTRAIN：FXS 青少年感觉过度唤醒和统计学习背后的神经动力学扰动

• 批准号: 10585050
• 负责人: Ernest Vijay Pedapati
• 金额: $ 71.6万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585050
• 关键词: 10 year old; Acute; Address; Age; Animal Model; Auditory; Behavior Therapy; Brain; Clinical; Cognition; Cognitive; Collection; Computer Models; Cross-Over Studies; Data; Development; Diagnosis; Disease; Double-Blind Method; Early Intervention; Electroencephalography; Electrophysiology (science); Event; FMR1; Fragile X Syndrome; Frequencies; Functional disorder; Genotype; Heterogeneity; Human; Impaired cognition; Impairment; Individual; Inherited; Intellectual functioning disability; Knock-out; Knockout Mice; Knowledge; Language; Learning; Link; Measures; Mechanics; Modeling; Molecular; Mus; Mutation; Neurobehavioral Manifestations; Neurodevelopmental Disorder; Noise; Participant; Patients; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Phenotype; Proxy; Publications; Publishing; Reaction Time; Reproducibility; Rest; Sampling; Sensory; Signal Transduction; Stimulus; Structure; Subgroup; Testing; Translating; Translational Research; United States National Institutes of Health; Variant; Visit; Wild Type Mouse; Youth; autism spectrum disorder; autistic; biophysical model; clinical investigation; clinical phenotype; cognitive disability; cognitive function; cognitive process; cognitive testing; cohort; computerized; disorder control; effective therapy; improved; individual variation; male; mosaic; mouse model; neural; neuromechanism; neuropsychiatric symptom; neuropsychiatry; novel; patient subsets; psychologic; response; sex; statistical learning; success; symptomatology; translational impact

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.

联系PI/PD：Pedapati，Ernest 项目摘要 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 大量的多物种转化研究已经阐明了潜在的分子机制， 病理生理学，以及最近的皮质功能的深入电生理学。到目前为止， 在动物模型中的表型拯救尚未导致在人类中的治疗突破。的核心 这种差异是对平均群体效应的组成神经动力学的理解不足 和人类大脑活动的个体差异与更高层次的认知功能学有关 和临床表型。我们收集的大量初步数据表明，FXS患者 不安装精确的神经反应的感官听觉啁啾，相反，有“嘈杂” 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，降低了从噪声中检测信号的能力， “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 解决，将确定潜在的机制，可能减轻感官和认知 损伤首先，我们将研究阿尔法的瞬时，非连续特征（神经动力学）， 静息状态EEG中的伽马振荡和模拟患者水平的感觉听觉啁啾 异质性和构成群体效应（目标1A）。我们还将确定，如果有的话，这些小说 使用预先存在的鼠EEG数据，在Fmr 1-/- KO中保留特征，并代表患者 亚组（目标1B）。其次，我们将通过研究神经动力学和电路扩展到认知 与统计学习（SL）相关的建模，与统计学习（SL）共享类似的神经机制。 感觉听觉啁啾（Aim 2）。第三，我们将使用个性化的闭环阿尔法听觉夹带 (AAE)尝试将感觉听觉啁啾和SL任务的神经特征标准化（目的 （3）第三章。目的1和2的研究结果将提供关键数据，以优化AAE的闭环参数， 作为一个“自下而上”的神经探针，通过以下方式了解与疾病相关的电路活动的机制： 丘脑皮层驱动的扰动确定这些变化的机制将 有很高的临床影响，特别是加强早期干预，以改变智力的轨迹， 没有明确的治疗方法的发展。