Electrophysiological Biomarkers of Neurocognitive Deficits in Fragile X Syndrome

脆性 X 综合征神经认知缺陷的电生理生物标志物

基本信息

批准号：
10621148
负责人：
Lauren Schmitt
金额：
$ 12.72万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621148
关键词：
Acceleration Adult Age Animal Model Anterior Area Attenuated Behavioral Biological Biological Markers Brain Child Clinical Clinical Psychology Cognition Cognitive Coupling Data Development Developmental Delay Disorders Disease Electroencephalography Electrophysiology (science)Ensure Event-Related Potentials Executive Dysfunction FMR1 Faculty Family Fragile X Syndrome Goals Housing Hypersensitivity Individual Inherited Intellectual functioning disability K-Series Research Career Programs Knockout Mice Knowledge Language Learning Learning Disabilities Link Measures Mentors Mentorship Neurocognitive Neurocognitive Deficit Neurodevelopmental Disorder Neuropsychology Neurosciences Outcome Parents Parietal Lobe Participant Patients Performance Phase Production Reporting Research Research Personnel Research Support Research Training Resources Rest Reversal Learning Sampling Seminal Sensory Severities Speech Speed Standardization System Testing Training Training Programs Translational Research Treatment Effectiveness United States National Institutes of Health Validation Work behavior observation behavioral phenotyping behavioral response biomarker discovery biomarker identification career clinical phenotype cognitive task density drug discovery effective therapy effectiveness measure flexibility frontal lobe functional disability improved insight language impairment neural neurophysiology preservation programs recruit reduce symptoms repetitive behavior research study response sex skills social anxiety social communication therapy development

项目摘要

PROJECT SUMMARY/ABSTRACT The primary objective of this K23 application is to provide the candidate with the necessary research training and mentorship to ensure her development as an independent clinical researcher. Her career goal is to investigate neurodevelopmental disorders, like Fragile X Syndrome (FXS), through the integrated use of translational biological and behavioral approaches to identify objective, quantifiable biomarkers to improve mechanistic understanding and advance treatment discovery. To achieve this goal, the candidate proposes a focused training program with an exceptional team of scientific advisors to develop her skills and knowledge in the areas of: 1) paradigm optimization and translational research, 2) advanced electrophysiology analysis and interpretation, and 3) neural systems relevant to sensorimotor and cognition and FXS. The candidate’s mentor (Dr. Sweeney) and co-mentor (Dr. Erickson) are co-project PIs on the U54 FXS Center, providing the candidate with necessary resources, recruitment pool, and scientific excellence to complete her proposed training program and research plan. This proposal is relevant to the NIH Research Plan on FXS and Associated Disorders based on overlap with goals: 3.3 develop biomarker discovery, incorporating diverse approaches to provide treatment targets, accelerate drug discovery, measure effectiveness 3.1 develop functional, objective measures to provide indicators of treatment effectiveness, 1.8 understand the relationship between behavioral phenotype in individuals with FXS and behavioral abnormalities in FXS animal models. Seminal work from the U54 FXS Center using high-density EEG has identified potential neural biomarkers of sensory hypersensitivity in FXS. Yet, electrophysiology studies of neurocognitive alterations is a remarkably under-studied area despite the devastating impact these behavioral features have on individuals with FXS and their families. The candidate proposes to use performance-based EEG to investigate the neurophysiological basis of speech production and behavioral flexibility issues—among the most functionally disabling behavioral features of FXS. The proposed research plan will consist of two phases. In Phase I, 15 adults with Fragile X Syndrome and 15 age-, sex-matched typically developing (TD) controls will complete testing in which key aspects of tasks will be parametrically varied to identify optimal testing conditions. In Phase II, 25 adults with FXS, 25 age-, and IQ-matched developmental delayed (DD) controls, and 25 matched TDC will complete testing using paradigms optimized in Phase I. To identify neural abnormalities during speech production and behavioral flexibility, event-related potentials (ERPs), phase and amplitude coupling and coherence, and gamma single-trial power (STP) in fronto-temporal and fronto-parietal regions, respectively, will be examined. Findings from the proposed studies will provide critical insight into our mechanistic understanding of FXS and assist in treatment discovery and establishment of biomarker identification/validation.

项目概要/摘要此 K23 申请的主要目标是为候选人提供必要的研究培训和指导，以确保她发展成为一名独立的临床研究员。她的职业目标是：通过综合使用来研究神经发育障碍，例如脆性 X 综合征 (FXS) 转化生物学和行为方法来识别客观的、可量化的生物标志物以改善为了实现这一目标，候选人提出了一个机制理解和先进的治疗发现。由杰出的科学顾问团队提供的重点培训计划，以培养她的技能和知识领域：1）范式优化和转化研究，2）高级电生理学分析和解释，以及 3) 与感觉运动和认知以及 FXS 相关的神经系统。（Sweeney 博士）和联合导师（Erickson 博士）是 U54 FXS 中心的联合项目 PI，提供候选人拥有必要的资源、招聘人才库和卓越的科学能力来完成她的提议该提案与 NIH 的 FXS 研究计划相关。基于与目标重叠的相关疾病：3.3 开发生物标志物发现，纳入不同的提供治疗目标、加速药物发现、衡量有效性的方法 3.1 开发功能性的、客观的措施提供治疗效果的指标，1.8 理解关系 FXS 个体的行为表型与 FXS 动物模型中的行为异常之间的关系。 U54 FXS 中心使用高密度脑电图的研讨会工作已经确定了潜在的神经然而，神经认知改变的电生理学研究是 FXS 感觉超敏反应的生物标志物。尽管这些行为特征对个人产生了毁灭性影响，但该领域的研究仍显着不足与 FXS 及其家人一起。候选人建议使用基于表现的脑电图来调查言语产生和行为灵活性问题的神经生理学基础——其中最具功能性的问题禁用 FXS 的行为特征拟议的研究计划将包括两个阶段：第一阶段。患有脆性 X 综合症的成年人和 15 名年龄、性别匹配的典型发育 (TD) 对照者将完成测试中任务的关键方面将进行参数变化以确定最佳测试条件。 II 期，25 名患有 FXS 的成年人，25 名年龄和智商匹配的发育迟缓 (DD) 对照，以及 25 名匹配的 TDC 将使用第一阶段优化的范式完成测试。以识别期间的神经异常言语产生和行为灵活性、事件相关电位 (ERP)、相位和幅度耦合额颞叶和额顶叶区域的一致性和伽玛单次试验功率（STP），拟议研究的结果将为我们提供重要的见解。了解 FXS 的机制并协助发现治疗方法和建立生物标志物识别/验证。