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.
Speech production deficits and behavioral inflexibility are among the most functionally disabling behavioral features of Fragile X Syndrome (FXS), but continue to lack effective treatments due to limited mechanistic understanding. The proposed study will investigate speech production and behavioral flexibility deficits in FXS using performance-based tasks during high-density electroencephalography (EEG) to measure fronto-temporal and fronto-parietal circuits in individuals with FXS, respectively. These electrophysiological studies have the potential to elucidate atypical local neural circuity and its integration in widely distributed brain networks underlying these behavioral features, thus this work will provide critical insight into underlying neurophysiological mechanisms and will assist in the identification of disorder-relevant biomarkers, ultimately, helping to speed treatment development to improve speech production and behavioral flexibility in FXS.
