Neurophysiological and Developmental Mechanisms Underlying Phenotypic Heterogeneity in Boy and Girls with FXS

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

Investigators

Abstract

PROJECT SUMMARY (P1) We first reported widespread gamma band (>30 Hz) abnormalities in adults with fragile X syndrome (FXS) linked to cortical hyperexcitability which were conserved in the Fmr1-/- knockout (KO) mouse across in vivo EEG and ex vivo cortical slices (Project 2 (P2) and 3 (P3)). Recent advances in our analytic techniques and methods have provided further mechanistic insight and supported EEG phenotypes as biomarkers for disease severity and drug response: 1) widespread alterations in both low- and high-frequency neural oscillations in FXS, 2) women with FXS have an intermediate EEG phenotype with comparable findings in the KO mouse, 3) our sensitive molecular assays show variation in fragile X messenger ribonucleoprotein (FMRP) levels relates to severity of cognitive and EEG phenotypes, 4) source estimation and network analyses provide evidence of both cortico-cortical and thalamocortical alterations, and 5) pharmacologic probe strategies in adults have enabled us to test mechanistic hypotheses and show the effects of mechanism-targeted drug treatments on neurophysiologic activity may be predicted by FMRP expression. Now, shifting our focus to FXS youth comes at a pivotal point as new therapeutic approaches, including genomic and cellular therapies, are rapidly emerging in the field. Furthermore, despite FXS being the leading inherited cause of intellectual disability, we have little understanding of alterations in brain neurophysiology underlying the cognitive deficits that define the disorder. Our central hypothesis posits that neurophysiologic and FMRP variation contribute to heterogeneous cognitive and developmental profiles and drug responses in FXS youth. The overarching aims of Project 1 (P1) are to identify the developmental time course of our established EEG biomarkers in FXS youth (2-17 years), determine contributions to cognitive variability in FXS youth, and initiate novel pharmacologic probe studies of synaptic and circuit mechanisms in FXS youth. With a profound appreciation for phenotypic heterogeneity in FXS, all aims will explore contributions of sex, age, and FMRP expression. P1 will be implemented in close synchrony with the research proposed in P2 and P3. Using the high-density brain EEG techniques we have established in adults, we will study 130 youth with FXS and 130 age- and sex-matched typically developing (TD) and 130 developmentally-delayed (DD) controls, we will collect resting and evoked auditory paradigms to examine the developmental time course of excitatory:inhibitory (E/I) imbalances using cross-sectional and longitudinal designs (Aim 1). Participants from Aim 1 will complete established reversal learning paradigms with and without EEG (in parallel with P3), passive implicit learning task during EEG, NIH Cognitive Toolbox, and standardized developmental and IQ measures. We will examine how EEG alterations and FMRP predict cognitive deficits (Aim 2). Last, in parallel with P2 and P3, we will conduct double-blind, placebo-controlled single-dose challenge studies of memantine and ethosuximide in 60 youth with FXS evaluating a novel synaptic and a novel circuit mechanism using our neurophysiological biomarkers from Aim 1 (Aim 3).