A resting EEG study of neocortical hyperexcitability and altered functional connectivity in fragile X syndrome

Jun Wang,Matthew J Byerly,Stormi P White,Devin K Binder,Lauren E Ethridge,Lauren E Ethridge,Matthew W Mosconi,Matthew W Mosconi,John A Sweeney,Ernest V Pedapati,Craig A Erickson

doi:10.1186/s11689-017-9191-z

Abstract

BackgroundCortical hyperexcitability due to abnormal fast-spiking inhibitory interneuron function has been documented in fmr1 KO mice, a mouse model of the fragile X syndrome which is the most common single gene cause of autism and intellectual disability.MethodsWe collected resting state dense-array electroencephalography data from 21 fragile X syndrome (FXS) patients and 21 age-matched healthy participants.ResultsFXS patients exhibited greater gamma frequency band power, which was correlated with social and sensory processing difficulties. Second, FXS patients showed increased spatial spreading of phase-synchronized high frequency neural activity in the gamma band. Third, we observed increased negative theta-to-gamma but decreased alpha-to-gamma band amplitude coupling, and the level of increased theta power was inversely related to the level of resting gamma power in FXS.ConclusionsIncreased theta band power and coupling from frontal sources may represent a mechanism providing compensatory inhibition of high-frequency gamma band activity, potentially contributing to the widely varying level of neurophysiological and behavioral abnormalities and treatment response seen in full-mutation FXS patients. These findings extend preclinical observations and provide new mechanistic insights into brain alterations and their variability across FXS patients. Electrophysiological measures may provide useful translational biomarkers for advancing drug development and individualizing treatments for neurodevelopmental disorders with associated neuronal hyperexcitability.

Highlights

Cortical hyperexcitability due to abnormal fast-spiking inhibitory interneuron function has been documented in fmr1 KO mice, a mouse model of the fragile X syndrome which is the most common single gene cause of autism and intellectual disability
Given the alterations we observed in EEG power and functional connectivity in Fragile X syndrome (FXS), we investigated the coupling between low frequency band activity that was abnormal and high-frequency gamma band activity both within and across electrodes
We found stronger theta-to-gamma amplitude coupling in FXS, possibly serving as a compensatory response to reduced top-down alpha-band inhibitory modulation and intrinsic pathology of local neural circuit excitability in sensory systems

Summary

Introduction

Cortical hyperexcitability due to abnormal fast-spiking inhibitory interneuron function has been documented in fmr KO mice, a mouse model of the fragile X syndrome which is the most common single gene cause of autism and intellectual disability. Studies in fmr knockout (KO) mice have shown enhanced activity of metabotropic glutamate receptors [2] and reduced GABAergic transmission [3]. The study investigated activity under 50 Hz, which excludes a significant component of the gamma frequency band (30–80 Hz) [17,18,19] This limitation is important because gamma band power reflects the level of high frequency spontaneous neural activity and is of special interest for FXS in light of fmr KO mouse studies that have identified abnormalities in fast-spiking inhibitory GABAergic interneurons [7, 20] which are critical generators of gamma power in cell populations [21]. The study was insufficiently powered to identify correlations between resting state oscillatory abnormalities in FXS and measures of clinical symptom severity

Objectives

Methods

Results

Discussion

Conclusion