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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-017-9191-z) contains supplementary material, which is available to authorized users.

Mechanisms underlying auditory processing deficits in Fragile X syndrome

“…Rojas et al showed that tone‐evoked responses measured using magnetic fields are higher in the auditory cortex of individuals with FXS . EEG recordings revealed increased gamma frequency band power in resting state EEG of FXS patients . Auditory event related potential (ERP) studies report abnormally high amplitudes of the N1 wave in response to tones and reduced habituation to repeated sound in FXS .…”

“…110 EEG recordings revealed increased gamma frequency band power in resting state EEG of FXS patients. 111 Auditory event related potential (ERP) studies report abnormally high amplitudes of the N1 wave in response to tones and reduced habituation to repeated sound in FXS. 110,[112][113][114][115] These data indicate a noisy resting state of auditory cortex in FXS that may lead to abnormal amplitude and synchronization of evoked responses.…”

Establishing Drug Effects on Electrocorticographic Activity in a Genetic Absence Epilepsy Model: Advances and Pitfalls

“…A large number of electrodes that are individually wired and connected with an external recording system quickly demands space on the animals head and this may be challenging. A solution can be found by the usage of multiplexed headstages: they overcome this limitation by combining the signals from many electrodes to a smaller number of connections directly on the animal's head (Wang et al, 2017).…”

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

“…Electroencephalography (EEG) analysis has revealed that FXS-affected individuals exhibit hyperexcitability in the neocortex and altered functional connectivity, suggesting impaired excitatory and inhibitory balance. [223][224][225][226] The Fmr1-KO mouse model enables cellular physiology analysis that is impossible in humans. Altered EEG has also been found in Fmr1-KO mice, and it has been used as a readout for pre-clinical assessment.…”

“…For example, recent work has indicated that variability in behavior and cognition in FXS could be linked to variability in electrical activity in the brain of FXSaffected individuals, as measured by EEG. 223,336 One solution is the establishment of high-quality iPSCs from individuals with well-characterized and stratified clinical features. Stratification of affected individuals and cells could enable more effective linkage of disease characteristics with cellular phenotypes and better design of clinical trials.…”