Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

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

doi:10.1186/s13229-017-0140-1

Abstract

BackgroundStudies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS.MethodsEEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0–100 Hz over 2 s.ResultsSingle trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits.ConclusionsThis represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from fmr1 KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics.

Highlights

Studies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex
Gamma band activity has been associated with bottomup sensory processing of stimulus characteristics [8] and primarily reflects local circuit GLU/GABA interactions involving excitation onto and inhibition originating from parvalbumin positive (PV+) fast-spiking interneurons [9, 10]
Similar to findings in Fmr1 KO mouse cortex [34], we found a shift toward reduced influence of alpha frequency oscillations on gamma power and synchronization in fragile X syndrome (FXS) compared to controls

Summary

Introduction

Studies in the fmr KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). Prolonged asynchronous UP states suggest that the ability to synchronize gamma power may be reduced, but simultaneously net gamma power may be increased because of increased nonspecific excitability in the gamma range These findings suggest a pattern of increased total high-frequency (gamma) neural activity but reduced temporally synchronous and spatially focused neural activity that may have broad neurobehavioral implications in addition to its impact on sensory processing [11]. Since gamma is the primary working frequency range of the human auditory system, it is possible to investigate hypotheses generated by pre-clinical models in a relatively non-invasive fashion in FXS using auditory processing paradigms and EEG [12]

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Results

Discussion

Conclusion