Increased aperiodic gamma power in young boys with Fragile X is associated with better language ability

Abstract

The lack of identified clinical biomarkers in Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, has limited the successful translation of bench-to-bedside therapeutics. While numerous drugs have shown promise in reversing synaptic and behavioral phenotypes in mouse models of FXS, none have demonstrated clinical efficacy in humans. Electroencephalographic (EEG) measures have been identified as candidate biomarkers as EEG recordings of both adults with FXS and mouse models of FXS consistently exhibit increased resting-state gamma power. However, the developmental timing of these EEG differences is not known as thus far EEG studies have not focused on young children with FXS. Further, understanding how EEG differences are associated to core symptoms of FXS is crucial to successful use of EEG as a biomarker, and may improve our understanding of the disorder. Resting-state EEG was collected from FXS boys with full mutation of Fmr1 (32-84 months old, n=11) and compared with both age-matched (n=12) and cognitive-matched (n=12) typically developing boys. Power spectra (including aperiodic and periodic components) were compared using non-parametric cluster-based permutation testing. Associations between 30-50Hz gamma power and cognitive, language, and behavioral measures were evaluated using Pearson correlation and linear regression with age as a covariate. FXS participants showed increased power in the beta/gamma range (~25-50Hz) across multiple brain regions. Both a reduction in the aperiodic (1/f) slope and increase in beta/gamma periodic activity contributed to the significant increase in high-frequency power. Increased gamma power, driven by the aperiodic component, was associated with better language ability in the FXS group. No association was observed between gamma power and parent report measures of behavioral challenges, sensory hypersensitivities, or adaptive behaviors. The observed positive association between increased aperiodic gamma power and language supports hypotheses that increased E/I ratios observed in FXS mouse models may reflect beneficial compensation.

Hippocampal gamma-band oscillopathy in a mouse model of Fragile X Syndrome

“…This will warrant the robust testing of potential pharmaceuticals in the treatment of neuronal hyperexcitability in FXS. It is important to note that human EEG studies have reported a similar enhancement of gamma power in individuals with FXS (Ethridge et al, 2019(Ethridge et al, , 2017(Ethridge et al, , 2016Wang et al, 2017;Wilkinson and Nelson, 2021). Thus, utilization of gamma oscillation power as a mesoscopic biomarker may pave the way in the diagnosis of neurodevelopmental disorders such as FXS and facilitate target identification for the treatment of neuronal hyperexcitability in FXS.…”