Electroencephalographic spectral power as a marker of cortical function and disease severity in girls with Rett syndrome

Abstract

Background Rett syndrome is a neurodevelopmental disorder caused by a mutation in the X-linked MECP2 gene. Individuals with Rett syndrome typically develop normally until around 18 months of age before undergoing a developmental regression, and the disorder can lead to cognitive, motor, sensory, and autonomic dysfunction. Understanding the mechanism of developmental regression represents a unique challenge when viewed through a neuroscience lens. Are circuits that were previously established erased, and are new ones built to supplant old ones? One way to examine circuit-level changes is with the use of electroencephalography (EEG). Previous studies of the EEG in individuals with Rett syndrome have focused on morphological characteristics, but few have explored spectral power, including power as an index of brain function or disease severity. This study sought to determine if EEG power differs in girls with Rett syndrome and typically developing girls and among girls with Rett syndrome based on various clinical characteristics in order to better understand neural connectivity and cortical organization in individuals with this disorder. Methods Resting state EEG data were acquired from girls with Rett syndrome ( n = 57) and typically developing children without Rett syndrome ( n = 37). Clinical data were also collected for girls with Rett syndrome. EEG power across several brain regions in numerous frequency bands was then compared between girls with Rett syndrome and typically developing children and power in girls with Rett syndrome was compared based on these clinical measures. 1/ ƒ slope was also compared between groups. Results Girls with Rett syndrome demonstrate significantly lower power in the middle frequency bands across multiple brain regions. Additionally, girls with Rett syndrome that are postregression demonstrate significantly higher power in the lower frequency delta and theta bands and a significantly more negative slope of the power spectrum. Increased power in these bands, as well as a more negative 1/ƒ slope, trended with lower cognitive assessment scores. Conclusions Increased power in lower frequency bands is consistent with previous studies demonstrating a “slowing” of the background EEG in Rett syndrome. This increase, particularly in the delta band, could represent abnormal cortical inhibition due to dysfunctional GABAergic signaling and could potentially be used as a marker of severity due to associations with more severe Rett syndrome phenotypes.

Detection of neurophysiological features in female R255X MeCP2 mutation mice

“…In both regions, changes in delta or alpha power was not seen in the MUT animals at the younger age. Elevation of delta power in MUT animals is consistent with similar observations in people with RTT ( Ammanuel et al, 2015 ; Roche et al, 2019 ), with correlation to clinical severity in people with RTT. Thus, increased delta power has the potential to serve as a translational neurophysiological biomarker ( Roche et al, 2019 ), but formal additional characterization and validation is needed.…”

“…Previous work in people with RTT used 1/f slope of the power spectrum between 2 and 24 Hz (log-log transformed) to investigate excitatory/inhibitory imbalance and the effect of neural noise ( Roche et al, 2019 ; Voytek et al, 2015 ), and found that people with RTT have a significantly more negative slope compared to typically developing controls. We conducted a similar analysis of the 1/f slope from the experimental animals ( Fig.…”

“…EEG and ERP recordings in individuals with RTT suggested that alterations in brain activity are associated with behavioral and cognitive deficits ( Ammanuel et al, 2015 ; Foxe et al, 2016 ; Key et al, 2019 ; LeBlanc et al, 2015 ; Roche et al, 2019 ; Stauder et al, 2006 ). Some electrophysiological features evaluated in people, such as basal EEG and ERP, have been preliminarily investigated in RTT animal models ( Goffin et al, 2012 ; Goffin et al, 2014 ; LeBlanc et al, 2015 ; Liao et al, 2012 ; Wither et al, 2012 ).…”

“…Mecp2 NULL heterozygous female mice and RTT individuals exhibited a similar decrease in visual evoked potential (VEP) amplitude and displayed a deficit in discriminating smaller patterns ( LeBlanc et al, 2015 ). EEG resting delta power was elevated in individuals with RTT and showed correlation with the severity of symptoms ( Roche et al, 2019 ). Gamma power in response to the mother’s voice was decreased in people with RTT ( Peters et al, 2015 ).…”

Early EEG and behavioral alterations in Dravet mice

“…3), these findings suggest that EEG power may serve as a marker for disease severity. In support of this, reduced EEG power has also been found to correlate with the severity of phenotype in Rett syndrome (Roche et al, 2019). Furthermore, in neonatal seizures and hypoxic ischemic encephalopathy, epileptic episodes during suppressed background EEG were correlated with more severe epilepsy (Korotchikova et al, 2011;Rowe et al, 1985).…”