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.

Keywords: Biomarker; EEG; Electroencephalography; Electrophysiology; Rett syndrome; Spectral power.

Fig. 1

Regions of interest utilized for power spectral analysis. Brain regions and electrode groupings were established based on prior literature and through mathematically determining the five closest electrodes to the electrodes associated with the underlying brain region based on the International 10–20 system. a Frontal electrodes included 18, 19, 20, 23, 24 (F3), and 27 on the left and 3, 4, 10, 118, 123, and 124 (F4) on the right. b Central electrodes included 29, 30, 35, 36 (C3), 41, and 42 on the left and 93, 103, 104 (C4), 105, 110, and 111 on the right. c Temporal electrodes included 39, 40, 45 (T3), 46, 50, and 57 on the left and electrodes 100, 101, 102, 108 (T4), 109, and 115 on the right. d Occipital electrodes included 59, 60, 65, 66, 67, and 70 (O1) on the left and 77, 83 (O2), 84, 85, 90, and 91 on the right

Fig. 2

Power spectrum based on clinical diagnosis (RTT or TD). a Frontal power spectrum demonstrating that girls with RTT (blue) have decreased power in the lower to middle frequency bands when compared to TD controls (black). b Differences in frontal power spectra presented with 95% CI from bootstrap analysis

Fig. 3

Power spectral density in each ROI by clinical diagnosis. Power (log10 transformed) in each frequency band compared based on clinical diagnosis (RTT versus TD) (left panel) as well as disease stage, with active regression (n = 20) defined as experiencing a significant skill loss within 12 months of data collection and postregression (n = 29) defined as having no significant skill loss during this time period (right panel). Data are presented as individual power values with lines representing mean with standard error of the mean. To correct for multiple comparisons, a p value of 0.002 (noted by three asterisks) was used to determine significance when comparing groups by clinical diagnosis and a p value of 0.0005 (noted by four asterisks) was used when comparing groups by disease stage. a Power in the frontal ROI. b Power in the central ROI. c Power in the temporal ROI. d Power in the occipital ROI. TD typically developing, RTT Rett syndrome, AR active regression, PR postregression. Asterisks indicate significance. *p < 0.05; **p < 0.01; ***p < 0.002; ****p < 0.0005

Fig. 4

EEG stability over time in girls with RTT versus TD controls. Change scores were calculated by subtracting power (log10 transformed) in each frequency band at visit 1 from power at visit 2. Data are reported as individual values with lines representing the mean and standard error of the mean. a Change scores in girls with RTT vs. TD controls in the frontal ROI. b Change scores in girls with RTT vs. TD controls in the central ROI. c Change scores in girls with RTT vs. TD controls in the temporal ROI. d Change scores in girls with RTT vs. TD controls in the occipital ROI. TD typically developing, RTT Rett syndrome. Asterisks indicate significance. *p < 0.05

Fig. 5

Increased low-frequency frontal power is seen with increasing age in girls with Rett syndrome. Spearman’s rho correlations between age and frontal low frequency power in girls with Rett syndrome and TD controls. Girls with Rett syndrome demonstrate opposite trajectories of baseline EEG frontal power with age in the delta (2–4 Hz) band (a) and theta (4–6 Hz) band (b) when compared to typically developing controls, with power increasing with age in girls with RTT and decreasing with age in controls. Linear regression was used to generate fit lines for each data set. TD typically developing; RTT Rett syndrome

Fig. 6

Increased delta power correlates with decreased developmental quotient on the Mullen Scales of Early Learning in girls with Rett syndrome. Spearman’s rho correlations (with fitted line) between frontal delta power and developmental quotient on the Mullen Scales of Early Learning (MSEL) in the receptive language (a), visual reception (b), expressive language (c), and fine motor (d) domains. Developmental quotients were calculated by dividing developmental age as predicted by MSEL scores in each domain by chronological age (in months)

Fig. 7

Girls with Rett syndrome demonstrate a significantly more negative 1/ƒ slope of the power spectrum when compared to typically developing controls. a The slope of the power spectrum was calculated and compared between girls with RTT and TD controls (top panel) as well as among TD controls, girls with RTT in active regression (AR), and girls with RTT that are postregression (PR) (bottom panel). b For girls with RTT, Spearman’s rho correlations (with fitted line) were utilized to relate slope to performance on the Mullen Scales of Early Learning (MSEL) in the receptive language, visual reception, fine motor, and expressive language domains (clockwise from top left). TD typically developing, RTT Rett syndrome, AR active regression, PR postregression