A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome

Abstract

BackgroundDuplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD). A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished children with Dup15q syndrome from those with non-syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome.MethodsIn the first study, we recorded spontaneous EEG from children with Dup15q syndrome (n = 11), age-and-IQ-matched children with ASD (n = 10) and age-matched typically developing (TD) children (n = 9) and computed relative power in 6 frequency bands for 9 regions of interest (ROIs). Group comparisons were made using a repeated measures analysis of variance. In the second study, we recorded spontaneous EEG from a larger cohort of individuals with Dup15q syndrome (n = 27) across two sites and examined age, epilepsy, and duplication type as predictors of beta power using simple linear regressions.ResultsIn the first study, spontaneous beta1 (12–20 Hz) and beta2 (20–30 Hz) power were significantly higher in Dup15q syndrome compared with both comparison groups, while delta (1–4 Hz) was significantly lower than both comparison groups. Effect sizes in all three frequency bands were large (|d| > 1). In the second study, we found that beta2 power was significantly related to epilepsy diagnosis in Dup15q syndrome.ConclusionsHere, we have identified an electrophysiological biomarker of Dup15q syndrome that may facilitate clinical stratification, treatment monitoring, and measurement of target engagement for future clinical trials. Future work will investigate the genetic and neural underpinnings of this electrophysiological signature as well as the functional consequences of excessive beta oscillations in Dup15q syndrome.

Nonrapid eye movement sleep and risk for autism spectrum disorder in early development: A topographical electroencephalogram pilot study

“…19-year-olds with a copy number of variants of ASD as Dup15q syndrome have shown excessive beta activity during resting state EEG (Frohlich et al, 2016;Kozhushko, 2018). These findings are consistent with the present pilot study where we identified increased beta power in the spectral features of the EEG.…”

“…Interestingly, altered beta activity has been reported in REM sleep (Daoust et al, ) and reported for EEG recorded during resting wakefulness in ASD (Kozhushko, ; Wang et al, ) and Dup15q syndrome (a genetic variation that is associated with ASD; Frohlich et al, ). Research with 4‐ to 9‐year‐olds with ASD (Kozhushko, ) and research with 2.5‐ to 19‐year‐olds with a copy number of variants of ASD as Dup15q syndrome have shown excessive beta activity during resting state EEG (Frohlich et al, ; Kozhushko, ). These findings are consistent with the present pilot study where we identified increased beta power in the spectral features of the EEG.…”

“…To our knowledge, research has yet to examine altered beta power during NREM sleep in ASD. Interestingly, altered beta activity has been reported in REM sleep (Daoust et al, 2004) and reported for EEG recorded during resting wakefulness in ASD (Kozhushko, 2018;Wang et al, 2013) and Dup15q syndrome (a genetic variation that is associated with ASD; Frohlich et al, 2016). Research with 4-to 9-year-olds with ASD (Kozhushko, 2018) and research with 2.5-to…”

“…Future research is needed to examine features of NREM sleep in ASD as well as across various categories of DD and other populations with genetic variations of ASD. Including participants with DD or a genetic variant such as Dup15q syndrome (Frohlich et al, ) could help decipher if alterations in NREM features are specific to ASD with idiopathic causes or shared secondary features. Such a comparison could increase the sample size of the study and thus increase statistical power, and including children with identified DD or disabilities would allow for further demarcation of subgroups (Walsh, Elsabbagh, Bolton, & Singh, ).…”

Single-cell and neuronal network alterations in an in vitro model of Fragile X syndrome

“…Previous mathematical work (Pulizzi et al 2016) suggests that the interplay between excitation and inhibition might be responsible for these oscillations. An altered balance between excitation and inhibition could therefore have manifested itself in the oscillations, which are interestingly reminiscent of an in vivo (EEG) biomarker of another autism spectrum disorder syndrome with aberrant GABA A activity (Frohlich et al 2016). However, an alternative hypothesis for this oscillatory activity may come from the known dysregulation of short-term synaptic plasticity in Fragile X (Testa-Silva et al 2012).…”