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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Molecular Autism 1/2018

Abnormal coherence and sleep composition in children with Angelman syndrome: a retrospective EEG study

Zeitschrift:
Molecular Autism > Ausgabe 1/2018
Autoren:
Hanna den Bakker, Michael S. Sidorov, Zheng Fan, David J. Lee, Lynne M. Bird, Catherine J. Chu, Benjamin D. Philpot
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13229-018-0214-8) contains supplementary material, which is available to authorized users.

Abstract

Background

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, speech and motor impairments, epilepsy, abnormal sleep, and phenotypic overlap with autism. Individuals with AS display characteristic EEG patterns including high-amplitude rhythmic delta waves. Here, we sought to quantitatively explore EEG architecture in AS beyond known spectral power phenotypes. We were motivated by studies of functional connectivity and sleep spindles in autism to study these EEG readouts in children with AS.

Methods

We analyzed retrospective wake and sleep EEGs from children with AS (age 4–11) and age-matched neurotypical controls. We assessed long-range and short-range functional connectivity by measuring coherence across multiple frequencies during wake and sleep. We quantified sleep spindles using automated and manual approaches.

Results

During wakefulness, children with AS showed enhanced long-range EEG coherence across a wide range of frequencies. During sleep, children with AS showed increased long-range EEG coherence specifically in the gamma band. EEGs from children with AS contained fewer sleep spindles, and these spindles were shorter in duration than their neurotypical counterparts.

Conclusions

We demonstrate two quantitative readouts of dysregulated sleep composition in children with AS—gamma coherence and spindles—and describe how functional connectivity patterns may be disrupted during wakefulness. Quantitative EEG phenotypes have potential as biomarkers and readouts of target engagement for future clinical trials and provide clues into how neural circuits are dysregulated in children with AS.
Zusatzmaterial
Additional file 1: Figure S1. Spatial analysis of long-range coherence during wakefulness. (A) Overall coherence (1–50 Hz) during wakefulness as a function of Euclidean distance. Dotted line represents the cutoff between short-range and long-range coherence. Two-way ANOVA for long-range coherence: genotype: F(1,774) = 40.53, p < 0.0001; distance: F(9,774) = 22.75, p < 0.0001; interaction: F(9,774) = 0.4326, p = 0.9187. (B) Raw and (C) grouped intra-hemispheric long-range coherence. Overall (1–50 Hz) intra-hemispheric coherence is increased in AS (p = 0.0145). Two-way ANOVA: genotype: F(1,390) = 32.77, p < 0.0001; genotype × frequency interaction: F(4,390) = 0.1419, p = 0.9665; post hoc tests: delta: p = 0.0646, theta: p = 0.1067, alpha: p = 0.1315, beta: p = 0.0521, gamma: p = 0.0078. (D) Topographic coherence maps for all intra-hemispheric electrode pairs. (E) Raw and (F) grouped inter-hemispheric long-range coherence. Overall (1–50 Hz) inter-hemispheric coherence was increased in AS (p = 0.0303). Two-way ANOVA: genotype: F(1,390) = 22.49, p < 0.0001; genotype × frequency interaction: F(4,390) = 0.3383, p = 0.8521; post hoc tests: delta: p = 0.2771, theta: p = 0.8276, alpha: p = 0.2657, beta: p = 0.0785, gamma: p = 0.0180. (G) Topographic coherence maps for all inter-hemispheric electrode pairs. (H) Overall (1–50 Hz) long-range coherence through individual electrodes and (I) electrodes grouped by region. Two-way ANOVA: genotype: F(1,390) = 23.11, p < 0.0001; genotype × region interaction: F(4,390) = 0.8003, p = 0.5255; post hoc tests: frontal: p = 0.0555, central: p = 0.0783, parietal: p = 0.0112, temporal: p > 0.9999, occipital: p = 0.2414. NT (black): n = 54, AS (red): n = 26. (PDF 271 kb)
13229_2018_214_MOESM1_ESM.pdf
Additional file 2: Figure S2. Spatial analysis of gamma-band coherence during sleep. (A) Gamma-band coherence during sleep as a function of Euclidean distance. Dotted line represents the dividing line between short-range and long-range coherence. Two-way ANOVA for long-range coherence: genotype: F(1,629) = 30.93, p < 0.0001; distance: F(9,629) = 15.46, p < 0.0001; interaction: F(9,629) = 0.8704, p = 0.5516. Asterisk indicates significance by post hoc Bonferroni tests. (B) Raw and (C) grouped intra-hemispheric long-range gamma-band coherence. Overall: p = 0.0565; two-way ANOVA: genotype: F(1,315) = 1.484, p = 0.2240; genotype × frequency interaction: F(4,315) = 2.943, p = 0.0206; post hoc tests: delta, theta, alpha, beta: p > 0.9999, gamma: p = 0.0070. (D) Topographic coherence maps for all intra-hemispheric electrode pairs. LR long-range. (E) Raw and (F) grouped inter-hemispheric long-range coherence. Overall: p = 0.1139; two-way ANOVA: genotype: F(1,315) = 0.409, p = 0.5230; genotype × frequency interaction: F(4,315) = 3.303, p = 0.0114; post hoc tests: delta: p > 0.9999, theta: p = 0.4283, alpha, beta: p > 0.9999, gamma: p = 0.0140. (G) Topographic coherence maps for all inter-hemispheric electrode pairs. (H) Gamma coherence through individual electrodes and (I) electrodes grouped by region. Two-way ANOVA for region: genotype: F(1,315) = 24.86, p < 0.0001; genotype × region interaction: F(4,315) = 0.9112, p = 0.4576; post hoc tests: frontal: p = 0.3285, central: p = 0.0465, parietal: p = 0.0022, temporal: p > 0.9999, occipital: p = 0.1522. NT (black): n = 53, AS (red): n = 12. (PDF 503 kb)
13229_2018_214_MOESM2_ESM.pdf
Additional file 3: Figure S3. Coherence phenotypes persist with conservative exclusion of volume conduction. (A) Cross-correlation during wakefulness across all frequencies (1–50 Hz). Left panel: short-range electrode pairs (p = 0.0549). Center panel: long-range electrode pairs (p < 0.0001). Right panel: long-range/short-range ratio (p = 0.0027). (B) Cross-correlation during sleep in the gamma band (30–50 Hz). Left panel: short-range (p = 0.0004). Center panel: long-range (p < 0.0001). Right panel: long-range/short-range ratio (p = 0.0016). (PDF 405 kb)
13229_2018_214_MOESM3_ESM.pdf
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