Sleep EEG in young people with 22q11.2 deletion syndrome: a cross-sectional study of slow-waves, spindles and correlations with memory and neurodevelopmental symptoms
- University of Bristol, United Kingdom
- Cardiff University, United Kingdom
- Böhringer Ingelheim, Germany
Abstract
Background: Young people living with 22q11.2 Deletion Syndrome (22q11.2DS) are at increased risk of schizophrenia, intellectual disability, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In common with these conditions, 22q11.2DS is also associated with sleep problems. We investigated whether abnormal sleep or sleep-dependent network activity in 22q11.2DS reflects convergent, early signatures of neural circuit disruption also evident in associated neurodevelopmental conditions.
Methods: In a cross-sectional design, we recorded high-density sleep EEG in young people (6-20 years) with 22q11.2DS (n=28) and their unaffected siblings (n=17), quantifying associations between sleep architecture, EEG oscillations (spindles and slow waves) and psychiatric symptoms. We also measured performance on a memory task before and after sleep.
Results: 22q11.2DS was associated with significant alterations in sleep architecture, including a greater proportion of N3 sleep and lower proportions of N1 and REM sleep than in siblings. During sleep, deletion carriers showed broadband increases in EEG power with increased slow-wave and spindle amplitudes, increased spindle frequency and density, and stronger coupling between spindles and slow-waves. Spindle and slow-wave amplitudes correlated positively with overnight memory in controls, but negatively in 22q11.2DS. Mediation analyses indicated that genotype effects on anxiety, ADHD and ASD were partially mediated by sleep EEG measures.
Conclusions: This study provides a detailed description of sleep neurophysiology in 22q11.2DS, highlighting alterations in EEG signatures of sleep which have been previously linked to neurodevelopment, some of which were associated with psychiatric symptoms. Sleep EEG features may therefore reflect delayed or compromised neurodevelopmental processes in 22q11.2DS, which could inform our understanding of the neurobiology of this condition and be biomarkers for neuropsychiatric disorders.
Funding: This research was funded by a Lilly Innovation Fellowship Award (UB), the National Institute of Mental Health (NIMH 5UO1MH101724; MvdB), a Wellcome Trust Institutional Strategic Support Fund (ISSF) award (MvdB), the Waterloo Foundation (918-1234; MvdB), the Baily Thomas Charitable Fund (2315/1; MvdB), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment (IMAGINE) (MR/L011166/1; JH, MvdB and MO), MRC grant Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment 2 (IMAGINE-2) (MR/T033045/1; MvdB, JH and MO); Wellcome Trust Strategic Award 'Defining Endophenotypes From Integrated Neurosciences' Wellcome Trust (100202/Z/12/Z MO, JH). NAD was supported by a National Institute for Health Research Academic Clinical Fellowship in Mental Health and MWJ by a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (202810/Z/16/Z). CE and HAM were supported by Medical Research Council Doctoral Training Grants (C.B.E. 1644194, H.A.M MR/K501347/1). HMM and UB were employed by Eli Lilly & Co during the study; HMM is currently an employee of Boehringer Ingelheim Pharma GmbH & Co KG.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided as a .zip file. Extensive additional information collected as part of the ongoing IMAGINE-ID study, of which the ECHO study forms part, can be obtained via https://imagine-id.org/healthcare-professionals/datasharing/
Article and author information
Author details
Nicholas A Donnelly
Funding
National Institute of Mental Health (NIMH 5UO1MH101724)
- Marianne BM van den Bree
Medical Research Council (1644194)
- Christopher Eaton
Medical Research Council (MR/K501347/1)
- Hayley A Moulding
Eli Lilly and Company (Lilly Innovation Fellowship Award)
- Ullrich Bartsch
National Institute for Health and Care Research (Academic Clinical Fellowship)
- Nicholas A Donnelly
Baily Thomas Charitable Fund (2315/1)
- Marianne BM van den Bree
Waterloo Foundation (918-1234)
- Marianne BM van den Bree
Medical Research Council (MR/L011166/1)
- Jeremy Hall
- Michael J Owen
- Marianne BM van den Bree
Medical Research Council (MR/T033045/1)
- Jeremy Hall
- Michael J Owen
- Marianne BM van den Bree
Wellcome Trust (100202/Z/12/Z)
- Jeremy Hall
- Michael J Owen
Wellcome Trust (202810/Z/16/Z)
- Matt W Jones
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The consent process and ethical approval is described in detail in the manuscript (page 32)
Copyright
© 2022, Donnelly et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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