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

  1. Nicholas A Donnelly  Is a corresponding author
  2. Ullrich Bartsch
  3. Hayley A Moulding
  4. Christopher Eaton
  5. Hugh Marston
  6. Jessica E Hall
  7. Jeremy Hall
  8. Michael J Owen
  9. Marianne BM van den Bree
  10. Matt W Jones
  1. University of Bristol, United Kingdom
  2. Cardiff University, United Kingdom
  3. 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

  1. Nicholas A Donnelly

    Centre for Academic Mental Health, University of Bristol, Bristol, United Kingdom
    For correspondence
    nick.donnelly@bristol.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2234-8545
  2. Ullrich Bartsch

    School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
    Competing interests
    Ullrich Bartsch, was a full-time employee of Eli Lilly UK during this study..
  3. Hayley A Moulding

    Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    No competing interests declared.
  4. Christopher Eaton

    Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6739-1999
  5. Hugh Marston

    Böhringer Ingelheim, Biberach, Germany
    Competing interests
    Hugh Marston, was a full-time employee of Eli Lilly UK during this study..
  6. Jessica E Hall

    Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    No competing interests declared.
  7. Jeremy Hall

    Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    No competing interests declared.
  8. Michael J Owen

    Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    Michael J Owen, reports a research grant from Takeda pharmaceuticals outside the scope of the currentstudy..
  9. Marianne BM van den Bree

    Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    Marianne BM van den Bree, reports a research grant from Takeda pharmaceuticals outside the scope of the currentstudy..
  10. Matt W Jones

    School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5396-3108

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)

Reviewing Editor

  1. Ole Jensen, University of Birmingham, United Kingdom

Publication history

  1. Preprint posted: November 11, 2021 (view preprint)
  2. Received: November 11, 2021
  3. Accepted: August 12, 2022
  4. Accepted Manuscript published: August 30, 2022 (version 1)
  5. Version of Record published: September 15, 2022 (version 2)

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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  1. Nicholas A Donnelly
  2. Ullrich Bartsch
  3. Hayley A Moulding
  4. Christopher Eaton
  5. Hugh Marston
  6. Jessica E Hall
  7. Jeremy Hall
  8. Michael J Owen
  9. Marianne BM van den Bree
  10. Matt W Jones
(2022)
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
eLife 11:e75482.
https://doi.org/10.7554/eLife.75482

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