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

Version 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.

Metrics

  • 2,333
    Page views
  • 477
    Downloads
  • 7
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Epidemiology and Global Health
    2. Medicine
    Jeffrey Thompson, Yidi Wang ... Ulrich H von Andrian
    Research Article Updated

    Background:

    Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.

    Methods:

    A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak.

    Results:

    A total of 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. A total of 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR = 0.22; 95%CI:0.21–0.23; p<0.001), COVID-19 diagnosis (OR = 0.23; 95%CI:0.22–0.24; p<0.001), and COVID-19-related hospitalization (OR = 0.26; 95%CI:0.24–0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR = 0.23; 95%CI:0.22–0.23; p<0.001) or pneumonia (OR = 0.32; 95%CI:0.31–0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.

    Conclusions:

    Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.

    Funding:

    This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to UHvA) and a CRI Irvington postdoctoral fellowship, CRI2453 (to PH).

    1. Medicine
    Runze Yang, Tianhao Xu ... Weili Fu
    Tools and Resources Updated

    Background:

    To systematically identify cell types in the human ligament, investigate how ligamental cell identities, functions, and interactions participated in the process of ligamental degeneration, and explore the changes of ligamental microenvironment homeostasis in the disease progression.

    Methods:

    Using single-cell RNA sequencing and spatial RNA sequencing of approximately 49,356 cells, we created a comprehensive cell atlas of healthy and degenerated human anterior cruciate ligaments. We explored the variations of the cell subtypes’ spatial distributions and the different processes involved in the disease progression, linked them with the ligamental degeneration process using computational analysis, and verified findings with immunohistochemical and immunofluorescent staining.

    Results:

    We identified new fibroblast subgroups that contributed to the disease, mapped out their spatial distribution in the tissue and revealed two dynamic trajectories in the process of the degenerative process. We compared the cellular interactions between different tissue states and identified important signaling pathways that may contribute to the disease.

    Conclusions:

    This cell atlas provides the molecular foundation for investigating how ligamental cell identities, biochemical functions, and interactions contributed to the ligamental degeneration process. The discoveries revealed the pathogenesis of ligamental degeneration at the single-cell and spatial level, which is characterized by extracellular matrix remodeling. Our results provide new insights into the control of ligamental degeneration and potential clues to developing novel diagnostic and therapeutic strategies.

    Funding:

    This study was funded by the National Natural Science Foundation of China (81972123, 82172508, 82372490) and 1.3.5 Project for Disciplines of Excellence of West China Hospital Sichuan University (ZYJC21030, ZY2017301).