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Towards robust and replicable sex differences in the intrinsic brain function of autism

Dorothea L. Floris, José O. A. Filho, View ORCID ProfileMeng-Chuan Lai, Steve Giavasis, Marianne Oldehinkel, Maarten Mennes, Tony Charman, Julian Tillmann, View ORCID ProfileGuillaume Dumas, Christine Ecker, Flavio Dell’Acqua, Tobias Banaschewski, Carolin Moessnang, Simon Baron-Cohen, Sarah Durston, Eva Loth, Declan G. M. Murphy, Jan K. Buitelaar, Christian F. Beckmann, Michael P. Milham, Adriana Di Martino
doi: https://doi.org/10.1101/2020.06.09.142471
Dorothea L. Floris
1Donders Center for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands
2Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands
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José O. A. Filho
3Child Mind Institute, New York City, New York, USA
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Meng-Chuan Lai
4The Margaret and Wallace McCain Centre for Child, Youth & Family Mental Health, Azrieli Adult Neurodevelopmental Centre, and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
5Department of Psychiatry and Autism Research Unit, The Hospital for Sick Children, Toronto, Canada
6Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Canada
7Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
8Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
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  • ORCID record for Meng-Chuan Lai
Steve Giavasis
3Child Mind Institute, New York City, New York, USA
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Marianne Oldehinkel
9Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Victoria, Australia
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Maarten Mennes
1Donders Center for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands
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Tony Charman
10Department of Psychology, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
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Julian Tillmann
10Department of Psychology, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
21Department of Applied Psychology: Health, Development, Enhancement, and Intervention, University of Vienna, Vienna, Austria
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Guillaume Dumas
11Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris (75015), France
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Christine Ecker
12Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
13Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University, Frankfurt, Germany
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Flavio Dell’Acqua
12Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
14Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
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Tobias Banaschewski
15Child and Adolescent Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
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Carolin Moessnang
16Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
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Simon Baron-Cohen
7Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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Sarah Durston
17Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
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Eva Loth
12Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
14Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
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Declan G. M. Murphy
12Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
14Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
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Jan K. Buitelaar
1Donders Center for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands
2Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands
18Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands
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Christian F. Beckmann
1Donders Center for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands
2Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands
19Centre for Functional MRI of the Brain, University of Oxford, Oxford, United Kingdom
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Michael P. Milham
3Child Mind Institute, New York City, New York, USA
20Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA
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Adriana Di Martino
3Child Mind Institute, New York City, New York, USA
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  • For correspondence: Adriana.Dimartino@childmind.org
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Abstract

Background Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data.

Methods We addressed this gap by using the largest sample of male and female autistic and neurotypical (NT) control individuals, to date (ABIDE; Autism: 362 males, 82 females; NT: 410 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics.

Secondary analyses assessed the robustness of primary results to different pre-processing approaches and their replicability in two independent samples, the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR).

Results Discovery analyses in ABIDE revealed significant main effects across the intrinsic functional connectivity (iFC) of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical and subcortical regions. Sex-by-diagnosis interactions were confined to VMHC in dorsolateral occipital cortex with reduced VMHC in females with autism. Findings were highly robust to different pre-processing steps and replicable in another sample. Specifically, the sex-by-diagnosis interaction replicated in the larger of the two replication samples - EU-AIMS LEAP.

Conclusions Results emphasize that atypical cross-hemispheric interactions are neurobiologically relevant to autism. Systematic assessments of the factors contributing to their replicability are needed and necessitate coordinated large-scale data collection across studies.

Competing Interest Statement

ADM receives royalties from the publication of the Italian version of the Social Responsiveness Scale-Child Version by Organization Speciali, Italy. JKB has been a consultant to, advisory board member of, and a speaker for Takeda/Shire, Medice, Roche, and Servier. He is not an employee of any of these companies and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, or royalties. CFB is director and shareholder in SBGneuro Ltd. TC has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. DM has been a consultant to, and advisory board member, for Roche and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker's fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. JT is a consultant to Roche. The remaining authors declare no competing interests.

  • Abbreviations

    ABIDE
    Autism Brain Imaging data exchange
    ADI-R
    Autism Diagnostic Interview-Revised
    ADOS-2
    Autism Diagnostic Observation Schedule-2
    ASD
    Autism Spectrum Disorder
    CSS
    Calibrated Severity Score
    F
    females
    IQ
    intellectual quotient
    M
    males
    Mean FD
    mean framewise displacement (Jenkinson et al., 2002)
    NT
    neurotypical
    RRB
    restricted repetitive behaviors.
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Towards robust and replicable sex differences in the intrinsic brain function of autism
    Dorothea L. Floris, José O. A. Filho, Meng-Chuan Lai, Steve Giavasis, Marianne Oldehinkel, Maarten Mennes, Tony Charman, Julian Tillmann, Guillaume Dumas, Christine Ecker, Flavio Dell’Acqua, Tobias Banaschewski, Carolin Moessnang, Simon Baron-Cohen, Sarah Durston, Eva Loth, Declan G. M. Murphy, Jan K. Buitelaar, Christian F. Beckmann, Michael P. Milham, Adriana Di Martino
    bioRxiv 2020.06.09.142471; doi: https://doi.org/10.1101/2020.06.09.142471
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    Towards robust and replicable sex differences in the intrinsic brain function of autism
    Dorothea L. Floris, José O. A. Filho, Meng-Chuan Lai, Steve Giavasis, Marianne Oldehinkel, Maarten Mennes, Tony Charman, Julian Tillmann, Guillaume Dumas, Christine Ecker, Flavio Dell’Acqua, Tobias Banaschewski, Carolin Moessnang, Simon Baron-Cohen, Sarah Durston, Eva Loth, Declan G. M. Murphy, Jan K. Buitelaar, Christian F. Beckmann, Michael P. Milham, Adriana Di Martino
    bioRxiv 2020.06.09.142471; doi: https://doi.org/10.1101/2020.06.09.142471

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