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

Molecular Autism

Steve Giavasis¹  José O. A. Filho¹  Adriana Di Martino¹  Michael P. Milham²  Simon Baron-Cohen³  Marianne Oldehinkel⁴  Tobias Banaschewski⁵  Carolin Moessnang⁶  Sarah Durston⁷  Tony Charman⁸  Julian Tillmann⁹  Maarten Mennes^1,10  Dorothea L. Floris^1,11  Christian F. Beckmann^1,12  Jan K. Buitelaar^1,13  Guillaume Dumas^1,14  Christine Ecker^1,15  Eva Loth^1,16  Flavio Dell’Acqua^1,16  Declan G. M. Murphy^1,16  Meng-Chuan Lai^1,17 

[1] Autism Center, The Child Mind Institute, 101 E 56 Street, 10026, New York City, New York, USA;Autism Center, The Child Mind Institute, 101 E 56 Street, 10026, New York City, New York, USA;Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA;Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK;Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands;Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany;Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany;Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands;Department of Psychology, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, UK;Department of Psychology, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, UK;Department of Applied Psychology: Health, Development, Enhancement, and Intervention, University of Vienna, Vienna, Austria;Donders Center for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands;Donders Center for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands;Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands;Donders Center for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands;Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands;Centre for Functional MRI of the Brain, University of Oxford, Oxford, UK;Donders Center for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands;Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands;Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, the Netherlands;Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, France;CHU Sainte-Justine Research Center, Department of Psychiatry, Université de Montréal, Montreal, QC, Canada;Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, UK;Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University, Frankfurt, Germany;Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, UK;Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, UK;The Margaret and Wallace McCain Centre for Child, Youth and Family Mental Health, Azrieli Adult Neurodevelopmental Centre, and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada;Department of Psychiatry and Autism Research Unit, The Hospital for Sick Children, Toronto, Canada;Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada;Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK;Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan;

关键词: Autism spectrum disorder;    Resting-state functional connectivity;    Sex differences;    Replication;    Robustness;    Voxel-mirrored homotopic connectivity;   

DOI  :  10.1186/s13229-021-00415-z

来源: Springer

【 摘 要 】

BackgroundMarked 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.MethodsWe addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 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 (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the 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.ResultsDiscovery analyses in ABIDE revealed significant main effects of diagnosis and sex across the intrinsic functional connectivity of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples—EU-AIMS LEAP.LimitationsGiven the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability.ConclusionsAtypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.

【 授权许可】

CC BY