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Differential neural circuitry behind autism subtypes with imbalanced social-communicative and restricted repetitive behavior symptoms

View ORCID ProfileNatasha Bertelsen, Isotta Landi, View ORCID ProfileRichard A. I. Bethlehem, View ORCID ProfileJakob Seidlitz, Elena Maria Busuoli, Veronica Mandelli, Eleonora Satta, Stavros Trakoshis, View ORCID ProfileBonnie Auyeung, View ORCID ProfilePrantik Kundu, View ORCID ProfileEva Loth, View ORCID ProfileGuillaume Dumas, Sarah Baumeister, View ORCID ProfileChristian F. Beckmann, View ORCID ProfileSven Bölte, View ORCID ProfileThomas Bourgeron, View ORCID ProfileTony Charman, Sarah Durston, Christine Ecker, Rosemary J. Holt, View ORCID ProfileMark H. Johnson, View ORCID ProfileEmily J. H. Jones, Luke Mason, View ORCID ProfileAndreas Meyer-Lindenberg, View ORCID ProfileCarolin Moessnang, Marianne Oldehinkel, View ORCID ProfileAntonio Persico, View ORCID ProfileJulian Tillmann, Steven C. R. Williams, Will Spooren, View ORCID ProfileDeclan G. M. Murphy, Jan K. Buitelaar, the EU-AIMS LEAP group, View ORCID ProfileSimon Baron-Cohen, View ORCID ProfileMeng-Chuan Lai, View ORCID ProfileMichael V. Lombardo
doi: https://doi.org/10.1101/2020.05.08.083758
Natasha Bertelsen
1Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto (TN), Italy
2Center for Mind/Brain Sciences, University of Trento, Rovereto (TN), Italy
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Isotta Landi
1Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto (TN), Italy
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Richard A. I. Bethlehem
3Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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Jakob Seidlitz
4Department of Child and Adolescent Psychiatry and Behavioral Science, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
5Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
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Elena Maria Busuoli
1Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto (TN), Italy
2Center for Mind/Brain Sciences, University of Trento, Rovereto (TN), Italy
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Veronica Mandelli
1Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto (TN), Italy
2Center for Mind/Brain Sciences, University of Trento, Rovereto (TN), Italy
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Eleonora Satta
1Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto (TN), Italy
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Stavros Trakoshis
1Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto (TN), Italy
6Department of Psychology, University of Cyprus, Nicosia, Cyprus
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Bonnie Auyeung
7Department of Psychology, School of Philosophy, Psychology, and Language Sciences, University of Edinburgh, Edinburgh, United Kingdom
8Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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Prantik Kundu
9Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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Eva Loth
10Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
11Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
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Guillaume Dumas
12Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, France
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Sarah Baumeister
13Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Christian F. Beckmann
14Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
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Sven Bölte
15Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research; Department of Women’s and Children’s Health, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden
16Child and Adolescent Psychiatry, Stockholm Health Care Services, Stockholm, Sweden
17Curtin Autism Research Group, School of Occupational Therapy, Social Work and Speech Pathology, Curtin University, Perth, Australia
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Thomas Bourgeron
12Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, France
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Tony Charman
18Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
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Sarah Durston
19Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
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Christine Ecker
20Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University, Frankfurt, Germany
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Rosemary J. Holt
8Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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Mark H. Johnson
21Department of Psychology, University of Cambridge, Cambridge, United Kingdom
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Emily J. H. Jones
22Centre for Brain and Cognitive Development, Birkbeck, University of London, Henry Wellcome Building, London, United Kingdom
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Luke Mason
22Centre for Brain and Cognitive Development, Birkbeck, University of London, Henry Wellcome Building, London, United Kingdom
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Andreas Meyer-Lindenberg
23Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Carolin Moessnang
23Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Marianne Oldehinkel
14Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
24Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Victoria, Australia
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Antonio Persico
25Child and Adolescent Neuropsychiatry Unit, Gaetano Martino University Hospital, University of Messina, Messina, Italy
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Julian Tillmann
18Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
26Department of Applied Psychology: Health, Development, Enhancement, and Intervention, University of Vienna, Vienna, Austria
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Steven C. R. Williams
27Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
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Will Spooren
28Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, Basel, Switzerland
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Declan G. M. Murphy
10Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
11Department 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
14Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
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Simon Baron-Cohen
8Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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Meng-Chuan Lai
8Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
29The 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
30Department of Psychiatry and Autism Research Unit, The Hospital for Sick Children, Toronto, Canada
31Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Canada
32Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
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Michael V. Lombardo
1Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto (TN), Italy
8Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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  • For correspondence: michael.lombardo@iit.it
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Abstract

Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here we developed a phenotypic stratification model that makes highly accurate (97-99%) out-of-sample SC=RRB, SC>RRB, and RRB>SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n=509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC>RRB and visual association circuitry in SC=RRB. The SC=RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry.

Competing Interest Statement

JKB has been a consultant to, advisory board member of, and a speaker for Janssen Cilag BV, Eli Lilly, Shire, Lundbeck, 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. SB discloses that he has in the last 5 years acted as an author, consultant, or lecturer for Shire/Takeda, Medice, Roche, Eli Lilly, and Prima Psychiatry. He receives royalties for textbooks and diagnostic tools from Huber/Hogrefe, Kohlhammer, and UTB. TC has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. DGMM 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. AML has received consultant fees from Boehringer Ingelheim, Elsevier, Brainsway, Lundbeck Int. Neuroscience Foundation, Lundbeck A/S, The Wolfson Foundation, Bloomfield Holding Ltd, Shanghai Research Center for Brain Science, Thieme Verlag, Sage Therapeutics, v Behring Rontgen Stiftung, Fondation FondaMental, Janssen-Cilag GmbH, MedinCell, Brain Mind Institute, Agence Nationale de la Recherche, CISSN (Catania Internat. Summer School of Neuroscience), Daimler und Benz Stiftung and American Association for the Advancement of Science. Additionally, he has received speaker fees from Italian Society of Biological Psychiatry, Merz-Stiftung, Forum Werkstatt Karlsruhe, Lundbeck SAS France, BAG Psychiatrie Oberbayern, Klinik fur Psychiatrie und Psychotherapie Ingolstadt, med Update GmbH, Society of Biological Psychiatry and Siemens Healthineers. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. JT is a consultant to Roche. The other authors report no biomedical financial interests or potential conflicts of interest.

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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Differential neural circuitry behind autism subtypes with imbalanced social-communicative and restricted repetitive behavior symptoms
Natasha Bertelsen, Isotta Landi, Richard A. I. Bethlehem, Jakob Seidlitz, Elena Maria Busuoli, Veronica Mandelli, Eleonora Satta, Stavros Trakoshis, Bonnie Auyeung, Prantik Kundu, Eva Loth, Guillaume Dumas, Sarah Baumeister, Christian F. Beckmann, Sven Bölte, Thomas Bourgeron, Tony Charman, Sarah Durston, Christine Ecker, Rosemary J. Holt, Mark H. Johnson, Emily J. H. Jones, Luke Mason, Andreas Meyer-Lindenberg, Carolin Moessnang, Marianne Oldehinkel, Antonio Persico, Julian Tillmann, Steven C. R. Williams, Will Spooren, Declan G. M. Murphy, Jan K. Buitelaar, the EU-AIMS LEAP group, Simon Baron-Cohen, Meng-Chuan Lai, Michael V. Lombardo
bioRxiv 2020.05.08.083758; doi: https://doi.org/10.1101/2020.05.08.083758
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Differential neural circuitry behind autism subtypes with imbalanced social-communicative and restricted repetitive behavior symptoms
Natasha Bertelsen, Isotta Landi, Richard A. I. Bethlehem, Jakob Seidlitz, Elena Maria Busuoli, Veronica Mandelli, Eleonora Satta, Stavros Trakoshis, Bonnie Auyeung, Prantik Kundu, Eva Loth, Guillaume Dumas, Sarah Baumeister, Christian F. Beckmann, Sven Bölte, Thomas Bourgeron, Tony Charman, Sarah Durston, Christine Ecker, Rosemary J. Holt, Mark H. Johnson, Emily J. H. Jones, Luke Mason, Andreas Meyer-Lindenberg, Carolin Moessnang, Marianne Oldehinkel, Antonio Persico, Julian Tillmann, Steven C. R. Williams, Will Spooren, Declan G. M. Murphy, Jan K. Buitelaar, the EU-AIMS LEAP group, Simon Baron-Cohen, Meng-Chuan Lai, Michael V. Lombardo
bioRxiv 2020.05.08.083758; doi: https://doi.org/10.1101/2020.05.08.083758

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