Atypical Brain Asymmetry in Autism-A Candidate for Clinically Meaningful Stratification

Dorothea L Floris; Thomas Wolfers; Mariam Zabihi; Nathalie E Holz; Marcel P Zwiers; Tony Charman; Julian Tillmann; Christine Ecker; Flavio Dell'Acqua; Tobias Banaschewski; Carolin Moessnang; Simon Baron-Cohen; Rosemary Holt; Sarah Durston; Eva Loth; Declan G M Murphy; Andre Marquand; Jan K Buitelaar; Christian F Beckmann; EU-AIMS Longitudinal European Autism Project Group

doi:10.1016/j.bpsc.2020.08.008

Atypical Brain Asymmetry in Autism-A Candidate for Clinically Meaningful Stratification

Biol Psychiatry Cogn Neurosci Neuroimaging. 2021 Aug;6(8):802-812. doi: 10.1016/j.bpsc.2020.08.008. Epub 2020 Aug 25.

Authors

Dorothea L Floris¹, Thomas Wolfers², Mariam Zabihi³, Nathalie E Holz⁴, Marcel P Zwiers⁵, Tony Charman⁶, Julian Tillmann⁷, Christine Ecker⁸, Flavio Dell'Acqua⁹, Tobias Banaschewski⁴, Carolin Moessnang¹⁰, Simon Baron-Cohen¹¹, Rosemary Holt¹¹, Sarah Durston¹², Eva Loth⁹, Declan G M Murphy⁹, Andre Marquand¹³, Jan K Buitelaar¹⁴, Christian F Beckmann¹⁵; EU-AIMS Longitudinal European Autism Project Group

Collaborators

EU-AIMS Longitudinal European Autism Project Group:
Jumana Ahmad, Sara Ambrosino, Bonnie Auyeung, Tobias Banaschewski, Simon Baron-Cohen, Sarah Baumeister, Christian F Beckmann, Sven Bölte, Thomas Bourgeron, Carsten Bours, Michael Brammer, Daniel Brandeis, Claudia Brogna, Yvette de Bruijn, Jan K Buitelaar, Bhismadev Chakrabarti, Tony Charman, Ineke Cornelissen, Daisy Crawley, Flavio Dell'Acqua, Guillaume Dumas, Sarah Durston, Christine Ecker, Jessica Faulkner, Vincent Frouin, Pilar Garcés, David Goyard, Lindsay Ham, Hannah Hayward, Joerg Hipp, Rosemary Holt, Mark H Johnson, Emily J H Jones, Prantik Kundu, Meng-Chuan Lai, Xavier Liogier d'Ardhuy, Michael V Lombardo, Eva Loth, David J Lythgoe, René Mandl, Andre Marquand, Luke Mason, Maarten Mennes, Andreas Meyer-Lindenberg, Carolin Moessnang, Nico Mueller, Declan G M Murphy, Bethany Oakley, Laurence O'Dwyer, Marianne Oldehinkel, Bob Oranje, Gahan Pandina, Antonio M Persico, Barbara Ruggeri, Amber Ruigrok, Jessica Sabet, Roberto Sacco, Antonia San José Cáceres, Emily Simonoff, Will Spooren, Julian Tillmann, Roberto Toro, Heike Tost, Jack Waldman, Steve C R Williams, Caroline Wooldridge, Marcel P Zwiers

Affiliations

¹ Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands; Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands. Electronic address: d.floris@donders.ru.nl.
² Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands; Department of Psychology, University of Oslo, Norway; Norwegian Center for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, University of Oslo Hospital and Oslo University Hospital, Oslo, Norway.
³ Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands; Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands.
⁴ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
⁵ Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands.
⁶ Department of Psychology, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
⁷ Department of Psychology, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Department of Applied Psychology: Health, Development, Enhancement, and Intervention, University of Vienna, Vienna, Austria.
⁸ Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Frankfurt am Main, Goethe University, Frankfurt, Germany; Department of Psychology, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
⁹ Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
¹⁰ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
¹¹ Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.
¹² Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
¹³ Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands; Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands; Department of Neuroimaging, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
¹⁴ Donders Institute 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.
¹⁵ Donders Institute 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, United Kingdom.

PMID: 33097470
DOI: 10.1016/j.bpsc.2020.08.008

Abstract

Background: Autism spectrum disorder ("autism") is a highly heterogeneous neurodevelopmental condition with few effective treatments for core and associated features. To make progress we need to both identify and validate neural markers that help to parse heterogeneity to tailor therapies to specific neurobiological profiles. Atypical hemispheric lateralization is a stable feature across studies in autism, but its potential as a neural stratification marker has not been widely examined.

Methods: In order to dissect heterogeneity in lateralization in autism, we used the large EU-AIMS (European Autism Interventions-A Multicentre Study for Developing New Medications) Longitudinal European Autism Project dataset comprising 352 individuals with autism and 233 neurotypical control subjects as well as a replication dataset from ABIDE (Autism Brain Imaging Data Exchange) (513 individuals with autism, 691 neurotypical subjects) using a promising approach that moves beyond mean group comparisons. We derived gray matter voxelwise laterality values for each subject and modeled individual deviations from the normative pattern of brain laterality across age using normative modeling.

Results: Individuals with autism had highly individualized patterns of both extreme right- and leftward deviations, particularly in language, motor, and visuospatial regions, associated with symptom severity. Language delay explained most variance in extreme rightward patterns, whereas core autism symptom severity explained most variance in extreme leftward patterns. Follow-up analyses showed that a stepwise pattern emerged, with individuals with autism with language delay showing more pronounced rightward deviations than individuals with autism without language delay.

Conclusions: Our analyses corroborate the need for novel (dimensional) approaches to delineate the heterogeneous neuroanatomy in autism and indicate that atypical lateralization may constitute a neurophenotype for clinically meaningful stratification in autism.

Keywords: Autism spectrum disorder; Brain asymmetry; Hemispheric specialization; Heterogeneity; Language delay; Normative modeling.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Autism Spectrum Disorder*
Autistic Disorder*
Brain
Functional Laterality
Humans
Magnetic Resonance Imaging

Abstract

Publication types

MeSH terms

Grants and funding