Atypical Brain Asymmetry in Autism—A Candidate for Clinically Meaningful Stratification
Dorothea L. Floris, Thomas Wolfers, Mariam Zabihi, Nathalie 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 Murphy, André F. Marquand, Jan K. Buitelaar, Christian F. Beckmann, 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 F. Hipp, Rosemary Holt, Mark H. Johnson, Emily J. H. Jones, Prantik Kundu, Meng‐Chuan Lai, Xavier Liogier D’ardhuy, Michael Lombardo, Eva Loth, David J. Lythgoe, René C.W. Mandl, André F. Marquand, Luke Mason, Maarten Mennes, Andreas Meyer‐Lindenberg, Carolin Moessnang, Nico Mueller, Declan 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, Steven Williams, Caroline Wooldridge, Marcel P. Zwiers
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.