TY - JOUR
T1 - Atypical Brain Asymmetry in Autism-A Candidate for Clinically Meaningful Stratification
AU - Floris, Dorothea L
AU - Wolfers, Thomas
AU - Zabihi, Mariam
AU - Holz, Nathalie E
AU - Zwiers, Marcel P
AU - Charman, Tony
AU - Tillmann, Julian
AU - Ecker, Christine
AU - Dell'Acqua, Flavio
AU - Banaschewski, Tobias
AU - Moessnang, Carolin
AU - Baron-Cohen, Simon
AU - Holt, Rosemary
AU - Durston, Sarah
AU - Loth, Eva
AU - Murphy, Declan G M
AU - Marquand, Andre
AU - Buitelaar, Jan K
AU - Beckmann, Christian F
N1 - Funding Information:
This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement Nos 115300 (for EU-AIMS) and 777394 (for AIMS-2-TRIALS). This Joint Undertaking receives support from the European Union's Horizon 2020 Research and Innovation Programme, the European Federation of Pharmaceutical Industries and Associations, Autism Speaks, Autistica, and the Simons Foundation Autism Research Initiative. This work was also supported by the Netherlands Organisation for Scientific Research through Vidi grants (Grant Nos. 864.12.003 [to CFB] and 016.156.415 [to AM]), the Seventh Framework Programme (Grant Nos. 602805 [AGGRESSOTYPE] [to JKB], 603016 [MATRICS] [to JKB], and 278948 [TACTICS] [to JKB]), and the European Community's Horizon 2020 Programme (H2020/2014-2020) (Grant Nos. 643051 [MiND] and 642996 [BRAINVIEW]). This work also received funding from the Wellcome Trust U.K. Strategic Award (Award No 098369/Z/12/Z) and the National Institute for Health Research Maudsley Biomedical Research Centre (to DGMM). TW gratefully acknowledges grant support from the Niels Stensen Fellowship. NEH gratefully acknowledges grant support from the German Research Foundation (Grant Nos. DFG HO 5674/2-1 and GRK2350/1) and the Olympia Morata Program of the University of Heidelberg. SB-C was funded by the Autism Research Trust, the Wellcome Trust, the Templeton World Charitable Foundation, and the National Institute for Health Research Biomedical Research Centre in Cambridge during the period of this work. TC has received consultancy fees from Roche and book royalties from Guildford Press and Sage. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg, Shire, and Infectopharm, received conference support or speaker's fees from Lilly, Medice, and Shire, and received royalties from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press; the present work is unrelated to these relationships. DGMM has been a consultant to and advisory board member for Roche and Servier; he is not an employee of nor stock shareholder in any of these companies. JKB has been a consultant to, advisory board member of, and speaker for Takeda/Shire, Medice, Roche, and Servier; he is not an employee of nor stock shareholder in 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. The other authors report no biomedical financial interests or potential conflicts of interest. We thank all participants and their families for participating in this study. We also gratefully acknowledge the contributions of all members of the EU-AIMS LEAP group.
Funding Information:
This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement Nos 115300 (for EU-AIMS) and 777394 (for AIMS-2-TRIALS). This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme , the European Federation of Pharmaceutical Industries and Associations , Autism Speaks, Autistica, and the Simons Foundation Autism Research Initiative. This work was also supported by the Netherlands Organisation for Scientific Research through Vidi grants (Grant Nos. 864.12.003 [to CFB] and 016.156.415 [to AM]), the Seventh Framework Programme (Grant Nos. 602805 [AGGRESSOTYPE] [to JKB], 603016 [MATRICS] [to JKB], and 278948 [TACTICS] [to JKB]), and the European Community’s Horizon 2020 Programme (H2020/2014-2020) (Grant Nos. 643051 [MiND] and 642996 [BRAINVIEW]). This work also received funding from the Wellcome Trust U.K. Strategic Award (Award No 098369/Z/12/Z) and the National Institute for Health Research Maudsley Biomedical Research Centre (to DGMM). TW gratefully acknowledges grant support from the Niels Stensen Fellowship. NEH gratefully acknowledges grant support from the German Research Foundation (Grant Nos. DFG HO 5674/2-1 and GRK2350/1) and the Olympia Morata Program of the University of Heidelberg . SB-C was funded by the Autism Research Trust , the Wellcome Trust , the Templeton World Charitable Foundation , and the National Institute for Health Research Biomedical Research Centre in Cambridge during the period of this work.
Publisher Copyright:
© 2020 Society of Biological Psychiatry
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - Autism spectrum disorder
KW - Brain asymmetry
KW - Hemispheric specialization
KW - Heterogeneity
KW - Language delay
KW - Normative modeling
UR - http://www.scopus.com/inward/record.url?scp=85093673855&partnerID=8YFLogxK
U2 - 10.1016/j.bpsc.2020.08.008
DO - 10.1016/j.bpsc.2020.08.008
M3 - Article
C2 - 33097470
SN - 2451-9022
VL - 6
SP - 802
EP - 812
JO - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
IS - 8
ER -