Objective: Neuroimaging studies show structural differences in both cortical and subcortical brain regions in children and adults with autism spectrum disorder (ASD) compared with healthy subjects. Findings are inconsistent, however, and it is unclear how differences develop across the lifespan. The authors investigated brain morphometry differences between individuals with ASD and healthy subjects, crosssectionally across the lifespan, in a large multinational sample from the Enhancing Neuroimaging Genetics Through Meta- Analysis (ENIGMA) ASD working group. Method: The sample comprised 1,571 patients with ASD and 1,651 healthy control subjects (age range, 2-64 years) from 49 participating sites. MRI scans were preprocessed at individual sites with a harmonized protocol based on a validated automated-segmentation software program. Mega-analyses were used to test for case-control differences in subcortical volumes, cortical thickness, and surface area. Development of brain morphometry over the lifespan was modeled using a fractional polynomial approach. Results: The case-control mega-analysis demonstrated that ASD was associated with smaller subcortical volumes of the pallidum, putamen, amygdala, and nucleus accumbens (effect sizes [Cohen'sd],0.13to-0.13), as well as increased cortical thickness in the frontal cortex and decreased thickness in the temporal cortex (effect sizes, 20.21 to 0.20). Analyses of age effects indicate that the development of cortical thickness is altered in ASD, with the largest differences occurring around adolescence.No age-by-ASD interactions were observed in the subcortical partitions. Conclusions: The ENIGMA ASD working group provides the largest study of brain morphometry differences in ASD to date, using a well-established, validated, publicly available analysis pipeline. ASD patients showed altered morphometry in the cognitive and affective parts of the striatum, frontal cortex, and temporal cortex. Complex developmental trajectories were observed for the different regions, with a developmental peak around adolescence. These findings suggest an interplay in the abnormal development of the striatal, frontal, and temporal regions in ASD across the lifespan.
Bibliographical noteFunding Information:
ENIGMA received funding from NIH Consortium grant U54 EB020403 to Paul Thompson, supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence (BD2K). This research was further supported by the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement number 278948 (TACTICS), and the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115300 (EU-AIMS), resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (FP7/2007–2013) and the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contribution. The Canadian samples were collected as part of the Province of Ontario Neurodevelopmental Disorders (POND) Network, funded by the Ontario Brain Institute (grant IDS-I l-02 to Dr. Anagnostou and Dr. Lerch).
University of Toronto, Toronto; the Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; the Behavioural Genetics Clinic, Adult Autism Service, Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley Foundation NHS Trust, London; the Laboratory of Neuroimaging, University of São Paulo Medical School, São Paulo, Brazil; the Imaging Genetics Center, Mark and Mary Stevens Institution for Neuroimaging and Informatics, University of Southern California, Marina del Rey; the Department of Speech, Language, and Hearing Sciences, George Washington University, Washington, D.C.; the College of Computer Science and Technology and the Key Laboratory of Symbolic Computation and Knowledge Engineering of the Ministry of Education, Jilin University, Changchun, Jilin, China.
From the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Donders Center for Cognitive Neuro-imaging, Radboud University Medical Center, Nijmegen, the Netherlands; the Karakter Child and Adolescent Psychiatry University Center, Nijmegen; the Bloorview Research Institute, University of Toronto, Toronto; the Child and Adolescent Psychiatry Department, Gregorio Marañón General University Hospital, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid; Institut de Neurosciences de la Timone, Aix Marseille Université, CNRS, Marseille, France; the Department of Psychology, Carnegie Mellon University, Pittsburgh; the IRCCS Stella Maris Foundation, Pisa, Italy; the Department of Forensic and Neurodevelopmental Sciences and the Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London; the Institute for Pediatric Neuroscience, Child Study Center, NYU Langone Health, New York; the Department of Psychology and Department of Brain and Cognitive Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, Israel; Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, the Netherlands; the Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital, Goethe University Frankfurt am Main, Frankfurt, Germany; the Department of Behavioral Neuroscience, Oregon Health and Science University, Portland; the Department of Psychiatry, University of Pittsburgh, Pittsburgh; the Department of Psychiatry, School of Medicine, and the Trinity College Institute of Neuroscience, Trinity College, Dublin; the National Institute for Nuclear Physics, Pisa Division, Pisa, Italy; the Mouse Imaging Centre and the Department of Diagnostic Imaging, Hospital for Sick Children,
Dr. Anagnostou has served as a consultant or advisory board member for Roche and Takeda; she has received funding from the Alva Foundation, Autism Speaks, Brain Canada, the Canadian Institutes of Health Research, the Department of Defense, the National Centers of Excellence, NIH, the Ontario Brain Institute, the Physicians’ Services Incorporated (PSI) Foundation, Sanofi-Aventis, and SynapDx, as well as in-kind research support from AMO Pharma; she receives royalties from American Psychiatric Press and Springer and an editorial honorarium from Wiley. Dr. Arango has served as a consultant for or received honoraria or grants from Acadia, Abbott, Amgen, CIBERSAM, Fundación Alicia Koplowitz, Instituto de Salud Carlos III, Janssen-Cilag, Lundbeck, Merck, Instituto de Salud Carlos III (co-financed by the European Regional Development Fund “A way of making Europe,” CIBERSAM, the Madrid Regional Government [S2010/BMD-2422 AGES], the European Union Structural Funds, and the European Union Seventh Framework Programme under grant agreements FP7-HEALTH-2009-2.2.1-2-241909, FP7-HEALTH-2009-2.2.1-3-242114, FP7-HEALTH-2013-2.2.1-2-603196, and FP7-HEALTH-2013-2.2.1-2-602478), Otsuka, Pfizer, Roche, Servier, Shire, Takeda, and Schering-Plough. Dr. Freitag has served as a consultant for Desitin regarding issues on ASD. Dr. De Martino is a coauthor of the Italian version of the Social Responsiveness Scale, for which she may receive royalties. Dr. Rubia has received speaking honoraria from Eli Lilly, Medice, and Shire. Dr. Buitelaar has served as a consultant, advisory board member, or speaker for Eli Lilly, Janssen-Cilag, Lundbeck, Medice, Novartis, Servier, Shire, and Roche, and he has received research support from Roche and Vifor. The other authors report no financial relationships with commercial interests.
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