ArticlemedRxiv : the preprint server for health sciences2026
Altered neurodevelopmental trajectories of brain structure in Tourette syndrome and Chronic Tic Disorders.
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89 authors.
Yin JinDepartment of Biological Science, Purdue University, West Lafayette, USA.
Yuxin GuoDepartment of Biological Science, Purdue University, West Lafayette, USA.
Jonathan M KollerDepartments of Psychiatry, Neurology, Radiology and Neuroscience, Washington University in St. Louis, USA.ORCID 0000-0002-1409-5608
Sarah C GrossenDepartments of Psychiatry, Neurology, Radiology and Neuroscience, Washington University in St. Louis, USA.
Anne UhlmannDepartment of Child and Adolescent Psychiatry, TU Dresden, Dresden, Germany.
Natalie J FordeDepartment of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands.ORCID 0000-0002-1452-0600
Jade-Jocelyne ZoukiCentre for Social and Early Emotional Development and School of Psychology, Deakin University, Burwood, Australia.
Renzo TorrecusoMax Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
Karsten MuellerMax Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
Juan F Martin-RodriguezUnidad de Trastornos del Movimiento, Servicio de Neurología, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain.ORCID 0000-0003-1392-8775
Pablo Franco-RosadoUnidad de Trastornos del Movimiento, Servicio de Neurología, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain.
Michel GrotheInstituto de Biomedicina de Sevilla (IBiS), Spain.
Catharina CramerDepartment of Psychiatry, Hannover University Medical School, Hannover, Germany.
Anne Kleine BüningDepartment of Psychiatry, Hannover University Medical School, Hannover, Germany.
Heike EicheleDepartment of Biological and Medical Psychology, University of Bergen, Norway.
Stefano PalmucciDepartment of Medical Surgical Sciences and Advanced Technologies, Radiology Unit 1, University of Catania, Italy.
Adriana PratoDeparment of Clinical and Experimental Medicine, Child and Adolescent Neurology and Psichiatry, University of Catania, Italy.
Federica SaiaChild Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, School of Medicine, University of Catania, Italy.
Silvia TommasinDepartment of Human Neurosciences, Sapienza University of Rome, Italy.ORCID 0000-0001-9088-7968
Giulia ConteDepartment of Human Neurosciences, Sapienza University of Rome, Italy.
Katharina A SchindlbeckDepartment of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Germany.
Christos GanosCharité, University Medicine Berlin, Germany.
Shukti ZimmermannDepartment of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany.
Tanja VeselinovicDepartment of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany.
Yulia WorbeDepartment of Clinical Neurophysiology, Sorbonne Université, APHP - Saint Antoine Hospital, Paris France.
Andreas HartmannDepartment of Neurology, Pitié-Salpêtrière Hospital, Paris, France.
Apostolia TopaloudiDepartment of Biological Science, Purdue University, West Lafayette, USA.
Mary KakaDepartment of Biological Science, Purdue University, West Lafayette, USA.
Guangxin ChenDepartment of Biological Science, Purdue University, West Lafayette, USA.
Qingyi ZhongDepartment of Biological Science, Purdue University, West Lafayette, USA.
Yuqi ZhangDepartment of Biological Science, Purdue University, West Lafayette, USA.
Natalia SzejkoDepartment of Child Psychiatry, Babinski Hospital, Lodz, Poland.
Piotr JanikDepartment of Neurology, Medical University of Warsaw, Warsaw, Poland.
Nanette M DebesDepartment of Pediatrics, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.
Zeynep TumerDepartment of Clinical Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.ORCID 0000-0002-4777-5802
Tomasz WolańczykDepartment of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland.
Gary A HeimanDepartment of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA.
Hreinn StefanssonAmgen deCODE genetics, Iceland.
Helga AskPsychGen Center for Genetic Epidemiology and Mental Health, Norwegian Institute of Public Health, Norway.
Ole AndreassenCentre for Precision Psychiatry, University of Oslo, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.ORCID 0000-0002-4461-3568
Anders D BørglumDepartment of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.
Joseph D BuxbaumIcahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, NY, USA.
Elizabeth C CorfieldPsychGen Center for Genetic Epidemiology and Mental Health, Norwegian Institute of Public Health, Norway.
Mark DalyHarvard Medical School, USA.
Dorothy E GriceDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
David Mataix-ColsCentre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
Aarno PalotieInstitute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
Christian RückCentre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
Matthew W HalvorsenDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Lea K DavisProfessor of Medicine, Department of Medicine, Division of Data Driven and Digital Medicine, USA.
James J CrowleyDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Manuel MattheisenDepartment of Community Health and Epidemiology and Faculty of Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada.
Dongmei YuPsychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Carol A MathewsUniversity of Florida, Department of Psychiatry, Genetics Institute, Center for OCD, Anxiety and Related Disorders, Evelyn F and William L McKnight Brain Institute, Gainesville, FL, USA.ORCID 0000-0003-2208-7058
Jeremiah M ScharfPsychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
members of the Tourette International TS-EUROTRAIN/TSGeneSEE
TAA Neuroimaging Consortium
Collaborative Genetics consortium
TAAICG
EMTICS
ENIGMA-TS Working Group
Dan J SteinSAMRC Unit on Risk & Resilience in Mental Disorders, Dept of Psychiatry & Neuroscience Institute, University of Cape Town, South Africa.
Irene NeunerDepartment of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Germany.
Richard MusilLudwig-Maximilians-University of Munich, Germany.
Francesco CardonaDepartment of Human Neurosciences, Sapienza University of Rome, Italy.
Danielle CathUniversity of Groningen, university Medical Center Groningen, department of Psychiatry &Drenthe MHC, Groningen, the Netherlands.
Dick J VeltmanDept. of Psychiatry, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands.
Tim J SilkCentre for Social and Early Emotional Development and School of Psychology, Deakin University, Burwood, Australia.
Alexander MunchauInstitute of Systems Motor Science, University of Lübeck, Lübeck, Germany.
Julius VerrelUnidad de Trastornos del Movimiento, Servicio de Neurología, Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
Valerie C BrandtDepartment of Psychology, University of Southampton, UK.
Tamara HersheyKennedy Krieger Institute, Baltimore MD, USA.
Deanna J GreeneDepartment of Cognitive Science, University of California, San Diego, La Jolla, CA, United States.ORCID 0000-0002-0739-7771
Bradley L SchlaggarKennedy Krieger Institute, Baltimore MD, USA.
Jan BuitelaarDepartment of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands.
Barbara FrankeDepartments of Genetics and of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical CentreRadboud University, The Netherlands.
Sophia ThomopoulosMark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, USA.ORCID 0000-0002-0046-4070
Renata RizzoDeparment of Clinical and Experimental Medicine, Child and Adolescent Neurology and Psichiatry, University of Catania, Italy.
Andrea DietrichUniversity of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry & Accare Child Study Center, Groningen, Netherlands.
Pieter J HoekstraUniversity of Groningen, University Medical Center Groningen, Department of Psychiatry & Accare Child Study Center, Groningen, Netherlands.
Pablo MirUnidad de Trastornos del Movimiento, Servicio de Neurología, Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.ORCID 0000-0003-1656-302X
Veit RoessnerDepartment of Child and Adolescent Psychiatry, TU Dresden, Dresden, Germany.ORCID 0000-0002-1873-7081
Odile A van den HeuvelDept. Psychiatry, Dept. Anatomy & Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, The Netherlands.
Kirsten Mueller-VahlDepartment of Psychiatry, Hannover University Medical School, Hannover, Germany.
Harald MöllerMax Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
Neda JahanshadMark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, USA.
Paul M ThompsonMark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, USA.ORCID 0000-0002-4720-8867
Kevin J BlackDepartments of Psychiatry, Neurology, Radiology and Neuroscience, Washington University in St. Louis, USA.ORCID 0000-0002-6921-9567
Peristera PaschouDepartment of Biological Science, Purdue University, West Lafayette, USA.
Funding
Vanderbilt Institute for Clinical and Translational Research (VICTR) -Identifying correlates of functional immunity in SARS-CoV-2 convalescent plasmaUL1TR002243 · NCATS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Paul A. Harris, Wesley H Self · 2017 to 2026
$130.7MWashington University Center for Cellular ImagingP30CA091842 · NCI · WASHINGTON UNIVERSITY · PI TIMOTHY J. EBERLEIN · 2001 to 2026
$128.0MWU INSTITUTE OF CLINICAL AND TRANSLATIONAL SCIENCESUL1TR002345 · NCATS · WASHINGTON UNIVERSITY · PI William G. Powderly · 2017 to 2026
$97.8MVANDERBILT UNIVERSITY CTSA FOR PEDIATRIC RESEARCHUL1RR024975 · NCRR · VANDERBILT UNIVERSITY · PI BERNARD, GORDON RAPHAEL · 2007 to 2011
$45.7MThe Vanderbilt Institute for Clinical and Translational Research (VICTR)UL1TR000445 · NCATS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BERNARD, GORDON RAPHAEL · 2012 to 2016
$41.4MWashington University Institute of Clinical and Translational SciencesUL1TR000448 · NCATS · WASHINGTON UNIVERSITY · PI EVANOFF, BRADLEY A · 2012 to 2016
$41.4MPharmacogenomics of Arrhythmia TherapyU19HL065962 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI RODEN, DAN M · 2010 to 2014
$17.4MTR&D3: Intrinsic Surface MappingP41EB015922 · NIBIB · UNIVERSITY OF SOUTHERN CALIFORNIA · PI TOGA, ARTHUR W · 2012 to 2022
$14.1MUnderstanding and preventing HLA-associated drug reactionsP50GM115305 · NIGMS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI PHILLIPS, ELIZABETH, RODEN, DAN M · 2015 to 2019
$13.0MTranslational Research to Enhance Cognitive ControlP50MH077248 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MCCRACKEN, JAMES T. · 2006 to 2011
$9.2MThe Genetic Epemiology of Multiple SclerosisR01NS032830 · NINDS · VANDERBILT UNIVERSITY · PI HAINES, JONATHAN L · 1995 to 2010
$8.9MEpidemiologic Architecture for Genes Linked to Environment (EAGLE)U01HG004798 · NHGRI · VANDERBILT UNIVERSITY · PI CRAWFORD, DANA C · 2008 to 2013
$8.8MNCATS NIH HHS UL1 TR000445NCATS NIH HHS UL1 TR000448NCATS NIH HHS UL1 TR002243NCATS NIH HHS UL1 TR002345NCI NIH HHS P30 CA091842NCRR NIH HHS S10 RR025141NCRR NIH HHS UL1 RR024975NHGRI NIH HHS U01 HG004798NHGRI NIH HHS U01 HG006378NHLBI NIH HHS U19 HL065962NIBIB NIH HHS P41 EB015922NICHD NIH HHS R01 HD070855NICHD NIH HHS R01 HD074711NICHD NIH HHS U54 HD087011NIDDK NIH HHS R01 DK064832NIGMS NIH HHS P50 GM115305NIGMS NIH HHS RC2 GM092618NIMH NIH HHS K01 MH104592NIMH NIH HHS K24 MH087913NIMH NIH HHS P50 MH077248NIMH NIH HHS R01 MH073856NIMH NIH HHS R01 MH104030NIMH NIH HHS R01 MH110427NIMH NIH HHS R01 MH115958NIMH NIH HHS R01 MH115959NIMH NIH HHS R01 MH115960NIMH NIH HHS R01 MH115961NIMH NIH HHS R01 MH115962NIMH NIH HHS R01 MH115963NIMH NIH HHS R01 MH115993NIMH NIH HHS R01 MH116147NIMH NIH HHS R01 MH118217NIMH NIH HHS R01 MH124679NIMH NIH HHS R01 MH126213NIMH NIH HHS R21 MH091512NIMH NIH HHS R21 MH098670NINDS NIH HHS R01 NS032830NINDS NIH HHS R01 NS102371NINDS NIH HHS R01 NS105746NINDS NIH HHS R21 NS091635
Abstract
Tourette syndrome (TS) is a neurodevelopmental disorder characterized by symptoms that emerge in childhood and often improve or even disappear in adulthood, providing a model for understanding how altered brain development shapes neural structure and function. We investigate brain structural alterations in TS and Chronic Tic Disorders (TS/CTD) across development, presenting the largest structural neuroimaging analysis for TS/CTD to date (1,803 individuals from the ENIGMA-TS Working Group), and integrating with large-scale genomewide association studies. Nonlinear age effects were observed in cortical thickness across development and in thalamic volume in children, indicating altered trajectories of brain maturation. Pediatric and adult TS/CTD showed distinct structural patterns, with widespread alterations in childhood and more focal changes in adulthood. Children also showed the most prominent effects highlighting the involvement of orbitofrontal cortex and putamen, alongside additional regions such as frontal and paralimbic areas. Genetic pleiotropy analyses identified overlap between TS/CTD-associated genetic effects on brain structure and neuroanatomical differences. Cross-disorder comparisons revealed correlations with ADHD and OCD and age-related patterns. These findings demonstrate altered neurodevelopmental trajectories in TS/CTD and implicate systems underlying inhibitory control and urge regulation.
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