ArticlebioRxiv : the preprint server for biology2026
Disrupted Higher-Order Topology in OCD Brain Networks Revealed by Hodge Laplacian - an ENIGMA Study.
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80 authors.
Hanyang RuanDepartment of Neuroradiology, TUM University Hospital, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.ORCID 0000-0002-0165-719X
Moo K ChungDepartment of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.
Willem B BruinDepartment of Anatomy & Neurosciences, Amsterdam University Medical Center, Amsterdam, the Netherlands.ORCID 0000-0002-0672-8903
Nadža DžinalijaDepartment of Anatomy & Neurosciences, Amsterdam University Medical Center, Amsterdam, the Netherlands.ORCID 0009-0001-8114-1299
Yoshinari AbeDepartment of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.ORCID 0000-0001-8348-0801
Pino AlonsoBellvitge Biomedical Research Insitute-IDIBELL, Bellvitge University Hospital, Barcelona, Spain.ORCID 0000-0002-5779-9111
Alan AnticevicDepartment of Psychiatry, Yale University, New Haven, CT, USA.
Srinivas BalachanderOCD clinic, Department of Psychiatry, National Institute of Mental Health And Neurosciences (NIMHANS), Bangalore, India.ORCID 0000-0001-6729-6414
Marcelo C BatistuzzoDepartment of Psychiatry, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.ORCID 0000-0003-1347-8241
Francesco BenedettiPsychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy.ORCID 0000-0003-4949-856X
Sara BertolínBellvitge Biomedical Research Insitute-IDIBELL, Bellvitge University Hospital, Barcelona, Spain.ORCID 0000-0003-1468-7862
Silvia BremDepartment of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Switzerland.ORCID 0000-0002-8031-1305
Youngsun ChoDepartment of Psychiatry, Yale University, New Haven, CT, USA.ORCID 0000-0001-8639-3869
Federica ColomboPsychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy.ORCID 0000-0001-5853-9912
Beatriz CoutoLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
Goi Khia EngDepartment of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA.ORCID 0000-0001-7189-2868
Sónia FerreiraLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.ORCID 0000-0002-3527-1623
Jamie D FeusnerDepartment of Psychiatry, Division of Neurosciences and Clinical Translation, University of Toronto, Toronto, ON, Canada.ORCID 0000-0002-0391-345X
Rachael G GraziopleneDepartment of Psychiatry, Yale University, New Haven, CT, USA.
Patricia GrunerDepartment of Psychiatry, Yale University, New Haven, CT, USA.ORCID 0000-0002-3685-146X
Kristen HagenBergen Center for Brain Plasticity, Haukeland University Hospital, Bergen, Norway.ORCID 0000-0002-4286-1277
Bjarne HansenBergen Center for Brain Plasticity, Haukeland University Hospital, Bergen, Norway.
Yoshiyuki HiranoResearch Center for Child Mental Development, Chiba University, Chiba, Japan.ORCID 0000-0003-3844-3061
Marcelo Q HoexterDepartment of Psychiatry, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.ORCID 0000-0002-9302-4380
Jonathan IpserDepartment of Psychiatry and Mental Health and Neuroscience Institute, Brain Behaviour Unit, University of Cape Town, Cape Town, South Africa.ORCID 0000-0003-1272-0032
Fern Jaspers-FayerDepartment of Psychiatry, University of British Columbia, Vancouver, Canada.ORCID 0000-0002-5107-4945
Minah KimDepartment of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.ORCID 0000-0001-8668-0817
Jun Soo KwonInstitute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea.ORCID 0000-0002-1060-1462
Luisa LazaroCIBERSAM, Instituto de Salud Carlos III, Madrid, Spain.ORCID 0000-0002-8425-5750
Chiang-Shan R LiDepartment of Psychiatry, Yale University, New Haven, CT, USA.ORCID 0000-0002-9393-1212
Christine LochnerSA MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch University, Stellenbosch, South Africa.ORCID 0000-0002-4766-3704
Rachel MarshColumbia University Medical College, Columbia University, New York, NY, USA.ORCID 0000-0003-2439-6305
Ignacio Martínez-ZalacaínBellvitge Biomedical Research Insitute-IDIBELL, Bellvitge University Hospital, Barcelona, Spain.ORCID 0000-0002-4036-0284
Jose M MenchónBellvitge Biomedical Research Insitute-IDIBELL, Bellvitge University Hospital, Barcelona, Spain.ORCID 0000-0002-6231-6524
Pedro S MoreiraLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.ORCID 0000-0002-2800-3903
Pedro MorgadoLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.ORCID 0000-0003-3880-3258
Emma MuñozMagnetic Resonance Image Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.ORCID 0000-0003-2104-7265
Akiko NakagawaResearch Center for Child Mental Development, Chiba University, Chiba, Japan.
Janardhanan C NarayanaswamyOCD clinic, Department of Psychiatry, National Institute of Mental Health And Neurosciences (NIMHANS), Bangalore, India.
Erika L NurmiDivision of Child and Adolescent Psychiatry, Jane & Terry Semel Institute For Neurosciences, University of California, Los Angeles, CA, USA.ORCID 0000-0003-4893-8957
Joseph O'NeillDivision of Child and Adolescent Psychiatry, Jane & Terry Semel Institute For Neurosciences, University of California, Los Angeles, CA, USA.ORCID 0000-0003-2216-3903
Jose C ParienteMagnetic Resonance Image Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.ORCID 0000-0002-7358-7602
John C PiacentiniDivision of Child and Adolescent Psychiatry, Jane & Terry Semel Institute For Neurosciences, University of California, Los Angeles, CA, USA.ORCID 0000-0003-4195-7194
Maria Picó-PérezLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.ORCID 0000-0002-1573-2445
Fabrizio PirasNeuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, IRCCS Santa Lucia Foundation, Rome, Italy.ORCID 0000-0003-3566-5494
Federica PirasNeuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, IRCCS Santa Lucia Foundation, Rome, Italy.ORCID 0000-0002-9546-7038
Christopher PittengerDepartments of Psychiatry, Neuroscience, Psychology, and Yale Child Study Center, Yale University, New Haven, CT, USA.ORCID 0000-0003-2117-9321
Janardhan Y C ReddyOCD clinic, Department of Psychiatry, National Institute of Mental Health And Neurosciences (NIMHANS), Bangalore, India.ORCID 0000-0002-9925-9631
Daniela Rodriguez-ManriqueDepartment of Neuroradiology, TUM University Hospital, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.ORCID 0000-0002-6867-0727
Yuki SakaiDepartment of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.ORCID 0000-0003-2475-8548
Joao R SatoCenter of Mathematics, Computing and Cognition, Universidade Federal do ABC, Santo André, Brazil.
Eiji ShimizuResearch Center for Child Mental Development, Chiba University, Chiba, Japan.ORCID 0000-0002-6741-9338
Venkataram ShivakumarDepartment of Integrative Medicine, National Institute of Mental Health And Neurosciences (NIMHANS), Bangalore, India.ORCID 0000-0003-0353-8597
Helen B SimpsonDepartment of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA.ORCID 0000-0002-9332-2839
Carles Soriano-MasBellvitge Biomedical Research Insitute-IDIBELL, Bellvitge University Hospital, Barcelona, Spain.ORCID 0000-0003-4574-6597
Nuno SousaLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.ORCID 0000-0002-8755-5126
Emily R SternDepartment of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA.ORCID 0000-0001-7805-594X
Evelyn StewartDepartment of Psychiatry, University of British Columbia, Vancouver, Canada.ORCID 0000-0002-0994-6383
Philip R SzeszkoDepartment of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, NY, USA.ORCID 0000-0002-6383-6142
Sophia I ThomopoulosImaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.ORCID 0000-0002-0046-4070
Anders L ThorsenBergen Center for Brain Plasticity, Haukeland University Hospital, Bergen, Norway.ORCID 0000-0003-2836-5223
Benedetta VaiPsychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy.ORCID 0000-0002-0748-4656
Anouk van der StratenDepartment of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands.ORCID 0000-0003-2436-4899
Ysbrand D van der WerfDepartment of Anatomy & Neurosciences, Amsterdam University Medical Center, Amsterdam, the Netherlands.ORCID 0000-0003-2370-9584
Wieke van LeeuwenDepartment of Psychiatry, Arkin Mental Health Center, Amsterdam, the Netherlands.ORCID 0000-0002-4722-0444
Hein van MarleDepartment of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands.ORCID 0000-0003-3543-4135
Guido van WingenDepartment of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands.ORCID 0000-0003-3076-5891
Daniela VecchioNeuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, IRCCS Santa Lucia Foundation, Rome, Italy.ORCID 0000-0001-8428-7376
Ganesan VenkatasubramanianOCD clinic, Department of Psychiatry, National Institute of Mental Health And Neurosciences (NIMHANS), Bangalore, India.ORCID 0000-0002-0949-898X
Chris VriendCompulsivity, Impulsivity and Attention program, Amsterdam Neuroscience, Amsterdam, the Netherlands.ORCID 0000-0003-3111-1304
Susanne WalitzaDepartment of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Switzerland.ORCID 0000-0002-8161-8683
Zhen WangShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.ORCID 0000-0003-4319-5314
Tokiko YoshidaUnited Graduate School of Child Development, The University of Osaka, Suita, Japan.ORCID 0000-0002-4410-7163
Je-Yeon YunDepartment of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea.ORCID 0000-0002-5531-2410
Qing ZhaoShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.ORCID 0009-0008-6253-5832
ENIGMA OCD Working Group
Paul M ThompsonImaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.ORCID 0000-0002-4720-8867
Dan J SteinSA MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.ORCID 0000-0001-7218-7810
Odile A van den HeuvelDepartment of Anatomy & Neurosciences, Amsterdam University Medical Center, Amsterdam, the Netherlands.ORCID 0000-0002-9804-7653
Kathrin KochDepartment of Neuroradiology, TUM University Hospital, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.ORCID 0000-0003-4664-8016
Funding
TR&D3: Intrinsic Surface MappingP41EB015922 · NIBIB · UNIVERSITY OF SOUTHERN CALIFORNIA · PI VAN HORN, JOHN DARRELL · 2012 to 2022
$14.1MTraining U54EB020403 · NIBIB · UNIVERSITY OF SOUTHERN CALIFORNIA · PI THOMPSON, PAUL M · 2014 to 2018
$10.1MBehavioral and Neural Heterogeneity in OCD and DepressionR01MH126981 · NIMH · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI STERN, EMILY R · 2021 to 2025
$3.7MBrain Network Changes Accompanying and Predicting Responses to Pharmacotherapy in OCDR01MH116038 · NIMH · YALE UNIVERSITY · PI ANTICEVIC, ALAN, PITTENGER, CHRISTOPHER JOHN · 2019 to 2023
$3.7MENIGMA World Aging CenterR01AG058854 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI THOMPSON, PAUL M · 2021 to 2025
$3.3MENIGMA Parkinson’s Initiative: A Global Initiative for Parkinson’s DiseaseR01NS107513 · NINDS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI POSTON, KATHLEEN LOMBARD, THOMPSON, PAUL M · 2021 to 2025
$3.2MNeurobiology of sensory phenomena in obsessive-compulsive disorderR01MH111794 · NIMH · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI STERN, EMILY R · 2017 to 2021
$3.0MCognitive-Behavioral Therapy & Glutametergic Neurometabolites in Pediatric OCDR01MH081864 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI O'NEILL, JOSEPH, PIACENTINI, JOHN C. · 2008 to 2012
$3.0MControl and Reward Circuits as Targets for Repetitive Thoughts and BehaviorsR01MH104648 · NIMH · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · PI MARSH, RACHEL, SIMPSON, HELEN BLAIR · 2014 to 2017
$2.8MNeural mechanisms of perceptual abnormalities and their malleability in bodydysmorphic disorderR01MH121520 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI FEUSNER, JAMIE · 2020 to 2025
$2.8MENIGMA-SD: Understanding Sex Differences in Global Mental Health through ENIGMAR01MH116147 · NIMH · UNIVERSITY OF SOUTHERN CALIFORNIA · PI THOMPSON, PAUL M · 2018 to 2021
$2.5MCognitive-Behavioral Therapy and Glutamate in Cingulate Gyrus in OCDR01MH085900 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI FEUSNER, JAMIE, O'NEILL, JOSEPH · 2011 to 2014
$1.8MNIA NIH HHS R01 AG058854NIBIB NIH HHS P41 EB015922NIBIB NIH HHS U54 EB020403NIMH NIH HHS K23 MH115206NIMH NIH HHS K24 MH121571NIMH NIH HHS R01 MH081864NIMH NIH HHS R01 MH085900NIMH NIH HHS R01 MH104648NIMH NIH HHS R01 MH111794NIMH NIH HHS R01 MH116038NIMH NIH HHS R01 MH116147NIMH NIH HHS R01 MH121520NIMH NIH HHS R01 MH126981NIMH NIH HHS R21 MH093889NIMH NIH HHS R21 MH101441NIMH NIH HHS R33 MH107589NIMH NIH HHS RF1 MH123163NINDS NIH HHS R01 NS107513Wellcome Trust
Abstract
Obsessive-compulsive disorder (OCD) is a disabling condition that is characterized by disruptions in distributed brain circuit dynamics. However, current network studies predominantly evaluate these circuits by measuring functional synchrony (connectivity) between pairs of regions of interest, potentially overlooking complex higher-order interactions. In this study, we applied a Hodge Laplacian topological framework to investigate these higher-order interactions in OCD. Using a large-scale resting-state fMRI dataset from the ENIGMA-OCD consortium (1,024 OCD patients and 1,028 healthy controls across 28 sites worldwide), we identified significant disruptions in topological loops spanning frontoparietal, default mode, and sensorimotor networks. Crucially, the edges constituting these abnormal loops largely lacked significant pairwise differences, highlighting higher-order multi-nodal disturbances. Subgroup analyses revealed that these disruptions were most pronounced in adult, medicated, and high-severity OCD patients. Our findings suggest that OCD pathology involves abnormal recurrent higher-order multi-region interactions, providing new insights into the brain's functional organization and offering potential biomarkers for clinical application.
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