Thalamocortical Structural Covariation Networks Are Related to Familial Risk for Schizophrenia in the Context of Lower Nuclei Volume Estimates in Patients: An ENIGMA Study

Annalisa Lella¹, Linda A Antonucci¹, Roberta Passiatore², Loredana Bellantuono³, Pierluigi Selvaggi⁴, Teresa Popolizio⁵, Guido Di Sciascio⁶, Alessandro Saponaro⁷, Patrizia Ricci⁸, Mario Altamura⁹, Giuseppe Blasi⁴, Antonio Rampino⁴, Chris Vriend¹⁰, Vince D Calhoun¹¹, Kelly Rootes-Murdy¹¹, Aaron L Goldman¹², Inmaculada Baeza¹³, Josefina Castro-Fornieles¹³, Gisela Sugranyes¹³, Elena De la Serna¹³, Edith Pomarol-Clotet¹⁴, Mar Fatjó-Vilas¹⁴, Raymond Salvador¹⁴, Andriana Karuk¹⁴, Paola Fuentes-Claramonte¹⁴, David C Glahn¹⁵, Amanda L Rodrigue¹⁶, John Blangero¹⁷, Lei Wang¹⁸, Taeyoung Lee¹⁹, Karolin E Einenkel²⁰, Saskia Hamers²¹, Oliver Gruber²⁰, Adrian Preda²², Young-Chul Chung²³, Soyolsaikhan Odkhuu²⁴, Corentin Vallée²⁵, Paola Dazzan²⁶, Machteld Marcelis²⁷, Stijn Michielse²⁷, Katharina Brosch²⁸, Frederike Stein²⁹, Igor Nenadić²⁹, Benjamin Straube²⁹, Florian Thomas-Odenthal²⁹, Tilo Kircher²⁹, Sean Carruthers³⁰, Susan L Rossell³⁰, Phillip J Sumner³⁰, Tamsyn E Van Rheenen³¹, Caroline Demro³², Ian S Ramsay³², Scott R Sponheim³³, Rebekka Lencer³⁴, Susanne Meinert³⁴, Tim Hahn³⁴, Udo Dannlowski³⁴, Dominik Grotegerd³⁴, Mariateresa Ciccarelli³⁵, Felice Iasevoli³⁵, Giuseppe Pontillo³⁶, Godfrey D Pearlson³⁷, Derin Cobia³⁸, Fabrizio Piras³⁹, Nerisa Banaj³⁹, Daniela Vecchio³⁹, Marjolein E A Barendse⁴⁰, Neeltje E M van Haren⁴⁰, Hang Joon Jo⁴¹, Kang Sim⁴², Yann Quidé⁴³, Melissa J Green⁴⁴, Rachael Slate⁴⁵, Giacomo Cecere⁴⁶, Wolfgang Omlor⁴⁶, Stephanie Homan⁴⁶, Philipp Homan⁴⁶, Sophia I Thomopoulos⁴⁷; Apulian Network on Risk for Psychosis; Jessica A Turner⁴⁸, Theo G M van Erp⁴⁹, Paul M Thompson⁴⁷, Alessandro Bertolino⁴, Giulio Pergola⁵⁰

Collaborators, Affiliations

Collaborators

Apulian Network on Risk for Psychosis:
Anna Manzari, Antonello Bellomo

Affiliations

¹ Department of Translational Biomedicine and Neuroscience-University of Bari Aldo Moro, Bari, Italy.
² Department of Translational Biomedicine and Neuroscience-University of Bari Aldo Moro, Bari, Italy; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
³ Department of Translational Biomedicine and Neuroscience-University of Bari Aldo Moro, Bari, Italy; Istituto Nazionale di Fisica Nucleare, Bari, Italy.
⁴ Department of Translational Biomedicine and Neuroscience-University of Bari Aldo Moro, Bari, Italy; Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy.
⁵ Neuroradiology Unit, Scientific Institute for Research, Hospitalization and Health Care, San Giovanni Rotondo, Foggia, Italy.
⁶ Department of Mental Health, Azienda Sanitaria Locale Bari, Bari, Italy.
⁷ Department of Mental Health, Azienda Sanitaria Locale Brindisi, Brindisi, Italy.
⁸ Department of Mental Health, Azienda Sanitaria Locale Barletta Andria Trani, Barletta-Andria-Trani, Italy.
⁹ Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
¹⁰ Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Department of Psychiatry and Department of Anatomy and Neuroscience, Amsterdam, the Netherlands; Compulsivity, Impulsivity and Attention, Amsterdam Neuroscience, Amsterdam, the Netherlands.
¹¹ Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia Institute of Technology, Georgia State University, Emory University, Atlanta, Georgia.
¹² Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
¹³ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neuroscience, Hospital Clínic Barcelona, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Spain.
¹⁴ FIDMAG Germanes Hospitalàries Research Foundation, Centro de Investigación Biomédica en Red de Salud Mental Instituto de Salud Carlos III, Barcelona, Spain.
¹⁵ Department of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Connecticut.
¹⁶ Department of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
¹⁷ Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine at University of Texas Rio Grande Valley, Brownsville, Texas.
¹⁸ Department of Psychiatry and Behavioral Health, Neuroscience, Ohio State University Wexner Medical Center, Columbus, Ohio.
¹⁹ Department of Psychiatry, Kyungpook National University School of Medicine, Daegu, South Korea; Department of Psychiatry, Kyungpook National University Hospital, Daegu, South Korea; Department of Biomedical Engineering, Graduate School of Biomedical Sciences and Engineering, Hanyang University, Seoul, South Korea.
²⁰ Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.
²¹ Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany; Division of Clinical Psychology and Sexual Medicine, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
²² Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, California.
²³ Department of Psychiatry, Jeonbuk National University, Medical School, Jeonju, South Korea; Department of Psychiatry, Jeonbuk National University Hospital, Jeonju, Korea; Research Institute of Clinical Medicine of Jeonbuk National University-, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.
²⁴ Department of Psychiatry, Jeonbuk National University, Medical School, Jeonju, South Korea; Research Institute of Clinical Medicine of Jeonbuk National University-, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.
²⁵ Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
²⁶ Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; National Institute for Health and Care Research Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, London, United Kingdom.
²⁷ Department of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, the Netherlands.
²⁸ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany; Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, New York.
²⁹ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
³⁰ Centre for Mental Health and Brain Sciences, Swinburne University, Melbourne, Victoria, Australia.
³¹ Centre for Mental Health and Brain Sciences, Swinburne University, Melbourne, Victoria, Australia; Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia.
³² Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, Minnesota.
³³ Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota; Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, Minnesota.
³⁴ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
³⁵ Section of Psychiatry, Department of Neuroscience, Reproductive Sciences, and Dentistry, University School of Medicine Federico II, Naples, Italy.
³⁶ Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy; Department of Electrical Engineering and Information Technology, University "Federico II," Naples, Italy.
³⁷ Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
³⁸ Department of Psychology and Neuroscience Center, Brigham Young University, Provo, Utah.
³⁹ Laboratory of Neuropsychiatry, Scientific Institute for Research, Hospitalization and Healthcare, Santa Lucia Foundation, Rome, Italy.
⁴⁰ Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center, Rotterdam, the Netherlands.
⁴¹ Department of Biomedical Engineering, Graduate School of Biomedical Sciences and Engineering, Hanyang University, Seoul, South Korea; Department of Physiology, College of Medicine, Hanyang University, Seoul, South Korea.
⁴² West Region, Institute of Mental Health, Singapore, Singapore.
⁴³ School of Psychology, University of New South Wales, Sydney, New South Wales, Australia; Neuroscience Research Australia, Randwick, New South Wales, Australia.
⁴⁴ Neuroscience Research Australia, Randwick, New South Wales, Australia; School of Clinical Medicine, Discipline of Psychiatry and Mental Health, UNSW Sydney, Sydney, New South Wales, Australia.
⁴⁵ Department of Psychiatry, Department of Physical Medicine and Rehabilitation, University of Toledo, Toledo, Ohio.
⁴⁶ Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
⁴⁷ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of University of Southern California, Los Angeles, California.
⁴⁸ Department of Psychiatry and Behavioral Health, Ohio State Wexner Medical Center, Columbus, Ohio.
⁴⁹ Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, California; Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, California.
⁵⁰ Department of Translational Biomedicine and Neuroscience-University of Bari Aldo Moro, Bari, Italy; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: giulio.pergola@uniba.it.

PMID: 40345610
DOI: 10.1016/j.biopsych.2025.03.027

Free article

Thalamocortical Structural Covariation Networks Are Related to Familial Risk for Schizophrenia in the Context of Lower Nuclei Volume Estimates in Patients: An ENIGMA Study

Annalisa Lella et al. Biol Psychiatry. 2025.

Free article

. 2025 Nov 1;98(9):698-711.

doi: 10.1016/j.biopsych.2025.03.027. Epub 2025 May 8.

Authors

Collaborators

Apulian Network on Risk for Psychosis:
Anna Manzari, Antonello Bellomo

Affiliations

¹ Department of Translational Biomedicine and Neuroscience-University of Bari Aldo Moro, Bari, Italy.
² Department of Translational Biomedicine and Neuroscience-University of Bari Aldo Moro, Bari, Italy; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
³ Department of Translational Biomedicine and Neuroscience-University of Bari Aldo Moro, Bari, Italy; Istituto Nazionale di Fisica Nucleare, Bari, Italy.
⁴ Department of Translational Biomedicine and Neuroscience-University of Bari Aldo Moro, Bari, Italy; Azienda Ospedaliero-Universitaria Consorziale Policlinico, Bari, Italy.
⁵ Neuroradiology Unit, Scientific Institute for Research, Hospitalization and Health Care, San Giovanni Rotondo, Foggia, Italy.
⁶ Department of Mental Health, Azienda Sanitaria Locale Bari, Bari, Italy.
⁷ Department of Mental Health, Azienda Sanitaria Locale Brindisi, Brindisi, Italy.
⁸ Department of Mental Health, Azienda Sanitaria Locale Barletta Andria Trani, Barletta-Andria-Trani, Italy.
⁹ Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
¹⁰ Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Department of Psychiatry and Department of Anatomy and Neuroscience, Amsterdam, the Netherlands; Compulsivity, Impulsivity and Attention, Amsterdam Neuroscience, Amsterdam, the Netherlands.
¹¹ Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia Institute of Technology, Georgia State University, Emory University, Atlanta, Georgia.
¹² Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
¹³ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neuroscience, Hospital Clínic Barcelona, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Spain.
¹⁴ FIDMAG Germanes Hospitalàries Research Foundation, Centro de Investigación Biomédica en Red de Salud Mental Instituto de Salud Carlos III, Barcelona, Spain.
¹⁵ Department of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Connecticut.
¹⁶ Department of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
¹⁷ Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine at University of Texas Rio Grande Valley, Brownsville, Texas.
¹⁸ Department of Psychiatry and Behavioral Health, Neuroscience, Ohio State University Wexner Medical Center, Columbus, Ohio.
¹⁹ Department of Psychiatry, Kyungpook National University School of Medicine, Daegu, South Korea; Department of Psychiatry, Kyungpook National University Hospital, Daegu, South Korea; Department of Biomedical Engineering, Graduate School of Biomedical Sciences and Engineering, Hanyang University, Seoul, South Korea.
²⁰ Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.
²¹ Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany; Division of Clinical Psychology and Sexual Medicine, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
²² Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, California.
²³ Department of Psychiatry, Jeonbuk National University, Medical School, Jeonju, South Korea; Department of Psychiatry, Jeonbuk National University Hospital, Jeonju, Korea; Research Institute of Clinical Medicine of Jeonbuk National University-, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.
²⁴ Department of Psychiatry, Jeonbuk National University, Medical School, Jeonju, South Korea; Research Institute of Clinical Medicine of Jeonbuk National University-, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.
²⁵ Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
²⁶ Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom; National Institute for Health and Care Research Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, London, United Kingdom.
²⁷ Department of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, the Netherlands.
²⁸ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany; Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, New York.
²⁹ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
³⁰ Centre for Mental Health and Brain Sciences, Swinburne University, Melbourne, Victoria, Australia.
³¹ Centre for Mental Health and Brain Sciences, Swinburne University, Melbourne, Victoria, Australia; Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia.
³² Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, Minnesota.
³³ Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota; Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, Minnesota.
³⁴ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
³⁵ Section of Psychiatry, Department of Neuroscience, Reproductive Sciences, and Dentistry, University School of Medicine Federico II, Naples, Italy.
³⁶ Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy; Department of Electrical Engineering and Information Technology, University "Federico II," Naples, Italy.
³⁷ Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Connecticut; Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
³⁸ Department of Psychology and Neuroscience Center, Brigham Young University, Provo, Utah.
³⁹ Laboratory of Neuropsychiatry, Scientific Institute for Research, Hospitalization and Healthcare, Santa Lucia Foundation, Rome, Italy.
⁴⁰ Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center, Rotterdam, the Netherlands.
⁴¹ Department of Biomedical Engineering, Graduate School of Biomedical Sciences and Engineering, Hanyang University, Seoul, South Korea; Department of Physiology, College of Medicine, Hanyang University, Seoul, South Korea.
⁴² West Region, Institute of Mental Health, Singapore, Singapore.
⁴³ School of Psychology, University of New South Wales, Sydney, New South Wales, Australia; Neuroscience Research Australia, Randwick, New South Wales, Australia.
⁴⁴ Neuroscience Research Australia, Randwick, New South Wales, Australia; School of Clinical Medicine, Discipline of Psychiatry and Mental Health, UNSW Sydney, Sydney, New South Wales, Australia.
⁴⁵ Department of Psychiatry, Department of Physical Medicine and Rehabilitation, University of Toledo, Toledo, Ohio.
⁴⁶ Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
⁴⁷ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of University of Southern California, Los Angeles, California.
⁴⁸ Department of Psychiatry and Behavioral Health, Ohio State Wexner Medical Center, Columbus, Ohio.
⁴⁹ Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, California; Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, California.
⁵⁰ Department of Translational Biomedicine and Neuroscience-University of Bari Aldo Moro, Bari, Italy; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: giulio.pergola@uniba.it.

PMID: 40345610
DOI: 10.1016/j.biopsych.2025.03.027

Abstract

Background: Structural brain differences in the thalamus and the cortex have been widely reported in schizophrenia (SCZ) relative to neurotypical control individuals (NCs). Most previous studies examined the thalamus as a whole as a single region of interest. In addition, findings in individuals at familial high risk for SCZ (FHRs) remain inconclusive. Here, we investigated whether local and network-wide thalamic-related structural alterations vary as a function of familial risk for SCZ.

Methods: Structural magnetic resonance imaging scans were obtained from 5197 participants (NC, n = 3409; FHR, n = 257; SCZ, n = 1531) across 32 cross-sectional samples within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Random-effects meta-analyses and network analyses were conducted on 1) local thalamic alterations (volume estimates of 7 thalamic subdivisions) and 2) network-wide thalamic alterations (thickness and surface-related thalamocortical/corticocortical covariation patterns) across groups (NC, FHR, SCZ).

Results: Individuals with SCZ showed significantly lower gray matter volume estimates in the anterior, pulvinar, medial, posterior, and ventral thalamic subdivisions compared with NCs (false discovery rate-corrected q [q_FDR] < .05). FHRs did not differ from NCs. At the network-wide level, thalamocortical covariations discriminated FHRs from NCs (q_FDR < .05), with FHRs showing intermediate covariation between individuals with SCZ and NCs. Corticocortical covariation patterns revealed that individuals with SCZ and FHRs shared similarly disconnected clustering configurations, distinct from NCs (q_FDR < .05).

Conclusions: Results revealed lower thalamic volume estimates in individuals with SCZ but not in FHRs, hence yielding no evidence of a familial risk trait, whereas thalamocortical and corticocortical covariation estimates were associated with familial risk for SCZ. These findings suggest that, once the thalamus is parsed into subdivisions, network-wide thalamocortical features may identify trait-dependent, neurobiological correlates of genetic risk for SCZ.

Keywords: Familial high risk for schizophrenia; Meta-analyses; Morphometric measures; Structural neuroimaging; Thalamic subdivisions; Thalamocortical networks.

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Thalamocortical Structural Covariation Networks Are Related to Familial Risk for Schizophrenia in the Context of Lower Nuclei Volume Estimates in Patients: An ENIGMA Study

Collaborators

Affiliations

Thalamocortical Structural Covariation Networks Are Related to Familial Risk for Schizophrenia in the Context of Lower Nuclei Volume Estimates in Patients: An ENIGMA Study

Authors

Collaborators

Affiliations

Abstract

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous