A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium

Boris A. Gutman, Theo G.M. van Erp, Kathryn Alpert, Christopher R.K. Ching, Dmitry Isaev, Anjani Ragothaman, Neda Jahanshad, Arvin Saremi, Artemis Zavaliangos-Petropulu, David C. Glahn, Li Shen, Shan Cong, Dag Alnæs, Ole Andreas Andreassen, Nhat Trung Doan, Lars T. Westlye, Peter Kochunov, Theodore D. Satterthwaite, Daniel H. Wolf, Alexander J. HuangCharles Kessler, Andrea Weideman, Dana Nguyen, Bryon A. Mueller, Lawrence Faziola, Steven G. Potkin, Adrian Preda, Daniel H. Mathalon, Juan Bustillo, Vince Calhoun, Judith M. Ford, Esther Walton, Stefan Ehrlich, Giuseppe Ducci, Nerisa Banaj, Fabrizio Piras, Federica Piras, Gianfranco Spalletta, Erick J. Canales-Rodríguez, Paola Fuentes-Claramonte, Edith Pomarol-Clotet, Joaquim Radua, Raymond Salvador, Salvador Sarró, Erin W. Dickie, Aristotle Voineskos, Diana Tordesillas-Gutiérrez, Benedicto Crespo-Facorro, Esther Setién-Suero, Jacqueline Mayoral van Son, Stefan Borgwardt, Fabienne Schönborn-Harrisberger, Derek Morris, Gary Donohoe, Laurena Holleran, Dara Cannon, Colm McDonald, Aiden Corvin, Michael Gill, Geraldo Busatto Filho, Pedro G.P. Rosa, Mauricio H. Serpa, Marcus V. Zanetti, Irina Lebedeva, Vasily Kaleda, Alexander Tomyshev, Tim Crow, Anthony James, Simon Cervenka, Carl M. Sellgren, Helena Fatouros-Bergman, Ingrid Agartz, Fleur Howells, Dan J. Stein, Henk Temmingh, Anne Uhlmann, Greig I. de Zubicaray, Katie L. McMahon, Margie Wright, Derin Cobia, John G. Csernansky, Paul M. Thompson, Jessica A. Turner, Lei Wang

Research output: Contribution to journalArticlepeer-review

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Abstract

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.

Original languageEnglish (US)
JournalHuman Brain Mapping
Early online dateSep 8 2021
DOIs
StateE-pub ahead of print - Sep 8 2021

Bibliographical note

Funding Information:
One of the authors (TGMvE) has had a research contract with Otsuka Pharmaceutical. One of the authors (AP) has served as a consultant for Boehringer Ingelheim. One of the authors (DJS) has received research grants and/or honoraria from Lundbeck and Sun. One of the authors (DHM) has served as a consultant for Boehringer Ingelheim, Aptinyx, and Greenwich Biosciences. One of the authors (SC) has received grant support from AstraZeneca as co‐investigator, and has served as a speaker for Otsuka Pharmaceuticals. Authors PMT, CRKC, and NJ received a research grant from Biogen, Inc. (Boston) for research unrelated to this manuscript. The remaining authors declare no potential conflict of interest.

Funding Information:
Center for Integrated Healthcare, U.S. Department of Veterans Affairs, Grant/Award Number: I01 CX000497; Commonwealth Health Research Board, Grant/Award Number: HRA_POR/2011/100; Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant/Award Numbers: 478466/2009, 480370/2009; Department of Energy, Labor and Economic Growth, Grant/Award Number: DE‐FG02‐99ER62764; Forskningsrådet om Hälsa, Arbetsliv och Välfärd, Grant/Award Numbers: K2009‐62X‐15077‐06‐3, K2012‐61X‐15077‐09‐3, 523‐2014‐3467, 2009‐7053, 2013‐2838; Fundação Amazônia Paraense de Amparo à Pesquisa, Grant/Award Numbers: 2009/14891‐9, 2010/18672‐7, 2012/23796‐2, 2013/039; Instituto de Salud Carlos III, Grant/Award Numbers: FIS 00/3095, 01/3129, PI020499, PI060507, PI10/001; National Health and Medical Research Council, Grant/Award Numbers: 1009064, 496682; National Institutes of Health, Grant/Award Numbers: 1RC1MH089257, MH 60722, MH019112, MH064045, MH085096, MH098130, MO1 RR025758, P41RR14075, P50 MH071616, R01 DA053028, R01 EB020062, R01 HD050735, R01 MH056584, R01 MH084803, R01 MH116147, R01 MH117601, R01EB005846, R01EB015611, R01MH074797, R21 MH097196, R21MH097196, R37MH43375, S10 OD023696, T32 AG058507, T32 MH073526, TR000153, U01 MH097435, U24 RR021382A, U24 RR021992, U24 RR025736, U24 RR21992, U24RR021992, U54 EB020403, U54EB020403, UL1 TR000153; National Science Foundation, Grant/Award Numbers: 1636893, 1734853; Norges Forskningsråd, Grant/Award Numbers: 213837, 217776, 223273; Science Foundation Ireland, Grant/Award Numbers: 08/IN.1/B1916, 12/IP/1359; Wellcome Trust, Grant/Award Number: 072894/2/03/Z Funding information

Funding Information:
Research reported in this publication was supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) of the National Institutes of Health under Award Number U54EB020403 and R01MH116147. For additional grant support and acknowledgments, see Supplementary Materials.

Publisher Copyright:
© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

Keywords

  • schizophrenia
  • structure
  • subcortical shape

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