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

ENIGMA Consortium

doi:10.1002/hbm.25625

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

ENIGMA Consortium

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36 Citations (SciVal)

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 language	English
Pages (from-to)	352-372
Number of pages	21
Journal	Human Brain Mapping
Volume	43
Issue number	1
Early online date	8 Sept 2021
DOIs	https://doi.org/10.1002/hbm.25625
Publication status	Published - Jan 2022

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

ASJC Scopus subject areas

Anatomy
Radiological and Ultrasound Technology
Radiology Nuclear Medicine and imaging
Neurology
Clinical Neurology

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10.1002/hbm.25625Licence: CC BY

Cite this

@article{d003aae124384fdfb44480f96f1fb995,

title = "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",

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.",

keywords = "schizophrenia, structure, subcortical shape",

author = "{ENIGMA Consortium} and Gutman, {Boris A} and {van Erp}, {Theo G M} and Kathryn Alpert and Ching, {Christopher R K} and Dmitry Isaev and Anjani Ragothaman and Neda Jahanshad and Arvin Saremi and Artemis Zavaliangos-Petropulu and Glahn, {David C} and Li Shen and Shan Cong and Dag Alnaes and Andreassen, {Ole Andreas} and Doan, {Nhat Trung} and Westlye, {Lars T} and Peter Kochunov and Satterthwaite, {Theodore D} and Wolf, {Daniel H} and Huang, {Alexander J} and Charles Kessler and Andrea Weideman and Dana Nguyen and Mueller, {Bryon A} and Lawrence Faziola and Potkin, {Steven G} and Adrian Preda and Mathalon, {Daniel H} and Juan Bustillo and Vince Calhoun and Ford, {Judith M} and Esther Walton and Stefan Ehrlich and Giuseppe Ducci and Nerisa Banaj and Fabrizio Piras and Federica Piras and Gianfranco Spalletta and Canales-Rodr{\'i}guez, {Erick J} and Paola Fuentes-Claramonte and Edith Pomarol-Clotet and Joaquim Radua and Raymond Salvador and Salvador Sarr{\'o} and Dickie, {Erin W} and Aristotle Voineskos and Diana Tordesillas-Guti{\'e}rrez and Benedicto Crespo-Facorro and Esther Seti{\'e}n-Suero and {van Son}, {Jacqueline Mayoral}",

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 Cient{\'i}fico e Tecnol{\'o}gico, Grant/Award Numbers: 478466/2009, 480370/2009; Department of Energy, Labor and Economic Growth, Grant/Award Number: DE‐FG02‐99ER62764; Forskningsr{\aa}det om H{\"a}lsa, Arbetsliv och V{\"a}lf{\"a}rd, Grant/Award Numbers: K2009‐62X‐15077‐06‐3, K2012‐61X‐15077‐09‐3, 523‐2014‐3467, 2009‐7053, 2013‐2838; Funda{\c c}{\~a}o Amaz{\^o}nia Paraense de Amparo {\`a} 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 Forskningsr{\aa}d, 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: {\textcopyright} 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.",

year = "2022",

month = jan,

doi = "10.1002/hbm.25625",

language = "English",

volume = "43",

pages = "352--372",

journal = "Human Brain Mapping",

issn = "1065-9471",

publisher = "Wiley-Liss Inc.",

number = "1",

}

TY - JOUR

T1 - 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

AU - ENIGMA Consortium

AU - Gutman, Boris A

AU - van Erp, Theo G M

AU - Alpert, Kathryn

AU - Ching, Christopher R K

AU - Isaev, Dmitry

AU - Ragothaman, Anjani

AU - Jahanshad, Neda

AU - Saremi, Arvin

AU - Zavaliangos-Petropulu, Artemis

AU - Glahn, David C

AU - Shen, Li

AU - Cong, Shan

AU - Alnaes, Dag

AU - Andreassen, Ole Andreas

AU - Doan, Nhat Trung

AU - Westlye, Lars T

AU - Kochunov, Peter

AU - Satterthwaite, Theodore D

AU - Wolf, Daniel H

AU - Huang, Alexander J

AU - Kessler, Charles

AU - Weideman, Andrea

AU - Nguyen, Dana

AU - Mueller, Bryon A

AU - Faziola, Lawrence

AU - Potkin, Steven G

AU - Preda, Adrian

AU - Mathalon, Daniel H

AU - Bustillo, Juan

AU - Calhoun, Vince

AU - Ford, Judith M

AU - Walton, Esther

AU - Ehrlich, Stefan

AU - Ducci, Giuseppe

AU - Banaj, Nerisa

AU - Piras, Fabrizio

AU - Piras, Federica

AU - Spalletta, Gianfranco

AU - Canales-Rodríguez, Erick J

AU - Fuentes-Claramonte, Paola

AU - Pomarol-Clotet, Edith

AU - Radua, Joaquim

AU - Salvador, Raymond

AU - Sarró, Salvador

AU - Dickie, Erin W

AU - Voineskos, Aristotle

AU - Tordesillas-Gutiérrez, Diana

AU - Crespo-Facorro, Benedicto

AU - Setién-Suero, Esther

AU - van Son, Jacqueline Mayoral

N1 - 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.

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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.

KW - schizophrenia

KW - structure

KW - subcortical shape

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U2 - 10.1002/hbm.25625

DO - 10.1002/hbm.25625

M3 - Article

C2 - 34498337

SN - 1065-9471

VL - 43

SP - 352

EP - 372

JO - Human Brain Mapping

JF - Human Brain Mapping

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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