Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group

ENIGMA Bipolar Disorder Working Group

doi:10.1016/j.biopsych.2021.09.008

Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group

ENIGMA Bipolar Disorder Working Group

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. Methods: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. Results: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18 < d < 0.22). More (hypo)manic episodes were associated with faster cortical thinning, primarily in the prefrontal cortex. Conclusions: In the hitherto largest longitudinal MRI study on BD, we did not detect accelerated cortical thinning but noted faster ventricular enlargements in BD. However, abnormal frontocortical thinning was observed in association with frequent manic episodes. Our study yields insights into disease progression in BD and highlights the importance of mania prevention in BD treatment.

Original language	English
Pages (from-to)	582-592
Number of pages	11
Journal	Biological psychiatry
Volume	91
Issue number	6
Early online date	16 Sept 2021
DOIs	https://doi.org/10.1016/j.biopsych.2021.09.008
Publication status	Published - 15 Mar 2022

Bibliographical note

Funding Information:
The St. Göran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish Foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain Foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant No. ALF 20170019 [to ML]). This study was funded by the South-Eastern Norway Regional Health Authority (to TE) and a research grant from Mrs. Throne-Holst (to TE). The National University of Ireland Galway study was supported by grant funding from the Health Research Board (Grant No. HRA_POR/2011/100). FOR2107 was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (Grant Nos. KI 588/14-1 , KI 588/14-2 , KR 3822/5-1 , KR 3822/7-2 , and NE 2254/1-2 ). This study was supported by Grants of Deutsche Forschungsgemeinschaft (Grant Nos. NE2254/2-1 , NE2254/3-1 , and NE2254/4-1 [to IN]). This study was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004 and SIG/05028 [to KS]), and the Singapore Bioimaging Consortium (Grant No. RP C009/2006 [to KS]). This study is supported by the European Research Council under the European Union’s Horizon 2020 Research and Innovation program (Grant No. 802998 [to LTW]), the Research Council of Norway (Grant No. 300767 [to LTW]), and the South-Eastern Norway Regional Health Authority (Grant No. 2019101 [to LTW]). The University of New South Wales “Kids and Sibs” Study was supported by the Australian National Medical and Health Research Council (Program Grant No. 1037196 and Investigator Grant No. 1177991 [to PBM] and Project Grant No. 1066177 [to JMF]), the Lansdowne Foundation, Good Talk and the Keith Pettigrew Family Bequest (to PM). This study was supported by the Janette Mary O’Neil Research Fellowship (to JMF). This study was supported by grants from the Deutsche Forschungsgemeinschaft (German Research Council) (Grant No. INST 2105/57-1 [to WH]). CRKC was supported by NIA (Grant No. T32AG058507; National Institutes of Health (Grant No. U54EB020403 ) from the Big Data to Knowledge Program; and has received partial research support from Biogen, Inc. for work unrelated to the topic of this manuscript. This study was supported by Deutsche Forschungsgemeinschaft (Grant Nos. NE 2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI15/00283 and CPII19/00009 [to EV, JR, JMG, and CdMB]), cofinanced by European Regional Development Fund Funds from the European Commission (A Way of Making Europe) (to EV, JR, JMG, and CdMB), Centro de Investigación Biomédica en Red de Salud Mental (to EV, JR, JMG, and CdMB), and the Departament de Salut de la Generalitat de Catalunya, CERCA Programme/Generalitat de Catalunya (Grant Nos. 2017SGR1365, SLT002/16/00331, and SLT006/17/00357 [to EV, JR, JMG, CdMB]). This study was funded by the South-Eastern Norway Regional Health Authority (Grant Nos. 2019107 and 2020086 [to DA]). This study was supported by Norwegian Centre of Excellence grant (Grant No. 223273 [to BH]) and KG Jebsen grant (Grant No. SKGJ-MED-008 [to BH]). This study was supported by funding from the Canadian Institutes of Health Research (Grant Nos. 103703 , 106469 , and 142255 [to TH]), Nova Scotia Health Research Foundation (to TH), Dalhousie Clinical Research Scholarship (to TH), Brain & Behavior Research Foundation (to TH), and 2007 Young Investigator and 2015 Independent Investigator Awards (to TH). This study was supported by the Research Council of Norway (Grant Nos. 223273 and 248828 [to OAA]), South-East Norway Health Authority (Grant No. 2019-108 [to OAA]), KG Jebsen Stiftelsen, University of Oslo Life:Science program, EU H2020 (Grant No. 847776 CoMorMent [to OAA]). This study was supported in part National Institutes of Health grants (Grant No. R01MH116147 , R01MH121246 , and R01MH111671 [to ENIGMA]).

Funding Information:
The St. G?ran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish Foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain Foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant No. ALF 20170019 [to ML]). This study was funded by the South-Eastern Norway Regional Health Authority (to TE) and a research grant from Mrs. Throne-Holst (to TE). The National University of Ireland Galway study was supported by grant funding from the Health Research Board (Grant No. HRA_POR/2011/100). FOR2107 was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (Grant Nos. KI 588/14-1, KI 588/14-2, KR 3822/5-1, KR 3822/7-2, and NE 2254/1-2). This study was supported by Grants of Deutsche Forschungsgemeinschaft (Grant Nos. NE2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004 and SIG/05028 [to KS]), and the Singapore Bioimaging Consortium (Grant No. RP C009/2006 [to KS]). This study is supported by the European Research Council under the European Union's Horizon 2020 Research and Innovation program (Grant No. 802998 [to LTW]), the Research Council of Norway (Grant No. 300767 [to LTW]), and the South-Eastern Norway Regional Health Authority (Grant No. 2019101 [to LTW]). The University of New South Wales ?Kids and Sibs? Study was supported by the Australian National Medical and Health Research Council (Program Grant No. 1037196 and Investigator Grant No. 1177991 [to PBM] and Project Grant No. 1066177 [to JMF]), the Lansdowne Foundation, Good Talk and the Keith Pettigrew Family Bequest (to PM). This study was supported by the Janette Mary O'Neil Research Fellowship (to JMF). This study was supported by grants from the Deutsche Forschungsgemeinschaft (German Research Council) (Grant No. INST 2105/57-1 [to WH]). CRKC was supported by NIA (Grant No. T32AG058507; National Institutes of Health (Grant No. U54EB020403) from the Big Data to Knowledge Program; and has received partial research support from Biogen, Inc. for work unrelated to the topic of this manuscript. This study was supported by Deutsche Forschungsgemeinschaft (Grant Nos. NE 2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI15/00283 and CPII19/00009 [to EV, JR, JMG, and CdMB]), cofinanced by European Regional Development Fund Funds from the European Commission (A Way of Making Europe) (to EV, JR, JMG, and CdMB), Centro de Investigaci?n Biom?dica en Red de Salud Mental (to EV, JR, JMG, and CdMB), and the Departament de Salut de la Generalitat de Catalunya, CERCA Programme/Generalitat de Catalunya (Grant Nos. 2017SGR1365, SLT002/16/00331, and SLT006/17/00357 [to EV, JR, JMG, CdMB]). This study was funded by the South-Eastern Norway Regional Health Authority (Grant Nos. 2019107 and 2020086 [to DA]). This study was supported by Norwegian Centre of Excellence grant (Grant No. 223273 [to BH]) and KG Jebsen grant (Grant No. SKGJ-MED-008 [to BH]). This study was supported by funding from the Canadian Institutes of Health Research (Grant Nos. 103703, 106469, and 142255 [to TH]), Nova Scotia Health Research Foundation (to TH), Dalhousie Clinical Research Scholarship (to TH), Brain & Behavior Research Foundation (to TH), and 2007 Young Investigator and 2015 Independent Investigator Awards (to TH). This study was supported by the Research Council of Norway (Grant Nos. 223273 and 248828 [to OAA]), South-East Norway Health Authority (Grant No. 2019-108 [to OAA]), KG Jebsen Stiftelsen, University of Oslo Life:Science program, EU H2020 (Grant No. 847776 CoMorMent [to OAA]). This study was supported in part National Institutes of Health grants (Grant No. R01MH116147, R01MH121246, and R01MH111671 [to ENIGMA]). CA is employed at Quantify Research (work unrelated to the present manuscript). TE is a consultant to BrainWaveBank and received speaker's honoraria from Lundbeck and Janssen-Cilag. LY has been on speaker/advisory boards for, or has received research grants from, Alkermes, AbbVie, Allergan, Canadian Network for Mood and Anxiety Treatments, Canadian Institutes of Health Research, DSP, Intracellular Therapies, Merck, Sanofi, and Sunovion. EV has received grants and served as consultant, advisor, or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. PMT received partial research support from Biogen, Inc. for research unrelated to this manuscript. PBM received honoraria for speaking or advisory committee membership from Sanofi and Janssen. ML has received lecture honoraria from Lundbeck. OAA is consultant to HealthLytix and received speaker's honorarium from Lundbeck and Sunovion. All other authors report no biomedical financial interests or potential conflicts of interest.

Funding Information:
CA is employed at Quantify Research (work unrelated to the present manuscript). TE is a consultant to BrainWaveBank and received speaker’s honoraria from Lundbeck and Janssen-Cilag. LY has been on speaker/advisory boards for, or has received research grants from, Alkermes, AbbVie, Allergan, Canadian Network for Mood and Anxiety Treatments, Canadian Institutes of Health Research, DSP, Intracellular Therapies, Merck, Sanofi, and Sunovion. EV has received grants and served as consultant, advisor, or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. PMT received partial research support from Biogen, Inc., for research unrelated to this manuscript. PBM received honoraria for speaking or advisory committee membership from Sanofi and Janssen. ML has received lecture honoraria from Lundbeck. OAA is consultant to HealthLytix and received speaker’s honorarium from Lundbeck and Sunovion. All other authors report no biomedical financial interests or potential conflicts of interest.

Publisher Copyright:
© 2021 Society of Biological Psychiatry

Funding

The St. Göran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish Foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain Foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant No. ALF 20170019 [to ML]). This study was funded by the South-Eastern Norway Regional Health Authority (to TE) and a research grant from Mrs. Throne-Holst (to TE). The National University of Ireland Galway study was supported by grant funding from the Health Research Board (Grant No. HRA_POR/2011/100). FOR2107 was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (Grant Nos. KI 588/14-1 , KI 588/14-2 , KR 3822/5-1 , KR 3822/7-2 , and NE 2254/1-2 ). This study was supported by Grants of Deutsche Forschungsgemeinschaft (Grant Nos. NE2254/2-1 , NE2254/3-1 , and NE2254/4-1 [to IN]). This study was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004 and SIG/05028 [to KS]), and the Singapore Bioimaging Consortium (Grant No. RP C009/2006 [to KS]). This study is supported by the European Research Council under the European Union’s Horizon 2020 Research and Innovation program (Grant No. 802998 [to LTW]), the Research Council of Norway (Grant No. 300767 [to LTW]), and the South-Eastern Norway Regional Health Authority (Grant No. 2019101 [to LTW]). The University of New South Wales “Kids and Sibs” Study was supported by the Australian National Medical and Health Research Council (Program Grant No. 1037196 and Investigator Grant No. 1177991 [to PBM] and Project Grant No. 1066177 [to JMF]), the Lansdowne Foundation, Good Talk and the Keith Pettigrew Family Bequest (to PM). This study was supported by the Janette Mary O’Neil Research Fellowship (to JMF). This study was supported by grants from the Deutsche Forschungsgemeinschaft (German Research Council) (Grant No. INST 2105/57-1 [to WH]). CRKC was supported by NIA (Grant No. T32AG058507; National Institutes of Health (Grant No. U54EB020403 ) from the Big Data to Knowledge Program; and has received partial research support from Biogen, Inc. for work unrelated to the topic of this manuscript. This study was supported by Deutsche Forschungsgemeinschaft (Grant Nos. NE 2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI15/00283 and CPII19/00009 [to EV, JR, JMG, and CdMB]), cofinanced by European Regional Development Fund Funds from the European Commission (A Way of Making Europe) (to EV, JR, JMG, and CdMB), Centro de Investigación Biomédica en Red de Salud Mental (to EV, JR, JMG, and CdMB), and the Departament de Salut de la Generalitat de Catalunya, CERCA Programme/Generalitat de Catalunya (Grant Nos. 2017SGR1365, SLT002/16/00331, and SLT006/17/00357 [to EV, JR, JMG, CdMB]). This study was funded by the South-Eastern Norway Regional Health Authority (Grant Nos. 2019107 and 2020086 [to DA]). This study was supported by Norwegian Centre of Excellence grant (Grant No. 223273 [to BH]) and KG Jebsen grant (Grant No. SKGJ-MED-008 [to BH]). This study was supported by funding from the Canadian Institutes of Health Research (Grant Nos. 103703 , 106469 , and 142255 [to TH]), Nova Scotia Health Research Foundation (to TH), Dalhousie Clinical Research Scholarship (to TH), Brain & Behavior Research Foundation (to TH), and 2007 Young Investigator and 2015 Independent Investigator Awards (to TH). This study was supported by the Research Council of Norway (Grant Nos. 223273 and 248828 [to OAA]), South-East Norway Health Authority (Grant No. 2019-108 [to OAA]), KG Jebsen Stiftelsen, University of Oslo Life:Science program, EU H2020 (Grant No. 847776 CoMorMent [to OAA]). This study was supported in part National Institutes of Health grants (Grant No. R01MH116147 , R01MH121246 , and R01MH111671 [to ENIGMA]). The St. G?ran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish Foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain Foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant No. ALF 20170019 [to ML]). This study was funded by the South-Eastern Norway Regional Health Authority (to TE) and a research grant from Mrs. Throne-Holst (to TE). The National University of Ireland Galway study was supported by grant funding from the Health Research Board (Grant No. HRA_POR/2011/100). FOR2107 was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (Grant Nos. KI 588/14-1, KI 588/14-2, KR 3822/5-1, KR 3822/7-2, and NE 2254/1-2). This study was supported by Grants of Deutsche Forschungsgemeinschaft (Grant Nos. NE2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004 and SIG/05028 [to KS]), and the Singapore Bioimaging Consortium (Grant No. RP C009/2006 [to KS]). This study is supported by the European Research Council under the European Union's Horizon 2020 Research and Innovation program (Grant No. 802998 [to LTW]), the Research Council of Norway (Grant No. 300767 [to LTW]), and the South-Eastern Norway Regional Health Authority (Grant No. 2019101 [to LTW]). The University of New South Wales ?Kids and Sibs? Study was supported by the Australian National Medical and Health Research Council (Program Grant No. 1037196 and Investigator Grant No. 1177991 [to PBM] and Project Grant No. 1066177 [to JMF]), the Lansdowne Foundation, Good Talk and the Keith Pettigrew Family Bequest (to PM). This study was supported by the Janette Mary O'Neil Research Fellowship (to JMF). This study was supported by grants from the Deutsche Forschungsgemeinschaft (German Research Council) (Grant No. INST 2105/57-1 [to WH]). CRKC was supported by NIA (Grant No. T32AG058507; National Institutes of Health (Grant No. U54EB020403) from the Big Data to Knowledge Program; and has received partial research support from Biogen, Inc. for work unrelated to the topic of this manuscript. This study was supported by Deutsche Forschungsgemeinschaft (Grant Nos. NE 2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI15/00283 and CPII19/00009 [to EV, JR, JMG, and CdMB]), cofinanced by European Regional Development Fund Funds from the European Commission (A Way of Making Europe) (to EV, JR, JMG, and CdMB), Centro de Investigaci?n Biom?dica en Red de Salud Mental (to EV, JR, JMG, and CdMB), and the Departament de Salut de la Generalitat de Catalunya, CERCA Programme/Generalitat de Catalunya (Grant Nos. 2017SGR1365, SLT002/16/00331, and SLT006/17/00357 [to EV, JR, JMG, CdMB]). This study was funded by the South-Eastern Norway Regional Health Authority (Grant Nos. 2019107 and 2020086 [to DA]). This study was supported by Norwegian Centre of Excellence grant (Grant No. 223273 [to BH]) and KG Jebsen grant (Grant No. SKGJ-MED-008 [to BH]). This study was supported by funding from the Canadian Institutes of Health Research (Grant Nos. 103703, 106469, and 142255 [to TH]), Nova Scotia Health Research Foundation (to TH), Dalhousie Clinical Research Scholarship (to TH), Brain & Behavior Research Foundation (to TH), and 2007 Young Investigator and 2015 Independent Investigator Awards (to TH). This study was supported by the Research Council of Norway (Grant Nos. 223273 and 248828 [to OAA]), South-East Norway Health Authority (Grant No. 2019-108 [to OAA]), KG Jebsen Stiftelsen, University of Oslo Life:Science program, EU H2020 (Grant No. 847776 CoMorMent [to OAA]). This study was supported in part National Institutes of Health grants (Grant No. R01MH116147, R01MH121246, and R01MH111671 [to ENIGMA]). CA is employed at Quantify Research (work unrelated to the present manuscript). TE is a consultant to BrainWaveBank and received speaker's honoraria from Lundbeck and Janssen-Cilag. LY has been on speaker/advisory boards for, or has received research grants from, Alkermes, AbbVie, Allergan, Canadian Network for Mood and Anxiety Treatments, Canadian Institutes of Health Research, DSP, Intracellular Therapies, Merck, Sanofi, and Sunovion. EV has received grants and served as consultant, advisor, or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. PMT received partial research support from Biogen, Inc. for research unrelated to this manuscript. PBM received honoraria for speaking or advisory committee membership from Sanofi and Janssen. ML has received lecture honoraria from Lundbeck. OAA is consultant to HealthLytix and received speaker's honorarium from Lundbeck and Sunovion. All other authors report no biomedical financial interests or potential conflicts of interest. CA is employed at Quantify Research (work unrelated to the present manuscript). TE is a consultant to BrainWaveBank and received speaker’s honoraria from Lundbeck and Janssen-Cilag. LY has been on speaker/advisory boards for, or has received research grants from, Alkermes, AbbVie, Allergan, Canadian Network for Mood and Anxiety Treatments, Canadian Institutes of Health Research, DSP, Intracellular Therapies, Merck, Sanofi, and Sunovion. EV has received grants and served as consultant, advisor, or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. PMT received partial research support from Biogen, Inc., for research unrelated to this manuscript. PBM received honoraria for speaking or advisory committee membership from Sanofi and Janssen. ML has received lecture honoraria from Lundbeck. OAA is consultant to HealthLytix and received speaker’s honorarium from Lundbeck and Sunovion. All other authors report no biomedical financial interests or potential conflicts of interest.

Funders	Funder number
Angelini Pharma
H. Lundbeck A/S
Spanish Ministry of Science, Innovation and Universities/Economy
Dainippon Sumitomo Pharma
Sunovion
Keith Pettigrew Family Bequest
Biogen
Cilag
Departament de Salut, Generalitat de Catalunya
European Commission
Abbott Laboratories
Nova Scotia Health Research Foundation
Centro de Investigación Biomédica en Red de Salud Mental
Lansdowne Foundation
AB-Biotics
European Research Council
Helse Sør-Øst RHF
Sanofi
European Regional Development Fund
Allergan
Biogen, Inc.
Horizon 2020
Vetenskapsrådet	2018-02653
Competitiveness/Instituto de Salud Carlos III	PI15/00283, CPII19/00009
KG Jebsen	SKGJ-MED-008
Brain and Behavior Research Foundation	248828
EU H2020	R01MH116147, R01MH111671, R01MH121246
Singapore Bioimaging Consortium	RP C009/2006
Horizon 2020 Framework Programme	802998, 847776
Australian National Medical and Health Research Council	1037196, 1177991, 1066177
Hjärnfonden	FO2020-0261
Norwegian Centre of Excellence	223273
Health Research Board	FOR2107, HRA_POR/2011/100
South-East Norway Health Authority	2019-108
National Institutes of Health	U54EB020403
National Healthcare Group, Singapore	SIG/05004, SIG/05028
Deutsche Forschungsgemeinschaft	NE 2254/2-1, NE 2254/1-2, KI 588/14-2, KI 588/14-1, NE2254/3-1, NE2254/4-1, INST 2105/57-1, KR 3822/7-2, KR 3822/5-1
National Institute on Aging	T32AG058507
Norges forskningsråd	2019101, 300767
Canadian Institutes of Health Research	142255, 106469
de Catalunya	SLT002/16/00331, 2020086, SLT006/17/00357, 2017SGR1365, 2019107
Stiftelsen för Strategisk Forskning	KF10-0039
Swedish Government	ALF 20170019
UK Research and Innovation	103703

Keywords

Bipolar disorder
ENIGMA
Longitudinal study
Neuroimaging
Neuroprogression
Psychiatry

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10.1016/j.biopsych.2021.09.008

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Cite this

@article{48b07fe4f5f1465c9064182d8300bc71,

title = "Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group",

abstract = "Background: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. Methods: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. Results: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18 < d < 0.22). More (hypo)manic episodes were associated with faster cortical thinning, primarily in the prefrontal cortex. Conclusions: In the hitherto largest longitudinal MRI study on BD, we did not detect accelerated cortical thinning but noted faster ventricular enlargements in BD. However, abnormal frontocortical thinning was observed in association with frequent manic episodes. Our study yields insights into disease progression in BD and highlights the importance of mania prevention in BD treatment.",

keywords = "Bipolar disorder, ENIGMA, Longitudinal study, Neuroimaging, Neuroprogression, Psychiatry",

author = "Christoph Ab{\'e} and Ching, \{Christopher R.K.\} and Benny Liberg and Lebedev, \{Alexander V.\} and Ingrid Agartz and Akudjedu, \{Theophilus N.\} and Martin Alda and Dag Aln{\ae}s and Silvia Alonso-Lana and Francesco Benedetti and Michael Berk and Erlend B{\o}en and Bonnin, \{Caterina del Mar\} and Fabian Breuer and Katharina Brosch and Brouwer, \{Rachel M.\} and Canales-Rodr{\'i}guez, \{Erick J.\} and Cannon, \{Dara M.\} and Yann Chye and Andreas Dahl and Orwa Dandash and Udo Dannlowski and Katharina Dohm and Torbj{\o}rn Elvs{\aa}shagen and Lukas Fisch and Fullerton, \{Janice M.\} and Goikolea, \{Jose M.\} and Dominik Grotegerd and Beathe Haatveit and Tim Hahn and Tomas Hajek and Walter Heindel and Martin Ingvar and Kang Sim and Kircher, \{Tilo T.J.\} and Lenroot, \{Rhoshel K.\} and Malt, \{Ulrik F.\} and Colm McDonald and McWhinney, \{Sean R.\} and Ingrid Melle and Tina Meller and Melloni, \{Elisa M.T.\} and Mitchell, \{Philip B.\} and Leila Nabulsi and Igor Nenadi{\'c} and Nils Opel and Overs, \{Bronwyn J.\} and Francesco Panicalli and Pfarr, \{Julia Katharina\} and Sara Poletti and Edith Pomarol-Clotet and Joaquim Radua and Jonathan Repple and Ringwald, \{Kai G.\} and Gloria Roberts and Elena Rodriguez-Cano and Raymond Salvador and Kelvin Sarink and Salvador Sarr{\'o} and Simon Schmitt and Frederike Stein and Chao Suo and Thomopoulos, \{Sophia I.\} and Giulia Tronchin and Eduard Vieta and Westlye, \{Lars T.\} and White, \{Adam G.\} and Yatham, \{Lakshmi N.\} and Nathalia Zak and Thompson, \{Paul M.\} and Andreassen, \{Ole A.\} and Mikael Land{\'e}n and \{ENIGMA Bipolar Disorder Working Group\}",

note = "Funding Information: The St. G{\"o}ran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish Foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain Foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant No. ALF 20170019 [to ML]). This study was funded by the South-Eastern Norway Regional Health Authority (to TE) and a research grant from Mrs. Throne-Holst (to TE). The National University of Ireland Galway study was supported by grant funding from the Health Research Board (Grant No. HRA\_POR/2011/100). FOR2107 was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (Grant Nos. KI 588/14-1 , KI 588/14-2 , KR 3822/5-1 , KR 3822/7-2 , and NE 2254/1-2 ). This study was supported by Grants of Deutsche Forschungsgemeinschaft (Grant Nos. NE2254/2-1 , NE2254/3-1 , and NE2254/4-1 [to IN]). This study was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004 and SIG/05028 [to KS]), and the Singapore Bioimaging Consortium (Grant No. RP C009/2006 [to KS]). This study is supported by the European Research Council under the European Union{\textquoteright}s Horizon 2020 Research and Innovation program (Grant No. 802998 [to LTW]), the Research Council of Norway (Grant No. 300767 [to LTW]), and the South-Eastern Norway Regional Health Authority (Grant No. 2019101 [to LTW]). The University of New South Wales “Kids and Sibs” Study was supported by the Australian National Medical and Health Research Council (Program Grant No. 1037196 and Investigator Grant No. 1177991 [to PBM] and Project Grant No. 1066177 [to JMF]), the Lansdowne Foundation, Good Talk and the Keith Pettigrew Family Bequest (to PM). This study was supported by the Janette Mary O{\textquoteright}Neil Research Fellowship (to JMF). This study was supported by grants from the Deutsche Forschungsgemeinschaft (German Research Council) (Grant No. INST 2105/57-1 [to WH]). CRKC was supported by NIA (Grant No. T32AG058507; National Institutes of Health (Grant No. U54EB020403 ) from the Big Data to Knowledge Program; and has received partial research support from Biogen, Inc. for work unrelated to the topic of this manuscript. This study was supported by Deutsche Forschungsgemeinschaft (Grant Nos. NE 2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI15/00283 and CPII19/00009 [to EV, JR, JMG, and CdMB]), cofinanced by European Regional Development Fund Funds from the European Commission (A Way of Making Europe) (to EV, JR, JMG, and CdMB), Centro de Investigaci{\'o}n Biom{\'e}dica en Red de Salud Mental (to EV, JR, JMG, and CdMB), and the Departament de Salut de la Generalitat de Catalunya, CERCA Programme/Generalitat de Catalunya (Grant Nos. 2017SGR1365, SLT002/16/00331, and SLT006/17/00357 [to EV, JR, JMG, CdMB]). This study was funded by the South-Eastern Norway Regional Health Authority (Grant Nos. 2019107 and 2020086 [to DA]). This study was supported by Norwegian Centre of Excellence grant (Grant No. 223273 [to BH]) and KG Jebsen grant (Grant No. SKGJ-MED-008 [to BH]). This study was supported by funding from the Canadian Institutes of Health Research (Grant Nos. 103703 , 106469 , and 142255 [to TH]), Nova Scotia Health Research Foundation (to TH), Dalhousie Clinical Research Scholarship (to TH), Brain \& Behavior Research Foundation (to TH), and 2007 Young Investigator and 2015 Independent Investigator Awards (to TH). This study was supported by the Research Council of Norway (Grant Nos. 223273 and 248828 [to OAA]), South-East Norway Health Authority (Grant No. 2019-108 [to OAA]), KG Jebsen Stiftelsen, University of Oslo Life:Science program, EU H2020 (Grant No. 847776 CoMorMent [to OAA]). This study was supported in part National Institutes of Health grants (Grant No. R01MH116147 , R01MH121246 , and R01MH111671 [to ENIGMA]). Funding Information: The St. G?ran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish Foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain Foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant No. ALF 20170019 [to ML]). This study was funded by the South-Eastern Norway Regional Health Authority (to TE) and a research grant from Mrs. Throne-Holst (to TE). The National University of Ireland Galway study was supported by grant funding from the Health Research Board (Grant No. HRA\_POR/2011/100). FOR2107 was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (Grant Nos. KI 588/14-1, KI 588/14-2, KR 3822/5-1, KR 3822/7-2, and NE 2254/1-2). This study was supported by Grants of Deutsche Forschungsgemeinschaft (Grant Nos. NE2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004 and SIG/05028 [to KS]), and the Singapore Bioimaging Consortium (Grant No. RP C009/2006 [to KS]). This study is supported by the European Research Council under the European Union's Horizon 2020 Research and Innovation program (Grant No. 802998 [to LTW]), the Research Council of Norway (Grant No. 300767 [to LTW]), and the South-Eastern Norway Regional Health Authority (Grant No. 2019101 [to LTW]). The University of New South Wales ?Kids and Sibs? Study was supported by the Australian National Medical and Health Research Council (Program Grant No. 1037196 and Investigator Grant No. 1177991 [to PBM] and Project Grant No. 1066177 [to JMF]), the Lansdowne Foundation, Good Talk and the Keith Pettigrew Family Bequest (to PM). This study was supported by the Janette Mary O'Neil Research Fellowship (to JMF). This study was supported by grants from the Deutsche Forschungsgemeinschaft (German Research Council) (Grant No. INST 2105/57-1 [to WH]). CRKC was supported by NIA (Grant No. T32AG058507; National Institutes of Health (Grant No. U54EB020403) from the Big Data to Knowledge Program; and has received partial research support from Biogen, Inc. for work unrelated to the topic of this manuscript. This study was supported by Deutsche Forschungsgemeinschaft (Grant Nos. NE 2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI15/00283 and CPII19/00009 [to EV, JR, JMG, and CdMB]), cofinanced by European Regional Development Fund Funds from the European Commission (A Way of Making Europe) (to EV, JR, JMG, and CdMB), Centro de Investigaci?n Biom?dica en Red de Salud Mental (to EV, JR, JMG, and CdMB), and the Departament de Salut de la Generalitat de Catalunya, CERCA Programme/Generalitat de Catalunya (Grant Nos. 2017SGR1365, SLT002/16/00331, and SLT006/17/00357 [to EV, JR, JMG, CdMB]). This study was funded by the South-Eastern Norway Regional Health Authority (Grant Nos. 2019107 and 2020086 [to DA]). This study was supported by Norwegian Centre of Excellence grant (Grant No. 223273 [to BH]) and KG Jebsen grant (Grant No. SKGJ-MED-008 [to BH]). This study was supported by funding from the Canadian Institutes of Health Research (Grant Nos. 103703, 106469, and 142255 [to TH]), Nova Scotia Health Research Foundation (to TH), Dalhousie Clinical Research Scholarship (to TH), Brain \& Behavior Research Foundation (to TH), and 2007 Young Investigator and 2015 Independent Investigator Awards (to TH). This study was supported by the Research Council of Norway (Grant Nos. 223273 and 248828 [to OAA]), South-East Norway Health Authority (Grant No. 2019-108 [to OAA]), KG Jebsen Stiftelsen, University of Oslo Life:Science program, EU H2020 (Grant No. 847776 CoMorMent [to OAA]). This study was supported in part National Institutes of Health grants (Grant No. R01MH116147, R01MH121246, and R01MH111671 [to ENIGMA]). CA is employed at Quantify Research (work unrelated to the present manuscript). TE is a consultant to BrainWaveBank and received speaker's honoraria from Lundbeck and Janssen-Cilag. LY has been on speaker/advisory boards for, or has received research grants from, Alkermes, AbbVie, Allergan, Canadian Network for Mood and Anxiety Treatments, Canadian Institutes of Health Research, DSP, Intracellular Therapies, Merck, Sanofi, and Sunovion. EV has received grants and served as consultant, advisor, or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. PMT received partial research support from Biogen, Inc. for research unrelated to this manuscript. PBM received honoraria for speaking or advisory committee membership from Sanofi and Janssen. ML has received lecture honoraria from Lundbeck. OAA is consultant to HealthLytix and received speaker's honorarium from Lundbeck and Sunovion. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: CA is employed at Quantify Research (work unrelated to the present manuscript). TE is a consultant to BrainWaveBank and received speaker{\textquoteright}s honoraria from Lundbeck and Janssen-Cilag. LY has been on speaker/advisory boards for, or has received research grants from, Alkermes, AbbVie, Allergan, Canadian Network for Mood and Anxiety Treatments, Canadian Institutes of Health Research, DSP, Intracellular Therapies, Merck, Sanofi, and Sunovion. EV has received grants and served as consultant, advisor, or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. PMT received partial research support from Biogen, Inc., for research unrelated to this manuscript. PBM received honoraria for speaking or advisory committee membership from Sanofi and Janssen. ML has received lecture honoraria from Lundbeck. OAA is consultant to HealthLytix and received speaker{\textquoteright}s honorarium from Lundbeck and Sunovion. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2021 Society of Biological Psychiatry",

year = "2022",

month = mar,

day = "15",

doi = "10.1016/j.biopsych.2021.09.008",

language = "English",

volume = "91",

pages = "582--592",

journal = "Biological psychiatry",

issn = "0006-3223",

publisher = "Elsevier Inc.",

number = "6",

}

TY - JOUR

T1 - Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group

AU - Abé, Christoph

AU - Ching, Christopher R.K.

AU - Liberg, Benny

AU - Lebedev, Alexander V.

AU - Agartz, Ingrid

AU - Akudjedu, Theophilus N.

AU - Alda, Martin

AU - Alnæs, Dag

AU - Alonso-Lana, Silvia

AU - Benedetti, Francesco

AU - Berk, Michael

AU - Bøen, Erlend

AU - Bonnin, Caterina del Mar

AU - Breuer, Fabian

AU - Brosch, Katharina

AU - Brouwer, Rachel M.

AU - Canales-Rodríguez, Erick J.

AU - Cannon, Dara M.

AU - Chye, Yann

AU - Dahl, Andreas

AU - Dandash, Orwa

AU - Dannlowski, Udo

AU - Dohm, Katharina

AU - Elvsåshagen, Torbjørn

AU - Fisch, Lukas

AU - Fullerton, Janice M.

AU - Goikolea, Jose M.

AU - Grotegerd, Dominik

AU - Haatveit, Beathe

AU - Hahn, Tim

AU - Hajek, Tomas

AU - Heindel, Walter

AU - Ingvar, Martin

AU - Sim, Kang

AU - Kircher, Tilo T.J.

AU - Lenroot, Rhoshel K.

AU - Malt, Ulrik F.

AU - McDonald, Colm

AU - McWhinney, Sean R.

AU - Melle, Ingrid

AU - Meller, Tina

AU - Melloni, Elisa M.T.

AU - Mitchell, Philip B.

AU - Nabulsi, Leila

AU - Nenadić, Igor

AU - Opel, Nils

AU - Overs, Bronwyn J.

AU - Panicalli, Francesco

AU - Pfarr, Julia Katharina

AU - Poletti, Sara

AU - Pomarol-Clotet, Edith

AU - Radua, Joaquim

AU - Repple, Jonathan

AU - Ringwald, Kai G.

AU - Roberts, Gloria

AU - Rodriguez-Cano, Elena

AU - Salvador, Raymond

AU - Sarink, Kelvin

AU - Sarró, Salvador

AU - Schmitt, Simon

AU - Stein, Frederike

AU - Suo, Chao

AU - Thomopoulos, Sophia I.

AU - Tronchin, Giulia

AU - Vieta, Eduard

AU - Westlye, Lars T.

AU - White, Adam G.

AU - Yatham, Lakshmi N.

AU - Zak, Nathalia

AU - Thompson, Paul M.

AU - Andreassen, Ole A.

AU - Landén, Mikael

AU - ENIGMA Bipolar Disorder Working Group

N1 - Funding Information: The St. Göran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish Foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain Foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant No. ALF 20170019 [to ML]). This study was funded by the South-Eastern Norway Regional Health Authority (to TE) and a research grant from Mrs. Throne-Holst (to TE). The National University of Ireland Galway study was supported by grant funding from the Health Research Board (Grant No. HRA_POR/2011/100). FOR2107 was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (Grant Nos. KI 588/14-1 , KI 588/14-2 , KR 3822/5-1 , KR 3822/7-2 , and NE 2254/1-2 ). This study was supported by Grants of Deutsche Forschungsgemeinschaft (Grant Nos. NE2254/2-1 , NE2254/3-1 , and NE2254/4-1 [to IN]). This study was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004 and SIG/05028 [to KS]), and the Singapore Bioimaging Consortium (Grant No. RP C009/2006 [to KS]). This study is supported by the European Research Council under the European Union’s Horizon 2020 Research and Innovation program (Grant No. 802998 [to LTW]), the Research Council of Norway (Grant No. 300767 [to LTW]), and the South-Eastern Norway Regional Health Authority (Grant No. 2019101 [to LTW]). The University of New South Wales “Kids and Sibs” Study was supported by the Australian National Medical and Health Research Council (Program Grant No. 1037196 and Investigator Grant No. 1177991 [to PBM] and Project Grant No. 1066177 [to JMF]), the Lansdowne Foundation, Good Talk and the Keith Pettigrew Family Bequest (to PM). This study was supported by the Janette Mary O’Neil Research Fellowship (to JMF). This study was supported by grants from the Deutsche Forschungsgemeinschaft (German Research Council) (Grant No. INST 2105/57-1 [to WH]). CRKC was supported by NIA (Grant No. T32AG058507; National Institutes of Health (Grant No. U54EB020403 ) from the Big Data to Knowledge Program; and has received partial research support from Biogen, Inc. for work unrelated to the topic of this manuscript. This study was supported by Deutsche Forschungsgemeinschaft (Grant Nos. NE 2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI15/00283 and CPII19/00009 [to EV, JR, JMG, and CdMB]), cofinanced by European Regional Development Fund Funds from the European Commission (A Way of Making Europe) (to EV, JR, JMG, and CdMB), Centro de Investigación Biomédica en Red de Salud Mental (to EV, JR, JMG, and CdMB), and the Departament de Salut de la Generalitat de Catalunya, CERCA Programme/Generalitat de Catalunya (Grant Nos. 2017SGR1365, SLT002/16/00331, and SLT006/17/00357 [to EV, JR, JMG, CdMB]). This study was funded by the South-Eastern Norway Regional Health Authority (Grant Nos. 2019107 and 2020086 [to DA]). This study was supported by Norwegian Centre of Excellence grant (Grant No. 223273 [to BH]) and KG Jebsen grant (Grant No. SKGJ-MED-008 [to BH]). This study was supported by funding from the Canadian Institutes of Health Research (Grant Nos. 103703 , 106469 , and 142255 [to TH]), Nova Scotia Health Research Foundation (to TH), Dalhousie Clinical Research Scholarship (to TH), Brain & Behavior Research Foundation (to TH), and 2007 Young Investigator and 2015 Independent Investigator Awards (to TH). This study was supported by the Research Council of Norway (Grant Nos. 223273 and 248828 [to OAA]), South-East Norway Health Authority (Grant No. 2019-108 [to OAA]), KG Jebsen Stiftelsen, University of Oslo Life:Science program, EU H2020 (Grant No. 847776 CoMorMent [to OAA]). This study was supported in part National Institutes of Health grants (Grant No. R01MH116147 , R01MH121246 , and R01MH111671 [to ENIGMA]). Funding Information: The St. G?ran study was supported by grants from the Swedish Research Council (Grant No. 2018-02653 [to ML]), the Swedish Foundation for Strategic Research (Grant No. KF10-0039 [to ML]), the Swedish Brain Foundation (Grant No. FO2020-0261 [to ML]), and the Swedish Government under the LUA/ALF agreement (Grant No. ALF 20170019 [to ML]). This study was funded by the South-Eastern Norway Regional Health Authority (to TE) and a research grant from Mrs. Throne-Holst (to TE). The National University of Ireland Galway study was supported by grant funding from the Health Research Board (Grant No. HRA_POR/2011/100). FOR2107 was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) (Grant Nos. KI 588/14-1, KI 588/14-2, KR 3822/5-1, KR 3822/7-2, and NE 2254/1-2). This study was supported by Grants of Deutsche Forschungsgemeinschaft (Grant Nos. NE2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by research grants from the National Healthcare Group, Singapore (Grant Nos. SIG/05004 and SIG/05028 [to KS]), and the Singapore Bioimaging Consortium (Grant No. RP C009/2006 [to KS]). This study is supported by the European Research Council under the European Union's Horizon 2020 Research and Innovation program (Grant No. 802998 [to LTW]), the Research Council of Norway (Grant No. 300767 [to LTW]), and the South-Eastern Norway Regional Health Authority (Grant No. 2019101 [to LTW]). The University of New South Wales ?Kids and Sibs? Study was supported by the Australian National Medical and Health Research Council (Program Grant No. 1037196 and Investigator Grant No. 1177991 [to PBM] and Project Grant No. 1066177 [to JMF]), the Lansdowne Foundation, Good Talk and the Keith Pettigrew Family Bequest (to PM). This study was supported by the Janette Mary O'Neil Research Fellowship (to JMF). This study was supported by grants from the Deutsche Forschungsgemeinschaft (German Research Council) (Grant No. INST 2105/57-1 [to WH]). CRKC was supported by NIA (Grant No. T32AG058507; National Institutes of Health (Grant No. U54EB020403) from the Big Data to Knowledge Program; and has received partial research support from Biogen, Inc. for work unrelated to the topic of this manuscript. This study was supported by Deutsche Forschungsgemeinschaft (Grant Nos. NE 2254/2-1, NE2254/3-1, and NE2254/4-1 [to IN]). This study was supported by the Spanish Ministry of Science, Innovation and Universities/Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI15/00283 and CPII19/00009 [to EV, JR, JMG, and CdMB]), cofinanced by European Regional Development Fund Funds from the European Commission (A Way of Making Europe) (to EV, JR, JMG, and CdMB), Centro de Investigaci?n Biom?dica en Red de Salud Mental (to EV, JR, JMG, and CdMB), and the Departament de Salut de la Generalitat de Catalunya, CERCA Programme/Generalitat de Catalunya (Grant Nos. 2017SGR1365, SLT002/16/00331, and SLT006/17/00357 [to EV, JR, JMG, CdMB]). This study was funded by the South-Eastern Norway Regional Health Authority (Grant Nos. 2019107 and 2020086 [to DA]). This study was supported by Norwegian Centre of Excellence grant (Grant No. 223273 [to BH]) and KG Jebsen grant (Grant No. SKGJ-MED-008 [to BH]). This study was supported by funding from the Canadian Institutes of Health Research (Grant Nos. 103703, 106469, and 142255 [to TH]), Nova Scotia Health Research Foundation (to TH), Dalhousie Clinical Research Scholarship (to TH), Brain & Behavior Research Foundation (to TH), and 2007 Young Investigator and 2015 Independent Investigator Awards (to TH). This study was supported by the Research Council of Norway (Grant Nos. 223273 and 248828 [to OAA]), South-East Norway Health Authority (Grant No. 2019-108 [to OAA]), KG Jebsen Stiftelsen, University of Oslo Life:Science program, EU H2020 (Grant No. 847776 CoMorMent [to OAA]). This study was supported in part National Institutes of Health grants (Grant No. R01MH116147, R01MH121246, and R01MH111671 [to ENIGMA]). CA is employed at Quantify Research (work unrelated to the present manuscript). TE is a consultant to BrainWaveBank and received speaker's honoraria from Lundbeck and Janssen-Cilag. LY has been on speaker/advisory boards for, or has received research grants from, Alkermes, AbbVie, Allergan, Canadian Network for Mood and Anxiety Treatments, Canadian Institutes of Health Research, DSP, Intracellular Therapies, Merck, Sanofi, and Sunovion. EV has received grants and served as consultant, advisor, or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. PMT received partial research support from Biogen, Inc. for research unrelated to this manuscript. PBM received honoraria for speaking or advisory committee membership from Sanofi and Janssen. ML has received lecture honoraria from Lundbeck. OAA is consultant to HealthLytix and received speaker's honorarium from Lundbeck and Sunovion. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: CA is employed at Quantify Research (work unrelated to the present manuscript). TE is a consultant to BrainWaveBank and received speaker’s honoraria from Lundbeck and Janssen-Cilag. LY has been on speaker/advisory boards for, or has received research grants from, Alkermes, AbbVie, Allergan, Canadian Network for Mood and Anxiety Treatments, Canadian Institutes of Health Research, DSP, Intracellular Therapies, Merck, Sanofi, and Sunovion. EV has received grants and served as consultant, advisor, or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi-Aventis, and Takeda. PMT received partial research support from Biogen, Inc., for research unrelated to this manuscript. PBM received honoraria for speaking or advisory committee membership from Sanofi and Janssen. ML has received lecture honoraria from Lundbeck. OAA is consultant to HealthLytix and received speaker’s honorarium from Lundbeck and Sunovion. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry

PY - 2022/3/15

Y1 - 2022/3/15

N2 - Background: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. Methods: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. Results: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18 < d < 0.22). More (hypo)manic episodes were associated with faster cortical thinning, primarily in the prefrontal cortex. Conclusions: In the hitherto largest longitudinal MRI study on BD, we did not detect accelerated cortical thinning but noted faster ventricular enlargements in BD. However, abnormal frontocortical thinning was observed in association with frequent manic episodes. Our study yields insights into disease progression in BD and highlights the importance of mania prevention in BD treatment.

AB - Background: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. Methods: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. Results: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18 < d < 0.22). More (hypo)manic episodes were associated with faster cortical thinning, primarily in the prefrontal cortex. Conclusions: In the hitherto largest longitudinal MRI study on BD, we did not detect accelerated cortical thinning but noted faster ventricular enlargements in BD. However, abnormal frontocortical thinning was observed in association with frequent manic episodes. Our study yields insights into disease progression in BD and highlights the importance of mania prevention in BD treatment.

KW - Bipolar disorder

KW - ENIGMA

KW - Longitudinal study

KW - Neuroimaging

KW - Neuroprogression

KW - Psychiatry

UR - https://www.scopus.com/pages/publications/85119415173

UR - https://www.scopus.com/inward/citedby.url?scp=85119415173&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2021.09.008

DO - 10.1016/j.biopsych.2021.09.008

M3 - Article

C2 - 34809987

AN - SCOPUS:85119415173

SN - 0006-3223

VL - 91

SP - 582

EP - 592

JO - Biological psychiatry

JF - Biological psychiatry

IS - 6

ER -

Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group

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