Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals

ENIGMA Bipolar Disorder Working Group

doi:10.1038/s41386-019-0485-6

Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals

ENIGMA Bipolar Disorder Working Group

Psychosis Studies

Neurospin Centre CEA, Saclay, Gif sur Yvette, France.
Unit of Chronic Inflammation, Institute of Environmental Medicine, Karolinska Institute, Sweden.
Dalhousie University of London
University of Edinburgh
FIDMAG Hermanas Hospitalarias Research Foundation
University of Oslo
Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Melbourne, Victoria, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria, Australia.
Vita-Salute San Raffaele University
Instituto de Radiologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
Cardiff University
University of California
University of Münster
1] Multimodal Imaging Laboratory, University of California at San Diego, La Jolla, CA, USA [2] Cognitive Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA [3] Center for Human Development, University of California at San Diego, La Jolla, CA, USA.
University of Cape Town
Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Muenster, Muenster, Germany.
Department of Clinical Surgery, Royal Infirmary of Edinburgh and Surgical Informatics, Centre for Medical Informatics, Usher Institute, University of Edinburgh, , Edinburgh, UK Department of Gastrointestinal Surgery, Stavanger University Hospital, , Stavanger, Norway Department of Clinical Medicine, University of Bergen, , Bergen, Norway
The Johannes Gutenberg University
Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia; Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York.
Univ. Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS), Grenoble, France
IDIBAPS, CIBERSAM, Instituto de Salud Carlos III
Neuroscience Research Australia, Randwick, Sydney, NSW, Australia.
National Institute of Mental Health (NIH)
USC University of Southern California

Research output: Contribution to journal › Article › peer-review

201 Citations (Scopus)

Abstract

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Original language	English
Pages (from-to)	2285-2293
Number of pages	9
Journal	Neuropsychopharmacology
Volume	44
Issue number	13
DOIs	https://doi.org/10.1038/s41386-019-0485-6
Publication status	Published - Dec 2019

Keywords

Adult
Bipolar Disorder/diagnostic imaging
Brain/diagnostic imaging
Corpus Callosum/diagnostic imaging
Diffusion Tensor Imaging
Female
Humans
Male
Neural Pathways/diagnostic imaging
White Matter/diagnostic imaging

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10.1038/s41386-019-0485-6

Cite this

@article{6d893e6a7105447aaedcfe7636578405,

title = "Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals",

abstract = "Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.",

keywords = "Adult, Bipolar Disorder/diagnostic imaging, Brain/diagnostic imaging, Corpus Callosum/diagnostic imaging, Diffusion Tensor Imaging, Female, Humans, Male, Neural Pathways/diagnostic imaging, White Matter/diagnostic imaging",

author = "Pauline Favre and Melissa Pauling and Jacques Stout and Franz Hozer and Samuel Sarrazin and Christoph Ab{\'e} and Martin Alda and Clara Alloza and Silvia Alonso-Lana and Andreassen, \{Ole A\} and Baune, \{Bernhard T\} and Francesco Benedetti and Busatto, \{Geraldo F\} and Canales-Rodr{\'i}guez, \{Erick J\} and Xavier Caseras and Chaim-Avancini, \{Tiffany Moukbel\} and Ching, \{Christopher R K\} and Udo Dannlowski and Michael Deppe and Eyler, \{Lisa T\} and Mar Fatjo-Vilas and Foley, \{Sonya F\} and Dominik Grotegerd and Tomas Hajek and Haukvik, \{Unn K\} and Howells, \{Fleur M\} and Neda Jahanshad and Harald Kugel and Lagerberg, \{Trine V\} and Lawrie, \{Stephen M\} and Linke, \{Julia O\} and Andrew McIntosh and Melloni, \{Elisa M T\} and Mitchell, \{Philip B\} and Mircea Polosan and Edith Pomarol-Clotet and Jonathan Repple and Gloria Roberts and Annerine Roos and Rosa, \{Pedro G P\} and Raymond Salvador and Salvador Sarr{\'o} and Schofield, \{Peter R\} and Serpa, \{Mauricio H\} and Kang Sim and Stein, \{Dan J\} and Sussmann, \{Jess E\} and Temmingh, \{Henk S\} and Thompson, \{Paul M\} and Norma Verdolini and \{ENIGMA Bipolar Disorder Working Group\}",

year = "2019",

month = dec,

doi = "10.1038/s41386-019-0485-6",

language = "English",

volume = "44",

pages = "2285--2293",

journal = "Neuropsychopharmacology",

issn = "0893-133X",

publisher = "Springer Nature [academic journals on nature.com]",

number = "13",

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TY - JOUR

T1 - Widespread white matter microstructural abnormalities in bipolar disorder

T2 - evidence from mega- and meta-analyses across 3033 individuals

AU - Favre, Pauline

AU - Pauling, Melissa

AU - Stout, Jacques

AU - Hozer, Franz

AU - Sarrazin, Samuel

AU - Abé, Christoph

AU - Alda, Martin

AU - Alloza, Clara

AU - Alonso-Lana, Silvia

AU - Andreassen, Ole A

AU - Baune, Bernhard T

AU - Benedetti, Francesco

AU - Busatto, Geraldo F

AU - Canales-Rodríguez, Erick J

AU - Caseras, Xavier

AU - Chaim-Avancini, Tiffany Moukbel

AU - Ching, Christopher R K

AU - Dannlowski, Udo

AU - Deppe, Michael

AU - Eyler, Lisa T

AU - Fatjo-Vilas, Mar

AU - Foley, Sonya F

AU - Grotegerd, Dominik

AU - Hajek, Tomas

AU - Haukvik, Unn K

AU - Howells, Fleur M

AU - Jahanshad, Neda

AU - Kugel, Harald

AU - Lagerberg, Trine V

AU - Lawrie, Stephen M

AU - Linke, Julia O

AU - McIntosh, Andrew

AU - Melloni, Elisa M T

AU - Mitchell, Philip B

AU - Polosan, Mircea

AU - Pomarol-Clotet, Edith

AU - Repple, Jonathan

AU - Roberts, Gloria

AU - Roos, Annerine

AU - Rosa, Pedro G P

AU - Salvador, Raymond

AU - Sarró, Salvador

AU - Schofield, Peter R

AU - Serpa, Mauricio H

AU - Sim, Kang

AU - Stein, Dan J

AU - Sussmann, Jess E

AU - Temmingh, Henk S

AU - Thompson, Paul M

AU - Verdolini, Norma

AU - ENIGMA Bipolar Disorder Working Group

PY - 2019/12

Y1 - 2019/12

N2 - Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

AB - Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

KW - Adult

KW - Bipolar Disorder/diagnostic imaging

KW - Brain/diagnostic imaging

KW - Corpus Callosum/diagnostic imaging

KW - Diffusion Tensor Imaging

KW - Female

KW - Humans

KW - Male

KW - Neural Pathways/diagnostic imaging

KW - White Matter/diagnostic imaging

U2 - 10.1038/s41386-019-0485-6

DO - 10.1038/s41386-019-0485-6

M3 - Article

C2 - 31434102

SN - 0893-133X

VL - 44

SP - 2285

EP - 2293

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

IS - 13

ER -

Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals

Abstract

Keywords

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