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Mol Psychiatry. 2018 May;23(5):1261-1269. doi: 10.1038/mp.2017.170. Epub 2017 Oct 17.

Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.

Kelly S1,2, Jahanshad N1, Zalesky A3, Kochunov P4, Agartz I5,6,7, Alloza C8, Andreassen OA9, Arango C10, Banaj N11, Bouix S12, Bousman CA3,13,14,15, Brouwer RM16, Bruggemann J17, Bustillo J18, Cahn W16, Calhoun V19,20, Cannon D21, Carr V17, Catts S22, Chen J23, Chen JX24, Chen X25, Chiapponi C26, Cho KK27, Ciullo V11, Corvin AS28, Crespo-Facorro B29,30, Cropley V3, De Rossi P11,31,32, Diaz-Caneja CM10, Dickie EW33, Ehrlich S34, Fan FM24, Faskowitz J1, Fatouros-Bergman H6, Flyckt L35,36, Ford JM37, Fouche JP38, Fukunaga M39, Gill M28, Glahn DC40, Gollub R2,41, Goudzwaard ED42, Guo H43, Gur RE44, Gur RC44, Gurholt TP5, Hashimoto R45,46, Hatton SN47, Henskens FA48,49,50, Hibar DP1, Hickie IB47, Hong LE4, Horacek J51,52, Howells FM38, Hulshoff Pol HE16, Hyde CL25, Isaev D1, Jablensky A53, Jansen PR54, Janssen J16,10, Jönsson EG5,6, Jung LA55, Kahn RS16, Kikinis Z12, Liu K3, Klauser P3,56,57, Knöchel C55, Kubicki M58, Lagopoulos J59, Langen C54, Lawrie S8, Lenroot RK17, Lim KO60, Lopez-Jaramillo C61, Lyall A12,62, Magnotta V63, Mandl RCW16, Mathalon DH37, McCarley RW64, McCarthy-Jones S65, McDonald C21, McEwen S66, McIntosh A8, Melicher T67,52, Mesholam-Gately RI68, Michie PT69,70,50, Mowry B71, Mueller BA60, Newell DT12, O'Donnell P25, Oertel-Knöchel V55, Oestreich L71, Paciga SA25, Pantelis C3,13,72,70, Pasternak O58, Pearlson G40, Pellicano GR11, Pereira A73, Pineda Zapata J74, Piras F11,75, Potkin SG42, Preda A42, Rasser PE50,76, Roalf DR44, Roiz R29,30, Roos A77, Rotenberg D33, Satterthwaite TD44, Savadjiev P58, Schall U50,76, Scott RJ50,75, Seal ML78, Seidman LJ2,62,68, Shannon Weickert C70,79,80, Whelan CD1, Shenton ME58,81, Kwon JS27, Spalletta G11,82, Spaniel F51,52, Sprooten E40, Stäblein M55, Stein DJ38,83, Sundram S13,84, Tan Y24, Tan S24, Tang S85, Temmingh HS38, Westlye LT5,86, Tønnesen S5, Tordesillas-Gutierrez D30,87, Doan NT5, Vaidya J88, van Haren NEM16, Vargas CD89, Vecchio D11, Velakoulis D90, Voineskos A91, Voyvodic JQ16, Wang Z24, Wan P43, Wei D92, Weickert TW70,79,80, Whalley H8, White T54, Whitford TJ35, Wojcik JD68, Xiang H85, Xie Z25, Yamamori H46, Yang F24, Yao N93, Zhang G94, Zhao J21,95, van Erp TGM42, Turner J96, Thompson PM1, Donohoe G21.

Author information

1
Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
2
Harvard Medical School, Boston, MA, USA.
3
Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.
4
Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
5
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
6
Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
7
Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
8
University of Edinburgh, Edinburgh, UK.
9
University of Oslo, Oslo, Norway.
10
Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain.
11
Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
12
Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
13
Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.
14
Department of General Practice, The University of Melbourne, Parkville, VIC, Australia.
15
Swinburne University of Technology, Melbourne, VIC, Australia.
16
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
17
Neuroscience Research Australia and School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
18
University of New Mexico, Albuquerque, NM, USA.
19
The Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM, USA.
20
The Mind Research Network, Albuquerque, NM, USA.
21
Centre for Neuroimaging and Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.
22
Discipline of Psychiatry, School of Medicine, University of Queensland, Herston, QLD, Australia.
23
Department of Computer Science and Engineering, The Ohio State University, Columbus, OH, USA.
24
Beijing Huilongguan Hospital, Beijing, China.
25
Worldwide Research and Development, Pfizer, Cambridge, MA, USA.
26
Santa Lucia Foundation, Rome, Italy.
27
Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea.
28
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
29
University Hospital Marqués de Valdecilla, IDIVAL, Department of Medicine and Psychiatry, School of Medicine, University of Cantabria, Santander, Spain.
30
CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Santander, Spain.
31
Department NESMOS, Faculty of Medicine and Psychology, University 'Sapienza' of Rome, Rome, Italy.
32
Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
33
Center for Addiction and Mental Health, Toronto, ON, Canada.
34
Division of Psychological and Social Medicine and Developmental Neurosciences, Technische Universität Dresden, Faculty of Medicine, University Hospital C.G. Carus, Dresden, Germany.
35
University of New South Wales, School of Psychiatry, Sydney, NSW, Australia.
36
The University of Queensland, Queensland Brain Institute and Centre for Advanced Imaging, Brisbane, QLD, Australia.
37
University of California, VAMC, San Francisco, CA, USA.
38
Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
39
Division of Cerebral Integration, National Institute for Physiological Sciences, Aichi, Japan.
40
Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital and Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
41
Departments of Psychiatry and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
42
Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA.
43
Zhumadian Psychiatry Hospital, Henan Province, China.
44
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
45
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan.
46
Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
47
Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
48
School of Electrical Engineering and Computer Science, University of Newcastle, Callaghan, NSW, Australia.
49
Health Behaviour Research Group, University of Newcastle, Callaghan, NSW, Australia.
50
Hunter Medical Research Institute, Newcastle, NSW, Australia.
51
National Institute of Mental Health, Klecany, Czech Republic.
52
Third Faculty of Medicine, Charles University, Prague, Czech Republic.
53
University of Western Australia, Perth, WA, Australia.
54
Erasmus University Medical Center, Rotterdam, The Netherlands.
55
Laboratory for Neuroimaging, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Frankfurt/Main, Germany.
56
Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, VIC, Australia.
57
Department of Psychiatry, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.
58
Departments of Psychiatry and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
59
Sunshine Coast Mind and Neuroscience Institute, University of the Sunshine Coast QLD, Australia, Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
60
Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.
61
Research Group in Psychiatry (GIPSI), Department of Psychiatry, Faculty of Medicine, Universidad de Antioquia, Mood Disorder Program, Hospital Universitario San Vicente Fundación, Medellín, Colombia.
62
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
63
University of Iowa, Iowa City, IA, USA.
64
VABHS, Harvard Medical School, Boston, MA, USA.
65
Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
66
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.
67
The University of Texas Health Science Center at Houston, Houston, TX, USA.
68
Harvard Medical School and Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess, Medical Center, Boston, MA, USA.
69
The University of Newcastle, Newcastle, NSW, Australia.
70
Schizophrenia Research Institute, Sydney, NSW, Australia.
71
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia and Queensland Centre for Mental Health Research, Brisbane and Queensland Centre for Mental Health Research, Brisbane, QLD, Australia.
72
Centre for Neural Engineering (CfNE), Department of Electrical and Electronic Engineering, University of Melbourne, Parkville, VIC, Australia.
73
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.
74
Instituto de Alta Tecnología Médica, Medellín, Colombia.
75
School of Biomedical Sciences, Faculty of Health, the University of Newcastle, Callaghan, NSW, Australia.
76
Priority Centre for Brain and Mental Health Research, The University of Newcastle, Newcastle, NSW, Australia.
77
SU/UCT MRC Unit on Anxiety and Stress Disorders, Department of Psychiatry, Stellenbosch University, Stellenbosch, South Africa.
78
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.
79
Neuroscience Research Australia, Sydney, NSW, Australia.
80
School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
81
VA Boston Healthcare System, Boston, MA, USA.
82
Division of Neuropsychiatry, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
83
Department of Psychiatry and MRC Unit on Anxiety and Stress Disorders, University of Cape Town, Cape Town, South Africa.
84
Department of Psychiatry, School of Clinical Sciences, Monash University and Monash Health, Clayton, VIC, Australia.
85
Chongqing Three Gorges Central Hospital, Chongqing, China.
86
Department of Psychology, University of Oslo, Oslo, Norway.
87
Neuroimaging Unit, Technological Facilities, Valdecilla Biomedical Research Institute IDIVAL, Santander, Spain.
88
Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
89
Research Group in Psychiatry (GIPSI), Department of Psychiatry, Faculty of Medicine, Universidad de Antioquia, Medellín, Colombia.
90
Neuropsychiatry Unit, Royal Melbourne Hospital, Parkville, VIC, Australia.
91
Kimel Family Translational Imaging-Genetics Research Laboratory, Campbell Family Mental Health Research Institute, CAMH Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
92
Luoyang Fifth People's Hospital, Henan Province, China.
93
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
94
Department of Computer Science and Electrical Engineering, University of Maryland, Baltimore, MD, USA.
95
School of Psychology, Shaanxi Normal University and Key Laboratory for Behavior and Cognitive Neuroscience of Shaanxi Province, Xi'an, Shaanxi, China.
96
Psychology Department & Neuroscience Institute, Georgia State University, Atlanta, GA, USA.

Abstract

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

PMID:
29038599
PMCID:
PMC5984078
DOI:
10.1038/mp.2017.170
[Indexed for MEDLINE]
Free PMC Article

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