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

      research-article

      1 , 2 , * , 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 3 , 13 , 14 , 15 , 16 , 17 , 18 , 16 , 19 , 20 , 21 , 17 , 22 , 23 , 24 , 25 , 26 , 27 , 11 , 28 , 29 , 30 , 3 , 11 , 31 , 32 , 10 , 33 , 34 , 24 , 1 , 6 , 35 , 36 , 37 , 38 , 39 , 28 , 40 , 2 , 41 , 42 , 43 , 44 , 44 , 5 , 45 , 46 , 47 , 48 , 49 , 50 , 1 , 47 , 4 , 51 , 52 , 38 , 16 , 25 , 1 , 53 , 54 , 16 , 10 , 5 , 6 , 55 , 16 , 12 , 3 , 3 , 56 , 57 , 55 , 58 , 59 , 54 , 8 , 17 , 60 , 61 , 12 , 62 , 63 , 16 , 37 , 64 , 65 , 21 , 66 , 8 , 67 , 52 , 68 , 69 , 70 , 50 , 71 , 60 , 12 , 25 , 55 , 71 , 25 , 3 , 13 , 72 , 70 , 58 , 40 , 11 , 73 , 74 , 11 , 75 , 42 , 42 , 50 , 76 , 44 , 29 , 30 , 77 , 33 , 44 , 58 , 50 , 76 , 50 , 75 , 78 , 2 , 62 , 68 , 70 , 79 , 80 , 1 , 58 , 81 , 27 , 11 , 82 , 51 , 52 , 40 , 55 , 38 , 83 , 13 , 84 , 24 , 24 , 85 , 38 , 5 , 86 , 5 , 30 , 87 , 5 , 88 , 16 , 89 , 11 , 90 , 91 , 16 , 24 , 43 , 92 , 70 , 79 , 80 , 8 , 54 , 35 , 68 , 85 , 25 , 46 , 24 , 93 , 94 , 21 , 95 , 42 , 96 , 1 , 21

      Molecular Psychiatry

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          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.

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          Most cited references 42

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          Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia.

          Neuropathological and brain imaging studies suggest that schizophrenia may result from neurodevelopmental defects. Cytoarchitectural studies indicate cellular abnormalities suggestive of a disruption in neuronal connectivity in schizophrenia, particularly in the dorsolateral prefrontal cortex. Yet, the molecular mechanisms underlying these findings remain unclear. To identify molecular substrates associated with schizophrenia, DNA microarray analysis was used to assay gene expression levels in postmortem dorsolateral prefrontal cortex of schizophrenic and control patients. Genes determined to have altered expression levels in schizophrenics relative to controls are involved in a number of biological processes, including synaptic plasticity, neuronal development, neurotransmission, and signal transduction. Most notable was the differential expression of myelination-related genes suggesting a disruption in oligodendrocyte function in schizophrenia.
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            Meta-analysis of diffusion tensor imaging studies in schizophrenia.

            The objective of the study was to identify whether there are consistent regional white matter changes in schizophrenia. A systematic search was conducted for voxel-based diffusion tensor imaging fractional anisotropy studies of patients with schizophrenia (or related disorders) in relation to comparison groups. The authors carried out meta-analysis of the co-ordinates of fractional anisotropy differences. For the meta-analysis they used the Activation Likelihood Estimation (ALE) method hybridized with the rank approach used in Genome Scan Meta-Analysis (GSMA). This system detects three-dimensional conjunctions of co-ordinates from multiple studies and permits the weighting of studies in relation to sample size. Fifteen articles were identified for inclusion in the meta-analysis, including a total of 407 patients with schizophrenia and 383 comparison subjects. The studies reported fractional anisotropy reductions at 112 co-ordinates in schizophrenia and no fractional anisotropy increases. Over all studies, significant reductions were present in two regions: the left frontal deep white matter and the left temporal deep white matter. The first region, in the left frontal lobe, is traversed by white matter tracts interconnecting the frontal lobe, thalamus and cingulate gyrus. The second region, in the temporal lobe, is traversed by white matter tracts interconnecting the frontal lobe, insula, hippocampus-amygdala, temporal and occipital lobe. This suggests that two networks of white matter tracts may be affected in schizophrenia, with the potential for 'disconnection' of the gray matter regions which they link.
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              Methodological considerations on tract-based spatial statistics (TBSS).

              Having gained a tremendous amount of popularity since its introduction in 2006, tract-based spatial statistics (TBSS) can now be considered as the standard approach for voxel-based analysis (VBA) of diffusion tensor imaging (DTI) data. Aiming to improve the sensitivity, objectivity, and interpretability of multi-subject DTI studies, TBSS includes a skeletonization step that alleviates residual image misalignment and obviates the need for data smoothing. Although TBSS represents an elegant and user-friendly framework that tackles numerous concerns existing in conventional VBA methods, it has limitations of its own, some of which have already been detailed in recent literature. In this work, we present general methodological considerations on TBSS and report on pitfalls that have not been described previously. In particular, we have identified specific assumptions of TBSS that may not be satisfied under typical conditions. Moreover, we demonstrate that the existence of such violations can severely affect the reliability of TBSS results. With TBSS being used increasingly, it is of paramount importance to acquaint TBSS users with these concerns, such that a well-informed decision can be made as to whether and how to pursue a TBSS analysis. Finally, in addition to raising awareness by providing our new insights, we provide constructive suggestions that could improve the validity and increase the impact of TBSS drastically.
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                Author and article information

                Journal
                Mol Psychiatry
                Mol. Psychiatry
                Molecular Psychiatry
                Nature Publishing Group
                1359-4184
                1476-5578
                May 2018
                17 October 2017
                : 23
                : 5
                : 1261-1269
                Affiliations
                [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
                Author notes
                [* ]Imaging Genetics Center, Keck School of Medicine, University of Southern California , Marina del Rey, CA 90292, USA. E-mail: kellys37@ 123456tcd.ie
                [97]

                These two authors contributed equally to this work.

                Article
                mp2017170
                10.1038/mp.2017.170
                5984078
                29038599
                36a2d123-d7c6-4c4f-80d2-816d8e358549
                Copyright © 2018 The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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                Original Article

                Molecular medicine

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