title: White Matter Disruptions in Schizophrenia Are Spatially Widespread and Topologically Converge on Brain Network Hubs.
abstract: White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brain's fiber bundles.
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.|Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia.|Lausanne University Hospital, Department of Psychiatry, Prilly, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Klauser
authors.affiliation: Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Baker
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Cropley
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.|Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Chad
authors.initials: C
authors.lastname: Bousman
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.|Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Fornito
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Luca
authors.initials: L
authors.lastname: Cocchi
authors.affiliation: Neuroscience Research Australia, Randwick, New South Wales, Australia.|School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Fullerton
authors.affiliation: Centre for Brain and Mental Health Research, University of Newcastle, Waratah, New South Wales, Australia.|Hunter Medical Research Institute, Newcastle, New South Wales, Australia.|Schizophrenia Research Institute, Randwick, New South Wales, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Rasser
authors.affiliation: Centre for Brain and Mental Health Research, University of Newcastle, Waratah, New South Wales, Australia.|Hunter Medical Research Institute, Newcastle, New South Wales, Australia.|Schizophrenia Research Institute, Randwick, New South Wales, Australia.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schall
authors.affiliation: School of Electrical Engineering and Computer Science, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Frans
authors.initials: F
authors.lastname: Henskens
authors.affiliation: Centre for Brain and Mental Health Research, University of Newcastle, Waratah, New South Wales, Australia.|Hunter Medical Research Institute, Newcastle, New South Wales, Australia.|Schizophrenia Research Institute, Randwick, New South Wales, Australia.|School of Psychology, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Michie
authors.affiliation: Neuroscience Research Australia, Randwick, New South Wales, Australia.|Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Carmel
authors.initials: C
authors.lastname: Loughland
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Qeensland, Australia.
authors.forename: Stanley V
authors.initials: SV
authors.lastname: Catts
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.|Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Bryan
authors.initials: B
authors.lastname: Mowry
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.|Neuroscience Research Australia, Randwick, New South Wales, Australia.|Schizophrenia Research Institute, Randwick, New South Wales, Australia.|School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Weickert
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.|Neuroscience Research Australia, Randwick, New South Wales, Australia.|Schizophrenia Research Institute, Randwick, New South Wales, Australia.|School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Shannon Weickert
authors.affiliation: Schizophrenia Research Institute, Randwick, New South Wales, Australia.|School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.|Department of Psychiatry, Monash University, Clayton, Victoria, Australia.
authors.forename: Vaughan
authors.initials: V
authors.lastname: Carr
authors.affiliation: Neuroscience Research Australia, Randwick, New South Wales, Australia.|Schizophrenia Research Institute, Randwick, New South Wales, Australia.|School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Rhoshel
authors.initials: R
authors.lastname: Lenroot
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.|Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.|Schizophrenia Research Institute, Randwick, New South Wales, Australia.|Centre for Neural Engineering, Department of Electrical and Electronic Engineering, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Christos
authors.initials: C
authors.lastname: Pantelis
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zalesky
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002540:Cerebral Cortex / Q000000981:diagnostic imaging; D063132:Connectome / Q000379:methods*; D003337:Corpus Callosum / Q000000981:diagnostic imaging; D056324:Diffusion Tensor Imaging / Q000379:methods*; D005260:Female; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000000981:diagnostic imaging*; D009434:Neural Pathways / Q000000981:diagnostic imaging; D011618:Psychotic Disorders / Q000000981:diagnostic imaging*; D012559:Schizophrenia / Q000000981:diagnostic imaging*; D013788:Thalamus / Q000000981:diagnostic imaging; D066127:White Matter / Q000000981:diagnostic imaging*; D055815:Young Adult
keywords: diffusion tensor imaging; fractional anisotropy; magnetic resonance imaging; mean diffusivity; rich club; schizophrenia; tractography; white matter