title: Patterns of regional gray matter loss at different stages of schizophrenia: A multisite, cross-sectional VBM study in first-episode and chronic illness.
abstract: Structural brain abnormalities in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, but it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression of brain abnormalities in schizophrenia, information from cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls may also be useful to further clarify this issue. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, age of onset, illness duration and overall illness severity.
  
  
  
  We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes.
  
  
  
  First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses (p < 0.05, FWE-corrected), including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). GM volumes in several of those brain regions were directly correlated with age of disease onset on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. There were also widespread foci of significant negative correlation between duration of illness and relative GM volumes, but such findings remained significant only for the right dorsolateral prefrontal cortex after accounting for the influence of age of disease onset. Finally, significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region.
  
  
  
  The above data indicate that brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients. Our findings also suggest that relative GM volume deficits may be greater in (presumably more severe) cases with earlier age of onset, as well as varying as a function of illness duration in specific frontal brain regions. Finally, our results highlight the potentially complex effects of the continued use of antipsychotic drugs on structural brain abnormalities in schizophrenia, as we found that cumulative doses of antipsychotics affected brain volumes globally rather than selectively on frontal-temporal regions.
authors.affiliation: Post-Graduation Program in Radiology, Institute of Radiology (INRAD), Faculty of Medicine, University of São Paulo, Brazil; Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
authors.forename: Ulysses S
authors.initials: US
authors.lastname: Torres
authors.affiliation: Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
authors.forename: Fabio L S
authors.initials: FL
authors.lastname: Duran
authors.affiliation: Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department of Neuroscience and Behaviour, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Maristela S
authors.initials: MS
authors.lastname: Schaufelberger
authors.affiliation: Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department of Neuroscience and Behaviour, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: José A S
authors.initials: JA
authors.lastname: Crippa
authors.affiliation: Department and Institute of Psychiatry, University of Sao Paulo Medical School, Brazil.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Louzã
authors.affiliation: Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department and Institute of Psychiatry, University of Sao Paulo Medical School, Brazil.
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Sallet
authors.affiliation: Department and Institute of Psychiatry, University of Sao Paulo Medical School, Brazil.
authors.forename: Caroline Y O
authors.initials: CY
authors.lastname: Kanegusuku
authors.affiliation: Department and Institute of Psychiatry, University of Sao Paulo Medical School, Brazil.
authors.forename: Helio
authors.initials: H
authors.lastname: Elkis
authors.affiliation: Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department and Institute of Psychiatry, University of Sao Paulo Medical School, Brazil; Laboratory of Neuroscience (LIM 27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil.
authors.forename: Wagner F
authors.initials: WF
authors.lastname: Gattaz
authors.affiliation: Department and Institute of Psychiatry, University of Sao Paulo Medical School, Brazil.
authors.forename: Débora P
authors.initials: DP
authors.lastname: Bassitt
authors.affiliation: Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department of Neuroscience and Behaviour, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Antonio W
authors.initials: AW
authors.lastname: Zuardi
authors.affiliation: Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department of Neuroscience and Behaviour, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Jaime Eduardo C
authors.initials: JE
authors.lastname: Hallak
authors.affiliation: Post-Graduation Program in Radiology, Institute of Radiology (INRAD), Faculty of Medicine, University of São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Leite
authors.affiliation: Post-Graduation Program in Radiology, Institute of Radiology (INRAD), Faculty of Medicine, University of São Paulo, Brazil; Department of Diagnostic Imaging, Heart Institute (InCor), Faculty of Medicine, University of São Paulo, Brazil.
authors.forename: Claudio C
authors.initials: CC
authors.lastname: Castro
authors.affiliation: Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department of Internal Medicine - Radiology Division, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Antonio Carlos
authors.initials: AC
authors.lastname: Santos
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College London, UK.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Murray
authors.affiliation: Post-Graduation Program in Radiology, Institute of Radiology (INRAD), Faculty of Medicine, University of São Paulo, Brazil; Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department and Institute of Psychiatry, University of Sao Paulo Medical School, Brazil.
authors.forename: Geraldo F
authors.initials: GF
authors.lastname: Busatto
mesh_terms: D000328:Adult; D001938:Brazil / Q000453:epidemiology; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000473:pathology*; D002908:Chronic Disease; D003430:Cross-Sectional Studies; D005260:Female; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000473:pathology*; D055815:Young Adult
keywords: MRI; Schizophrenia; Voxel-based morphometry