Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.

The authors have declared no competing interest.

FIDMAG: Supported by Instituto de Salud Carlos III (Co-funded by European Regional Development Fund/European Social Fund) "Investing in your future"): Miguel Servet Research Contract (CPII16/00018 to E. Pomarol-Clotet and CP14/00041 to J. Radua.). SWIFT (Homan, Zurich): Supported by a NARSAD grant from the Brain & Behavior Research Foundation (28445) and by a Research Grant from the Novartis Foundation (20A058). FOR2107 Marburg: This work was funded by the German Research Foundation (DFG), Tilo Kircher (speaker FOR2107; DFG grant numbers KI 588/14-1, KI 588/14-2), Axel Krug (KR 3822/5-1, KR 3822/7-2), Igor Nenadic (NE 2254/1-2), Carsten Konrad (KO 4291/3-1). FOR2107 Muenster: This work is part of the German multicenter consortium "Neurobiology of Affective Disorders. A translational perspective on brain structure and function", funded by the German Research Foundation (Deutsche Forschungsgemeinschaft DFG; Forschungsgruppe/Research Unit FOR2107). Work Package WP1, FOR2107/MACS cohort and brainimaging: Udo Dannlowski (co-speaker FOR2107; DA 1151/5-1, DA 1151/5-2) IGP: The Imaging Genetics in Psychosis (IGP) study was funded by Project Grants from the Australian National Health and Medical Research Council (NHMRC; APP630471 and APP1081603), and the Macquarie University's ARC Centre of Excellence in Cognition and its Disorders (CE110001021). This project used participants from the Australian Schizophrenia Research Bank (ASRB), funded by the NHMRC Enabling Grant (386500 held by V. Carr, U. Schall, R. Scott, A. Jablensky, B. Mowry, P. Michie, S. Catts, F. Henskens and C.Pantelis; Chief Investigators), and the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, as well the Schizophrenia Research Institute, using an infrastructure grant from the NSW Ministry of Health. RomeSL: This study was supported by grants (RC10-11-12-13-14-15/A) from the Italian Ministry of Health and by the ERANET NEURON from the European Commission. COBRE: The COBRE project was supported by NIH grants R01EB006841 and P20GM103472, and NSF grant 1539067. Jessica A. Turner and Vince D. Calhoun are supported by 5R01MH094524 and 5R01MH121246. Singapore: This study was supported by research grants from the National Healthcare Group, Singapore (SIG/05004), and the Singapore Bioimaging Consortium (RP C009/2006) research grants awarded to K.S. Conflicts: None UCISZ: The UCISZ study was supported by the National Institutes of Mental Health grant number R21MH097196 to TGMvE. UCISZ data was processed by the UCI High Performance Computing cluster supported by Joseph Farran, Harry Mangalam, and Adam Brenner and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153. T.N.-J. was supported by the Andrew H. Woods Professorship.

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