PMID- 32182575 OWN - NLM STAT- MEDLINE DCOM- 20210222 LR - 20210222 IS - 2213-1582 (Electronic) IS - 2213-1582 (Print) IS - 2213-1582 (Linking) VI - 26 DP - 2020 TI - Atypical processing of uncertainty in individuals at risk for psychosis. PG - 102239 LID - S2213-1582(20)30076-0 [pii] LID - 10.1016/j.nicl.2020.102239 [doi] LID - 102239 AB - Current theories of psychosis highlight the role of abnormal learning signals, i.e., prediction errors (PEs) and uncertainty, in the formation of delusional beliefs. We employed computational analyses of behaviour and functional magnetic resonance imaging (fMRI) to examine whether such abnormalities are evident in clinical high risk (CHR) individuals. Non-medicated CHR individuals (n = 13) and control participants (n = 13) performed a probabilistic learning paradigm during fMRI data acquisition. We used a hierarchical Bayesian model to infer subject-specific computations from behaviour - with a focus on PEs and uncertainty (or its inverse, precision) at different levels, including environmental 'volatility' - and used these computational quantities for analyses of fMRI data. Computational modelling of CHR individuals' behaviour indicated volatility estimates converged to significantly higher levels than in controls. Model-based fMRI demonstrated increased activity in prefrontal and insular regions of CHR individuals in response to precision-weighted low-level outcome PEs, while activations of prefrontal, orbitofrontal and anterior insula cortex by higher-level PEs (that serve to update volatility estimates) were reduced. Additionally, prefrontal cortical activity in response to outcome PEs in CHR was negatively associated with clinical measures of global functioning. Our results suggest a multi-faceted learning abnormality in CHR individuals under conditions of environmental uncertainty, comprising higher levels of volatility estimates combined with reduced cortical activation, and abnormally high activations in prefrontal and insular areas by precision-weighted outcome PEs. This atypical representation of high- and low-level learning signals might reflect a predisposition to delusion formation. CI - Copyright (c) 2020 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Cole, David M AU - Cole DM AD - Translational Neuromodeling Unit (TNU), Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland; Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zurich, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland. Electronic address: dcole.neurosci@gmail.com. FAU - Diaconescu, Andreea O AU - Diaconescu AO AD - Translational Neuromodeling Unit (TNU), Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland; Department of Psychiatry (UPK), University of Basel, Basel, Switzerland; Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, Canada. FAU - Pfeiffer, Ulrich J AU - Pfeiffer UJ AD - Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany. FAU - Brodersen, Kay H AU - Brodersen KH AD - Translational Neuromodeling Unit (TNU), Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland. FAU - Mathys, Christoph D AU - Mathys CD AD - Translational Neuromodeling Unit (TNU), Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland; Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy; Interacting Minds Centre, Aarhus University, Aarhus, Denmark. FAU - Julkowski, Dominika AU - Julkowski D AD - Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany. FAU - Ruhrmann, Stephan AU - Ruhrmann S AD - Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany. FAU - Schilbach, Leonhard AU - Schilbach L AD - Independent Max Planck Research Group for Social Neuroscience, Max Planck Institute of Psychiatry, Munich, Germany; Graduate School for Systemic Neuroscience, Munich, Germany; International Max Planck Research School for Translational Psychiatry, Munich, Germany; Ludwig-Maximilians-Universitat Munchen, Munich, Germany; Kliniken der Heinrich-Heine-Universitat/LVR-Klinik Dusseldorf, Dusseldorf, Germany. FAU - Tittgemeyer, Marc AU - Tittgemeyer M AD - Max Planck Institute for Metabolism Research, Cologne, Germany; Cologne Cluster of Excellence in Cellular Stress and Aging associated Disease (CECAD), Germany. FAU - Vogeley, Kai AU - Vogeley K AD - Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany; Institute for Neuroscience and Medicine - Cognitive Neuroscience (INM3), Research Center Juelich, Juelich, Germany. FAU - Stephan, Klaas E AU - Stephan KE AD - Translational Neuromodeling Unit (TNU), Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland; Max Planck Institute for Metabolism Research, Cologne, Germany; Wellcome Centre for Human Neuroimaging, University College London, London, United Kingdom. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200307 PL - Netherlands TA - Neuroimage Clin JT - NeuroImage. Clinical JID - 101597070 SB - IM MH - Brain/*physiopathology MH - Female MH - Humans MH - Learning/*physiology MH - Magnetic Resonance Imaging MH - Male MH - Psychotic Disorders/*physiopathology MH - *Uncertainty MH - Young Adult PMC - PMC7076146 OTO - NOTNLM OT - At-risk mental state OT - Computational psychiatry OT - Decision-making OT - Hierarchical Bayesian learning OT - Prodromal OT - Volatility COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2020/03/18 06:00 MHDA- 2021/02/23 06:00 PMCR- 2020/03/07 CRDT- 2020/03/18 06:00 PHST- 2019/12/09 00:00 [received] PHST- 2020/02/24 00:00 [revised] PHST- 2020/03/06 00:00 [accepted] PHST- 2020/03/18 06:00 [pubmed] PHST- 2021/02/23 06:00 [medline] PHST- 2020/03/18 06:00 [entrez] PHST- 2020/03/07 00:00 [pmc-release] AID - S2213-1582(20)30076-0 [pii] AID - 102239 [pii] AID - 10.1016/j.nicl.2020.102239 [doi] PST - ppublish SO - Neuroimage Clin. 2020;26:102239. doi: 10.1016/j.nicl.2020.102239. Epub 2020 Mar 7.