Advertisement

Integrative brain network and salience models of psychopathology and cognitive dysfunction in schizophrenia

  • Vinod Menon
    Correspondence
    Address correspondence to: Vinod Menon
    Affiliations
    Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, United States of America

    Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, California, United States of America

    Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, California, United States of America
    Search for articles by this author
  • Author Footnotes
    ∗ Equal contribution
    Lena Palaniyappan
    Footnotes
    ∗ Equal contribution
    Affiliations
    Department of Psychiatry and Robarts Research Institute, University of Western Ontario

    Lawson Health Research Institute, London, Ontario, Canada

    Douglas Mental Health University Institute

    Department of Psychiatry, McGill University, Montreal, Quebec, Canada
    Search for articles by this author
  • Author Footnotes
    ∗ Equal contribution
    Kaustubh Supekar
    Footnotes
    ∗ Equal contribution
    Affiliations
    Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, United States of America

    Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, California, United States of America
    Search for articles by this author
  • Author Footnotes
    ∗ Equal contribution

      Abstract

      Brain network models of cognitive control are central to advancing our understanding of psychopathology and cognitive dysfunction in schizophrenia. This review examines the role of large-scale brain organization in schizophrenia, with a particular focus on a ‘triple network model’ of cognitive control and its role in aberrant salience processing. We first provide an overview of the triple network involving the salience, frontoparietal and default mode networks and highlight the central role of the insula-anchored salience network in the aberrant mapping of salient external and internal events in schizophrenia. We summarize the extensive evidence that has emerged from structural, neurochemical, and functional brain imaging studies for aberrancies in these networks and their dynamic temporal interactions in schizophrenia. We then consider the hypothesis that atypical striatal dopamine release results in misattribution of salience to irrelevant external stimuli and self-referential mental events. We propose an integrated triple-network salience-based model incorporating striatal dysfunction and sensitivity to perceptual and cognitive prediction errors in the insula node of the salience network, and postulate that dysregulated dopamine modulation of salience network-centered processes contributes to the core clinical phenotype of schizophrenia. A powerful paradigm to characterize the neurobiology of schizophrenia thus emerges when we combine conceptual models of salience with large-scale cognitive control networks in a unified manner. We conclude by discussing potential therapeutic leads on restoring brain network dysfunction in schizophrenia.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Saha S.
        • Chant D.
        • Welham J.
        • McGrath J.
        A systematic review of the prevalence of schizophrenia.
        PLoS Med. 2005; 2: e141
        • Shivashankar S.
        • Telfer S.
        • Arunagiriraj J.
        • McKinnon M.
        • Jauhar S.
        • Krishnadas R.
        • et al.
        Has the prevalence, clinical presentation and social functioning of schizophrenia changed over the last 25 years? Nithsdale schizophrenia survey revisited.
        Schizophr Res. 2013; 146: 349-356
      1. APA (1994): Diagnostic and statistical manual of mental disorders : DSM-IV. 4th ed. ed. Washington, D.C.: American Psychiatric Association.

      2. Oyebode F, Sims ACPSitm (2008): Sims' symptoms in the mind : an introduction to descriptive psychopathology. 4th ed. ed. Edinburgh: W. B. Saunders.

        • Correll C.U.
        • Schooler N.R.
        Negative Symptoms in Schizophrenia: A Review and Clinical Guide for Recognition, Assessment, and Treatment.
        Neuropsychiatr Dis Treat. 2020; 16: 519-534
        • Kapur S.
        Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia.
        Am J Psychiatry. 2003; 160: 13-23
        • Kapur S.
        • Mizrahi R.
        • Li M.
        From dopamine to salience to psychosis--linking biology, pharmacology and phenomenology of psychosis.
        Schizophr Res. 2005; 79: 59-68
        • Miller R.
        Schizophrenic psychology, associative learning and the role of forebrain dopamine.
        Med Hypotheses. 1976; 2: 203-211
        • Spitzer M.
        A neurocomputational approach to delusions.
        Compr Psychiatry. 1995; 36: 83-105
        • Horne C.M.
        • Vanes L.D.
        • Verneuil T.
        • Mouchlianitis E.
        • Szentgyorgyi T.
        • Averbeck B.
        • et al.
        Cognitive control network connectivity differentially disrupted in treatment resistant schizophrenia.
        Neuroimage Clin. 2021; 30102631
        • Kesby J.P.
        • Murray G.K.
        • Knolle F.
        Neural circuitry of salience and reward processing in psychosis.
        Biological Psychiatry Global Open Science. 2021;
        • Roiser J.P.
        • Stephan K.E.
        • den Ouden H.E.
        • Barnes T.R.
        • Friston K.J.
        • Joyce E.M.
        Do patients with schizophrenia exhibit aberrant salience?.
        Psychol Med. 2009; 39: 199-209
        • Katthagen T.
        • Kaminski J.
        • Heinz A.
        • Buchert R.
        • Schlagenhauf F.
        Striatal Dopamine and Reward Prediction Error Signaling in Unmedicated Schizophrenia Patients.
        Schizophr Bull. 2020; 46: 1535-1546
        • Bressler S.L.
        • Menon V.
        Large-scale brain networks in cognition: emerging methods and principles.
        Trends Cogn Sci. 2010;
        • Menon V.
        • D'Esposito M.
        The role of PFC networks in cognitive control and executive function.
        Neuropsychopharmacology. 2022; 47: 90-103
        • Dong D.
        • Wang Y.
        • Chang X.
        • Luo C.
        • Yao D.
        Dysfunction of Large-Scale Brain Networks in Schizophrenia: A Meta-analysis of Resting-State Functional Connectivity.
        Schizophr Bull. 2017;
        • Menon V.
        Large-scale brain networks and psychopathology: a unifying triple network model.
        Trends Cogn Sci. 2011; 15: 483-506
        • Keefe R.S.
        • Harvey P.D.
        Cognitive impairment in schizophrenia.
        Handb Exp Pharmacol. 2012; : 11-37
        • Jonas K.
        • Lian W.
        • Callahan J.
        • Ruggero C.J.
        • Clouston S.
        • Reichenberg A.
        • et al.
        The Course of General Cognitive Ability in Individuals With Psychotic Disorders.
        JAMA Psychiatry. 2022; 79: 659-666
        • Greicius M.D.
        • Krasnow B.
        • Reiss A.L.
        • Menon V.
        Functional connectivity in the resting brain: a network analysis of the default mode hypothesis.
        Proceedings of the National Academy of Sciences of the United States of America. 2003; 100: 253-258
        • Seeley W.W.
        • Menon V.
        • Schatzberg A.F.
        • Keller J.
        • Glover G.H.
        • Kenna H.
        • et al.
        Dissociable intrinsic connectivity networks for salience processing and executive control.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2007; 27: 2349-2356
        • Sridharan D.
        • Levitin D.J.
        • Menon V.
        A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks.
        Proceedings of the National Academy of Sciences of the United States of America. 2008; 105: 12569-12574
        • Cai W.
        • Ryali S.
        • Pasumarthy R.
        • Talasila V.
        • Menon V.
        Dynamic causal brain circuits during working memory and their functional controllability.
        Nat Commun. 2021; 12: 3314
        • Palaniyappan L.
        • Liddle P.F.
        Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction.
        J Psychiatry Neurosci. 2012; 37: 17-27
        • Owen M.J.
        • Sawa A.
        • Mortensen P.B.
        Schizophrenia.
        Lancet. 2016; 388: 86-97
        • Haijma S.V.
        • Van Haren N.
        • Cahn W.
        • Koolschijn P.C.
        • Hulshoff Pol H.E.
        • Kahn R.S.
        Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects.
        Schizophr Bull. 2013; 39: 1129-1138
        • Glahn D.C.
        • Laird A.R.
        • Ellison-Wright I.
        • Thelen S.M.
        • Robinson J.L.
        • Lancaster J.L.
        • et al.
        Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis.
        Biol Psychiatry. 2008; 64: 774-781
        • Linden D.E.
        The challenges and promise of neuroimaging in psychiatry.
        Neuron. 2012; 73: 8-22
        • Fornito A.
        • Bullmore E.T.
        Connectomics: A new paradigm for understanding brain disease.
        European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2014;
        • Meyer-Lindenberg A.
        From maps to mechanisms through neuroimaging of schizophrenia.
        Nature. 2010; 468: 194-202
        • Stephan K.E.
        • Baldeweg T.
        • Friston K.J.
        Synaptic plasticity and dysconnection in schizophrenia.
        Biol Psychiatry. 2006; 59: 929-939
        • Friston K.J.
        • Frith C.D.
        Schizophrenia: a disconnection syndrome?.
        Clin Neurosci. 1995; 3: 89-97
        • Tan H.Y.
        • Callicott J.H.
        • Weinberger D.R.
        Dysfunctional and compensatory prefrontal cortical systems, genes and the pathogenesis of schizophrenia.
        Cereb Cortex. 2007; 17: i171-181
        • Liloia D.
        • Brasso C.
        • Cauda F.
        • Mancuso L.
        • Nani A.
        • Manuello J.
        • et al.
        Updating and characterizing neuroanatomical markers in high-risk subjects, recently diagnosed and chronic patients with schizophrenia: A revised coordinate-based meta-analysis.
        Neurosci Biobehav Rev. 2021; 123: 83-103
        • Goodkind M.
        • Eickhoff S.B.
        • Oathes D.J.
        • Jiang Y.
        • Chang A.
        • Jones-Hagata L.B.
        • et al.
        Identification of a common neurobiological substrate for mental illness.
        JAMA Psychiatry. 2015; 72: 305-315
        • O'Neill A.
        • Mechelli A.
        • Bhattacharyya S.
        Dysconnectivity of Large-Scale Functional Networks in Early Psychosis: A Meta-analysis.
        Schizophr Bull. 2019; 45: 579-590
        • Whitfield-Gabrieli S.
        • Thermenos H.W.
        • Milanovic S.
        • Tsuang M.T.
        • Faraone S.V.
        • McCarley R.W.
        • et al.
        Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia.
        Proc Natl Acad Sci U S A. 2009; 106: 1279-1284
        • Skudlarski P.
        • Jagannathan K.
        • Anderson K.
        • Stevens M.C.
        • Calhoun V.D.
        • Skudlarska B.A.
        • et al.
        Brain connectivity is not only lower but different in schizophrenia: a combined anatomical and functional approach.
        Biol Psychiatry. 2010; 68: 61-69
        • Rotarska-Jagiela A.
        • van de Ven V.
        • Oertel-Knochel V.
        • Uhlhaas P.J.
        • Vogeley K.
        • Linden D.E.
        Resting-state functional network correlates of psychotic symptoms in schizophrenia.
        Schizophr Res. 2010; 117: 21-30
        • Manoliu A.
        • Riedl V.
        • Doll A.
        • Bauml J.G.
        • Muhlau M.
        • Schwerthoffer D.
        • et al.
        Insular Dysfunction Reflects Altered Between-Network Connectivity and Severity of Negative Symptoms in Schizophrenia during Psychotic Remission.
        Front Hum Neurosci. 2013; 7: 216
        • Manoliu A.
        • Riedl V.
        • Zherdin A.
        • Muhlau M.
        • Schwerthoffer D.
        • Scherr M.
        • et al.
        Aberrant dependence of default mode/central executive network interactions on anterior insular salience network activity in schizophrenia.
        Schizophr Bull. 2014; 40: 428-437
        • Liu H.
        • Kaneko Y.
        • Ouyang X.
        • Li L.
        • Hao Y.
        • Chen E.Y.
        • et al.
        Schizophrenic patients and their unaffected siblings share increased resting-state connectivity in the task-negative network but not its anticorrelated task-positive network.
        Schizophr Bull. 2012; 38: 285-294
        • Guo W.
        • Yao D.
        • Jiang J.
        • Su Q.
        • Zhang Z.
        • Zhang J.
        • et al.
        Abnormal default-mode network homogeneity in first-episode, drug-naive schizophrenia at rest.
        Prog Neuropsychopharmacol Biol Psychiatry. 2014; 49: 16-20
        • Lee W.H.
        • Doucet G.E.
        • Leibu E.
        • Frangou S.
        Resting-state network connectivity and metastability predict clinical symptoms in schizophrenia.
        Schizophr Res. 2018; 201: 208-216
        • Pu W.
        • Li L.
        • Zhang H.
        • Ouyang X.
        • Liu H.
        • Zhao J.
        • et al.
        Morphological and functional abnormalities of salience network in the early-stage of paranoid schizophrenia.
        Schizophr Res. 2012; 141: 15-21
        • Zhou Y.
        • Liang M.
        • Jiang T.
        • Tian L.
        • Liu Y.
        • Liu Z.
        • et al.
        Functional dysconnectivity of the dorsolateral prefrontal cortex in first-episode schizophrenia using resting-state fMRI.
        Neurosci Lett. 2007; 417: 297-302
        • Guo S.
        • He N.
        • Liu Z.
        • Linli Z.
        • Tao H.
        • Palaniyappan L.
        Brain-Wide Functional Dysconnectivity in Schizophrenia: Parsing Diathesis, Resilience, and the Effects of Clinical Expression.
        Can J Psychiatry. 2020; 65: 21-29
        • Woodward N.D.
        • Rogers B.
        • Heckers S.
        Functional resting-state networks are differentially affected in schizophrenia.
        Schizophr Res. 2011; 130: 86-93
        • Alonso-Solis A.
        • Vives-Gilabert Y.
        • Grasa E.
        • Portella M.J.
        • Rabella M.
        • Sauras R.B.
        • et al.
        Resting-state functional connectivity alterations in the default network of schizophrenia patients with persistent auditory verbal hallucinations.
        Schizophr Res. 2015; 161: 261-268
        • Wang H.
        • Zeng L.L.
        • Chen Y.
        • Yin H.
        • Tan Q.
        • Hu D.
        Evidence of a dissociation pattern in default mode subnetwork functional connectivity in schizophrenia.
        Sci Rep. 2015; 514655
        • Xi Y.B.
        • Guo F.
        • Liu W.M.
        • Fu Y.F.
        • Li J.M.
        • Wang H.N.
        • et al.
        Triple network hypothesis-related disrupted connections in schizophrenia: A spectral dynamic causal modeling analysis with functional magnetic resonance imaging.
        Schizophr Res. 2021; 233: 89-96
        • Palaniyappan L.
        • Simmonite M.
        • White T.P.
        • Liddle E.B.
        • Liddle P.F.
        Neural primacy of the salience processing system in schizophrenia.
        Neuron. 2013; 79: 814-828
        • Moran L.V.
        • Tagamets M.A.
        • Sampath H.
        • O'Donnell A.
        • Stein E.A.
        • Kochunov P.
        • et al.
        Disruption of anterior insula modulation of large-scale brain networks in schizophrenia.
        Biol Psychiatry. 2013; 74: 467-474
        • Dong D.
        • Wang Y.
        • Chang X.
        • Luo C.
        • Yao D.
        Dysfunction of Large-Scale Brain Networks in Schizophrenia: A Meta-analysis of Resting-State Functional Connectivity.
        Schizophr Bull. 2018; 44: 168-181
        • Liang S.
        • Wang Q.
        • Greenshaw A.J.
        • Li X.
        • Deng W.
        • Ren H.
        • et al.
        Aberrant triple-network connectivity patterns discriminate biotypes of first-episode medication-naive schizophrenia in two large independent cohorts.
        Neuropsychopharmacology. 2021; 46: 1502-1509
        • Hare S.M.
        • Ford J.M.
        • Mathalon D.H.
        • Damaraju E.
        • Bustillo J.
        • Belger A.
        • et al.
        Salience-Default Mode Functional Network Connectivity Linked to Positive and Negative Symptoms of Schizophrenia.
        Schizophr Bull. 2019; 45: 892-901
        • Lefebvre S.
        • Demeulemeester M.
        • Leroy A.
        • Delmaire C.
        • Lopes R.
        • Pins D.
        • et al.
        Network dynamics during the different stages of hallucinations in schizophrenia.
        Hum Brain Mapp. 2016; 37: 2571-2586
        • Supekar K.
        • Cai W.
        • Krishnadas R.
        • Palaniyappan L.
        • Menon V.
        Dysregulated Brain Dynamics in a Triple-Network Saliency Model of Schizophrenia and Its Relation to Psychosis.
        Biological psychiatry. 2019; 85: 60-69
        • Walter A.
        • Suenderhauf C.
        • Smieskova R.
        • Lenz C.
        • Harrisberger F.
        • Schmidt A.
        • et al.
        Altered Insular Function during Aberrant Salience Processing in Relation to the Severity of Psychotic Symptoms.
        Front Psychiatry. 2016; 7: 189
        • White T.P.
        • Joseph V.
        • Francis S.T.
        • Liddle P.F.
        Aberrant salience network (bilateral insula and anterior cingulate cortex) connectivity during information processing in schizophrenia.
        Schizophr Res. 2010; 123: 105-115
        • Luo Q.
        • Pan B.
        • Gu H.
        • Simmonite M.
        • Francis S.
        • Liddle P.F.
        • et al.
        Effective connectivity of the right anterior insula in schizophrenia: The salience network and task-negative to task-positive transition.
        Neuroimage Clin. 2020; 28102377
        • Gradin V.B.
        • Waiter G.
        • O'Connor A.
        • Romaniuk L.
        • Stickle C.
        • Matthews K.
        • et al.
        Salience network-midbrain dysconnectivity and blunted reward signals in schizophrenia.
        Psychiatry Res. 2013; 211: 104-111
        • White T.P.
        • Gilleen J.
        • Shergill S.S.
        Dysregulated but not decreased salience network activity in schizophrenia.
        Front Hum Neurosci. 2013; 7: 65
        • Liddle E.B.
        • Price D.
        • Palaniyappan L.
        • Brookes M.J.
        • Robson S.E.
        • Hall E.L.
        • et al.
        Abnormal salience signaling in schizophrenia: The role of integrative beta oscillations.
        Hum Brain Mapp. 2016; 37: 1361-1374
        • Hasenkamp W.
        • James G.A.
        • Boshoven W.
        • Duncan E.
        Altered engagement of attention and default networks during target detection in schizophrenia.
        Schizophr Res. 2011; 125: 169-173
        • Pomarol-Clotet E.
        • Salvador R.
        • Sarro S.
        • Gomar J.
        • Vila F.
        • Martinez A.
        • et al.
        Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network?.
        Psychol Med. 2008; 38: 1185-1193
        • Zhou L.
        • Pu W.
        • Wang J.
        • Liu H.
        • Wu G.
        • Liu C.
        • et al.
        Inefficient DMN Suppression in Schizophrenia Patients with Impaired Cognitive Function but not Patients with Preserved Cognitive Function.
        Sci Rep. 2016; 621657
        • Holt D.J.
        • Cassidy B.S.
        • Andrews-Hanna J.R.
        • Lee S.M.
        • Coombs G.
        • Goff D.C.
        • et al.
        An anterior-to-posterior shift in midline cortical activity in schizophrenia during self-reflection.
        Biol Psychiatry. 2011; 69: 415-423
        • Menon V.
        • Uddin L.Q.
        Saliency, switching, attention and control: a network model of insula function.
        Brain Struct Funct. 2010; 214: 655-667
        • Sheffield J.M.
        • Kandala S.
        • Tamminga C.A.
        • Pearlson G.D.
        • Keshavan M.S.
        • Sweeney J.A.
        • et al.
        Transdiagnostic Associations Between Functional Brain Network Integrity and Cognition.
        JAMA Psychiatry. 2017; 74: 605-613
        • Baker J.T.
        • Holmes A.J.
        • Masters G.A.
        • Yeo B.T.
        • Krienen F.
        • Buckner R.L.
        • et al.
        Disruption of cortical association networks in schizophrenia and psychotic bipolar disorder.
        JAMA Psychiatry. 2014; 71: 109-118
        • Wang X.
        • Zhang W.
        • Sun Y.
        • Hu M.
        • Chen A.
        Aberrant intra-salience network dynamic functional connectivity impairs large-scale network interactions in schizophrenia.
        Neuropsychologia. 2016; 93: 262-270
        • van Os J.
        A salience dysregulation syndrome.
        Br J Psychiatry. 2009; 194: 101-103
        • Heinz A.
        • Schlagenhauf F.
        Dopaminergic dysfunction in schizophrenia: salience attribution revisited.
        Schizophr Bull. 2010; 36: 472-485
        • Radua J.
        • Schmidt A.
        • Borgwardt S.
        • Heinz A.
        • Schlagenhauf F.
        • McGuire P.
        • et al.
        Ventral Striatal Activation During Reward Processing in Psychosis: A Neurofunctional Meta-Analysis.
        JAMA Psychiatry. 2015; 72: 1243-1251
        • Deserno L.
        • Boehme R.
        • Heinz A.
        • Schlagenhauf F.
        Reinforcement learning and dopamine in schizophrenia: dimensions of symptoms or specific features of a disease group?.
        Front Psychiatry. 2013; 4: 172
        • Nour M.M.
        • Dahoun T.
        • Schwartenbeck P.
        • Adams R.A.
        • FitzGerald T.H.B.
        • Coello C.
        • et al.
        Dopaminergic basis for signaling belief updates, but not surprise, and the link to paranoia.
        Proceedings of the National Academy of Sciences of the United States of America. 2018; 115: E10167-E10176
        • Katthagen T.
        • Fromm S.
        • Wieland L.
        • Schlagenhauf F.
        Models of Dynamic Belief Updating in Psychosis-A Review Across Different Computational Approaches.
        Front Psychiatry. 2022; 13814111
        • Nassar M.R.
        • Waltz J.A.
        • Albrecht M.A.
        • Gold J.M.
        • Frank M.J.
        All or nothing belief updating in patients with schizophrenia reduces precision and flexibility of beliefs.
        Brain. 2021; 144: 1013-1029
        • Hamilton H.K.
        • Woods S.W.
        • Roach B.J.
        • Llerena K.
        • McGlashan T.H.
        • Srihari V.H.
        • et al.
        Auditory and Visual Oddball Stimulus Processing Deficits in Schizophrenia and the Psychosis Risk Syndrome: Forecasting Psychosis Risk With P300.
        Schizophr Bull. 2019; 45: 1068-1080
        • Waltz J.A.
        • Gold J.M.
        Motivational Deficits in Schizophrenia and the Representation of Expected Value.
        Curr Top Behav Neurosci. 2016; 27: 375-410
        • Gold J.M.
        • Waltz J.A.
        • Prentice K.J.
        • Morris S.E.
        • Heerey E.A.
        Reward processing in schizophrenia: a deficit in the representation of value.
        Schizophr Bull. 2008; 34: 835-847
        • Steinberg E.E.
        • Keiflin R.
        • Boivin J.R.
        • Witten I.B.
        • Deisseroth K.
        • Janak P.H.
        A causal link between prediction errors, dopamine neurons and learning.
        Nature neuroscience. 2013; 16: 966-973
        • Den Ouden H.E.
        • Kok P.
        • De Lange F.P.
        How prediction errors shape perception, attention, and motivation.
        Frontiers in psychology. 2012; 3: 548
        • Schultz W.
        • Dayan P.
        • Montague P.R.
        A neural substrate of prediction and reward.
        Science. 1997; 275: 1593-1599
        • Watabe-Uchida M.
        • Eshel N.
        • Uchida N.
        Neural circuitry of reward prediction error.
        Annual review of neuroscience. 2017; 40: 373-394
        • Powers A.R.
        • Mathys C.
        • Corlett P.R.
        Pavlovian conditioning–induced hallucinations result from overweighting of perceptual priors.
        Science. 2017; 357: 596-600
        • Strauss G.P.
        • Frank M.J.
        • Waltz J.A.
        • Kasanova Z.
        • Herbener E.S.
        • Gold J.M.
        Deficits in positive reinforcement learning and uncertainty-driven exploration are associated with distinct aspects of negative symptoms in schizophrenia.
        Biological psychiatry. 2011; 69: 424-431
        • Koch K.
        • Schachtzabel C.
        • Wagner G.
        • Schikora J.
        • Schultz C.
        • Reichenbach J.R.
        • et al.
        Altered activation in association with reward-related trial-and-error learning in patients with schizophrenia.
        Neuroimage. 2010; 50: 223-232
        • Millard S.J.
        • Bearden C.E.
        • Karlsgodt K.H.
        • Sharpe M.J.
        The prediction-error hypothesis of schizophrenia: new data point to circuit-specific changes in dopamine activity.
        Neuropsychopharmacology. 2021; : 1-13
        • Diederen K.M.
        • Fletcher P.C.
        Dopamine, prediction error and beyond.
        The Neuroscientist. 2021; 27: 30-46
        • Heinz A.
        • Murray G.K.
        • Schlagenhauf F.
        • Sterzer P.
        • Grace A.A.
        • Waltz J.A.
        Towards a Unifying Cognitive, Neurophysiological, and Computational Neuroscience Account of Schizophrenia.
        Schizophr Bull. 2019; 45: 1092-1100
        • Deserno L.
        • Schlagenhauf F.
        • Heinz A.
        Striatal dopamine, reward, and decision making in schizophrenia.
        Dialogues Clin Neurosci. 2016; 18: 77-89
        • Sterzer P.
        • Voss M.
        • Schlagenhauf F.
        • Heinz A.
        Decision-making in schizophrenia: A predictive-coding perspective.
        Neuroimage. 2019; 190: 133-143
        • Winton-Brown T.T.
        • Fusar-Poli P.
        • Ungless M.A.
        • Howes O.D.
        Dopaminergic basis of salience dysregulation in psychosis.
        Trends in neurosciences. 2014; 37: 85-94
        • Roiser J.P.
        • Howes O.D.
        • Chaddock C.A.
        • Joyce E.M.
        • McGuire P.
        Neural and behavioral correlates of aberrant salience in individuals at risk for psychosis.
        Schizophrenia bulletin. 2013; 39: 1328-1336
        • Howes O.D.
        • Hird E.J.
        • Adams R.A.
        • Corlett P.R.
        • McGuire P.
        Aberrant salience, information processing, and dopaminergic signaling in people at clinical high risk for psychosis.
        Biological psychiatry. 2020; 88: 304-314
        • McCutcheon R.A.
        • Krystal J.H.
        • Howes O.D.
        Dopamine and glutamate in schizophrenia: biology, symptoms and treatment.
        World Psychiatry. 2020; 19: 15-33
        • McCutcheon R.A.
        • Abi-Dargham A.
        • Howes O.D.
        Schizophrenia, dopamine and the striatum: from biology to symptoms.
        Trends in neurosciences. 2019; 42: 205-220
        • Ermakova A.O.
        • Knolle F.
        • Justicia A.
        • Bullmore E.T.
        • Jones P.B.
        • Robbins T.W.
        • et al.
        Abnormal reward prediction-error signalling in antipsychotic naive individuals with first-episode psychosis or clinical risk for psychosis.
        Neuropsychopharmacology. 2018; 43: 1691-1699
        • Maia T.V.
        • Frank M.J.
        An integrative perspective on the role of dopamine in schizophrenia.
        Biological psychiatry. 2017; 81: 52-66
        • Howes O.D.
        • Kambeitz J.
        • Kim E.
        • Stahl D.
        • Slifstein M.
        • Abi-Dargham A.
        • et al.
        The nature of dopamine dysfunction in schizophrenia and what this means for treatment: meta-analysis of imaging studies.
        Archives of general psychiatry. 2012; 69: 776-786
        • Howes O.D.
        • Bose S.K.
        • Turkheimer F.
        • Valli I.
        • Egerton A.
        • Valmaggia L.R.
        • et al.
        Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study.
        American Journal of Psychiatry. 2011; 168: 1311-1317
        • Murray G.K.
        • Corlett P.R.
        • Clark L.
        • Pessiglione M.
        • Blackwell A.D.
        • Honey G.
        • et al.
        Substantia nigra/ventral tegmental reward prediction error disruption in psychosis.
        Mol Psychiatry. 2008; 13: 267-276
        • Howes O.D.
        • Montgomery A.J.
        • Asselin M.-C.
        • Murray R.M.
        • Valli I.
        • Tabraham P.
        • et al.
        Elevated striatal dopamine function linked to prodromal signs of schizophrenia.
        Archives of general psychiatry. 2009; 66: 13-20
        • Kegeles L.S.
        • Abi-Dargham A.
        • Frankle W.G.
        • Gil R.
        • Cooper T.B.
        • Slifstein M.
        • et al.
        Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.
        Archives of general psychiatry. 2010; 67: 231-239
        • Eisenberg D.P.
        • Kohn P.D.
        • Hegarty C.E.
        • Smith N.R.
        • Grogans S.E.
        • Czarapata J.B.
        • et al.
        Clinical correlation but no elevation of striatal dopamine synthesis capacity in two independent cohorts of medication-free individuals with schizophrenia.
        Mol Psychiatry. 2021;
        • Howes O.D.
        • Nour M.M.
        Dopamine and the aberrant salience hypothesis of schizophrenia.
        World Psychiatry. 2016; 15: 3-4
        • Fletcher P.C.
        • Frith C.D.
        Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia.
        Nat Rev Neurosci. 2009; 10: 48-58
      3. Corlett PR, Mollick JA, Kober H (2021): Substrates of Human Prediction Error for Incentives, Perception, Cognition, and Action.

        • Ficco L.
        • Mancuso L.
        • Manuello J.
        • Teneggi A.
        • Liloia D.
        • Duca S.
        • et al.
        Disentangling predictive processing in the brain: a meta-analytic study in favour of a predictive network.
        Sci Rep. 2021; 1116258
        • Kutlu M.G.
        • Zachry J.E.
        • Melugin P.R.
        • Cajigas S.A.
        • Chevee M.F.
        • Kelly S.J.
        • et al.
        Dopamine release in the nucleus accumbens core signals perceived saliency.
        Curr Biol. 2021; 31: 4748-4761 e4748
        • Parr T.
        • Friston K.J.
        Attention or salience?.
        Curr Opin Psychol. 2019; 29: 1-5
        • Craig A.D.
        How do you feel--now? The anterior insula and human awareness.
        Nat Rev Neurosci. 2009; 10: 59-70
        • Seeley W.W.
        The Salience Network: A Neural System for Perceiving and Responding to Homeostatic Demands.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2019; 39: 9878-9882
        • Huang Z.
        • Tarnal V.
        • Vlisides P.E.
        • Janke E.L.
        • McKinney A.M.
        • Picton P.
        • et al.
        Anterior insula regulates brain network transitions that gate conscious access.
        Cell Rep. 2021; 35109081
        • McCutcheon R.A.
        • Nour M.M.
        • Dahoun T.
        • Jauhar S.
        • Pepper F.
        • Expert P.
        • et al.
        Mesolimbic Dopamine Function Is Related to Salience Network Connectivity: An Integrative Positron Emission Tomography and Magnetic Resonance Study.
        Biol Psychiatry. 2019; 85: 368-378
        • Avram M.
        • Brandl F.
        • Knolle F.
        • Cabello J.
        • Leucht C.
        • Scherr M.
        • et al.
        Aberrant striatal dopamine links topographically with cortico-thalamic dysconnectivity in schizophrenia.
        Brain. 2020; 143: 3495-3505
        • Conio B.
        • Martino M.
        • Magioncalda P.
        • Escelsior A.
        • Inglese M.
        • Amore M.
        • et al.
        Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders.
        Mol Psychiatry. 2020; 25: 82-93
        • Shafiei G.
        • Zeighami Y.
        • Clark C.A.
        • Coull J.T.
        • Nagano-Saito A.
        • Leyton M.
        • et al.
        Dopamine Signaling Modulates the Stability and Integration of Intrinsic Brain Networks.
        Cereb Cortex. 2019; 29: 397-409
        • Cole D.M.
        • Oei N.Y.
        • Soeter R.P.
        • Both S.
        • van Gerven J.M.
        • Rombouts S.A.
        • et al.
        Dopamine-dependent architecture of cortico-subcortical network connectivity.
        Cereb Cortex. 2013; 23: 1509-1516
        • McCabe C.
        • Huber A.
        • Harmer C.J.
        • Cowen P.J.
        The D2 antagonist sulpiride modulates the neural processing of both rewarding and aversive stimuli in healthy volunteers.
        Psychopharmacology (Berl). 2011; 217: 271-278
        • Rossler J.
        • Rossler W.
        • Seifritz E.
        • Unterrassner L.
        • Wyss T.
        • Haker H.
        • et al.
        Dopamine-Induced Dysconnectivity Between Salience Network and Auditory Cortex in Subjects With Psychotic-like Experiences: A Randomized Double-Blind Placebo-Controlled Study.
        Schizophr Bull. 2020; 46: 732-740
        • Yang Z.
        • Kelly C.
        • Castellanos F.X.
        • Leon T.
        • Milham M.P.
        • Adler L.A.
        Neural Correlates of Symptom Improvement Following Stimulant Treatment in Adults with Attention-Deficit/Hyperactivity Disorder.
        J Child Adolesc Psychopharmacol. 2016; 26: 527-536
        • Stip E.
        • Lungu O.V.
        Salience network and olanzapine in schizophrenia: implications for treatment in anorexia nervosa.
        Can J Psychiatry. 2015; 60: S35-39
        • Han S.
        • Becker B.
        • Duan X.
        • Cui Q.
        • Xin F.
        • Zong X.
        • et al.
        Distinct striatum pathways connected to salience network predict symptoms improvement and resilient functioning in schizophrenia following risperidone monotherapy.
        Schizophr Res. 2020; 215: 89-96
        • Wang Y.
        • Jiang Y.
        • Collin G.
        • Liu D.
        • Su W.
        • Xu L.
        • et al.
        The effects of antipsychotics on interactions of dynamic functional connectivity in the triple-network in first episode schizophrenia.
        Schizophr Res. 2021; 236: 29-37
        • Kraguljac N.V.
        • White D.M.
        • Hadley J.A.
        • Visscher K.
        • Knight D.
        • ver Hoef L.
        • et al.
        Abnormalities in large scale functional networks in unmedicated patients with schizophrenia and effects of risperidone.
        Neuroimage Clin. 2016; 10: 146-158
        • Herms E.N.
        • Bishop J.R.
        • Okuneye V.T.
        • Tamminga C.A.
        • Keshavan M.S.
        • Pearlson G.D.
        • et al.
        No connectivity alterations for striatum, default mode, or salience network in association with self-reported antipsychotic medication dose in a large chronic patient group.
        Schizophr Res. 2020; 223: 359-360
        • Ye Z.
        • Hammer A.
        • Camara E.
        • Munte T.F.
        Pramipexole modulates the neural network of reward anticipation.
        Hum Brain Mapp. 2011; 32: 800-811
        • Chakroun K.
        • Mathar D.
        • Wiehler A.
        • Ganzer F.
        • Peters J.
        Dopaminergic modulation of the exploration/exploitation trade-off in human decision-making.
        Elife. 2020; 9
        • Corlett P.R.
        • Murray G.K.
        • Honey G.D.
        • Aitken M.R.
        • Shanks D.R.
        • Robbins T.W.
        • et al.
        Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions.
        Brain. 2007; 130: 2387-2400
        • Morris R.
        • Griffiths O.
        • Le Pelley M.E.
        • Weickert T.W.
        Attention to irrelevant cues is related to positive symptoms in schizophrenia.
        Schizophrenia bulletin. 2013; 39: 575-582
        • Ioakeimidis V.
        • Haenschel C.
        • Yarrow K.
        • Kyriakopoulos M.
        • Dima D.
        A meta-analysis of structural and functional brain abnormalities in early-onset schizophrenia.
        Schizophrenia Bulletin Open. 2020; 1 (sgaa016)
        • Nielsen J.D.
        • Madsen K.H.
        • Wang Z.
        • Liu Z.
        • Friston K.J.
        • Zhou Y.
        Working Memory Modulation of Frontoparietal Network Connectivity in First-Episode Schizophrenia.
        Cereb Cortex. 2017; 27: 3832-3841
        • Collins A.G.
        • Brown J.K.
        • Gold J.M.
        • Waltz J.A.
        • Frank M.J.
        Working memory contributions to reinforcement learning impairments in schizophrenia.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2014; 34: 13747-13756
        • Collins A.G.E.
        • Ciullo B.
        • Frank M.J.
        • Badre D.
        Working Memory Load Strengthens Reward Prediction Errors.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2017; 37: 4332-4342
        • Palaniyappan L.
        Dissecting the neurobiology of linguistic disorganisation and impoverishment in schizophrenia.
        Semin Cell Dev Biol. 2021;
        • Tran The J.
        • Magistretti P.J.
        • Ansermet F.
        Interoception Disorder and Insular Cortex Abnormalities in Schizophrenia: A New Perspective Between Psychoanalysis and Neuroscience.
        Front Psychol. 2021; 12628355
        • Yeshurun Y.
        • Nguyen M.
        • Hasson U.
        The default mode network: where the idiosyncratic self meets the shared social world.
        Nat Rev Neurosci. 2021; 22: 181-192
        • Green M.F.
        • Horan W.P.
        • Lee J.
        Social cognition in schizophrenia.
        Nat Rev Neurosci. 2015; 16: 620-631
        • Seyhan A.A.
        Lost in translation: the valley of death across preclinical and clinical divide–identification of problems and overcoming obstacles.
        Translational Medicine Communications. 2019; 4: 1-19
        • Mandino F.
        • Vrooman R.M.
        • Foo H.E.
        • Yeow L.Y.
        • Bolton T.A.W.
        • Salvan P.
        • et al.
        A triple-network organization for the mouse brain.
        Mol Psychiatry. 2022; 27: 865-872
        • Tsai P.J.
        • Keeley R.J.
        • Carmack S.A.
        • Vendruscolo J.C.M.
        • Lu H.
        • Gu H.
        • et al.
        Converging Structural and Functional Evidence for a Rat Salience Network.
        Biol Psychiatry. 2020; 88: 867-878
        • Downar J.
        • Blumberger D.M.
        • Daskalakis Z.J.
        The Neural Crossroads of Psychiatric Illness: An Emerging Target for Brain Stimulation.
        Trends Cogn Sci. 2016; 20: 107-120
        • Picard F.
        • Sadaghiani S.
        • Leroy C.
        • Courvoisier D.S.
        • Maroy R.
        • Bottlaender M.
        High density of nicotinic receptors in the cingulo-insular network.
        Neuroimage. 2013; 79: 42-51
        • Hawco C.
        • Voineskos A.N.
        • Steeves J.K.E.
        • Dickie E.W.
        • Viviano J.D.
        • Downar J.
        • et al.
        Spread of activity following TMS is related to intrinsic resting connectivity to the salience network: A concurrent TMS-fMRI study.
        Cortex. 2018; 108: 160-172
        • Iwabuchi S.J.
        • Raschke F.
        • Auer D.P.
        • Liddle P.F.
        • Lankappa S.T.
        • Palaniyappan L.
        Targeted transcranial theta-burst stimulation alters fronto-insular network and prefrontal GABA.
        Neuroimage. 2017; 146: 395-403
        • Scangos K.W.
        • Khambhati A.N.
        • Daly P.M.
        • Makhoul G.S.
        • Sugrue L.P.
        • Zamanian H.
        • et al.
        Closed-loop neuromodulation in an individual with treatment-resistant depression.
        Nat Med. 2021; 27: 1696-1700
        • Cella M.
        • Price T.
        • Corboy H.
        • Onwumere J.
        • Shergill S.
        • Preti A.
        Cognitive remediation for inpatients with psychosis: a systematic review and meta-analysis.
        Psychol Med. 2020; 50: 1062-1076
        • Weickert T.W.
        • Salimuddin H.
        • Lenroot R.K.
        • Bruggemann J.
        • Loo C.
        • Vercammen A.
        • et al.
        Preliminary findings of four-week, task-based anodal prefrontal cortex transcranial direct current stimulation transferring to other cognitive improvements in schizophrenia.
        Psychiatry Res. 2019; 280112487
        • Northoff G.
        • Duncan N.W.
        How do abnormalities in the brain's spontaneous activity translate into symptoms in schizophrenia? From an overview of resting state activity findings to a proposed spatiotemporal psychopathology.
        Prog Neurobiol. 2016; 145-146: 26-45