Integrative Brain Network and Salience Models of Psychopathology and Cognitive Dysfunction in Schizophrenia

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. First, we 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. Next, we 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. Thus, a powerful paradigm to characterize the neurobiology of schizophrenia 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.