An umbrella review of neuroimaging studies and conceptual framework linking pathophysiology and psychopathology in schizophrenia

Schizophrenia is a chronic psychotic syndrome with elusive neurobiological underpinnings, partly owing to heterogeneity and inconsistency of existing data. Here, to address this, we conduct an umbrella review of meta-analyses of neuroimaging studies to identify the most consistent brain alterations in schizophrenia. A systematic PubMed search (until October 2022) identified 50 articles reporting high-resolution neuroimaging meta-analyses examining brain structure and function—gray matter, white matter, intrinsic activity and task-based activation—by comparing brain alterations between individuals with prodromal symptoms or schizophrenia (distinguishing early and chronic stages) and healthy controls, or by correlating brain alterations with schizophrenia symptoms. The synthesis uncovers a core spatiotemporal set of brain alterations. The prodromal stage shows gray matter deficits in midline structures (especially the medial prefrontal cortex), alongside central executive network dysfunction. The first-episode/early psychosis stage features additional gray matter damage to the operculum (insula, superior temporal gyrus and adjacent cortices) and white matter disruptions in fronto-temporal regions near the lateral ventricles (affecting the fornix, cingulum and long-range fasciculi), alongside default-mode network dysfunction. The chronic/deteriorative stage involves widespread alterations, prominently affecting the thalamus and lateral prefrontal cortex. Damage to opercular areas (especially the superior temporal gyrus/auditory cortex) correlates with auditory hallucinations, while default-mode network dysfunction correlates with delusions and hallucinations. These alterations may be limited to prototypical schizophrenia. Integrating these findings, we developed a conceptual framework that links the spatiotemporal pattern of brain alterations to pathophysiology and psychopathology, forming the basis for a working model of schizophrenia.