Brain-wide analysis of functional connectivity in first-episode and chronic stages of schizophrenia Running title: Functional connectivity changes in schizophrenia Authors

Title Brain-wide analysis of functional connectivity in first-episode and chronic stages of schizophrenia Running title: Functional connectivity changes in schizophrenia Word Count: Abstract: 250; MS: 3823 3 figures, 2 tables and a supplement document involving 1 figure and 8 tables. Abstract Published reports of functional abnormalities in schizophrenia remain divergent due to lack of staging point-of-view and whole-brain analysis. To identify key functional-connectivity differences of first-episode and chronic patients from controls using resting-state fMRI, and determine changes that are specifically associated with disease onset, a clinical staging model is adopted. We analyze functional-connectivity differences in prodromal, first-episode (drug naï ve), and chronic patients from their matched controls from 6 independent datasets involving a total of 789 participants (360 patients). Brain-wide functional-connectivity analysis was performed in different datasets and the results from the datasets of the same stage were then integrated by meta-analysis, with Bonfferoni correction for multiple comparison. Prodromal patients differed from controls in their pattern of functional-connectivity involving the inferior frontal gyri (Broca's area). In first-episode patients, 90% of the functional-connectivity changes involved the frontal lobes, mostly the inferior frontal gyrus including Broca's area, and these changes were correlated with delusions/blunted affect. For chronic patients, functional-connectivity differences extended to wider areas of the brain, including reduced thalamo-frontal connectivity, and increased thalamo-temporal and thalamo-sensorimoter connectivity that were correlated with the positive, negative and general symptoms, respectively. Thalamic changes became 5 5 prominent at the chronic stage. These results provide evidence for distinct patterns of functional-dysconnectivity across first-episode and chronic stages of schizophrenia. Importantly, abnormalities in the frontal language networks appear early, at the time of disease onset. The identification of stage-specific pathological processes may help to understand the disease course of schizophrenia and identify neurobiological markers crucial for early diagnosis.