Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia

Schizophr Bull. 2017 Mar 1;43(2):436-448. doi: 10.1093/schbul/sbw099.


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 (FE) and chronic patients from controls using resting-state functional MRI, and determine changes that are specifically associated with disease onset, a clinical staging model is adopted. We analyze functional-connectivity differences in prodromal, FE (mostly drug naïve), and chronic patients from their matched controls from 6 independent datasets involving a total of 789 participants (343 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 Bonferroni correction for multiple comparisons. Prodromal patients differed from controls in their pattern of functional-connectivity involving the inferior frontal gyri (Broca's area). In FE 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 prominent at the chronic stage. These results provide evidence for distinct patterns of functional-dysconnectivity across FE 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.

Keywords: Broca’s area; clinical staging model; resting-state fMRI; thalamus; whole brain functional-connectivity analysis.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cerebral Cortex / diagnostic imaging
  • Cerebral Cortex / physiopathology*
  • Chronic Disease
  • Connectome / methods*
  • Disease Progression
  • Female
  • Humans
  • Male
  • Neural Pathways / diagnostic imaging
  • Neural Pathways / physiopathology
  • Prefrontal Cortex / diagnostic imaging
  • Prefrontal Cortex / physiopathology
  • Prodromal Symptoms*
  • Risk
  • Schizophrenia / diagnostic imaging
  • Schizophrenia / physiopathology*
  • Thalamus / diagnostic imaging
  • Thalamus / physiopathology*
  • Young Adult