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

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 (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.

Fig. 1.

Significantly altered functional connectivity for first-episode schizophrenia by meta-analysis involving Datasets 2^#, 3^#, and 6^#. The color of the 3 circles (from outside to inside) denotes: the 90 different automatic anatomical labelling (AAL) regions (First circle); the number of increased links (Second circle, deep red means a region has more increased links); the number of decreased links (Third circle, deep blue means a region has more decreased links). The thickness of the links is proportional to –log10 (P value). The right of the brain is on the right of each circular diagram. (a) illustrates altered links of the inferior frontal lobe (51 links, including the opercular, triangular and orbital part), and (b) is for the remaining links. Red links indicate that patients have a higher mean functional connectivity than controls (ie, mean (FC_patient) − mean(FC_control) > 0), and blue links indicate the opposite.

Fig. 1.

Significantly altered functional connectivity for first-episode schizophrenia by meta-analysis involving Datasets 2^#, 3^#, and 6^#. The color of the 3 circles (from outside to inside) denotes: the 90 different automatic anatomical labelling (AAL) regions (First circle); the number of increased links (Second circle, deep red means a region has more increased links); the number of decreased links (Third circle, deep blue means a region has more decreased links). The thickness of the links is proportional to –log10 (P value). The right of the brain is on the right of each circular diagram. (a) illustrates altered links of the inferior frontal lobe (51 links, including the opercular, triangular and orbital part), and (b) is for the remaining links. Red links indicate that patients have a higher mean functional connectivity than controls (ie, mean (FC_patient) − mean(FC_control) > 0), and blue links indicate the opposite.

Fig. 2.

Significantly altered functional connectivity for chronic stage schizophrenia by meta-analysis involving Datasets 4^#, 5^#, and 6^#. (a) illustrates altered links involving the thalamus (58 links), and (b) is for links involving the cingulate cortex (49 links). (c) is for the remaining significantly different links.

Fig. 2.

Significantly altered functional connectivity for chronic stage schizophrenia by meta-analysis involving Datasets 4^#, 5^#, and 6^#. (a) illustrates altered links involving the thalamus (58 links), and (b) is for links involving the cingulate cortex (49 links). (c) is for the remaining significantly different links.

Fig. 2.

Significantly altered functional connectivity for chronic stage schizophrenia by meta-analysis involving Datasets 4^#, 5^#, and 6^#. (a) illustrates altered links involving the thalamus (58 links), and (b) is for links involving the cingulate cortex (49 links). (c) is for the remaining significantly different links.

Fig. 3.

The number of significantly different functional connectivity links of each brain region for (a) first-episode (FE) and (b) chronic stage schizophrenia patients. (a) and (b) were obtained by counting the number of different links in supplementary tables S2 and S3 for each pair of symmetric brain regions (ie, we added the number of links of the left and right corresponding regions). For FE patients, 46 regions (out of 90 automatic anatomical labelling [AAL] regions) showed differences from controls, and for chronic stage patients, 67 regions demonstrated differences from controls. Regions marked green are those demonstrating common changes in both FE and chronic stages (these regions have more than 2.5% altered-links in both stages), including the middle frontal gyrus, posterior cingulate cortex, the fusiform gyrus, and the temporal pole. Regions marked pink are those demonstrating stage-specific changes. Inferior and medial frontal gyrus changes were found in FE schizophrenia, and cingulate, subcortical (especially the thalamus), and occipital changes were found in the chronic stage.