Dysfunction of Large-Scale Brain Networks in Schizophrenia: A Meta-analysis of Resting-State Functional Connectivity

Abstract

Schizophrenia is a complex mental disorder with disorganized communication among large-scale brain networks, as demonstrated by impaired resting-state functional connectivity (rsFC). Individual rsFC studies, however, vary greatly in their methods and findings. We searched for consistent patterns of network dysfunction in schizophrenia by using a coordinate-based meta-analysis. Fifty-six seed-based voxel-wise rsFC datasets from 52 publications (2115 patients and 2297 healthy controls) were included in this meta-analysis. Then, coordinates of seed regions of interest (ROI) and between-group effects were extracted and coded. Seed ROIs were categorized into seed networks by their location within an a priori template. Multilevel kernel density analysis was used to identify brain networks in which schizophrenia was linked to hyper-connectivity or hypo-connectivity with each a priori network. Our results showed that schizophrenia was characterized by hypo-connectivity within the default network (DN, self-related thought), affective network (AN, emotion processing), ventral attention network (VAN, processing of salience), thalamus network (TN, gating information) and somatosensory network (SS, involved in sensory and auditory perception). Additionally, hypo-connectivity between the VAN and TN, VAN and DN, VAN and frontoparietal network (FN, external goal-directed regulation), FN and TN, and FN and DN were found in schizophrenia. Finally, the only instance of hyper-connectivity in schizophrenia was observed between the AN and VAN. Our meta-analysis motivates an empirical foundation for a disconnected large-scale brain networks model of schizophrenia in which the salience processing network (VAN) plays the core role, and its imbalanced communication with other functional networks may underlie the core difficulty of patients to differentiate self-representation (inner world) and environmental salience processing (outside world).

Keywords: brain networks; disconnected model; meta-analysis; resting-state; salience network; schizophrenia.

Fig. 1.

Meta-analysis of abnormal resting-state functional connectivity (rsFC) in schizophrenia (SCZ). The first 3 columns represent the seed regions of interest (ROI) indicated by dots with 6 mm radius and categorized by an a priori functional network. The last 2 columns represent altered rsFC in SCZ. (A) SCZ exhibited hypo-connectivity within the default network (DN) between the DN seeds and the medial prefrontal cortex (MPFC) extending to the anterior cingulate cortex (ACC) and hypo-connectivity between the DN seeds and 2 regions within the ventral attention network (VAN), the ACC and insula; hypo-connectivity was also observed between the DN seeds and the dorsolateral prefrontal cortex (DLPFC), a key hub of the frontoparietal network (FN). (B) SCZ was related to hypo-connectivity within the AN between the AN seeds and the MPFC and hyper-connectivity between the AN seeds and a region of the putamen extending to a region of the caudate within the VAN. (C) SCZ was associated with hypo-connectivity between the FN seeds and the thalamus network (TN) and extending into regions of the insula and putamen within the VAN. (D) SCZ was linked to hypo-connectivity within the somatosensory network (SS), mainly in the language network between the SS seeds and the superior temporal cortex (STC). (E) SCZ exhibited hypo-connectivity between the VAN seeds and a region of the posterior parietal cortex (PPC) extending to the precuneus (PCS) and inferior parietal lobule (IPL) within the DN, hypo-connectivity between the VAN seeds and a region of the caudate within the FN, hypo-connectivity between the VAN seeds and the TN, and hypo-connectivity within the VAN between the VAN seeds and the regions of the putamen and ACC. (F) Individuals with schizophrenia had hypo-connectivity between the TN seeds and regions of the MCC extending to the superior frontal gyrus (SFG) and cerebellum within the VAN, hypo-connectivity within the TN between the TN seeds and thalamus, and hypo-connectivity between the TN seeds and regions of the cerebellum within the VAN. The results are shown with both height-based (hb) thresholding (the proportion of studies reporting an effect at that voxel exceeds chance) and extent-based (eb) thresholding (the proportion of studies reporting an effect at the contiguous voxels exceeds chance). All results are significant at P < .05, corrected for family-wise error rate.

Fig. 2.

A disconnected large-scale brain networks model of schizophrenia. Reduced connectivity within the salience monitoring systems (ventral attention network [VAN]; thalamus network [TN]) and imbalanced connectivity among the salience systems and networks involved in internal thought (default network [DN]) and external goal-direction regulation (frontoparietal network [FN]) may reflect a weakness in salience processing that contributes to the general deficits in both external goal-directed behavior and self-awareness. Meanwhile, reduced connectivity between the FN and TN, which are involved in gating information, may underlie the loss of salient information management control. Furthermore, decreased connectivity within neural systems involved in emotion processing and hyper-connectivity between the emotion system (AN) and the salience processing system (VAN) may relate to the deficits in emotion perception and regulation. Circles refer to reduced connectivity within the corresponding networks.