Large-scale network dysfunction in the acute state compared to the remitted state of bipolar disorder: A meta-analysis of resting-state functional connectivity

Abstract

Background: Bipolar disorder (BD) is a mental disorder characterized by mood fluctuations between an acute episodic state of either mania or depression and a clinically remitted state. Dysfunction of large-scale intrinsic brain networks has been demonstrated in this disorder, but it remains unknown whether those network alterations are related to different states.

Methods: In the present study, we performed a meta-analysis of whole-brain seed-based resting-state functional connectivity (rsFC) studies in BD patients to compare the intrinsic function of brain networks between episodic and remitted states. Thirty-nine seed-based voxel-wise rsFC datasets from thirty publications (1047 BD patients vs 1081 controls) were included in the meta-analysis. Seeds were categorized into networks by their locations within a priori functional networks. Seed-based d mapping analysis of between-state effects identified brain systems in which different states were associated with increased connectivity or decreased connectivity within and between each seed network.

Findings: We found that BD patients presented decreased connectivity within the affective network (AN) in acute episodes but not in the remitted state of the illness. Similar decreased connectivity within the default-mode network (DMN) was also found in the acute state, but it was replaced by increased connectivity in the remitted state. In addition, different patterns of between-network dysconnectivity were observed between the acute and remitted states.

Interpretation: This study is the first to identify different patterns of intrinsic function in large-scale brain networks between the acute and remitted states of BD through meta-analysis. The findings suggest that a shift in network function between the acute and remitted states may be related to distinct emotional and cognitive dysfunctions in BD, which may have important implications for identifying clinically relevant biomarkers to guide alternative treatment strategies for BD patients during active episodes or remission.

Funding: This study was supported by grants from the National Natural Science Foundation of China (81171488, 81671669 and 81820108018) and by a Sichuan Provincial Youth Grant (2017JQ0001).

Keywords: Bipolar disorder (BD); Functional network; Meta-analysis; Mood states; Resting-state functional connectivity (rsFC).

Fig. 1

Flowchart of the research strategy and literature selection. Abbreviations: bipolar disorder (BD); healthy controls (HC); affective network (AN); default mode network (DMN); regional homogeneity (ReHo); amplitude of low-frequency fluctuation (ALFF); fractional ALFF (fALFF); independent component analysis (ICA).

Fig. 2

Results of meta-analysis of altered resting-state functional connectivity for the affective network (AN) in patients with bipolar disorder (BD) compared with the healthy control (HC) group. The top line shows seeds (indicated by white dots) located in the a priori AN mask (yellow). The second-to-last line separately illustrates patients with BD in the acute state (BDA) relative to the HC group, patients with BD in remission (BDR) relative to the HC group and a comparison between BDA (vs. HC) and BDR (vs. HC). Red refers to hyperconnectivity (BD>HC), and blue refers to hypoconnectivity (BD

Fig. 3

Results of meta-analysis of altered resting-state functional connectivity for the default mode network (DMN) in patients with bipolar disorder (BD) compared with the healthy control (HC) group. The top line shows seeds (indicated by white dots) located within the a priori DMN mask (red). The second-to-last line separately illustrates patients with BD in the acute state (BDA) relative to the HC group, patients with BD in remission (BDR) relative to the HC group and a comparison between BDA (vs. HC) and BDR (vs. HC). Red refers to hyperconnectivity (BD>HC), and blue refers to hypoconnectivity (BD

Fig. 4

Dissociated abnormalities in large-scale brain networks between acute and remitted patients with bipolar disorder (BD). Acute-state-related hypoconnectivity within the AN and DMN and AN–DMN hyperconnectivity might reflect dysregulated emotional processing and cognition in BD patients during the active phase. However, there is also remitted-state-related hyperconnectivity within the DMN and between the AN and DMN, which may underlie abnormal cognitive regulation during remission. Both findings indicate that abnormal emotional processing is a state-related impairment that is evident in acutely ill patients but normalized with remission. Cognitive dysregulation is a trait-related impairment in BD patients that is common in both acute and remission states. BDA, BD in acute state; BDR, BD in remission; HC, healthy control.