Synopsis

Keywords: Neuroinflammation, fMRI (resting state)

This study provided preliminary evidence of the association between disrupted brain functional network topology and neuroinflammation in BD. The current study demonstrated disrupted topological organization in the whole brain and regional connectivity was associated with inflammatory cytokines of the IL-4, IL-8 and IL-10 levels in BD. Moreover, our results indicated that higher IL-4 levels and impaired regional connectivity in the temporal pole may be associated with the severer depressive symptoms in BD.

Background

Recent studies have indicated that inflammation may contribute to the etiology and progression of BD [1, 2]. Although evolving structural and functional neuroimaging studies have reported abnormalities in specific brain regions and connections in BD, the neuroimmunology of BD is not fully understood. Graph theoretical methods have been extensively applied to resting-state functional magnetic resonance imaging (rs-fMRI) to study the topological organization of functional brain networks [3]. However, until now, there is no study concentrating on the correlation between functional brain network topology and peripheral inflammation in BD. In this study, we tried to explore the disrupted brain functional network topology, peripheral cytokines and their correlations to demonstrate the role of inflammation in brain functional network topology in BD.

Methods

In this study, 53 BD patients and 47 healthy controls (HCs) underwent resting-state magnetic resonance imaging scans. Graph theory analysis was performed to investigate the topological properties of whole-brain functional connectome at both global and nodal levels. Serum levels of interleukin-4 (IL-4), interleukin-6 (IL-6) interleukin-8 (IL-8), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) were measured in all participants. Correlations between topological properties, clinical variables and cytokines levels in BD were calculated. Furthermore, mediation analysis was employed to determine whether inflammatory cytokines affect depressive symptoms by affecting brain network properties.

Results

Global and nodal parameters of the brain functional network
Figure 1 shows the global parameters (the AUC of C_p, L_p, λ, γ, σ , E_glo, and E_loc) for the BD and HCs group. Statistical analyses revealed that BD group showed significantly greater AUC of L_p (t = 2.130, p = 0.036, FDR-p = 0.084) and λ (t = 2.919, p = 0.004, FDR-p = 0.028), and lower AUC of E_glo (t = -2.125, p = 0.036, FDR-p = 0.084) when compared with HCs group. Figure 2 shows the significantly different brain regions in nodal parameters (the AUC of Deg_i and E_nodal) between BD group and HCs group (p < 0.0086). Of note, we found lower Deg_i in the bilateral lingual, lower E_nodal in the right superior frontal gyrus (SFG), left middle temporal pole (MTP), right postcentral gyrus, and bilateral lingual in BD group when compared with HCs group.

Inflammatory cytokines levels between two groups
The BD group showed greater levels of IL-4 , IL-6, IL-8, IL-10 when compared with the HCs group.

Correlation analyses
For the correlations between abnormal global parameters and inflammatory cytokines levels, in BD group, the AUC of L_p was significantly positively correlated with IL-10 level (r =0.334, p = 0.038), and the AUC of λ was significantly positively correlated with IL-8 level (r = 0.399, p = 0.012), and the AUC of E_glo was significantly inversely correlated with IL-10 (r = -0.333, p = 0.038) level (Figure 3A).
For the correlation between abnormal nodal parameters and inflammatory cytokines levels, in BD group, the AUC of E_nodal of the left MTP was significantly negatively correlated with IL-4 level (r = -0.418, p = 0.008) and IL-8 level (r = -0.341, p = 0.034) (Figure 3B).
For the correlation between abnormal network parameters and clinical variable, the AUC of L_p was significantly inversely correlated with onset age of illness (r = -0.322, p = 0.045), and the AUC of E_glo was significantly positive with onset age of illness (r = 0.364, p = 0.023), and the AUC of E_nodal of the left MTP was significantly positively correlated with 24-item HDRS scores (r = 0.431, p = 0.006) (Figure 3C).
For the correlation between abnormal inflammatory cytokines levels and clinical variable, IL-4 level was significantly negatively correlated with 24-item HDRS scores (r = -0.381, p = 0.022) (Figure 3C).

“Inflammatory-network-depression” mediation pathway analysis
Mediation analysis reported that the IL-4 level was associated with 24-item HDRS scores (total effect: β = -74.393, t = -2.2213, p = 0.034, 95% CI: [-142.776, -6.010]), and there was significant full mediation effect by E_nodal of the left MTP (indirect effect: p < 0.01, β= -21.511, 95%CI: [-57.753, -0.237]) for the association between IL-4 level and on 24-item HDRS scores. After considering the significant effect via E_nodal of the left MTP, the direct effect of IL-4 level on 24-item HDRS scores did not significant (β = -52.882, t = -1.583, p = 0.123, 95% CI: [-120.924, 15.160]) (Figure 3D).

Conclusion

In conclusion, our study provided preliminary evidence of the association between disrupted brain functional network topology and neuroinflammation in BD. The current study demonstrated disrupted topological organization in the whole brain and regional connectivity were associated with inflammatory cytokines of the IL-10, IL-8 and IL-4 levels in BD. Moreover, our results indicated that higher IL-4 levels and impaired regional connectivity in the temporal pole may be associated with the severer depressive symptoms in BD.

References

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3. Bullmore, E. and O. Sporns, Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci, 2009. 10(3): p. 186-98.

4. Yan, C.G., et al., DPABI: Data Processing & Analysis for (Resting-State) Brain Imaging. Neuroinformatics, 2016. 14(3): p. 339-51.

5. Zhang, J., et al., Disrupted brain connectivity networks in drug-naive, first-episode major depressive disorder. Biol Psychiatry, 2011. 70(4): p. 334-42.