Impaired coupling of local and global functional feedbacks underlies abnormal synchronization and negative symptoms of schizophrenia

Abstract

Background: Abnormal synchronization of brain oscillations is found to be associated with various core symptoms of schizophrenia. However, the underlying mechanism of this association remains yet to be elucidated.

Results: In this study, we found that coupled local and global feedback (CLGF) circuits in the cortical functional network are related to the abnormal synchronization and also correlated to the negative symptom of schizophrenia. Analysis of the magnetoencephalography data obtained from patients with chronic schizophrenia during rest revealed an increase in beta band synchronization and a reduction in gamma band power compared to healthy controls. Using a feedback identification method based on non-causal impulse responses, we constructed functional feedback networks and found that CLGF circuits were significantly reduced in schizophrenia. From computational analysis on the basis of the Wilson-Cowan model, we unraveled that the CLGF circuits are critically involved in the abnormal synchronization and the dynamical switching between beta and gamma bands power in schizophrenia. Moreover, we found that the abundance of CLGF circuits was negatively correlated with the development of negative symptoms of schizophrenia, suggesting that the negative symptom is closely related to the impairment of this circuit.

Conclusions: Our study implicates that patients with schizophrenia might have the impaired coupling of inter- and intra-regional functional feedbacks and that the CLGF circuit might serve as a critical bridge between abnormal synchronization and the negative symptoms of schizophrenia.

Figure 1

Modeling of the coupled local and global feedback circuits and the dynamical switching of beta-gamma power. (A) Frequency spectrum of the coupled local and global feedback circuits along with the varying local connection strength. Schematic diagram of the local and global feedback circuit was shown. Bottom figure represents the frequency spectrum in the case of local connection strength of 0 and 3, which correspond to 2-node positive feedback and the CLGF circuit, respectively. (B) (Top) Changes in the gamma power of oscillators a and b along with the increase of local connection strength. (Bottom) Changes in beta band phase locking value between oscillators a and b. (C) (Top) Representative example of the beta-gamma power switching in MEG data. Time-frequency pattern of beta and gamma bands power. (Bottom) Averaged power plot of beta and gamma bands. (D) Schematic representation of beta-gamma power switching. In each 1 ms time step, 0 was assigned for no switching and 1 for beta-gamma power switching. The duration of beta-gamma switching was determined by summing all these values, and the frequency of switching events was determined by counting the number of time steps changing from 0 to 1. (E) The duration and (F) the frequency of beta-gamma power switching in both normal and schizophrenia patients groups. Both measurements are significantly reduced in the patients group (p = 0.00015 and p = 0.000065). Bars and vertical lines indicate mean and standard errors, respectively.

Figure 2

Comparison of functional feedback networks and coupled local and global feedback circuits between two groups. (A) (Left and Middle) Total number of positive feedback connections in the normal and schizophrenia patients groups, and (Right) bar plot of the total number of positive feedback connections. Patients group exhibits the reduced number of positive feedback connections (p = 0.042). (B) (Top row) The number of global and (Bottom row) local positive feedback connections in the normal and schizophrenia patients groups. The reduced number of local positive feedback connections can be seen in the patients group (p = 0.0036). (C) (Left) Coupled local and global feedback circuits existing in the cortical functional network and (Right) statistical comparison of the number of this circuit in the normal and schizophrenia patients groups. Coupled local and global feedback circuits are reduced in the patients group (p = 0.031). Bars and vertical lines denote mean and standard errors, respectively.

Figure 3

Spectral power and phase synchronization of beta and gamma bands. (A) Averaged power spectrum of normal (blue) and schizophrenia patients (red) group. Patients group exhibits reduced mean power above 25 Hz frequency range. (B) Bar plot of beta and gamma band power in normal and schizophrenia patients groups. Gamma band was significantly reduced in the patients group (p = 0.041). (C) Bar plot of beta and gamma band phase synchronization in the normal and schizophrenia patients groups. Beta band phase locking value (PLV) increased in the schizophrenia patients group (p = 0.0056). Bars and vertical lines indicate mean and standard errors, respectively. (D) Topological comparison of beta band phase locking value between two groups. Each edge represents significantly stronger beta band phase locking value than the other group based on p-value of 0.01 (Top) and 0.001 (Bottom).

Figure 4

Correlation of the CLGF circuit with clinical variables. (A) PANSS negative symptom score was correlated with the number of CLGF circuits in the functional feedback networks of schizophrenia (R = -0.5376, p = 0.039) whereas PANSS positive, negative, general, and total symptom scores did not show significant correlations. (B) Schematic diagram summarizing this study. Relative to healthy controls, schizophrenia patients exhibit reduced interaction between interregional and intraregional connections, leading to impairment of CLGF circuit. Deficits in the coupled feedback circuit result in abnormal oscillations such as reduced gamma power and increased beta synchronization in the schizophrenia patients group. Reduced beta-gamma power switching might also be attributed to the impairment of CLGF circuit. Schizophrenia patients exhibited that PANSS negative symptom score is inversely proportional to the number of CLGF circuits. This suggests that negative symptoms of schizophrenia is also involved in the disconnectivity of coupled cortical connections.