Decreased hemispheric connectivity and decreased intra- and inter- hemisphere asymmetry of resting state functional network connectivity in schizophrenia

Abstract

Many studies have shown that schizophrenia patients have aberrant functional network connectivity (FNC) among brain regions, suggesting schizophrenia manifests with significantly diminished (in majority of the cases) connectivity. Schizophrenia is also associated with a lack of hemispheric lateralization. Hoptman et al. (2012) reported lower inter-hemispheric connectivity in schizophrenia patients compared to controls using voxel-mirrored homotopic connectivity. In this study, we merge these two points of views together using a group independent component analysis (gICA)-based approach to generate hemisphere-specific timecourses and calculate intra-hemisphere and inter-hemisphere FNC on a resting state fMRI dataset consisting of age- and gender-balanced 151 schizophrenia patients and 163 healthy controls. We analyzed the group differences between patients and healthy controls in each type of FNC measures along with age and gender effects. The results reveal that FNC in schizophrenia patients shows less hemispheric asymmetry compared to that of the healthy controls. We also found a decrease in connectivity in all FNC types such as intra-left (L_FNC), intra-right (R_FNC) and inter-hemisphere (Inter_FNC) in the schizophrenia patients relative to healthy controls, but general patterns of connectivity were preserved in patients. Analyses of age and gender effects yielded results similar to those reported in whole brain FNC studies.

Keywords: Functional network connectivity; Hemisphere; Heterotopic connectivity; Homotopic connectivity; Lateral connectivity; Laterality; Schizophrenia.

Figure 1

Symmetrized aggregated spatial maps of the 43 RSNs are displayed at the three most informative slices. RSNs are divided into groups based on their anatomical and functional properties and include sub-cortical (SC), sensorimotor (SM), auditory (AUD), visual (VIS), attention/cognitive control (CC), default-mode (DMN), and cerebellar (CB) networks.

Figure 2

Averages of Patients (left column) and Healthy Control (right column) subgroups for all FNC types (L_FNC, R_FNC and Inter_FNC from top to bottom respectively) are displayed as t-statistics thresholded with 0.01 levels FDR. Homotopic FNCs are displayed in bar plots for visualization purposes and they have the highest connectivity strength. In all FNC types, we observe diminished connectivity strength in patients.

Figure 3

Comparing strength of connectivity in different FNC types for patients and healthy control groups. LL is the L_FNC, RR is the R_FNC, LR is the lower triangular of Inter_FNC, and RL is the upper triangular of Inter_FNC. Dark blue shows the number of regions significant in both of the corresponding FNCs, light blue shows the significant regions with same sign, yellow shows the number of regions having greater connectivity strength in FNC written in first, while red shows the number of regions having greater connectivity strength in FNC written in the second. The first and the second is the FNC type written in the subtitle consecutively. For instance, on the first comparison, we compare the strength of L_FNC in patients and R_FNC in patients therefore first is the L_FNC in patients and second is the R_FNC in patients.

Figure 4

Paired t-test (L_FNC minus R_FNC) results in – log10(p-value)*sign(beta) format to compare left and right FNC on the left, and after 0.05 levels FDR correction on the right. A lot of networks pairs exhibit significant differences, mostly suggesting right hemisphere having more connectivity strength.

Figure 5

Regression results of age, gender and diagnosis effects on L_FNC and intra R_FNC asymmetry differences, presented in – log10(p-value)*sign(beta) format. With a cross check with on the mean L_FNC and R_FNC differences (Figure 4) leads the observation that patients have diminished left and right connectivity differences, consistent with our findings in comparing connectivity strength. Age and gender seems to affect both FNCs in similar ways.

Figure 6

Schizophrenia effect on all FNC types, displayed as – log10(p-value)*sign(beta) format (at left column); after 0.05 levels FDR correction (at right column). General patterns look similar, for almost all pairs patients have weaker connectivity. Especially, the highly positively connected regions of auditory, visual, sensorimotor networks show less connectivity in patients.

Figure 7

Linear regression results of Euclidian distance and connectivity strength. Both homotopic connectivity and heterotopic connectivity have an inverse relationship. Our findings of significant strength differences between L_FNC and R_FNC support that Euclidian distance difference cannot explain the strength differences between different FNC types.