Working memory related brain network connectivity in individuals with schizophrenia and their siblings

Abstract

A growing number of studies have reported altered functional connectivity in schizophrenia during putatively "task-free" states and during the performance of cognitive tasks. However, there have been few systematic examinations of functional connectivity in schizophrenia across rest and different task states to assess the degree to which altered functional connectivity reflects a stable characteristic or whether connectivity changes vary as a function of task demands. We assessed functional connectivity during rest and during three working memory loads of an N-back task (0-back, 1-back, 2-back) among: (1) individuals with schizophrenia (N = 19); (2) the siblings of individuals with schizophrenia (N = 28); (3) healthy controls (N = 10); and (4) the siblings of healthy controls (N = 17). We examined connectivity within and between four brain networks: (1) frontal-parietal (FP); (2) cingulo-opercular (CO); (3) cerebellar (CER); and (4) default mode (DMN). In terms of within-network connectivity, we found that connectivity within the DMN and FP increased significantly between resting state and 0-back, while connectivity within the CO and CER decreased significantly between resting state and 0-back. Additionally, we found that connectivity within both the DMN and FP was further modulated by memory load. In terms of between network connectivity, we found that the DMN became significantly more "anti-correlated" with the FP, CO, and CER networks during 0-back as compared to rest, and that connectivity between the FP and both CO and CER networks increased with memory load. Individuals with schizophrenia and their siblings showed consistent reductions in connectivity between both the FP and CO networks with the CER network, a finding that was similar in magnitude across rest and all levels of working memory load. These findings are consistent with the hypothesis that altered functional connectivity in schizophrenia reflects a stable characteristic that is present across cognitive states.

Keywords: cerebellum; cognitive control; functional connectivity; risk; schizophrenia; task; working memory.

Figure 1

Figure illustrating the location of regions within each of the four networks. Regions of the Frontal–Parietal network (FP) are marked in green, the Cingulo-Opercular network (CO) in yellow, the Default Mode Network (DMN) in blue, and the Cerebellar network (CER) in red.

Figure 2

Graph illustrating 0-back task versus rest within-network connectivity collapsed across siblings. SCZ, individuals with schizophrenia and siblings of individuals with schizophrenia; CON, healthy controls and siblings of healthy controls; DMN, Default Mode Network; FP, Frontal–Parietal Network; CO, Cingulo-Opercular Network; CER, Cerebellar Network; w, within. Segments marked in blue indicate networks that showed significant main effects of task (0-back versus rest). The main effect of task is further illustrated by blue lines and shading showing data collapsed across all groups (mean and standard error). See Figure S4 in Supplementary Material for data plotted for each of the four groups separately.

Figure 3

Graph illustrating 0-back versus rest between network connectivity collapsed across siblings. SCZ, individuals with schizophrenia and siblings of individuals with schizophrenia; CON, healthy controls and siblings of healthy controls; DMN, Default Mode Network; FP, Frontal–Parietal Network; CO, Cingulo-Opercular Network; CER, Cerebellar Network; b, between. Segments marked in blue indicate networks which showed significant main effects of task (0-back versus rest). The main effect of task is further illustrated by blue lines and shading showing data collapsed across all groups (mean and standard error). Segments marked in red indicate networks that showed a significant main effect of genetic liability (SCZ versus CON). The main effect of genetic liability is further illustrated by red lines and shading showing data collapsed across task conditions (mean and standard error for each group across task and rest). See Figure S5 in Supplementary Material for data plotted for each of the four groups separately.

Figure 4

Graph illustrating within-network connectivity as a function of working memory load collapsed across siblings. SCZ, individuals with schizophrenia and siblings of individuals with schizophrenia; CON, healthy controls and siblings of healthy controls; DMN, Default Mode Network; FP, Frontal–Parietal Network; CO, Cingulo-Opercular Network; CER, Cerebellar Network; w, within. Segments marked in green indicate networks that showed significant main effects of working memory load (0B, 1B, 2B) and the gray lines further illustrate the significant main effect of load across groups (mean across groups). See Figure S6 in Supplementary Material for data plotted for each of the four groups separately.

Figure 5

Graph illustrating between network connectivity as a function of working memory load collapsed across siblings. SCZ, individuals with schizophrenia and siblings of individuals with schizophrenia; CON, healthy controls and siblings of healthy controls; DMN, Default Mode Network; FP, Frontal–Parietal Network; CO, Cingulo-Opercular Network; CER, Cerebellar Network; b, between. Segments marked in green indicate networks that showed significant main effects of working memory load (0B, 1B, 2B) and the gray lines further illustrate the significant main effect of load across groups (mean across groups). Segment marked in orange showed both a significant main effect of load and a significant main effect of genetic liability (SCZ versus CON). The segment marked red indicates the network that showed only a significant main effect of genetic liability (SCZ versus CON). The red lines further illustrate the statistically significant effects of genetic liability (mean and standard error for each group across memory loads). See Figure S7 in Supplementary Material for data plotted for each of the four groups separately.

Figure 6

Figure illustrating the pattern of changes in connectivity both within and between networks as a function of task state, memory load, and genetic liability.