Dynamic functional network reconfiguration underlying the pathophysiology of schizophrenia and autism spectrum disorder

Abstract

The dynamics of the human brain span multiple spatial scales, from connectivity associated with a specific region/network to the global organization, each representing different brain mechanisms. Yet brain reconfigurations at different spatial scales are seldom explored and whether they are associated with the neural aspects of brain disorders is far from understood. In this study, we introduced a dynamic measure called step-wise functional network reconfiguration (sFNR) to characterize how brain configuration rewires at different spatial scales. We applied sFNR to two independent datasets, one includes 160 healthy controls (HCs) and 151 patients with schizophrenia (SZ) and the other one includes 314 HCs and 255 individuals with autism spectrum disorder (ASD). We found that both SZ and ASD have increased whole-brain sFNR and sFNR between cerebellar and subcortical/sensorimotor domains. At the ICN level, the abnormalities in SZ are mainly located in ICNs within subcortical, sensory, and cerebellar domains, while the abnormalities in ASD are more widespread across domains. Interestingly, the overlap SZ-ASD abnormality in sFNR between cerebellar and sensorimotor domains was correlated with the reasoning-problem-solving performance in SZ (r = -.1652, p = .0058) as well as the Autism Diagnostic Observation Schedule in ASD (r = .1853, p = .0077). Our findings suggest that dynamic reconfiguration deficits may represent a key intersecting point for SZ and ASD. The investigation of brain dynamics at different spatial scales can provide comprehensive insights into the functional reconfiguration, which might advance our knowledge of cognitive decline and other pathophysiology in brain disorders.

Keywords: autism spectrum disorder; dynamic functional connectivity; network reconfiguration at different spatial scales; schizophrenia.

FIGURE 1

sFNR abnormalities in SZ. (a) Difference in the whole‐brain sFNR between HCs and SZ. (b) Average within/between‐domain sFNR across all subjects. (c) Difference in within‐domain sFNR between HC and SZ. (d) Difference in between‐domain sFNR between HC and SZ. Boxplots display the mean sFNR across subjects (red line), the 95% confidence interval for the mean (green area), and the SD (orange area). ***Significance p < .01, Bonferroni corrected. HC, healthy control; sFNR, step‐wise functional network reconfiguration; SZ, schizophrenia

FIGURE 2

sFNR abnormalities for ICNs in SZ patients. (a) sFNR across ICNs. (b) Highlighted ICNs with sFNR difference between HCs and SZ patients. (c) Exemplar ICNs with sFNR difference from five different functional domains. Boxplots display the mean sFNR across subjects (red line), the 95% confidence interval for the mean (green area), and the SD (orange area). **Significance p < .05, Bonferroni corrected. HC, healthy control; ICN, intrinsic connectivity network; sFNR, step‐wise functional network reconfiguration; SZ, schizophrenia

FIGURE 3

sFNR abnormalities in ASD. (a) Difference in the whole‐brain sFNR between HCs and individuals with ASD. (b) Average within/between‐domain sFNR across all subjects. (c) Difference in between‐domain sFNR between HC and ASD. Boxplots display the mean sFNR across subjects (red line), the 95% confidence interval for the mean (green area), and the SD (orange area). *Significance p < .05, FDR corrected. ASD, autism spectrum disorder; FDR, false discovery rate; HC, healthy control; sFNR, step‐wise functional network reconfiguration

FIGURE 4

sFNR abnormalities for ICNs in ASD patients. (a) sFNR across ICNs. (b) Highlighted ICNs with sFNR difference between HCs and individuals with ASD. (c) Exemplar ICNs with sFNR difference from six different functional domains. Boxplots display the mean sFNR across subjects (red line), the 95% confidence interval for the mean (green area), and the SD (orange area). *Significance p < .05, FDR corrected. ASD, autism spectrum disorder; FDR, false discovery rate; HC, healthy control; ICN, intrinsic connectivity network; sFNR, step‐wise functional network reconfiguration

FIGURE 5

Correlations between sFNR and reasoning‐problem‐solving score/ADOS. Two sFNR calculations show negative correlations with reasoning‐problem‐solving and two sFNR calculations show positive correlations with ADOS: (a) sFNR between SM and CB domains in SZ; (b) sFNR of SPL in SZ; (c) sFNR between SM and CB domains in ASD; and (d) sFNR of thalamus in ASD. Each dot represents the value of each subject and the black line represents the relationship between sFNR and score. *Significance p < .05, FDR corrected. ADOS, the Autism Diagnostic Observation Schedule; ASD, autism spectrum disorder; CB, cerebellar domain; sFNR, step‐wise functional network reconfiguration; SM, sensorimotor domain; SPL, superior parietal lobule; SZ, schizophrenia