Disentangling age- and disease-related alterations in schizophrenia brain network using structural equation modeling: A graph theoretical study based on minimum spanning tree.

Functional brain networks have been shown to undergo fundamental changes associated with aging or schizophrenia. However, the mechanism of how these factors exert influences jointly or interactively on brain networks remains elusive. A unified recognition of connectomic alteration patterns was also hampered by heterogeneities in network construction and thresholding methods. Recently, an unbiased network representation method regardless of network thresholding, so called minimal spanning tree algorithm, has been applied to study the critical skeleton of the brain network. In this study, we aimed to use minimum spanning tree (MST) as an unbiased network reconstruction and employed structural equation modeling (SEM) to unravel intertwined relationships among multiple phenotypic and connectomic variables in schizophrenia. First, we examined global and local brain network properties in 40 healthy subjects and 40 schizophrenic patients aged 21-55 using resting-state functional magnetic resonance imaging (rs-fMRI). Global network alterations are measured by graph theoretical metrics of MSTs and a connectivity-transitivity two-dimensional approach was proposed to characterize nodal roles. We found that networks of schizophrenic patients exhibited a more star-like global structure compared to controls, indicating excessive integration, and a loss of regional transitivity in the dorsal frontal cortex (corrected p <.05). Regional analysis of MST network topology revealed that schizophrenia patients had more network hubs in frontal regions, which may be linked to the "overloading" hypothesis. Furthermore, using SEM, we found that the level of MST integration mediated the influence of age on negative symptom severity (indirect effect 95% CI [0.026, 0.449]). These findings highlighted an altered network skeleton in schizophrenia and suggested that aging-related enhancement of network integration may undermine functional specialization of distinct neural systems and result in aggravated schizophrenic symptoms.