Impaired interactions among white-matter functional networks in antipsychotic-naive first-episode schizophrenia

Abstract

Schizophrenia has been conceptualized as a disorder arising from structurally pathological alterations to white-matter fibers in the brain. However, few studies have focused on white-matter functional changes in schizophrenia. Considering that converging evidence suggests that white-matter resting state functional MRI (rsfMRI) signals can effectively depict neuronal activity and psychopathological status, this study examined white-matter network-level interactions in antipsychotic-naive first-episode schizophrenia (FES) to facilitate the interpretation of the psychiatric pathological mechanisms in schizophrenia. We recruited 42 FES patients (FESs) and 38 healthy controls (HCs), all of whom underwent rsfMRI. We identified 11 white-matter functional networks, which could be further classified into deep, middle, and superficial layers of networks. We then examined network-level interactions among these 11 white-matter functional networks using coefficient Granger causality analysis. We employed group comparisons on the influences among 11 networks using network-based statistic. Excitatory influences from the middle superior corona radiate network to the superficial orbitofrontal and deep networks were disrupted in FESs compared with HCs. Additionally, an extra failure of suppression within superficial networks (including the frontoparietal network, temporofrontal network, and the orbitofrontal network) was observed in FESs. We additionally recruited an independent cohort (13 FESs and 13 HCs) from another center to examine the replicability of our findings across centers. Similar replication results further verified the white-matter functional network interaction model of schizophrenia. The novel findings of impaired interactions among white-matter functional networks in schizophrenia indicate that the pathophysiology of schizophrenia may also lie in white-matter functional abnormalities.

Keywords: first-episode schizophrenia; functional networks; interactions; rsfMRI; white-matter.

Figure 1

Within‐group white‐matter functional networks influence patterns across all subjects in the primary cohort (N = 80) determined by one‐sample t test (p < .05). Red and blue arrow lines in the left wheel represent significant excitatory influence and inhibitory influence, separately. Positive/negative values in the right T‐value matrix also denote excitatory/inhibitory influence. Excitatory influence represents that source activity predicts subsequent increases in target activity, and inhibitory influence represents source predicts subsequent decrease in target. The circle size of each network on the wheel represents the sum of absolute values of all significant influences whether outflow or inflow this network. In each circle, the light and dark portions refer to inflow and outflow influence strengths, respectively. The 11 networks outside the wheel are presented in clockwise order

Figure 2

Between‐group white‐matter functional networks influence differences in the primary cohort examined by two‐sample t test with 5,000 permutations (p < .05, NBS corrected). FESs exhibited significantly decreased excitatory influence from the middle network to the superficial network (t = −3.62, p < .001) as well as the deep network (t = −3.25, p = .001) compared to HCs. FESs exhibited additional decreased inhibitory influences within superficial networks. The out strength of the middle networks was decreased in FESs compared with HCs (t = −2.90, p = .004). FES, antipsychotic‐naive first‐episode schizophrenia patient; HC, healthy control; FDR, false discovery rate. ★★ denotes p _{FDR‐corrected} < .05

Figure 3

Replications of networks influence patterns and tri‐layer networks influence differences in an independent cohort (N = 24). (a) Within‐group influence patterns determined by one‐sample t tests across FESs and HCs. Positive and negative values represent excitatory influence and inhibitory influence, separately. (b) In the replication cohort, compared with HCs, the middle￫superficial excitatory influence (t = −2.38, p = .03) showed significant decrease in FESs, which was similar with the primary cohort. (c) In the replication cohort, no significant decrease on the excitatory influence of middle￫deep network (t = −0.65, p = .52) was observed in FESs compared to HCs. (d) The out strength of middle network influence was significantly reduced (t = −2.25, p = .03) in FESs compared to HCs. Additionally, the outflow influence of the superficial network was significantly decreased in FESs (t = −2.94, p = .008). ★ denotes p < .05. ★★ denotes p _{FDR‐corrected} < .05. FES, antipsychotic‐naive first‐episode schizophrenia patient; HC, healthy control