Controllability of Functional Brain Networks and Its Clinical Significance in First-Episode Schizophrenia

Abstract

Background and hypothesis: Disrupted control of brain state transitions may contribute to the diverse dysfunctions of cognition, emotion, and behavior that are fundamental to schizophrenia. Control theory provides the rationale for evaluating brain state transitions from a controllability perspective, which may help reveal the brain mechanism for clinical features such as cognitive control deficits associated with schizophrenia. We hypothesized that brain controllability would be altered in patients with schizophrenia, and that controllability of brain networks would be related to clinical symptomatology.

Study design: Controllability measurements of functional brain networks, including average controllability and modal controllability, were calculated and compared between 125 first-episode never-treated patients with schizophrenia and 133 healthy controls (HCs). Associations between controllability metrics and clinical symptoms were evaluated using sparse canonical correlation analysis.

Study results: Compared to HCs, patients showed significantly increased average controllability (PFDR = .023) and decreased modal controllability (PFDR = .023) in dorsal anterior cingulate cortex (dACC). General psychopathology symptoms and positive symptoms were positively correlated with average controllability in regions of default mode network and negatively associated with average controllability in regions of sensorimotor, dorsal attention, and frontoparietal networks.

Conclusions: Our findings suggest that altered controllability of functional activity in dACC may play a critical role in the pathophysiology of schizophrenia, consistent with the importance of this region in cognitive and brain state control operations. The demonstration of associations of functional controllability with psychosis symptoms suggests that the identified alterations in average controllability of brain function may contribute to the severity of acute psychotic illness in schizophrenia.

Keywords: controllability; resting-state functional magnetic resonance imaging; schizophrenia; sparse canonical correlation analysis.

Fig. 1.

The 227 functional brain regions included in our analysis belonged to 10 major networks (A). The altered controllability of dorsal anterior cingulate cortex was found in first-episode never-treated patients with schizophrenia compared to controls (B). The nodes represent brain areas in the Power functional template and the color of the node indicates the brain network to which it belongs.

Fig. 2.

Association patterns between controllability and clinical symptom in patients. The positive symptoms were predominantly positively correlated with average controllability in regions of DMN, while mainly negatively associated with average controllability in regions of FPN, DAN, and SMN. The significant brain regions denoted by nodes were identified by sparse canonical correlation analysis in the first canonical variate of average controllability associated with symptoms (A). Loadings of average controllability at a brain network level and loadings of symptomatology dimension (B). Abbreviations: CON, cingulo-opercular network; DAN, dorsal attention network; DMN, default mode network; FPN, frontoparietal network; GP, general psychopathology; PANSS, Positive and Negative Syndrome Scale; PS, positive symptoms; SAN, salience network; SMN, sensorimotor network; Sub, subcortical network; Vis, visual network.