Parkes, Linden; Tyler M. Moore; Monica E. Calkins; Matthew Cieslak; David R. Roalf; Daniel H. Wolf; Ruben C. Gur; Raquel E. Gur; Theodore D. Satterthwaite and Danielle S. Bassett

BACKGROUND: The psychosis spectrum (PS) is associated with structural dysconnectivity concentrated in trans modal cortex. However, understanding of this pathophysiology has been limited by an overreliance on examining direct interregional connectivity. Using network control theory, we measured variation in both direct and indirect connectivity to a region to gain new insights into the pathophysiology of the PS. METHODS: We used psychosis symptom data and structural connectivity in 1068 individuals from the Philadelphia Neurodevelopmental Cohort. Applying a network control theory metric called average controllability, we estimated each brain region's capacity to leverage its direct and indirect structural connections to control linear brain dynamics. Using nonlinear regression, we determined the accuracy with which average controllability could predict PS symptoms in out-of-sample testing. We also examined the predictive performance of regional strength, which indexes only direct connections to a region, as well as several graph-theoretic measures of centrality that index indirect connectivity. Finally, we assessed how the prediction performance for PS symptoms varied over the functional hierarchy spanning unimodal to transmodal cortex. RESULTS: Average controllability outperformed all other connectivity features at predicting positive PS symptoms and was the only feature to yield above-chance predictive performance. Improved prediction for average controllability was concentrated in transmodal cortex, whereas prediction performance for strength was uniform across the cortex, suggesting that indexing indirect connections through average controllability is crucial in association cortex. CONCLUSIONS: Examining interindividual variation in direct and indirect structural connections to transmodal cortex is crucial for accurate prediction of positive PS symptoms.