Developing Multimodal Dynamic Functional Connectivity as a Neuroimaging Biomarker.

In spite of increasing evidence highlighting the role of dynamic functional connectivity (FC) in characterizing mental disorders, there is a lack of (a) reliable statistical methods to compute dynamic connectivity and (b) rigorous dynamic FC-based approaches for predicting mental health outcomes in heterogeneous disorders such as post-traumatic stress disorder (PTSD). In one of the first such efforts, we develop a reliable and accurate approach for estimating dynamic FC guided by brain structural connectivity (SC) computed using diffusion tensor imaging data and investigate the potential of the proposed multimodal dynamic FC to predict continuous mental health outcomes. We develop concrete measures of temporal network variability that are predictive of PTSD resilience, and identify regions whose temporal connectivity fluctuations are significantly related to resilience. Our results illustrate that the multimodal approach is more sensitive to connectivity change points, it can clearly detect localized brain regions with the dynamic network features such as small-worldedness, clustering coefficients, and efficiency associated with resilience, and that it has superior predictive performance compared with existing static and dynamic network models when modeling PTSD resilience. While the majority of resting-state network modeling in psychiatry has focused on static FC, our novel multimodal dynamic network analyses that are sensitive to network fluctuations allowed us to provide a model of neural correlates of resilience with high accuracy compared with existing static connectivity approaches or those that do not use brain SC information, and provided us with an expanded understanding of the neurobiological causes for PTSD. Impact statement The methods developed in this article provide reliable and accurate dynamic functional connectivity (FC) approaches by fusing multimodal imaging data that are highly predictive of continuous clinical phenotypes in heterogeneous mental disorders. Currently, there is very little theoretical work to explain how network dynamics might contribute to individual differences in behavior or psychiatric symptoms. Our analysis conclusively discovers localized brain resting-state networks, regions, and connections where variations in dynamic FC (that is estimated after incorporating brain structural connectivity information) are associated with post-traumatic stress disorder resilience, which could potentially provide valuable tools for the development of neural circuit modeling in psychiatry in the future.