We generated asynchronous functional networks (aFNs) using a novel method called optimal causation entropy and compared aFN topology with the correlation-based synchronous functional networks (sFNs), which are commonly used in network neuroscience studies. Functional magnetic resonance imaging (fMRI) time series from 212 participants of the National Consortium on Alcohol and Neurodevelopment in Adolescence study were used to generate aFNs and sFNs. As a demonstration of how aFNs and sFNs can be used in tandem, we used multivariate mixed effects models to determine whether age interacted with node efficiency to influence connection probabilities in the two networks. After adjusting for differences in network density, aFNs had higher global efficiency but lower local efficiency than the sFNs. In the aFNs, nodes with the highest outgoing global efficiency tended to be in the brainstem and orbitofrontal cortex. aFN nodes with the highest incoming global efficiency tended to be members of the default mode network in sFNs. Age interacted with node global efficiency in aFNs and node local efficiency in sFNs to influence connection probability. We conclude that the sFN and aFN both offer information about functional brain connectivity that the other type of network does not. Author Summary In recent years, the network neuroscience field has increasingly grown toward the study of “dynamic” networks, which depict second-to-second changes in functional connectivity. However, it is unclear how the brain is able to self-direct shifts between distinct states of connectivity. Prior investigation of information dynamics in complex systems suggests that these shifts may be governed by underlying asynchronous relationships between brain regions. For the first time, this work applies a novel methodology to generate asynchronous functional brain networks from fMRI data. The topology of these asynchronous networks is contrasted with the topology of the synchronous correlation-based networks, which currently dominate the network neuroscience literature. Finally, asynchronous networks are shown to yield novel information about brain connectivity that is not captured by synchronous networks alone.

Author Summary In recent years, a growing body of studies have aimed at analyzing the brain as a complex dynamic system by using various neuroimaging data. This has opened new avenues to answer compelling questions about the brain function in health and disease. However, methods that allow for providing statistical inference about how the complex interactions of the brain are associated with desired phenotypes are to be developed for a more profound insight. This study introduces a promising regression-based model to relate dynamic brain networks to desired phenotypes and provide statistical inference. Moreover, it can be used for simulating dynamic brain networks with respect to desired phenotypes at the group and individual levels. Abstract The emerging area of dynamic brain network analysis has gained considerable attention in recent years. However, development of multivariate statistical frameworks that allow for examining the associations between phenotypic traits and dynamic patterns of system-level properties of the brain, and drawing statistical inference about such associations, has largely lagged behind. To address this need we developed a mixed-modeling framework that allows for assessing the relationship between any desired phenotype and dynamic patterns of whole-brain connectivity and topology. This novel framework also allows for simulating dynamic brain networks with respect to desired covariates. Unlike current tools, which largely use data-driven methods, our model-based method enables aligning neuroscientific hypotheses with the analytic approach. We demonstrate the utility of this model in identifying the relationship between fluid intelligence and dynamic brain networks by using resting-state fMRI (rfMRI) data from 200 participants in the Human Connectome Project (HCP) study. We also demonstrate the utility of this model to simulate dynamic brain networks at both group and individual levels. To our knowledge, this approach provides the first model-based statistical method for examining dynamic patterns of system-level properties of the brain and their relationships to phenotypic traits as well as simulating dynamic brain networks.