Brain network analyses have exploded in recent years and hold great potential in helping us understand normal and abnormal brain function. Network science approaches have facilitated these analyses and our understanding of how the brain is structurally and functionally organized. However, the development of statistical methods that allow relating this organization to phenotypic traits has lagged behind. Our previous work developed a novel analytic framework to assess the relationship between brain network architecture and phenotypic differences while controlling for confounding variables. More specifically, this innovative regression framework related distances (or similarities) between brain network features from a single task to functions of absolute differences in continuous covariates and indicators of difference for categorical variables. Here we extend that work to the multitask and multisession context to allow for multiple brain networks per individual. We explore several similarity metrics for comparing distances between connection matrices and adapt several standard methods for estimation and inference within our framework: standard F test, F test with scan-level effects (SLE), and our proposed mixed model for multitask (and multisession) BrAin NeTwOrk Regression (3M_BANTOR). A novel strategy is implemented to simulate symmetric positive-definite (SPD) connection matrices, allowing for the testing of metrics on the Riemannian manifold. Via simulation studies, we assess all approaches for estimation and inference while comparing them with existing multivariate distance matrix regression (MDMR) methods. We then illustrate the utility of our framework by analyzing the relationship between fluid intelligence and brain network distances in Human Connectome Project (HCP) data.

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.

Analyzing brain networks has long been a prominent research topic in neuroimaging. However, statistical methods to detect differences between these networks and relate them to phenotypic traits are still sorely needed. Our previous work developed a novel permutation testing framework to detect differences between two groups. Here we advance that work to allow both assessing differences by continuous phenotypes and controlling for confounding variables. To achieve this, we propose an innovative regression framework to relate distances (or similarities) between brain network features to functions of absolute differences in continuous covariates and indicators of difference for categorical variables. We explore several similarity metrics for comparing distances (or similarities) between connection matrices, and adapt several standard methods for estimation and inference within our framework: standard F test, F test with individual level effects (ILE), feasible generalized least squares (FGLS), and permutation. Via simulation studies, we assess all approaches for estimation and inference while comparing them with existing multivariate distance matrix regression (MDMR) methods. We then illustrate the utility of our framework by analyzing the relationship between fluid intelligence and brain network distances in Human Connectome Project (HCP) data.

The emerging area of brain network analysis considers the brain as a system, providing profound insight into links between system-level properties and health outcomes. Network science has facilitated these analyses and our understanding of how the brain is organized. While network science has catalyzed a paradigmatic shift in neuroscience, methods for statistically analyzing networks have lagged behind. To address this for cross-sectional network data, we developed a mixed-modeling framework that enables quantifying the relationship between phenotype and connectivity patterns, predicting connectivity structure based on phenotype, simulating networks to gain a better understanding of topological variability, and thresholding individual networks leveraging group information. Here we extend this comprehensive approach to enable studying system-level brain properties across multiple tasks. We focus on rest-to-task network changes, but this extension is equally applicable to the assessment of network changes for any repeated task paradigm. Our approach allows (a) assessing population network differences in changes between tasks, and how these changes relate to health outcomes; (b) assessing individual variability in network differences in changes between tasks, and how this variability relates to health outcomes; and (c) deriving more accurate and precise estimates of the relationships between phenotype and health outcomes within a given task.