Multiframe Evolving Dynamic Functional Connectivity (EVOdFNC): A Method for Constructing and Investigating Functional Brain Motifs

ABSTRACT The study of brain network connectivity as a time-varying property began relatively recently and to date has remained primarily concerned with capturing a handful of discrete static states that characterize connectivity as measured on a timescale shorter than that of the full scan. Capturing group-level representations of temporally evolving patterns of connectivity is a challenging and important next step in fully leveraging the information available in large resting state functional magnetic resonance imaging (rs-fMRI) studies. We introduce a flexible, extensible data-driven framework for the stable identification of group-level multiframe (movie-style) dynamic functional network connectivity (dFNC) states. Our approach employs uniform manifold approximation and embedding (UMAP) to produce a continuity-preserving planar embedding of high-dimensional time-varying measurements of whole-brain functional network connectivity. Planar linear exemplars summarizing dominant dynamic trends across the population are computed from local linear approximations to the 2D embedded trajectories. A high-dimensional representation of each 2D exemplar segment is obtained by averaging the dFNC observations corresponding to the n planar nearest neighbors of τ evenly spaced points along the 2D line segment representation (where n is the UMAP number-of-neighbors parameter and τ is the temporal duration of trajectory segments being approximated). Each of the 2D exemplars thus “lifts” to a multiframe high-dimensional dFNC trajectory of length τ. The collection of high-dimensional temporally evolving dFNC representations (EVOdFNCs) derived in this manner are employed as dynamic basis objects with which to characterize observed high-dimensional dFNC trajectories, which are then expressed as weighted combination of these basis objects. Our approach yields new insights into anomalous patterns of fluidly varying whole brain connectivity that are significantly associated with schizophrenia as a broad diagnosis as well as with certain symptoms of this serious disorder. Importantly, we show that relative to conventional hidden Markov modeling with single-frame unvarying dFNC summary states, EVOdFNCs are more sensitive to positive symptoms of schizophrenia including hallucinations and delusions, suggesting a more dynamic characterization is needed to help illuminate such a complex brain disorder.