A novel method for tri-clustering dynamic functional network connectivity (dFNC) identifies significant schizophrenia effects across multiple states in distinct subgroups of individuals

Background Brain imaging data collected from individuals are highly complex with unique variation; however, such variation is typically ignored in approaches that focus on group averages or even supervised prediction. State-of-the-art methods for analyzing dynamic functional network connectivity (dFNC) subdivide the entire time course into several (possibly overlapping) connectivity states (i.e., sliding window clusters). Though, such an approach does not factor in the homogeneity of underlying data and may end up with a less meaningful subgrouping of the dataset. Methods Dynamic-N-way tri-clustering (dNTiC) incorporates a homogeneity benchmark to approximate clusters that provide a more apples-to-apples comparison between groups within analogous subsets of time-space and subjects. dNTiC sorts the dFNC states by maximizing similarity across individuals and minimizing variance among the pairs of components within a state. Results Resulting tri-clusters show significant differences between schizophrenia (SZ) and healthy control (HC) in distinct brain regions. Compared to HC, SZ in most tri-clusters show hypoconnectivity (low positive) among subcortical, default mode, cognitive control but hyper-connectivity (high positive) between sensory networks. In tri-cluster 3, HC subjects show significantly stronger connectivity among sensory networks and anticorrelation between subcortical and sensory networks compared to SZ. Results also provide statistically significant difference in reoccurrence time between SZ and HC subjects for two distinct dFNC states. Conclusions Outcomes emphasize the utility of the proposed method for characterizing and leveraging variance within high-dimensional data to enhance the interpretability and sensitivity of measurements in the study of a heterogeneous disorder like schizophrenia and in unconstrained experimental conditions such as resting fMRI. ### Competing Interest Statement The authors have declared no competing interest.