Hierarchical organization of spontaneous co-fluctuations in densely sampled individuals using fMRI.

Edge time series decompose functional connectivity into its framewise contributions. Previous studies have focused on characterizing the properties of high-amplitude frames (time points when the global co-fluctuation amplitude takes on its largest value), including their cluster structure. Less is known about middle- and low-amplitude co-fluctuations (peaks in co-fluctuation time series but of lower amplitude). Here, we directly address those questions, using data from two dense-sampling studies: the MyConnectome project and Midnight Scan Club. We develop a hierarchical clustering algorithm to group peak co-fluctuations of all magnitudes into nested and multiscale clusters based on their pairwise concordance. At a coarse scale, we find evidence of three large clusters that, collectively, engage virtually all canonical brain systems. At finer scales, however, each cluster is dissolved, giving way to increasingly refined patterns of co-fluctuations involving specific sets of brain systems. We also find an increase in global co-fluctuation magnitude with hierarchical scale. Finally, we comment on the amount of data needed to estimate co-fluctuation pattern clusters and implications for brain-behavior studies. Collectively, the findings reported here fill several gaps in current knowledge concerning the heterogeneity and richness of co-fluctuation patterns as estimated with edge time series while providing some practical guidance for future studies.

High-amplitude network co-fluctuations linked to variation in hormone concentrations over the menstrual cycle.

Many studies have shown that the human endocrine system modulates brain function, reporting associations between fluctuations in hormone concentrations and brain connectivity. However, how hormonal fluctuations impact fast changes in brain network organization over short timescales remains unknown. Here, we leverage a recently proposed framework for modeling co-fluctuations between the activity of pairs of brain regions at a framewise timescale. In previous studies we showed that time points corresponding to high-amplitude co-fluctuations disproportionately contributed to the time-averaged functional connectivity pattern and that these co-fluctuation patterns could be clustered into a low-dimensional set of recurring "states." Here, we assessed the relationship between these network states and quotidian variation in hormone concentrations. Specifically, we were interested in whether the frequency with which network states occurred was related to hormone concentration. We addressed this question using a dense-sampling dataset (N = 1 brain). In this dataset, a single individual was sampled over the course of two endocrine states: a natural menstrual cycle and while the subject underwent selective progesterone suppression via oral hormonal contraceptives. During each cycle, the subject underwent 30 daily resting-state fMRI scans and blood draws. Our analysis of the imaging data revealed two repeating network states. We found that the frequency with which state 1 occurred in scan sessions was significantly correlated with follicle-stimulating and luteinizing hormone concentrations. We also constructed representative networks for each scan session using only "event frames"-those time points when an event was determined to have occurred. We found that the weights of specific subsets of functional connections were robustly correlated with fluctuations in the concentration of not only luteinizing and follicle-stimulating hormones, but also progesterone and estradiol.

Individualized event structure drives individual differences in whole-brain functional connectivity.

Resting-state functional connectivity is typically modeled as the correlation structure of whole-brain regional activity. It is studied widely, both to gain insight into the brain's intrinsic organization but also to develop markers sensitive to changes in an individual's cognitive, clinical, and developmental state. Despite this, the origins and drivers of functional connectivity, especially at the level of densely sampled individuals, remain elusive. Here, we leverage novel methodology to decompose functional connectivity into its precise framewise contributions. Using two dense sampling datasets, we investigate the origins of individualized functional connectivity, focusing specifically on the role of brain network "events" - short-lived and peaked patterns of high-amplitude cofluctuations. Here, we develop a statistical test to identify events in empirical recordings. We show that the patterns of cofluctuation expressed during events are repeated across multiple scans of the same individual and represent idiosyncratic variants of template patterns that are expressed at the group level. Lastly, we propose a simple model of functional connectivity based on event cofluctuations, demonstrating that group-averaged cofluctuations are suboptimal for explaining participant-specific connectivity. Our work complements recent studies implicating brief instants of high-amplitude cofluctuations as the primary drivers of static, whole-brain functional connectivity. Our work also extends those studies, demonstrating that cofluctuations during events are individualized, positing a dynamic basis for functional connectivity.

Modularity maximization as a flexible and generic framework for brain network exploratory analysis.

The modular structure of brain networks supports specialized information processing, complex dynamics, and cost-efficient spatial embedding. Inter-individual variation in modular structure has been linked to differences in performance, disease, and development. There exist many data-driven methods for detecting and comparing modular structure, the most popular of which is modularity maximization. Although modularity maximization is a general framework that can be modified and reparamaterized to address domain-specific research questions, its application to neuroscientific datasets has, thus far, been narrow. Here, we highlight several strategies in which the "out-of-the-box" version of modularity maximization can be extended to address questions specific to neuroscience. First, we present approaches for detecting "space-independent" modules and for applying modularity maximization to signed matrices. Next, we show that the modularity maximization frame is well-suited for detecting task- and condition-specific modules. Finally, we highlight the role of multi-layer models in detecting and tracking modules across time, tasks, subjects, and modalities. In summary, modularity maximization is a flexible and general framework that can be adapted to detect modular structure resulting from a wide range of hypotheses. This article highlights multiple frontiers for future research and applications.