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The brain's functional architecture and organization undergo continual development and modification throughout adolescence. While it is well known that multiple factors govern brain maturation, the constantly evolving patterns of time‐resolved functional connectivity are still unclear and understudied. We systematically evaluated over 47,000 youth and adult brains to bridge this gap, highlighting replicable time‐resolved developmental and aging functional brain patterns. The largest difference between the two life stages was captured in a brain state that indicated coherent strengthening and modularization of functional coupling within the auditory, visual, and motor subdomains, supplemented by anticorrelation with other subdomains in adults. This distinctive pattern, which we replicated in independent data, was consistently less modular or absent in children and presented a negative association with age in adults, thus indicating an overall inverted U‐shaped trajectory. This indicates greater synchrony, strengthening, modularization, and integration of the brain's functional connections beyond adolescence, and gradual decline of this pattern during the healthy aging process. We also found evidence that the developmental changes may also bring along a departure from the canonical static functional connectivity pattern in favor of more efficient and modularized utilization of the vast brain interconnections. State‐based statistical summary measures presented robust and significant group differences that also showed significant age‐related associations. The findings reported in this article support the idea of gradual developmental and aging brain state adaptation processes in different phases of life and warrant future research via lifespan studies to further authenticate the projected time‐resolved brain state trajectories. We highlight the replicable time‐resolved developmental and aging functional brain patterns in a systematic evaluation of over 47,000 youth and adult brains. Our study captured the most contrastive difference between the two life stages in a brain state that indicated coherent strengthening and modularization of functional coupling within the auditory, visual, and motor sub‐domains, supplemented by anticorrelation with other subdomains in adults, a pattern that was consistently less modular or absent in adolescents and presented a negative association with age in adults, thus indicating an overall inverted U‐shaped trajectory. This indicates greater synchrony, strengthening, modularization, and integration of the brain's functional connections beyond adolescence, and the gradual decline of this pattern during the healthy aging process.

Correlation-based sliding window analysis (CSWA) is the most commonly used method to estimate time-resolved functional MRI (fMRI) connectivity. However, instantaneous phase synchrony analysis (IPSA) is gaining popularity mainly because it offers single time-point resolution of time-resolved fMRI connectivity. We aim to provide a systematic comparison between these two approaches, on temporal, topological and anatomical levels. For this purpose, we used resting-state fMRI data from two separate cohorts with different temporal resolutions (45 healthy subjects from Human Connectome Project fMRI data with repetition time of 0.72 s and 25 healthy subjects from a separate validation fMRI dataset with a repetition time of 3 s). For time-resolved functional connectivity analysis, we calculated tapered CSWA over a wide range of different window lengths that were compared to IPSA. We found a strong association in connectivity dynamics between IPSA and CSWA when considering the absolute values of CSWA. The association between CSWA and IPSA was stronger for a window length of ∼20 s (shorter than filtered fMRI wavelength) than ∼100 s (longer than filtered fMRI wavelength), irrespective of the sampling rate of the underlying fMRI data. Narrow-band filtering of fMRI data (0.03–0.07 Hz) yielded a stronger relationship between IPSA and CSWA than wider-band (0.01–0.1 Hz). On a topological level, time-averaged IPSA and CSWA nodes were non-linearly correlated for both short (∼20 s) and long (∼100 s) windows, mainly because nodes with strong negative correlations (CSWA) displayed high phase synchrony (IPSA). IPSA and CSWA were anatomically similar in the default mode network, sensory cortex, insula and cerebellum. Our results suggest that IPSA and CSWA provide comparable characterizations of time-resolved fMRI connectivity for appropriately chosen window lengths. Although IPSA requires narrow-band fMRI filtering, it does not mandate a (semi-)arbitrary choice of window length and window overlap. A code for calculating IPSA is provided. •Correlation-based sliding windows (CSWA) is a common dynamic fMRI connectivity method.•Contrary to CSWA, Instantaneous Phase Synchrony (IPSA) offers single image resolution.•We found that CSWA was highly correlated with IPSA at a 20 s window length.•Narrow-band fMRI data yielded strongest relationship between IPSA and CSWA.•IPSA is advantageous as it does not mandate (semi-)arbitrary choice of window length/overlap.

Structural white matter connections are thought to facilitate integration of neural information across functionally segregated systems. Recent studies have demonstrated that changes in the balance between segregation and integration in brain networks can be tracked by time-resolved functional connectivity derived from resting-state functional magnetic resonance imaging (rs-fMRI) data and that fluctuations between segregated and integrated network states are related to human behavior. However, how these network states relate to structural connectivity is largely unknown. To obtain a better understanding of structural substrates for these network states, we investigated how the relationship between structural connectivity, derived from diffusion tractography, and functional connectivity, as measured by rs-fMRI, changes with fluctuations between segregated and integrated states in the human brain. We found that the similarity of edge weights between structural and functional connectivity was greater in the integrated state, especially at edges connecting the default mode and the dorsal attention networks. We also demonstrated that the similarity of network partitions, evaluated between structural and functional connectivity, increased and the density of direct structural connections within modules in functional networks was elevated during the integrated state. These results suggest that, when functional connectivity exhibited an integrated network topology, structural connectivity and functional connectivity were more closely linked to each other and direct structural connections mediated a larger proportion of neural communication within functional modules. Our findings point out the possibility of significant contributions of structural connections to integrative neural processes underlying human behavior.

Modularity is an important topological attribute for functional brain networks. Recent human fMRI studies have reported that modularity of functional networks varies not only across individuals being related to demographics and cognitive performance, but also within individuals co-occurring with fluctuations in network properties of functional connectivity, estimated over short time intervals. However, characteristics of these time-resolved functional networks during periods of high and low modularity have remained largely unexplored. In this study we investigate basic spatiotemporal properties of time-resolved networks in the high and low modularity periods during rest, with a particular focus on their spatial connectivity patterns, temporal homogeneity and test-retest reliability. We show that spatial connectivity patterns of time-resolved networks in the high and low modularity periods are represented by increased and decreased dissociation of the default mode network module from task-positive network modules, respectively. We also find that the instances of time-resolved functional connectivity sampled from within the high (respectively, low) modularity period are relatively homogeneous (respectively, heterogeneous) over time, indicating that during the low modularity period the default mode network interacts with other networks in a variable manner. We confirmed that the occurrence of the high and low modularity periods varies across individuals with moderate inter-session test-retest reliability and that it is correlated with previously-reported individual differences in the modularity of functional connectivity estimated over longer timescales. Our findings illustrate how time-resolved functional networks are spatiotemporally organized during periods of high and low modularity, allowing one to trace individual differences in long-timescale modularity to the variable occurrence of network configurations at shorter timescales. •Time-resolved functional connectivity in high/low modularity periods is investigated.•High modularity is tied to increased dissociation of task-positive/negative networks.•Low modularity is associated with heterogeneous connectivity patterns over time.•Frequency of high/low modularity periods has moderate inter-session reproducibility.•An interpretation of individual differences in long-timescale modularity is provided.

Sliding-window correlation is an emerging method for mapping time-resolved, resting-state functional connectivity. To avoid mapping spurious connectivity fluctuations (false positives), Leonardi and Van De Ville recently recommended choosing a window length exceeding the longest wavelength composing the BOLD signal, usually assumed to be ~100s. Here, we provide further statistical support for this rule of thumb. However, we demonstrate that non-stationary fluctuations in functional connectivity can in theory be detected with much shorter window lengths (e.g. 40s), while maintaining nominal control of false positives. We find that statistical power is near-maximal for window lengths chosen according to Leonardi and Van De Ville's rule of thumb. Furthermore, we lay some foundations for a parametric test to identify non-stationary fluctuations in functional connectivity, also noting limitations of the sinusoidal model upon which our work, and the work of Leonardi and Van De Ville, is based. Most notably, our analytical results pertain to covariances, as does our statistical test, whereas functional connectivity is more commonly measured using correlations. •We consider window length choice when computing dynamic functional connectivity.•We provide statistical support for Leonardi and Van De Ville's 1/f rule of thumb.•We discuss limitations of Leonardi and Van De Ville's sinusoidal model.•We develop a test to identify non-stationary connectivity fluctuations.

Though the organization of functional brain networks is modular at its core, modularity does not capture the full range of dynamic interactions between individual brain areas nor at the level of subnetworks. In this paper we present a hierarchical model that represents both flexible and modular aspects of intrinsic brain organization across time by constructing spatiotemporally flexible subnetworks. We also demonstrate that segregation and integration are complementary and simultaneous events. The method is based on combining the instantaneous phase synchrony analysis (IPSA) framework with community detection to identify a small, yet representative set of subnetwork components at the finest level of spatial granularity. At the next level, subnetwork components are combined into spatiotemporally flexibly subnetworks where temporal lag in the recruitment of areas within subnetworks is captured. Since individual brain areas are permitted to be part of multiple interleaved subnetworks, both modularity as well as more flexible tendencies of connectivity are accommodated for in the model. Importantly, we show that assignment of subnetworks to the same community (integration) corresponds to positive phase coherence within and between subnetworks, while assignment to different communities (segregation) corresponds to negative phase coherence or orthogonality. Together with disintegration, i.e. the breakdown of internal coupling within subnetwork components, orthogonality facilitates reorganization between subnetworks. In addition, we show that the duration of periods of integration is a function of the coupling strength within subnetworks and subnetwork components which indicates an underlying metastable dynamical regime. Based on the main tendencies for either integration or segregation, subnetworks are further clustered into larger meta-networks that are shown to correspond to combinations of core resting-state networks. We also demonstrate that subnetworks and meta-networks are coarse graining strategies that captures the quasi-cyclic recurrence of global patterns of integration and segregation in the brain. Finally, the method allows us to estimate in broad terms the spectrum of flexible and/or modular tendencies for individual brain areas.

Time-resolved analysis of resting-state functional magnetic resonance imaging (rs-fMRI) data allows researchers to extract more information about brain function than traditional functional connectivity analysis, yet a number of challenges in data analysis and interpretation remain. This article briefly summarizes common methods for time-resolved analysis and presents some of the pressing issues and opportunities in the field. From there, the discussion moves to interpretation of the network dynamics observed with rs-fMRI and the role that rs-fMRI can play in elucidating the large-scale organization of brain activity.