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Brain activity continuously fluctuates over time, even if the brain is in controlled (e.g., experimentally induced) states. Recent years have seen an increasing interest in understanding the complexity of these temporal variations, for example with respect to developmental changes in brain function or between-person differences in healthy and clinical populations. However, the psychometric reliability of brain signal variability and complexity measures-which is an important precondition for robust individual differences as well as longitudinal research-is not yet sufficiently studied. We examined reliability (split-half correlations) and test-retest correlations for task-free (resting-state) BOLD fMRI as well as split-half correlations for seven functional task data sets from the Human Connectome Project to evaluate their reliability. We observed good to excellent split-half reliability for temporal variability measures derived from rest and task fMRI activation time series (standard deviation, mean absolute successive difference, mean squared successive difference), and moderate test-retest correlations for the same variability measures under rest conditions. Brain signal complexity estimates (several entropy and dimensionality measures) showed moderate to good reliabilities under both, rest and task activation conditions. We calculated the same measures also for time-resolved (dynamic) functional connectivity time series and observed moderate to good reliabilities for variability measures, but poor reliabilities for complexity measures derived from functional connectivity time series. Global (i.e., mean across cortical regions) measures tended to show higher reliability than region-specific variability or complexity estimates. Larger subcortical regions showed similar reliability as cortical regions, but small regions showed lower reliability, especially for complexity measures. Lastly, we also show that reliability scores are only minorly dependent on differences in scan length and replicate our results across different parcellation and denoising strategies. These results suggest that the variability and complexity of BOLD activation time series are robust measures well-suited for individual differences research. Temporal variability of global functional connectivity over time provides an important novel approach to robustly quantifying the dynamics of brain function. PRACTITIONER POINTS: Variability and complexity measures of BOLD activation show good split-half reliability and moderate test-retest reliability. Measures of variability of global functional connectivity over time can robustly quantify neural dynamics. Length of fMRI data has only a minor effect on reliability., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

The macroscale connectome is the network of physical, white-matter tracts between brain areas. The connections are generally weighted and their values interpreted as measures of communication efficacy. In most applications, weights are either assigned based on imaging features-e.g. diffusion parameters-or inferred using statistical models. In reality, the ground-truth weights are unknown, motivating the exploration of alternative edge weighting schemes. Here, we explore a multi-modal, regression-based model that endows reconstructed fiber tracts with directed and signed weights. We find that the model fits observed data well, outperforming a suite of null models. The estimated weights are subject-specific and highly reliable, even when fit using relatively few training samples, and the networks maintain a number of desirable features. In summary, we offer a simple framework for weighting connectome data, demonstrating both its ease of implementation while benchmarking its utility for typical connectome analyses, including graph theoretic modeling and brain-behavior associations., (© 2024. The Author(s).)

Individual differences in general cognitive ability (GCA) have a biological basis within the structure and function of the human brain. Network neuroscience investigations revealed neural correlates of GCA in structural as well as in functional brain networks. However, whether the relationship between structural and functional networks, the structural-functional brain network coupling (SC-FC coupling), is related to individual differences in GCA remains an open question. We used data from 1030 adults of the Human Connectome Project, derived structural connectivity from diffusion weighted imaging, functional connectivity from resting-state fMRI, and assessed GCA as a latent g-factor from 12 cognitive tasks. Two similarity measures and six communication measures were used to model possible functional interactions arising from structural brain networks. SC-FC coupling was estimated as the degree to which these measures align with the actual functional connectivity, providing insights into different neural communication strategies. At the whole-brain level, higher GCA was associated with higher SC-FC coupling, but only when considering path transitivity as neural communication strategy. Taking region-specific variations in the SC-FC coupling strategy into account and differentiating between positive and negative associations with GCA, allows for prediction of individual cognitive ability scores in a cross-validated prediction framework (correlation between predicted and observed scores: r = 0.25, p < .001). The same model also predicts GCA scores in a completely independent sample (N = 567, r = 0.19, p < .001). Our results propose structural-functional brain network coupling as a neurobiological correlate of GCA and suggest brain region-specific coupling strategies as neural basis of efficient information processing predictive of cognitive ability., Competing Interests: Declaration of competing interest None, (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The brain connectome is an embedded network of anatomically interconnected brain regions, and the study of its topological organization in mammals has become of paramount importance due to its role in scaffolding brain function and behavior. Unlike many other observable networks, brain connections incur material and energetic cost, and their length and density are volumetrically constrained by the skull. Thus, an open question is how differences in brain volume impact connectome topology. We address this issue using the MaMI database, a diverse set of mammalian connectomes reconstructed from 201 animals, covering 103 species and 12 taxonomy orders, whose brain size varies over more than 4 orders of magnitude. Our analyses focus on relationships between volume and modular organization. After having identified modules through a multiresolution approach, we observed how connectivity features relate to the modular structure and how these relations vary across brain volume. We found that as the brain volume increases, modules become more spatially compact and dense, comprising more costly connections. Furthermore, we investigated how spatial embedding shapes network communication, finding that as brain volume increases, nodes' distance progressively impacts communication efficiency. We identified modes of variation in network communication policies, as smaller and bigger brains show higher efficiency in routing- and diffusion-based signaling, respectively. Finally, bridging network modularity and communication, we found that in larger brains, modular structure imposes stronger constraints on network signaling. Altogether, our results show that brain volume is systematically related to mammalian connectome topology and that spatial embedding imposes tighter restrictions on larger brains., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Puxeddu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Previous studies have adopted an edge-centric framework to study fine-scale network dynamics in human fMRI. To date, however, no studies have applied this framework to data collected from model organisms. Here, we analyze structural and functional imaging data from lightly anesthetized mice through an edge-centric lens. We find evidence of "bursty" dynamics and events - brief periods of high-amplitude network connectivity. Further, we show that on a per-frame basis events best explain static FC and can be divided into a series of hierarchically-related clusters. The co-fluctuation patterns associated with each cluster centroid link distinct anatomical areas and largely adhere to the boundaries of algorithmically detected functional brain systems. We then investigate the anatomical connectivity undergirding high-amplitude co-fluctuation patterns. We find that events induce modular bipartitions of the anatomical network of inter-areal axonal projections. Finally, we replicate these same findings in a human imaging dataset. In summary, this report recapitulates in a model organism many of the same phenomena observed in previously edge-centric analyses of human imaging data. However, unlike human subjects, the murine nervous system is amenable to invasive experimental perturbations. Thus, this study sets the stage for future investigation into the causal origins of fine-scale brain dynamics and high-amplitude co-fluctuations. Moreover, the cross-species consistency of the reported findings enhances the likelihood of future translation., (© 2024. The Author(s).)

Network neuroscience has emphasized the connectional properties of neural elements - cells, populations, and regions. This has come at the expense of the anatomical and functional connections that link these elements to one another. A new perspective - namely one that emphasizes 'edges' - may prove fruitful in addressing outstanding questions in network neuroscience. We highlight one recently proposed 'edge-centric' method and review its current applications, merits, and limitations. We also seek to establish conceptual and mathematical links between this method and previously proposed approaches in the network science and neuroimaging literature. We conclude by presenting several avenues for future work to extend and refine existing edge-centric analysis., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Human functional brain connectivity can be temporally decomposed into states of high and low cofluctuation, defined as coactivation of brain regions over time. Rare states of particularly high cofluctuation have been shown to reflect fundamentals of intrinsic functional network architecture and to be highly subject-specific. However, it is unclear whether such network-defining states also contribute to individual variations in cognitive abilities - which strongly rely on the interactions among distributed brain regions. By introducing CMEP, a new eigenvector-based prediction framework, we show that as few as 16 temporally separated time frames (< 1.5% of 10 min resting-state fMRI) can significantly predict individual differences in intelligence (N = 263, p < .001). Against previous expectations, individual's network-defining time frames of particularly high cofluctuation do not predict intelligence. Multiple functional brain networks contribute to the prediction, and all results replicate in an independent sample (N = 831). Our results suggest that although fundamentals of person-specific functional connectomes can be derived from few time frames of highest connectivity, temporally distributed information is necessary to extract information about cognitive abilities. This information is not restricted to specific connectivity states, like network-defining high-cofluctuation states, but rather reflected across the entire length of the brain connectivity time series., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Both cortical and subcortical regions can be functionally organized into networks. Regions of the basal ganglia are extensively interconnected with the cortex via reciprocal connections that relay and modulate cortical function. Here we employ an edge-centric approach, which computes co-fluctuations among region pairs in a network to investigate the role and interaction of subcortical regions with cortical systems. By clustering edges into communities, we show that cortical systems and subcortical regions couple via multiple edge communities, with hippocampus and amygdala having a distinct pattern from striatum and thalamus. We show that the edge community structure of cortical networks is highly similar to one obtained from cortical nodes when the subcortex is present in the network. Additionally, we show that the edge community profile of both cortical and subcortical nodes can be estimates solely from cortico-subcortical interactions. Finally, we used a motif analysis focusing on edge community triads where a subcortical region coupled to two cortical regions and found that two community triads where one community couples the subcortex to the cortex were overrepresented. In summary, our results show organized coupling of the subcortex to the cortex that may play a role in cortical organization of primary sensorimotor/attention and heteromodal systems and puts forth the motif analysis of edge community triads as a promising method for investigation of communication patterns in networks., Competing Interests: Declaration of Interest None., (Published by Elsevier Inc.)

The subthalamic nucleus (STN) is commonly used as a surgical target for deep brain stimulation in movement disorders such as Parkinson's Disease. Tractography-derived connectivity-based parcellation (CBP) has been recently proposed as a suitable tool for non-invasive in vivo identification and pre-operative targeting of specific functional territories within the human STN. However, a well-established, accurate and reproducible protocol for STN parcellation is still lacking. The present work aims at testing the effects of different tractography-based approaches for the reconstruction of STN functional territories. We reconstructed functional territories of the STN on the high-quality dataset of 100 unrelated healthy subjects and on the test-retest dataset of the Human Connectome Project (HCP) repository. Connectivity-based parcellation was performed with a hypothesis-driven approach according to cortico-subthalamic connectivity, after dividing cortical areas into three groups: associative, limbic and sensorimotor. Four parcellation pipelines were compared, combining different signal modeling techniques (single-fiber vs multi-fiber) and different parcellation approaches (winner takes all parcellation vs fiber density thresholding). We tested these procedures on STN regions of interest obtained from three different, commonly employed, subcortical atlases. We evaluated the pipelines both in terms of between-subject similarity, assessed on the cohort of 100 unrelated healthy subjects, and of within-subject similarity, using a second cohort of 44 subjects with available test-retest data. We found that each parcellation provides converging results in terms of location of the identified parcels, but with significative variations in size and shape. All pipelines obtained very high within-subject similarity, with tensor-based approaches outperforming multi-fiber pipelines. On the other hand, higher between-subject similarity was found with multi-fiber signal modeling techniques combined with fiber density thresholding. We suggest that a fine-tuning of tractography-based parcellation may lead to higher reproducibility and aid the development of an optimized surgical targeting protocol., Competing Interests: Declaration of Competing Interest The authors have nothing to declare, (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The human brain is composed of functionally specialized systems that support cognition. Recently, we proposed an edge-centric model for detecting overlapping communities. It remains unclear how these communities and brain systems are related. Here, we address this question using data from the Midnight Scan Club and show that all brain systems are linked via at least two edge communities. We then examine the diversity of edge communities within each system, finding that heteromodal systems are more diverse than sensory systems. Next, we cluster the entire cortex to reveal it according to the regions' edge-community profiles. We find that regions in heteromodal systems are more likely to form their own clusters. Finally, we show that edge communities are personalized. Our work reveals the pervasive overlap of edge communities across the cortex and their relationship with brain systems. Our work provides pathways for future research using edge-centric brain networks., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The connectome, a comprehensive map of the brain's anatomical connections, is often summarized as a matrix comprising all dyadic connections among pairs of brain regions. This representation cannot capture higher-order relations within the brain graph. Connectome embedding (CE) addresses this limitation by creating compact vectorized representations of brain nodes capturing their context in the global network topology. Here, nodes "context" is defined as random walks on the brain graph and as such, represents a generative model of diffusive communication around nodes. Applied to group-averaged structural connectivity, CE was previously shown to capture relations between inter-hemispheric homologous brain regions and uncover putative missing edges from the network reconstruction. Here we extend this framework to explore individual differences with a novel embedding alignment approach. We test this approach in two lifespan datasets (NKI: n = 542; Cam-CAN: n = 601) that include diffusion-weighted imaging, resting-state fMRI, demographics and behavioral measures. We demonstrate that modeling functional connectivity with CE substantially improves structural to functional connectivity mapping both at the group and subject level. Furthermore, age-related differences in this structure-function mapping, are preserved and enhanced. Importantly, CE captures individual differences by out-of-sample prediction of age and intelligence. The resulting predictive accuracy was higher compared to using structural connectivity and functional connectivity. We attribute these findings to the capacity of the CE to incorporate aspects of both anatomy (the structural graph) and function (diffusive communication). Our novel approach allows mapping individual differences in the connectome through structure to function and behavior., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Group-level studies do not capture individual differences in network organization, an important prerequisite for understanding neural substrates shaping behavior and for developing interventions in clinical conditions. Recent studies have employed 'fingerprinting' analyses on functional connectivity to identify subjects' idiosyncratic features. Here, we develop a complementary approach based on an edge-centric model of functional connectivity, which focuses on the co-fluctuations of edges. We first show whole-brain edge functional connectivity (eFC) to be a robust substrate that improves identifiability over nodal FC (nFC) across different datasets and parcellations. Next, we characterize subjects' identifiability at different spatial scales, from single nodes to the level of functional systems and clusters using k-means clustering. Across spatial scales, we find that heteromodal brain regions exhibit consistently greater identifiability than unimodal, sensorimotor, and limbic regions. Lastly, we show that identifiability can be further improved by reconstructing eFC using specific subsets of its principal components. In summary, our results highlight the utility of the edge-centric network model for capturing meaningful subject-specific features and sets the stage for future investigations into individual differences using edge-centric models., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The network architecture of the human brain contributes in shaping neural activity, influencing cognitive and behavioral processes. The availability of neuroimaging data across the lifespan allows us to monitor how this architecture reorganizes, influenced by processes like learning, adaptation, maturation, and senescence. Changing patterns in brain connectivity can be analyzed with the tools of network science, which can be used to reveal organizational principles such as modular network topology. The identification of network modules is fundamental, as they parse the brain into coherent sub-systems and allow for both functional integration and segregation among different brain areas. In this work we examined the brain's modular organization by developing an ensemble-based multilayer network approach, allowing us to link changes of structural connectivity patterns to development and aging. We show that modular structure exhibits both linear and nonlinear age-related trends. In the early and late lifespan, communities are more modular, and we track the origins of this high modularity to two different substrates in brain connectivity, linked to the number and the weights of the intra-clusters edges. We also demonstrate that aging leads to a progressive and increasing reconfiguration of modules and a redistribution across hemispheres. Finally, we identify those brain regions that most contribute to network reconfiguration and those that remain more stable across the lifespan., Competing Interests: Declaration of competing interest The authors declare no conflicting interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Functional connectivity - the co-activation of brain regions - forms the basis of the brain's functional architecture. Often measured during resting-state (i.e., in a task-free setting), patterns of functional connectivity within and between brain networks change with age. These patterns are of interest to aging researchers because age differences in resting-state connectivity relate to older adults' relative cognitive declines. Less is known about age differences in large-scale brain networks during directed tasks. Recent work in younger adults has shown that patterns of functional connectivity are highly correlated between rest and task states. Whether this finding extends to older adults remains largely unexplored. To this end, we assessed younger and older adults' functional connectivity across the whole brain using fMRI while participants underwent resting-state or completed directed tasks (e.g., a reasoning judgement task). Resting-state and task functional connectivity were less strongly correlated in older as compared to younger adults. This age-dependent difference could be attributed to significantly lower consistency in network organization between rest and task states among older adults. Older adults had less distinct or segregated networks during resting-state. This more diffuse pattern of organization was exacerbated during directed tasks. Finally, the default mode network, often implicated in neurocognitive aging, contributed strongly to this pattern. These findings establish that age differences in functional connectivity are state-dependent, providing greater insight into the mechanisms by which aging may lead to cognitive declines., (Copyright © 2020. Published by Elsevier Inc.)

The anatomical architecture of the mammalian brain can be modeled as the connectivity between functionally distinct areas of cortex and sub-cortex, which we refer to as the connectome. The community structure of the connectome describes how the network can be parsed into meaningful groups of nodes. This process, called community detection, is commonly carried out to find internally densely connected communities-a modular topology. However, other community structure patterns are possible. Here we employ the weighted stochastic block model (WSBM), which can identify a wide range of topologies, to the rat cerebral cortex connectome, to probe the network for evidence of modular, core, periphery, and disassortative organization. Despite its algorithmic flexibility, the WSBM identifies substantial modular and assortative topology throughout the rat cerebral cortex connectome, significantly aligning to the modular approach in some parts of the network. Significant deviations from modular partitions include the identification of communities that are highly enriched in core (rich club) areas. A comparison of the WSBM and modular models demonstrates that the former, when applied as a generative model, more closely captures several nodal network attributes. An analysis of variation across an ensemble of partitions reveals that certain parts of the network participate in multiple topological regimes. Overall, our findings demonstrate the potential benefits of adopting the WSBM, which can be applied to a single weighted and directed matrix such as the rat cerebral cortex connectome, to identify community structure with a broad definition that transcends the common modular approach.

The human brain can be described as a complex network of anatomical connections between distinct areas, referred to as the human connectome. Fundamental characteristics of connectome organization can be revealed using the tools of network science and graph theory. Of particular interest is the network's community structure, commonly identified by modularity maximization, where communities are conceptualized as densely intra-connected and sparsely inter-connected. Here we adopt a generative modeling approach called weighted stochastic block models (WSBM) that can describe a wider range of community structure topologies by explicitly considering patterned interactions between communities. We apply this method to the study of changes in the human connectome that occur across the life span (between 6-85 years old). We find that WSBM communities exhibit greater hemispheric symmetry and are spatially less compact than those derived from modularity maximization. We identify several network blocks that exhibit significant linear and non-linear changes across age, with the most significant changes involving subregions of prefrontal cortex. Overall, we show that the WSBM generative modeling approach can be an effective tool for describing types of community structure in brain networks that go beyond modularity.

We present a continuous model for structural brain connectivity based on the Poisson point process. The model treats each streamline curve in a tractography as an observed event in connectome space, here the product space of the gray matter/white matter interfaces. We approximate the model parameter via kernel density estimation. To deal with the heavy computational burden, we develop a fast parameter estimation method by pre-computing associated Legendre products of the data, leveraging properties of the spherical heat kernel. We show how our approach can be used to assess the quality of cortical parcellations with respect to connectivity. We further present empirical results that suggest that "discrete" connectomes derived from our model have substantially higher test-retest reliability compared to standard methods. In this, the expanded form of this paper for journal publication, we also explore parcellation free analysis techniques that avoid the use of explicit partitions of the cortical surface altogether. We provide an analysis of sex effects on our proposed continuous representation, demonstrating the utility of this approach., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A large body of research suggests that oxytocin receptor (OXTR) gene polymorphisms may influence both social behaviors and psychiatric conditions related to social deficits, such as autism spectrum disorders (ASDs), schizophrenia, and mood and anxiety disorders. However, the neural mechanism underlying these associations is still unclear. Relative to controls, patients with these psychiatric conditions show differences in brain structure, and in resting state fMRI (rs-fMRI) signal synchronicity among default mode network (DMN) regions (also known as functional connectivity). We used a stepwise imaging genetics approach in 328 healthy young adults to test the hypothesis that 10 SNPs in OXTR are associated with differences in DMN synchronicity and structure of some of the associated brain regions. As OXTR effects may be sex-dependent, we also tested whether our findings were modulated by sex. OXTR rs2254298 A allele carriers had significantly lower rsFC with PCC in a cluster extending from the right fronto-insular cortex to the putamen and globus pallidus, and in bilateral dorsal anterior cingulate cortex (dACC) compared to individuals with the GG genotype; all observed effects were found only in males. Moreover, compared to the male individuals with GG genotype ofrs2254298, the male A allele carriers demonstrated significantly thinner cortical gray matter in the bilateral dACC. Our findings suggest that there may be sexually dimorphic mechanisms by which a naturally occurring variation of the OXTR gene may influence brain structure and function in DMN-related regions implicated in neuropsychiatric disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We present a continuous model for structural brain connectivity based on the Poisson point process. The model treats each stream-line curve in a tractography as an observed event in connectome space, here a product space of cortical white matter boundaries. We approximate the model parameter via kernel density estimation. To deal with the heavy computational burden, we develop a fast parameter estimation method by pre-computing associated Legendre products of the data, leveraging properties of the spherical heat kernel. We show how our approach can be used to assess the quality of cortical parcellations with respect to connectivty. We further present empirical results that suggest the "discrete" connectomes derived from our model have substantially higher test-retest reliability compared to standard methods.