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A growing body of research predicts individual cognitive ability levels from brain characteristics including functional brain connectivity. The majority of this research achieves statistically significant prediction performance but provides limited insight into neurobiological processes underlying the predicted concepts. The insufficient identification of predictive brain characteristics may present an important factor critically contributing to this constraint. Here, we encourage to design predictive modeling studies with an emphasis on interpretability to enhance our conceptual understanding of human cognition. As an example, we investigated in a preregistered study which functional brain connections successfully predict general, crystallized, and fluid intelligence in a sample of 806 healthy adults (replication: N = 322). The choice of the predicted intelligence component as well as the task during which connectivity was measured proved crucial for better understanding intelligence at the neural level. Further, intelligence could be predicted not solely from one specific set of brain connections, but from various combinations of connections with system-wide locations. Such partially redundant, brain-wide functional connectivity characteristics complement intelligence-relevant connectivity of brain regions proposed by established intelligence theories. In sum, our study showcases how future prediction studies on human cognition can enhance explanatory value by prioritizing a systematic evaluation of predictive brain characteristics over maximizing prediction performance., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Pregnancy is a period of profound hormonal and physiological changes experienced by millions of women annually, yet the neural changes unfolding in the maternal brain throughout gestation are not well studied in humans. Leveraging precision imaging, we mapped neuroanatomical changes in an individual from preconception through 2 years postpartum. Pronounced decreases in gray matter volume and cortical thickness were evident across the brain, standing in contrast to increases in white matter microstructural integrity, ventricle volume and cerebrospinal fluid, with few regions untouched by the transition to motherhood. This dataset serves as a comprehensive map of the human brain across gestation, providing an open-access resource for the brain imaging community to further explore and understand the maternal brain., (© 2024. The Author(s).)

How does the human brain respond to novelty? Here, we address this question using fMRI data wherein human participants watch the same movie scene four times. On the first viewing, this movie scene is novel, and on later viewings it is not. We find that brain activity is lower-dimensional in response to novelty. At a finer scale, we find that this reduction in the dimensionality of brain activity is the result of increased coupling in specific brain systems, most specifically within and between the control and dorsal attention systems. Additionally, we found that novelty induced an increase in between-subject synchronization of brain activity in the same brain systems. We also find evidence that adaptation to novelty, herein operationalized as the difference between baseline coupling and novelty-response coupling, is related to fluid intelligence. Finally, using separately collected out-of-sample data, we find that the above results may be linked to psychological arousal.

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).)

Neuroscience is advancing standardization and tool development to support rigor and transparency. Consequently, data pipeline complexity has increased, hindering FAIR (findable, accessible, interoperable and reusable) access. brainlife.io was developed to democratize neuroimaging research. The platform provides data standardization, management, visualization and processing and automatically tracks the provenance history of thousands of data objects. Here, brainlife.io is described and evaluated for validity, reliability, reproducibility, replicability and scientific utility using four data modalities and 3,200 participants., (© 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 human brain is never at "rest"; its activity is constantly fluctuating over time, transitioning from one brain state-a whole-brain pattern of activity-to another. Network control theory offers a framework for understanding the effort - energy - associated with these transitions. One branch of control theory that is especially useful in this context is "optimal control", in which input signals are used to selectively drive the brain into a target state. Typically, these inputs are introduced independently to the nodes of the network (each input signal is associated with exactly one node). Though convenient, this input strategy ignores the continuity of cerebral cortex - geometrically, each region is connected to its spatial neighbors, allowing control signals, both exogenous and endogenous, to spread from their foci to nearby regions. Additionally, the spatial specificity of brain stimulation techniques is limited, such that the effects of a perturbation are measurable in tissue surrounding the stimulation site. Here, we adapt the network control model so that input signals have a spatial extent that decays exponentially from the input site. We show that this more realistic strategy takes advantage of spatial dependencies in structural connectivity and activity to reduce the energy (effort) associated with brain state transitions. We further leverage these dependencies to explore near-optimal control strategies such that, on a per-transition basis, the number of input signals required for a given control task is reduced, in some cases by two orders of magnitude. This approximation yields network-wide maps of input site density, which we compare to an existing database of functional, metabolic, genetic, and neurochemical maps, finding a close correspondence. Ultimately, not only do we propose a more efficient framework that is also more adherent to well-established brain organizational principles, but we also posit neurobiologically grounded bases for optimal control.

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).)

Brain signal irreversibility has been shown to be a promising approach to study neural dynamics. Nevertheless, the relation with cortical hierarchy and the influence of different electrophysiological features is not completely understood. In this study, we recorded local field potentials (LFPs) during spontaneous behavior, including awake and sleep periods, using custom micro-electrocorticographic (μECoG) arrays implanted in ferrets. In contrast to humans, ferrets remain less time in each state across the sleep-wake cycle. We deployed a diverse set of metrics in order to measure the levels of complexity of the different behavioral states. In particular, brain irreversibility, which is a signature of non-equilibrium dynamics, captured by the arrow of time of the signal, revealed the hierarchical organization of the ferret's cortex. We found different signatures of irreversibility and functional hierarchy of large-scale dynamics in three different brain states (active awake, quiet awake, and deep sleep), showing a lower level of irreversibility in the deep sleep stage, compared to the other. Irreversibility also allowed us to disentangle the influence of different cortical areas and frequency bands in this process, showing a predominance of the parietal cortex and the theta band. Furthermore, when inspecting the embedded dynamic through a Hidden Markov Model, the deep sleep stage was revealed to have a lower switching rate and lower entropy production. These results suggest functional hierarchies in organization that can be revealed through thermodynamic features and information theory metrics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Idesis 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.)

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.)

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., (© 2023 Massachusetts Institute of Technology.)

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., (© 2023 Massachusetts Institute of Technology.)

Large-scale brain networks reveal structural connections as well as functional synchronization between distinct regions of the brain. The latter, referred to as functional connectivity (FC), can be derived from neuroimaging techniques such as functional magnetic resonance imaging (fMRI). FC studies have shown that brain networks are severely disrupted by stroke. However, since FC data are usually large and high-dimensional, extracting clinically useful information from this vast amount of data is still a great challenge, and our understanding of the functional consequences of stroke remains limited. Here, we propose a dimensionality reduction approach to simplify the analysis of this complex neural data. By using autoencoders, we find a low-dimensional representation encoding the fMRI data which preserves the typical FC anomalies known to be present in stroke patients. By employing the latent representations emerging from the autoencoders, we enhanced patients' diagnostics and severity classification. Furthermore, we showed how low-dimensional representation increased the accuracy of recovery prediction., (© 2023. Springer Nature Limited.)

Dynamic models of ongoing BOLD fMRI brain dynamics and models of communication strategies have been two important approaches to understanding how brain network structure constrains function. However, dynamic models have yet to widely incorporate one of the most important insights from communication models: the brain may not use all of its connections in the same way or at the same time. Here we present a variation of a phase delayed Kuramoto coupled oscillator model that dynamically limits communication between nodes on each time step. An active subgraph of the empirically derived anatomical brain network is chosen in accordance with the local dynamic state on every time step, thus coupling dynamics and network structure in a novel way. We analyze this model with respect to its fit to empirical time-averaged functional connectivity, finding that, with the addition of only one parameter, it significantly outperforms standard Kuramoto models with phase delays. We also perform analyses on the novel time series of active edges it produces, demonstrating a slowly evolving topology moving through intermittent episodes of integration and segregation. We hope to demonstrate that the exploration of novel modeling mechanisms and the investigation of dynamics of networks in addition to dynamics on networks may advance our understanding of the relationship between brain structure and function., Competing Interests: Declaration of Competing Interest There are no declarations of interest., (Copyright © 2023. Published by Elsevier Inc.)

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.)

Neuroscience research has expanded dramatically over the past 30 years by advancing standardization and tool development to support rigor and transparency. Consequently, the complexity of the data pipeline has also increased, hindering access to FAIR data analysis to portions of the worldwide research community. brainlife.io was developed to reduce these burdens and democratize modern neuroscience research across institutions and career levels. Using community software and hardware infrastructure, the platform provides open-source data standardization, management, visualization, and processing and simplifies the data pipeline. brainlife.io automatically tracks the provenance history of thousands of data objects, supporting simplicity, efficiency, and transparency in neuroscience research. Here brainlife.io's technology and data services are described and evaluated for validity, reliability, reproducibility, replicability, and scientific utility. Using data from 4 modalities and 3,200 participants, we demonstrate that brainlife.io's services produce outputs that adhere to best practices in modern neuroscience research., Competing Interests: Competing interests. The authors declare no competing financial interests.

The standard approach to modeling the human brain as a complex system is with a network, where the basic unit of interaction is a pairwise link between two brain regions. While powerful, this approach is limited by the inability to assess higher-order interactions involving three or more elements directly. In this work, we explore a method for capturing higher-order dependencies in multivariate data: the partial entropy decomposition (PED). Our approach decomposes the joint entropy of the whole system into a set of nonnegative atoms that describe the redundant, unique, and synergistic interactions that compose the system's structure. PED gives insight into the mathematics of functional connectivity and its limitation. When applied to resting-state fMRI data, we find robust evidence of higher-order synergies that are largely invisible to standard functional connectivity analyses. Our approach can also be localized in time, allowing a frame-by-frame analysis of how the distributions of redundancies and synergies change over the course of a recording. We find that different ensembles of regions can transiently change from being redundancy-dominated to synergy-dominated and that the temporal pattern is structured in time. These results provide strong evidence that there exists a large space of unexplored structures in human brain data that have been largely missed by a focus on bivariate network connectivity models. This synergistic structure is dynamic in time and likely will illuminate interesting links between brain and behavior. Beyond brain-specific application, the PED provides a very general approach for understanding higher-order structures in a variety of complex systems.

One of the most well-established tools for modeling the brain is the functional connectivity network, which is constructed from pairs of interacting brain regions. While powerful, the network model is limited by the restriction that only pairwise dependencies are considered and potentially higher-order structures are missed. Here, we explore how multivariate information theory reveals higher-order dependencies in the human brain. We begin with a mathematical analysis of the O-information, showing analytically and numerically how it is related to previously established information theoretic measures of complexity. We then apply the O-information to brain data, showing that synergistic subsystems are widespread in the human brain. Highly synergistic subsystems typically sit between canonical functional networks, and may serve an integrative role. We then use simulated annealing to find maximally synergistic subsystems, finding that such systems typically comprise ≈10 brain regions, recruited from multiple canonical brain systems. Though ubiquitous, highly synergistic subsystems are invisible when considering pairwise functional connectivity, suggesting that higher-order dependencies form a kind of shadow structure that has been unrecognized by established network-based analyses. We assert that higher-order interactions in the brain represent an under-explored space that, accessible with tools of multivariate information theory, may offer novel scientific insights., (© 2023. The Author(s).)

Functional connectivity (FC) profiles contain subject-specific features that are conserved across time and have potential to capture brain-behavior relationships. Most prior work has focused on spatial features (nodes and systems) of these FC fingerprints, computed over entire imaging sessions. We propose a method for temporally filtering FC, which allows selecting specific moments in time while also maintaining the spatial pattern of node-based activity. To this end, we leverage a recently proposed decomposition of FC into edge time series (eTS). We systematically analyze functional magnetic resonance imaging frames to define features that enhance identifiability across multiple fingerprinting metrics, similarity metrics, and data sets. Results show that these metrics characteristically vary with eTS cofluctuation amplitude, similarity of frames within a run, transition velocity, and expression of functional systems. We further show that data-driven optimization of features that maximize fingerprinting metrics isolates multiple spatial patterns of system expression at specific moments in time. Selecting just 10% of the data can yield stronger fingerprints than are obtained from the full data set. Our findings support the idea that FC fingerprints are differentially expressed across time and suggest that multiple distinct fingerprints can be identified when spatial and temporal characteristics are considered simultaneously., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Network models of anatomical connections allow for the extraction of quantitative features describing brain organization, and their comparison across brains from different species. Such comparisons can inform our understanding of between-species differences in brain architecture and can be compared to existing taxonomies and phylogenies. Here we performed a quantitative comparative analysis using the MaMI database (Tel Aviv University), a collection of brain networks reconstructed from ex vivo diffusion MRI spanning 125 species and 12 taxonomic orders or superorders. We used a broad range of metrics to measure between-mammal distances and compare these estimates to the separation of species as derived from taxonomy and phylogeny. We found that within-taxonomy order network distances are significantly closer than between-taxonomy network distances, and this relation holds for several measures of network distance. Furthermore, to estimate the evolutionary divergence between species, we obtained phylogenetic distances across 10,000 plausible phylogenetic trees. The anatomical network distances were rank-correlated with phylogenetic distances 10,000 times, creating a distribution of coefficients that demonstrate significantly positive correlations between network and phylogenetic distances. Collectively, these analyses demonstrate species-level organization across scales and informational sources: we relate brain networks distances, derived from MRI, with evolutionary distances, derived from genotyping data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Faskowitz, Puxeddu, van den Heuvel, Mišić, Yovel, Assaf, Betzel and Sporns.)

The human brain is a complex network of anatomically interconnected brain areas. Spontaneous neural activity is constrained by this architecture, giving rise to patterns of statistical dependencies between the activity of remote neural elements. The non-trivial relationship between structural and functional connectivity poses many unsolved challenges about cognition, disease, development, learning and aging. While numerous studies have focused on statistical relationships between edge weights in anatomical and functional networks, less is known about dependencies between their modules and communities. In this work, we investigate and characterize the relationship between anatomical and functional modular organization of the human brain, developing a novel multi-layer framework that expands the classical concept of multi-layer modularity. By simultaneously mapping anatomical and functional networks estimated from different subjects into communities, this approach allows us to carry out a multi-subject and multi-modal analysis of the brain's modular organization. Here, we investigate the relationship between anatomical and functional modules during resting state, finding unique and shared structures. The proposed framework constitutes a methodological advance in the context of multi-layer network analysis and paves the way to further investigate the relationship between structural and functional network organization in clinical cohorts, during cognitively demanding tasks, and in developmental or lifespan studies., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Intelligence describes the general cognitive ability level of a person. It is one of the most fundamental concepts in psychological science and is crucial for the effective adaption of behavior to varying environmental demands. Changing external task demands have been shown to induce reconfiguration of functional brain networks. However, whether neural reconfiguration between different tasks is associated with intelligence has not yet been investigated. We used functional magnetic resonance imaging data from 812 subjects to show that higher scores of general intelligence are related to less brain network reconfiguration between resting state and seven different task states as well as to network reconfiguration between tasks. This association holds for all functional brain networks except the motor system and replicates in two independent samples (n = 138 and n = 184). Our findings suggest that the intrinsic network architecture of individuals with higher intelligence scores is closer to the network architecture as required by various cognitive demands. Multitask brain network reconfiguration may, therefore, represent a neural reflection of the behavioral positive manifold - the essence of the concept of general intelligence. Finally, our results support neural efficiency theories of cognitive ability and reveal insights into human intelligence as an emergent property from a distributed multitask brain network., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Copyright © 2022. Published by Elsevier Inc.)

A growing number of studies have used stylized network models of communication to predict brain function from structure. Most have focused on a small set of models applied globally. Here, we compare a large number of models at both global and regional levels. We find that globally most predictors perform poorly. At the regional level, performance improves but heterogeneously, both in terms of variance explained and the optimal model. Next, we expose synergies among predictors by using pairs to jointly predict FC. Finally, we assess age-related differences in global and regional coupling across the human lifespan. We find global decreases in the magnitude of structure-function coupling with age. We find that these decreases are driven by reduced coupling in sensorimotor regions, while higher-order cognitive systems preserve local coupling with age. Our results describe patterns of structure-function coupling across the cortex and how this may change with age., (© 2022. The Author(s).)

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.)

Network models describe the brain as sets of nodes and edges that represent its distributed organization. So far, most discoveries in network neuroscience have prioritized insights that highlight distinct groupings and specialized functional contributions of network nodes. Importantly, these functional contributions are determined and expressed by the web of their interrelationships, formed by network edges. Here, we underscore the important contributions made by brain network edges for understanding distributed brain organization. Different types of edges represent different types of relationships, including connectivity and similarity among nodes. Adopting a specific definition of edges can fundamentally alter how we analyze and interpret a brain network. Furthermore, edges can associate into collectives and higher order arrangements, describe time series, and form edge communities that provide insights into brain network topology complementary to the traditional node-centric perspective. Focusing on the edges, and the higher order or dynamic information they can provide, discloses previously underappreciated aspects of structural and functional network organization., (© 2021 Massachusetts Institute of Technology.)

Most neuroimaging studies of post-stroke recovery rely on analyses derived from standard node-centric functional connectivity to map the distributed effects in stroke patients. Here, given the importance of nonlocal and diffuse damage, we use an edge-centric approach to functional connectivity in order to provide an alternative description of the effects of this disorder. These techniques allow for the rendering of metrics such as normalized entropy, which describes the diversity of edge communities at each node. Moreover, the approach enables the identification of high amplitude co-fluctuations in fMRI time series. We found that normalized entropy is associated with stroke lesion severity and continually increases across the time of patients' recovery. Furthermore, high amplitude co-fluctuations not only relate to the lesion severity but are also associated with patients' level of recovery. The current study is the first edge-centric application for a clinical population in a longitudinal dataset and demonstrates how a different perspective for functional data analysis can further characterize topographic modulations of brain dynamics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 The Authors. 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.)

Functional connectivity (FC) describes the statistical dependence between neuronal populations or brain regions in resting-state fMRI studies and is commonly estimated as the Pearson correlation of time courses. Clustering or community detection reveals densely coupled sets of regions constituting resting-state networks or functional systems. These systems manifest most clearly when FC is sampled over longer epochs but appear to fluctuate on shorter timescales. Here, we propose a new approach to reveal temporal fluctuations in neuronal time series. Unwrapping FC signal correlations yields pairwise co-fluctuation time series, one for each node pair or edge, and allows tracking of fine-scale dynamics across the network. Co-fluctuations partition the network, at each time step, into exactly two communities. Sampled over time, the overlay of these bipartitions, a binary decomposition of the original time series, very closely approximates functional connectivity. Bipartitions exhibit characteristic spatiotemporal patterns that are reproducible across participants and imaging runs, capture individual differences, and disclose fine-scale temporal expression of functional systems. Our findings document that functional systems appear transiently and intermittently, and that FC results from the overlay of many variable instances of system expression. Potential applications of this decomposition of functional connectivity into a set of binary patterns are discussed., (© 2021 Massachusetts Institute of Technology.)

We describe a dataset of processed data with associated reproducible preprocessing pipeline collected from two collegiate athlete groups and one non-athlete group. The dataset shares minimally processed diffusion-weighted magnetic resonance imaging (dMRI) data, three models of the diffusion signal in the voxel, full-brain tractograms, segmentation of the major white matter tracts as well as structural connectivity matrices. There is currently a paucity of similar datasets openly shared. Furthermore, major challenges are associated with collecting this type of data. The data and derivatives shared here can be used as a reference to study the effects of long-term exposure to collegiate athletics, such as the effects of repetitive head impacts. We use advanced anatomical and dMRI data processing methods publicly available as reproducible web services at brainlife.io.

Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date., Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide., Design, Setting, and Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019., Main Outcomes and Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status., Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] β = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004)., Conclusions and Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.

Network neuroscience has relied on a node-centric network model in which cells, populations and regions are linked to one another via anatomical or functional connections. This model cannot account for interactions of edges with one another. In this study, we developed an edge-centric network model that generates constructs 'edge time series' and 'edge functional connectivity' (eFC). Using network analysis, we show that, at rest, eFC is consistent across datasets and reproducible within the same individual over multiple scan sessions. We demonstrate that clustering eFC yields communities of edges that naturally divide the brain into overlapping clusters, with regions in sensorimotor and attentional networks exhibiting the greatest levels of overlap. We show that eFC is systematically modulated by variation in sensory input. In future work, the edge-centric approach could be useful for identifying novel biomarkers of disease, characterizing individual variation and mapping the architecture of highly resolved neural circuits.

Resting-state functional connectivity is used throughout neuroscience to study brain organization and to generate biomarkers of development, disease, and cognition. The processes that give rise to correlated activity are, however, poorly understood. Here we decompose resting-state functional connectivity using a temporal unwrapping procedure to assess the contributions of moment-to-moment activity cofluctuations to the overall connectivity pattern. This approach temporally resolves functional connectivity at a timescale of single frames, which enables us to make direct comparisons of cofluctuations of network organization with fluctuations in the blood oxygen level-dependent (BOLD) time series. We show that surprisingly, only a small fraction of frames exhibiting the strongest cofluctuation amplitude are required to explain a significant fraction of variance in the overall pattern of connection weights as well as the network's modular structure. These frames coincide with frames of high BOLD activity amplitude, corresponding to activity patterns that are remarkably consistent across individuals and identify fluctuations in default mode and control network activity as the primary driver of resting-state functional connectivity. Finally, we demonstrate that cofluctuation amplitude synchronizes across subjects during movie watching and that high-amplitude frames carry detailed information about individual subjects (whereas low-amplitude frames carry little). Our approach reveals fine-scale temporal structure of resting-state functional connectivity and discloses that frame-wise contributions vary across time. These observations illuminate the relation of brain activity to functional connectivity and open a number of directions for future research., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Cortical folds help drive the parcellation of the human cortex into functionally specific regions. Variations in the length, depth, width, and surface area of these sulcal landmarks have been associated with disease, and may be genetically mediated. Before estimating the heritability of sulcal variation, the extent to which these metrics can be reliably extracted from in-vivo MRI must be established. Using four independent test-retest datasets, we found high reliability across the brain (intraclass correlation interquartile range: 0.65-0.85). Heritability estimates were derived for three family-based cohorts using variance components analysis and pooled (total N > 3000); the overall sulcal heritability pattern was correlated to that derived for a large population cohort (N > 9000) calculated using genomic complex trait analysis. Overall, sulcal width was the most heritable metric, and earlier forming sulci showed higher heritability. The inter-hemispheric genetic correlations were high, yet select sulci showed incomplete pleiotropy, suggesting hemisphere-specific genetic influences.

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.)