An integrative dynamical perspective for graph theory and the analysis of complex networks.

Built upon the shoulders of graph theory, the field of complex networks has become a central tool for studying real systems across various fields of research. Represented as graphs, different systems can be studied using the same analysis methods, which allows for their comparison. Here, we challenge the widespread idea that graph theory is a universal analysis tool, uniformly applicable to any kind of network data. Instead, we show that many classical graph metrics-including degree, clustering coefficient, and geodesic distance-arise from a common hidden propagation model: the discrete cascade. From this perspective, graph metrics are no longer regarded as combinatorial measures of the graph but as spatiotemporal properties of the network dynamics unfolded at different temporal scales. Once graph theory is seen as a model-based (and not a purely data-driven) analysis tool, we can freely or intentionally replace the discrete cascade by other canonical propagation models and define new network metrics. This opens the opportunity to design-explicitly and transparently-dedicated analyses for different types of real networks by choosing a propagation model that matches their individual constraints. In this way, we take stand that network topology cannot always be abstracted independently from network dynamics but shall be jointly studied, which is key for the interpretability of the analyses. The model-based perspective here proposed serves to integrate into a common context both the classical graph analysis and the more recent network metrics defined in the literature which were, directly or indirectly, inspired by propagation phenomena on networks.

Integration and segregation manifolds in the brain ensure cognitive flexibility during tasks and rest.

Adapting to a constantly changing environment requires the human brain to flexibly switch among many demanding cognitive tasks, processing both specialized and integrated information associated with the activity in functional networks over time. In this study, we investigated the nature of the temporal alternation between segregated and integrated states in the brain during rest and six cognitive tasks using functional MRI. We employed a deep autoencoder to explore the 2D latent space associated with the segregated and integrated states. Our results show that the integrated state occupies less space in the latent space manifold compared to the segregated states. Moreover, the integrated state is characterized by lower entropy of occupancy than the segregated state, suggesting that integration plays a consolidating role, while segregation may serve as cognitive expertness. Comparing rest and the tasks, we found that rest exhibits higher entropy of occupancy, indicating a more random wandering of the mind compared to the expected focus during task performance. Our study demonstrates that both transient, short-lived integrated and segregated states are present during rest and task performance, flexibly switching between them, with integration serving as information compression and segregation related to information specialization.

The impact of regional heterogeneity in whole-brain dynamics in the presence of oscillations.

Large variability exists across brain regions in health and disease, considering their cellular and molecular composition, connectivity, and function. Large-scale whole-brain models comprising coupled brain regions provide insights into the underlying dynamics that shape complex patterns of spontaneous brain activity. In particular, biophysically grounded mean-field whole-brain models in the asynchronous regime were used to demonstrate the dynamical consequences of including regional variability. Nevertheless, the role of heterogeneities when brain dynamics are supported by synchronous oscillating state, which is a ubiquitous phenomenon in brain, remains poorly understood. Here, we implemented two models capable of presenting oscillatory behavior with different levels of abstraction: a phenomenological Stuart-Landau model and an exact mean-field model. The fit of these models informed by structural- to functional-weighted MRI signal (T1w/T2w) allowed us to explore the implication of the inclusion of heterogeneities for modeling resting-state fMRI recordings from healthy participants. We found that disease-specific regional functional heterogeneity imposed dynamical consequences within the oscillatory regime in fMRI recordings from neurodegeneration with specific impacts on brain atrophy/structure (Alzheimer's patients). Overall, we found that models with oscillations perform better when structural and functional regional heterogeneities are considered, showing that phenomenological and biophysical models behave similarly at the brink of the Hopf bifurcation.

Whole-brain analyses indicate the impairment of posterior integration and thalamo-frontotemporal broadcasting in disorders of consciousness.

The study of the brain's dynamical activity is opening a window to help the clinical assessment of patients with disorders of consciousness. For example, glucose uptake and the dysfunctional spread of naturalistic and synthetic stimuli has proven useful to characterize hampered consciousness. However, understanding of the mechanisms behind loss of consciousness following brain injury is still missing. Here, we study the propagation of endogenous and in-silico exogenous perturbations in patients with disorders of consciousness, based upon directed and causal interactions estimated from resting-state fMRI data, fitted to a linear model of activity propagation. We found that patients with disorders of consciousness suffer decreased capacity for neural propagation and responsiveness to events, and that this can be related to severe reduction of glucose metabolism as measured with [18 F]FDG-PET. In particular, we show that loss of consciousness is related to the malfunctioning of two neural circuits: the posterior cortical regions failing to convey information, in conjunction with reduced broadcasting of information from subcortical, temporal, parietal and frontal regions. These results shed light on the mechanisms behind disorders of consciousness, triangulating network function with basic measures of brain integrity and behavior.

Inhibitory neurons control the consolidation of neural assemblies via adaptation to selective stimuli.

Brain circuits display modular architecture at different scales of organization. Such neural assemblies are typically associated to functional specialization but the mechanisms leading to their emergence and consolidation still remain elusive. In this paper we investigate the role of inhibition in structuring new neural assemblies driven by the entrainment to various inputs. In particular, we focus on the role of partially synchronized dynamics for the creation and maintenance of structural modules in neural circuits by considering a network of excitatory and inhibitory [Formula: see text]-neurons with plastic Hebbian synapses. The learning process consists of an entrainment to temporally alternating stimuli that are applied to separate regions of the network. This entrainment leads to the emergence of modular structures. Contrary to common practice in artificial neural networks-where the acquired weights are typically frozen after the learning session-we allow for synaptic adaptation even after the learning phase. We find that the presence of inhibitory neurons in the network is crucial for the emergence and the post-learning consolidation of the modular structures. Indeed networks made of purely excitatory neurons or of neurons not respecting Dale's principle are unable to form or to maintain the modular architecture induced by the stimuli. We also demonstrate that the number of inhibitory neurons in the network is directly related to the maximal number of neural assemblies that can be consolidated, supporting the idea that inhibition has a direct impact on the memory capacity of the neural network.

Loss of consciousness reduces the stability of brain hubs and the heterogeneity of brain dynamics.

Low-level states of consciousness are characterized by disruptions of brain activity that sustain arousal and awareness. Yet, how structural, dynamical, local and network brain properties interplay in the different levels of consciousness is unknown. Here, we study fMRI brain dynamics from patients that suffered brain injuries leading to a disorder of consciousness and from healthy subjects undergoing propofol-induced sedation. We show that pathological and pharmacological low-level states of consciousness display less recurrent, less connected and more segregated synchronization patterns than conscious state. We use whole-brain models built upon healthy and injured structural connectivity to interpret these dynamical effects. We found that low-level states of consciousness were associated with reduced network interactions, together with more homogeneous and more structurally constrained local dynamics. Notably, these changes lead the structural hub regions to lose their stability during low-level states of consciousness, thus attenuating the differences between hubs and non-hubs brain dynamics.

Signature of consciousness in brain-wide synchronization patterns of monkey and human fMRI signals.

During the sleep-wake cycle, the brain undergoes profound dynamical changes, which manifest subjectively as transitions between conscious experience and unconsciousness. Yet, neurophysiological signatures that can objectively distinguish different consciousness states based are scarce. Here, we show that differences in the level of brain-wide signals can reliably distinguish different stages of sleep and anesthesia from the awake state in human and monkey fMRI resting state data. Moreover, a whole-brain computational model can faithfully reproduce changes in global synchronization and other metrics such as functional connectivity, structure-function relationship, integration and segregation across vigilance states. We demonstrate that the awake brain is close to a Hopf bifurcation, which naturally coincides with the emergence of globally correlated fMRI signals. Furthermore, simulating lesions of individual brain areas highlights the importance of connectivity hubs in the posterior brain and subcortical nuclei for maintaining the model in the awake state, as predicted by graph-theoretical analyses of structural data.

Modulation of cortical slow oscillations and complexity across anesthesia levels.

The ability of different groups of cortical neurons to engage in causal interactions that are at once differentiated and integrated results in complex dynamic patterns. Complexity is low during periods of unconsciousness (deep sleep, anesthesia, unresponsive wakefulness syndrome) in which the brain tends to generate a stereotypical pattern consisting of alternating active and silent periods of neural activity-slow oscillations- and is high during wakefulness. But how is cortical complexity built up? Is it a continuum? An open question is whether cortical complexity can vary within the same brain state. Here we recorded with 32-channel multielectrode arrays from the cortical surface of the mouse and used both spontaneous dynamics (wave propagation entropy and functional complexity) and a perturbational approach (a variation of the perturbation complexity index) to measure complexity at different anesthesia levels. Variations in anesthesia level within the bistable regime of slow oscillations (0.1-1.5 Hz) resulted in a modulation of the slow oscillation frequency. Both perturbational and spontaneous complexity increased with decreasing anesthesia levels, in correlation with the decrease in coherence of the underlying network. Changes in complexity level are related to, but not dependent on, changes in excitability. We conclude that cortical complexity can vary within a single brain state dominated by slow oscillations, building up to the higher complexity associated with consciousness.

Model-based whole-brain effective connectivity to study distributed cognition in health and disease.

Neuroimaging techniques are now widely used to study human cognition. The functional associations between brain areas have become a standard proxy to describe how cognitive processes are distributed across the brain network. Among the many analysis tools available, dynamic models of brain activity have been developed to overcome the limitations of original connectivity measures such as functional connectivity. This goes in line with the many efforts devoted to the assessment of directional interactions between brain areas from the observed neuroimaging activity. This opinion article provides an overview of our model-based whole-brain effective connectivity to analyze fMRI data, while discussing the pros and cons of our approach with respect to other established approaches. Our framework relies on the multivariate Ornstein-Uhlenbeck (MOU) process and is thus referred to as MOU-EC. Once tuned, the model provides a directed connectivity estimate that reflects the dynamical state of BOLD activity, which can be used to explore cognition. We illustrate this approach using two applications on task-evoked fMRI data. First, as a connectivity measure, MOU-EC can be used to extract biomarkers for task-specific brain coordination, understood as the patterns of areas exchanging information. The multivariate nature of connectivity measures raises several challenges for whole-brain analysis, for which machine-learning tools present some advantages over statistical testing. Second, we show how to interpret changes in MOU-EC connections in a collective and model-based manner, bridging with network analysis. Our framework provides a comprehensive set of tools that open exciting perspectives to study distributed cognition, as well as neuropathologies.

Network analysis of whole-brain fMRI dynamics: A new framework based on dynamic communicability.

Neuroimaging techniques such as MRI have been widely used to explore the associations between brain areas. Structural connectivity (SC) captures the anatomical pathways across the brain and functional connectivity (FC) measures the correlation between the activity of brain regions. These connectivity measures have been much studied using network theory in order to uncover the distributed organization of brain structures, in particular FC for task-specific brain communication. However, the application of network theory to study FC matrices is often "static" despite the dynamic nature of time series obtained from fMRI. The present study aims to overcome this limitation by introducing a network-oriented analysis applied to whole-brain effective connectivity (EC) useful to interpret the brain dynamics. Technically, we tune a multivariate Ornstein-Uhlenbeck (MOU) process to reproduce the statistics of the whole-brain resting-state fMRI signals, which provides estimates for MOU-EC as well as input properties (similar to local excitabilities). The network analysis is then based on the Green function (or network impulse response) that describes the interactions between nodes across time for the estimated dynamics. This model-based approach provides time-dependent graph-like descriptor, named communicability, that characterize the roles that either nodes or connections play in the propagation of activity within the network. They can be used at both global and local levels, and also enables the comparison of estimates from real data with surrogates (e.g. random network or ring lattice). In contrast to classical graph approaches to study SC or FC, our framework stresses the importance of taking the temporal aspect of fMRI signals into account. Our results show a merging of functional communities over time, moving from segregated to global integration of the network activity. Our formalism sets a solid ground for the analysis and interpretation of fMRI data, including task-evoked activity.

Traces of statistical learning in the brain's functional connectivity after artificial language exposure.

Our environment is full of statistical regularities, and we are attuned to learn about these regularities by employing Statistical Learning (SL), a domain-general ability that enables the implicit detection of probabilistic regularities in our surrounding environment. The role of brain connectivity on SL has been previously explored, highlighting the relevance of structural and functional connections between frontal, parietal, and temporal cortices. However, whether SL can induce changes in the functional connections of the resting state brain has yet to be investigated. To address this question, we applied a pre-post design where participants (n = 38) were submitted to resting-state fMRI acquisition before and after in-scanner exposure to either an artificial language stream (formed by 4 concatenated words) or a random audio stream. Our results showed that exposure to an artificial language stream significantly changed (corrected p < 0.05) the functional connectivity between Right Posterior Cingulum and Left Superior Parietal Lobule. This suggests that functional connectivity between brain networks supporting attentional and working memory processes may play an important role in statistical learning.

Functional complexity emerging from anatomical constraints in the brain: the significance of network modularity and rich-clubs.

The large-scale structural ingredients of the brain and neural connectomes have been identified in recent years. These are, similar to the features found in many other real networks: the arrangement of brain regions into modules and the presence of highly connected regions (hubs) forming rich-clubs. Here, we examine how modules and hubs shape the collective dynamics on networks and we find that both ingredients lead to the emergence of complex dynamics. Comparing the connectomes of C. elegans, cats, macaques and humans to surrogate networks in which either modules or hubs are destroyed, we find that functional complexity always decreases in the perturbed networks. A comparison between simulated and empirically obtained resting-state functional connectivity indicates that the human brain, at rest, lies in a dynamical state that reflects the largest complexity its anatomical connectome can host. Last, we generalise the topology of neural connectomes into a new hierarchical network model that successfully combines modular organisation with rich-club forming hubs. This is achieved by centralising the cross-modular connections through a preferential attachment rule. Our network model hosts more complex dynamics than other hierarchical models widely used as benchmarks.

Chimera-like States in Modular Neural Networks.

Chimera states, namely the coexistence of coherent and incoherent behavior, were previously analyzed in complex networks. However, they have not been extensively studied in modular networks. Here, we consider a neural network inspired by the connectome of the C. elegans soil worm, organized into six interconnected communities, where neurons obey chaotic bursting dynamics. Neurons are assumed to be connected with electrical synapses within their communities and with chemical synapses across them. As our numerical simulations reveal, the coaction of these two types of coupling can shape the dynamics in such a way that chimera-like states can happen. They consist of a fraction of synchronized neurons which belong to the larger communities, and a fraction of desynchronized neurons which are part of smaller communities. In addition to the Kuramoto order parameter ρ, we also employ other measures of coherence, such as the chimera-like χ and metastability λ indices, which quantify the degree of synchronization among communities and along time, respectively. We perform the same analysis for networks that share common features with the C. elegans neural network. Similar results suggest that under certain assumptions, chimera-like states are prominent phenomena in modular networks, and might provide insight for the behavior of more complex modular networks.

Transcriptomic profile reveals gender-specific molecular mechanisms driving multiple sclerosis progression.

BACKGROUND: Although the most common clinical presentation of multiple sclerosis (MS) is the so called Relapsing-Remitting MS (RRMS), the molecular mechanisms responsible for its progression are currently unknown. To tackle this problem, a whole-genome gene expression analysis has been performed on RRMS patients. RESULTS: The comparative analysis of the Affymetrix Human Gene 1.0 ST microarray data from peripheral blood leucocytes obtained from 25 patients in remission and relapse and 25 healthy subjects has revealed 174 genes altered in both remission and relapse, a high proportion of them showing what we have called "mirror pattern": they are upregulated in remission and downregulated in relapse or vice versa. The coexpression analysis of these genes has shown that they are organized in three female-specific and one male-specific modules. CONCLUSIONS: The interpretation of the modules of the coexpression network suggests that Epstein-Barr virus (EBV) reactivation of B cells happens in MS relapses; however, qPCR expression data of the viral genes supports that hypothesis only in female patients, reinforcing the notion that different molecular processes drive disease progression in females and males. Besides, we propose that the "primed" state showed by neutrophils in women is an endogenous control mechanism triggered to keep EBV reactivation under control through vitamin B12 physiology. Finally, our results also point towards an important sex-specific role of non-coding RNA in MS.

Order Patterns Networks (ORPAN)-a method to estimate time-evolving functional connectivity from multivariate time series.

Complex networks provide an excellent framework for studying the function of the human brain activity. Yet estimating functional networks from measured signals is not trivial, especially if the data is non-stationary and noisy as it is often the case with physiological recordings. In this article we propose a method that uses the local rank structure of the data to define functional links in terms of identical rank structures. The method yields temporal sequences of networks which permits to trace the evolution of the functional connectivity during the time course of the observation. We demonstrate the potentials of this approach with model data as well as with experimental data from an electrophysiological study on language processing.

Characterizing the complexity of brain and mind networks.

Recent studies of brain connectivity and language with methods of complex networks have revealed common features of organization. These observations open a window to better understand the intrinsic relationship between the brain and the mind by studying how information is either physically stored or mentally represented. In this paper, we review some of the results in both brain and linguistic networks, and we illustrate how modelling approaches can serve to comprehend the relationship between the structure of the brain and its function. On the one hand, we show that brain and neural networks display dynamical behaviour with optimal complexity in terms of a balance between their capacity to simultaneously segregate and integrate information. On the other hand, we show how principles of neural organization can be implemented into models of memory storage and recognition to reproduce spontaneous transitions between memories, resembling phenomena of memory association studied in psycholinguistic experiments.

Exploring brain function from anatomical connectivity.

The intrinsic relationship between the architecture of the brain and the range of sensory and behavioral phenomena it produces is a relevant question in neuroscience. Here, we review recent knowledge gained on the architecture of the anatomical connectivity by means of complex network analysis. It has been found that cortico-cortical networks display a few prominent characteristics: (i) modular organization, (ii) abundant alternative processing paths, and (iii) the presence of highly connected hubs. Additionally, we present a novel classification of cortical areas of the cat according to the role they play in multisensory connectivity. All these properties represent an ideal anatomical substrate supporting rich dynamical behaviors, facilitating the capacity of the brain to process sensory information of different modalities segregated and to integrate them toward a comprehensive perception of the real world. The results here exposed are mainly based on anatomical data of cats' brain, but further observations suggest that, from worms to humans, the nervous system of all animals might share these fundamental principles of organization.

Functional network analysis reveals differences in the semantic priming task.

The recent years have seen the emergence of graph theoretical analysis of complex, functional brain networks estimated from neurophysiological measurements. The research has mainly focused on the graph characterization of the resting-state/default network, and its potential for clinical application. Functional resting-state networks usually display the characteristics of small-world networks and their statistical properties have been observed to change due to pathological conditions or aging. In the present paper we move forward in the application of graph theoretical tools in functional connectivity by investigating high-level cognitive processing in healthy adults, in a manner similar to that used in psychological research in the framework of event-related potentials (ERPs). More specifically we aim at investigating how graph theoretical approaches can help to discover systematic and task-dependent differences in high-level cognitive processes such as language perception. We will show that such an approach is feasible and that the results coincide well with the findings from neuroimaging studies.

From modular to centralized organization of synchronization in functional areas of the cat cerebral cortex.

Recent studies have pointed out the importance of transient synchronization between widely distributed neural assemblies to understand conscious perception. These neural assemblies form intricate networks of neurons and synapses whose detailed map for mammals is still unknown and far from our experimental capabilities. Only in a few cases, for example the C. elegans, we know the complete mapping of the neuronal tissue or its mesoscopic level of description provided by cortical areas. Here we study the process of transient and global synchronization using a simple model of phase-coupled oscillators assigned to cortical areas in the cerebral cat cortex. Our results highlight the impact of the topological connectivity in the developing of synchronization, revealing a transition in the synchronization organization that goes from a modular decentralized coherence to a centralized synchronized regime controlled by a few cortical areas forming a Rich-Club connectivity pattern.