Understanding how different areas of the human brain communicate with each other is a crucial issue in neuroscience. The concepts of structural, functional and effective connectivity have been widely exploited to describe the human connectome, consisting of brain networks, their structural connections and functional interactions. Despite high-spatial-resolution imaging techniques such as functional magnetic resonance imaging (fMRI) being widely used to map this complex network of multiple interactions, electroencephalographic (EEG) recordings claim high temporal resolution and are thus perfectly suitable to describe either spatially distributed and temporally dynamic patterns of neural activation and connectivity. In this work, we provide a technical account and a categorization of the most-used data-driven approaches to assess brain-functional connectivity, intended as the study of the statistical dependencies between the recorded EEG signals. Different pairwise and multivariate, as well as directed and non-directed connectivity metrics are discussed with a pros–cons approach, in the time, frequency, and information-theoretic domains. The establishment of conceptual and mathematical relationships between metrics from these three frameworks, and the discussion of novel methodological approaches, will allow the reader to go deep into the problem of inferring functional connectivity in complex networks. Furthermore, emerging trends for the description of extended forms of connectivity (e.g., high-order interactions) are also discussed, along with graph-theory tools exploring the topological properties of the network of connections provided by the proposed metrics. Applications to EEG data are reviewed. In addition, the importance of source localization, and the impacts of signal acquisition and pre-processing techniques (e.g., filtering, source localization, and artifact rejection) on the connectivity estimates are recognized and discussed. By going through this review, the reader could delve deeply into the entire process of EEG pre-processing and analysis for the study of brain functional connectivity and learning, thereby exploiting novel methodologies and approaches to the problem of inferring connectivity within complex networks.

While the standard network description of complex systems is based on quantifying the link between pairs of system units, higher-order interactions (HOIs) involving three or more units often play a major role in governing the collective network behavior. This work introduces a new approach to quantify pairwise and HOIs for multivariate rhythmic processes interacting across multiple time scales. We define the so-called O-information rate (OIR) as a new metric to assess HOIs for multivariate time series, and present a framework to decompose the OIR into measures quantifying Granger-causal and instantaneous influences, as well as to expand all measures in the frequency domain. The framework exploits the spectral representation of vector autoregressive and state space models to assess the synergistic and redundant interaction among groups of processes, both in specific bands of interest and in the time domain after whole-band integration. Validation of the framework on simulated networks illustrates how the spectral OIR can highlight redundant and synergistic HOIs emerging at specific frequencies, which cannot be detected using time-domain measures. The applications to physiological networks described by heart period, arterial pressure and respiration variability measured in healthy subjects during a protocol of paced breathing, and to brain networks described by electrocorticographic signals acquired in an animal experiment during anesthesia, document the capability of our approach to identify informational circuits relevant to well-defined cardiovascular oscillations and brain rhythms and related to specific physiological mechanisms involving autonomic control and altered consciousness. The proposed framework allows a hierarchically-organized evaluation of time- and frequency-domain interactions in dynamic networks mapped by multivariate time series, and its high flexibility and scalability make it suitable for the investigation of networks beyond pairwise interactions in neuroscience, physiology and many other fields.

The recovery of motor functions after stroke is fostered by the functional integration of large-scale brain networks, including the motor network (MN) and high-order cognitive controls networks, such as the default mode (DMN) and executive control (ECN) networks. In this paper, electroencephalography signals are used to investigate interactions among these three resting state networks (RSNs) in subacute stroke patients after motor rehabilitation. A novel metric, the O-information rate (OIR), is used to quantify the balance between redundancy and synergy in the complex high-order interactions among RSNs, as well as its causal decomposition to identify the direction of information flow. The paper also employs conditional spectral Granger causality to assess pairwise directed functional connectivity between RSNs. After rehabilitation, a synergy increase among these RSNs is found, especially driven by MN. From the pairwise description, a reduced directed functional connectivity towards MN is enhanced after treatment. Besides, inter-network connectivity changes are associated with motor recovery, for which the mediation role of ECN seems to play a relevant role, both from pairwise and high-order interactions perspective.

This work presents a comparison between different approaches for the model-free estimation of information-theoretic measures of the dynamic coupling between short realizations of random processes. The measures considered are the mutual information rate (MIR) between two random processes $X$ and $Y$ and the terms of its decomposition evidencing either the individual entropy rates of $X$ and $Y$ and their joint entropy rate, or the transfer entropies from $X$ to $Y$ and from $Y$ to $X$ and the instantaneous information shared by $X$ and $Y$ . All measures are estimated through discretization of the random variables forming the processes, performed either via uniform quantization (binning approach) or rank ordering (permutation approach). The binning and permutation approaches are compared on simulations of two coupled non-identical Hènon systems and on three datasets, including short realizations of cardiorespiratory (CR, heart period and respiration flow), cardiovascular (CV, heart period and systolic arterial pressure), and cerebrovascular (CB, mean arterial pressure and cerebral blood flow velocity) measured in different physiological conditions, i.e., spontaneous vs paced breathing or supine vs upright positions. Our results show that, with careful selection of the estimation parameters (i.e., the embedding dimension and the number of quantization levels for the binning approach), meaningful patterns of the MIR and of its components can be achieved in the analyzed systems. On physiological time series, we found that paced breathing at slow breathing rates induces less complex and more coupled CR dynamics, while postural stress leads to unbalancing of CV interactions with prevalent baroreflex coupling and to less complex pressure dynamics with preserved CB interactions. These results are better highlighted by the permutation approach, thanks to its more parsimonious representation of the discretized dynamic patterns, which allows one to explore interactions with longer memory while limiting the curse of dimensionality.

Goal: The network representation is becoming increasingly popular for the description of cardiovascular interactions based on the analysis of multiple simultaneously collected variables. However, the traditional methods to assess network links based on pairwise interaction measures cannot reveal high-order effects involving more than two nodes, and are not appropriate to infer the underlying network topology. To address these limitations, here we introduce a framework which combines the assessment of high-order interactions with statistical inference for the characterization of the functional links sustaining physiological networks. Methods: The framework develops information-theoretic measures quantifying how two nodes interact in a redundant or synergistic way with the rest of the network, and employs these measures for reconstructing the functional structure of the network. The measures are implemented for both static and dynamic networks mapped respectively by random variables and random processes using plug-in and model-based entropy estimators. Results: The validation on theoretical and numerical simulated networks documents the ability of the framework to represent high-order interactions as networks and to detect statistical structures associated to cascade, common drive and common target effects. The application to cardiovascular networks mapped by the beat-to-beat variability of heart rate, respiration, arterial pressure, cardiac output and vascular resistance allowed noninvasive characterization of several mechanisms of cardiovascular control operating in resting state and during orthostatic stress. Conclusion: Our approach brings to new comprehensive assessment of physiological interactions and complements existing strategies for the classification of pathophysiological states.

Keeping up with the shift towards personalized neuroscience essentially requires the derivation of meaningful insights from individual brain signal recordings by analyzing the descriptive indexes of physio-pathological states through statistical methods that prioritize subject-specific differences under varying experimental conditions. Within this framework, the current study presents a methodology for assessing the value of the single-subject fingerprints of brain functional connectivity, assessed both by standard pairwise and novel high-order measures. Functional connectivity networks, which investigate the inter-relationships between pairs of brain regions, have long been a valuable tool for modeling the brain as a complex system. However, their usefulness is limited by their inability to detect high-order dependencies beyond pairwise correlations. In this study, by leveraging multivariate information theory, we confirm recent evidence suggesting that the brain contains a plethora of high-order, synergistic subsystems that would go unnoticed using a pairwise graph structure. The significance and variations across different conditions of functional pairwise and high-order interactions (HOIs) between groups of brain signals are statistically verified on an individual level through the utilization of surrogate and bootstrap data analyses. The approach is illustrated on the single-subject recordings of resting-state functional magnetic resonance imaging (rest-fMRI) signals acquired using a pediatric patient with hepatic encephalopathy associated with a portosystemic shunt and undergoing liver vascular shunt correction. Our results show that (i) the proposed single-subject analysis may have remarkable clinical relevance for subject-specific investigations and treatment planning, and (ii) the possibility of investigating brain connectivity and its post-treatment functional developments at a high-order level may be essential to fully capture the complexity and modalities of the recovery.