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Abstract Devices that safely interface with the brain are critical to advancing neuroengineering. Thin and flexible neural implants show great promise alongside established silicon technologies. They therefore require a physical stiffener to allow their insertion into brain tissue. Bioresorbable polymer shanks are novel transient guides enabling accurate implantation using biocompatible materials that will be absorbed by the body over time. The development of materials with optimized stiffness and degradation is needed to provide minimally invasive probes with precise insertion capability under surgical conditions. A microfabrication protocol for the patterning of polyvinyl alcohol and its physical cross‐linking is presented, resulting in insertion guides with precise shapes and tunable degradation and stiffness. The results demonstrate a remarkable improvement in batch fabricating micro‐scale neural shanks with designed crystallinity. It results in their prolonged degradation time, evaluated in agarose gel, and remarkably improved penetrability due to the increase in mechanical stiffness. In vitro and in vivo studies support the high acceptability of this combination in interfacing with neural cells and tissue. This work represents a novel approach to the material and process engineering of bioresorbable polymers for developing fully organic and safe implants.

Epilepsy is a chronic neurological disorder characterized by recurrent seizures resulting from abnormal neuronal hyperexcitability. In the case of pharmacoresistant epilepsy requiring resection surgery, the identification of the Epileptogenic Zone (EZ) is critical. Fast Ripples (FRs; 200–600 Hz) are one of the promising biomarkers that can aid in EZ delineation. However, recording FRs requires physically small electrodes. These microelectrodes suffer from high impedance, which significantly impacts FRs’ observability and detection. In this study, we investigated the potential of a conductive polymer coating to enhance FR observability. We employed biophysical modeling to compare two types of microelectrodes: Gold (Au) and Au coated with the conductive polymer poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate) (Au/PEDOT:PSS). These electrodes were then implanted into the CA1 hippocampal neural network of epileptic mice to record FRs during epileptogenesis. The results showed that the polymer-coated electrodes had a two-order lower impedance as well as a higher transfer function amplitude and cut-off frequency. Consequently, FRs recorded with the PEDOT:PSS-coated microelectrode yielded significantly higher signal energy compared to the uncoated one. The PEDOT:PSS coating improved the observability of the recorded FRs and thus their detection. This work paves the way for the development of signal-specific microelectrode designs that allow for better targeting of pathological biomarkers.

Among the cognitive symptoms that are associated with Parkinson's disease (PD), alterations in cognitive action control (CAC) are commonly reported in patients. CAC enables the suppression of an automatic action, in favor of a goal-directed one. The implementation of CAC is time-resolved and arguably associated with dynamic changes in functional brain networks. However, the electrophysiological functional networks involved, their dynamic changes, and how these changes are affected by PD, still remain unknown. In this study, to address this gap of knowledge, 10 PD patients and 10 healthy controls (HC) underwent a Simon task while high-density electroencephalography (HD-EEG) was recorded. Source-level dynamic connectivity matrices were estimated using the phase-locking value in the beta (12-25 Hz) and gamma (30-45 Hz) frequency bands. Temporal independent component analyses were used as a dimension reduction tool to isolate the task-related brain network states. Typical microstate metrics were quantified to investigate the presence of these states at the subject-level. Our results first confirmed that PD patients experienced difficulties in inhibiting automatic responses during the task. At the group-level, we found three functional network states in the beta band that involved fronto-temporal, temporo-cingulate and fronto-frontal connections with typical CAC-related prefrontal and cingulate nodes (e.g., inferior frontal cortex). The presence of these networks did not differ between PD patients and HC when analyzing microstates metrics, and no robust correlations with behavior were found. In the gamma band, five networks were found, including one fronto-temporal network that was identical to the one found in the beta band. These networks also included CAC-related nodes previously identified in different neuroimaging modalities. Similarly to the beta networks, no subject-level differences were found between PD patients and HC. Interestingly, in both frequency bands, the dominant network at the subject-level was never the one that was the most durably modulated by the task. Altogether, this study identified the dynamic functional brain networks observed during CAC, but did not highlight PD-related changes in these networks that might explain behavioral changes. Although other new methods might be needed to investigate the presence of task-related networks at the subject-level, this study still highlights that task-based dynamic functional connectivity is a promising approach in understanding the cognitive dysfunctions observed in PD and beyond.

PurposeTranscranial electrical current stimulation (tES or tCS, as it is sometimes referred to) has been proposed as non-invasive therapy for pharmacoresistant epilepsy. This technique, which includes direct current (tDCS) and alternating current (tACS) stimulation involves the application of weak currents across the cortex to change cortical excitability. Although clinical trials have demonstrated the therapeutic efficacy of tES, its specific effects on epileptic brain activity are poorly understood. We sought to summarize the clinical and fundamental effects underlying the application of tES in epilepsy.MethodsA systematic review was performed in accordance with the PRISMA guidelines. A database search was performed in PUBMED, MEDLINE, Web of Science and Cochrane CENTRAL for articles corresponding to the keywords “epilepsy AND (transcranial current stimulation OR transcranial electrical stimulation)”.ResultsA total of 56 studies were included in this review. Through these records, we show that tDCS and tACS epileptic patients are safe and clinically relevant techniques for epilepsy. Recent articles reported changes of functional connectivity in epileptic patients after tDCS. We argue that tDCS may act by affecting brain networks, rather than simply modifying local activity in the targeted area. To explain the mechanisms of tES, various cellular effects have been identified. Among them, reduced cell loss, mossy fiber sprouting, and hippocampal BDNF protein levels. Brain modeling and human studies highlight the influence of individual brain anatomy and physiology on the electric field distribution. Computational models may optimize the stimulation parameters and bring new therapeutic perspectives.ConclusionBoth tDCS and tACS are promising techniques for epilepsy patients. Although the clinical effects of tDCS have been repeatedly assessed, only one clinical trial has involved a consistent number of epileptic patients and little knowledge is present about the clinical outcome of tACS. To fill this gap, multicenter studies on tES in epileptic patients are needed involving novel methods such as personalized stimulation protocols based on computational modeling. Furthermore, there is a need for more in vivo studies replicating the tES parameters applied in patients. Finally, there is a lack of clinical studies investigating changes in intracranial epileptiform discharges during tES application, which could clarify the nature of tES-related local and network dynamics in epilepsy.

AbstractGraph theoretical approach has proved an effective tool to understand, characterize, and quantify the complex brain network. However, much less attention has been paid to methods that quantitatively compare two graphs, a crucial issue in the context of brain networks. Comparing brain networks is indeed mandatory in several network neuroscience applications. Here, we discuss the current state of the art, challenges, and a collection of analysis tools that have been developed in recent years to compare brain networks. We first introduce the graph similarity problem in brain network application. We then describe the methodological background of the available metrics and algorithms of comparing graphs, their strengths, and limitations. We also report results obtained in concrete applications from normal brain networks. More precisely, we show the potential use of brain network similarity to build a “network of networks” that may give new insights into the object categorization in the human brain. Additionally, we discuss future directions in terms of network similarity methods and applications.

The human brain is a dynamic networked system that continually reconfigures its functional connectivity patterns over time. Thus, developing approaches able to adequately detect fast brain dynamics is critical. Of particular interest are the methods that analyze the modular structure of brain networks, that is, the presence of clusters of regions that are densely interconnected. In this paper, we propose a novel framework to identify fast modular states that dynamically fluctuate over time during rest and task. We started by demonstrating the feasibility and relevance of this framework using simulated data. Compared with other methods, our algorithm was able to identify the simulated networks with high temporal and spatial accuracies. We further applied the proposed framework on MEG data recorded during a finger movement task, identifying modular states linking somatosensory and primary motor regions. The algorithm was also performed on dense-EEG data recorded during a picture naming task, revealing the subsecond transition between several modular states that relate to visual processing, semantic processing, and language. Next, we tested our method on a dataset of resting-state dense-EEG signals recorded from 124 patients with Parkinson’s disease. Results disclosed brain modular states that differentiate cognitively intact patients, patients with moderate cognitive deficits, and patients with severe cognitive deficits. Our new approach complements classical methods, offering a new way to track the brain modular states, in healthy subjects and patients, on an adequate task-specific timescale. The brain is a dynamic modular network. Thus, exploring the dynamic behavior of the brain can reveal insights about its characteristics during rest and task, in healthy and pathological conditions. In this paper, we propose a new framework that aims to track the dynamic changes of the modular brain organization. The method presents two algorithms that can be applied during task-free or task-related paradigms. Using simulations, we demonstrated the advantages of the proposed algorithm over existing methods. The proposed algorithm was also tested on three datasets recorded from real EEG and MEG acquisitions. Overall, results showed the capacity of the proposed algorithm to track brain network dynamics with good spatial and temporal accuracy.

Epilepsy is a dynamic and complex neurological disease affecting about 1% of the worldwide population, among which 30% of the patients are drug-resistant. Epilepsy is characterized by recurrent episodes of paroxysmal neural discharges (the so-called seizures), which manifest themselves through a large-amplitude rhythmic activity observed in depth-EEG recordings, in particular in local field potentials (LFPs). The signature characterizing the transition to seizures involves complex oscillatory patterns, which could serve as a marker to prevent seizure initiation by triggering appropriate therapeutic neurostimulation methods. To investigate such protocols, neurophysiological lumped-parameter models at the mesoscopic scale, namely neural mass models, are powerful tools that not only mimic the LFP signals but also give insights on the neural mechanisms related to different stages of seizures. Here, we analyze the multiple time-scale dynamics of a neural mass model and explain the underlying structure of the complex oscillations observed before seizure initiation. We investigate population-specific effects of the stimulation and the dependence of stimulation parameters on synaptic timescales. In particular, we show that intermediate stimulation frequencies (>20 Hz) can abort seizures if the timescale difference is pronounced. Those results have the potential in the design of therapeutic brain stimulation protocols based on the neurophysiological properties of tissue.

Abstract Neurostimulation is an emerging treatment for drug-resistant epilepsies when surgery is contraindicated. Recent clinical results demonstrate significant seizure frequency reduction in epileptic patients, however the mechanisms underlying this therapeutic effect are largely unknown. This study aimed at gaining insights into local direct current stimulation (LDCS) effects on hyperexcitable tissue, by i) analyzing the impact of electrical currents locally applied on epileptogenic brain regions, and ii) characterizing currents achieving an “anti-epileptic” effect (excitability reduction). First, a neural mass model of hippocampal circuits was extended to accurately reproduce the features of hippocampal paroxysmal discharges (HPD) observed in a mouse model of epilepsy. Second, model predictions regarding current intensity and stimulation polarity were confronted to in vivo mice recordings during LDCS (n = 8). The neural mass model was able to generate realistic hippocampal discharges. Simulation of LDCS in the model pointed at a significant decrease of simulated HPD (in duration and occurrence rate, not in amplitude) for cathodal stimulation, which was successfully verified experimentally in epileptic mice. Despite the simplicity of our stimulation protocol, these results contribute to a better understanding of clinical benefits observed in epileptic patients with implanted neurostimulators. Our results also provide further support for model-guided design of neuromodulation therapy.

Understanding the origin of the main physiological processes involved in consciousness is a major challenge of contemporary neuroscience, with crucial implications for the study of Disorders of Consciousness (DOC). The difficulties in achieving this task include the considerable quantity of experimental data in this field, along with the non-intuitive, nonlinear nature of neuronal dynamics. One possibility of integrating the main results from the experimental literature into a cohesive framework, while accounting for nonlinear brain dynamics, is the use of physiologically-inspired computational models. In this study, we present a physiologically-grounded computational model, attempting to account for the main micro-circuits identified in the human cortex, while including the specificities of each neuronal type. More specifically, the model accounts for thalamo-cortical (vertical) regulation of cortico-cortical (horizontal) connectivity, which is a central mechanism for brain information integration and processing. The distinct neuronal assemblies communicate through feedforward and feedback excitatory and inhibitory synaptic connections implemented in a template brain accounting for long-range connectome. The EEG generated by this physiologically-based simulated brain is validated through comparison with brain rhythms recorded in humans in two states of consciousness (wakefulness, sleep). Using the model, it is possible to reproduce the local disynaptic disinhibition of basket cells (fast GABAergic inhibition) and glutamatergic pyramidal neurons through long-range activation of vasoactive intestinal-peptide (VIP) interneurons that induced inhibition of somatostatin positive (SST) interneurons. The model (COALIA) predicts that the strength and dynamics of the thalamic output on the cortex control the local and long-range cortical processing of information. Furthermore, the model reproduces and explains clinical results regarding the complexity of transcranial magnetic stimulation TMS-evoked EEG responses in DOC patients and healthy volunteers, through a modulation of thalamo-cortical connectivity that governs the level of cortico-cortical communication. This new model provides a quantitative framework to accelerate the study of the physiological mechanisms involved in the emergence, maintenance and disruption (sleep, anesthesia, DOC) of consciousness.

In this work, we aim to investigate whether information based metrics of neural activity are a useful tool for the quantification of consciousness before and shortly after birth. Neural activity is measured using fetal magnetoencephalography (fMEG) in human fetuses and neonates. Based on recent theories on consciousness, information-based metrics are established to measure brain complexity and to assess different levels of consciousness. Different metrics (measures of entropy, compressibility and fractality) are, thus, explored in a reference population and their usability is evaluated. For comparative analysis, two fMEG channels were selected: one where brain activity was previously detected and one at least 15 cm away, that represented a control channel. The usability of each metric was evaluated and results from the brain and control channel were compared. Concerning the ease of use with fMEG data, Lempel-Ziv-Complexity (LZC) was evaluated as best, as it is unequivocal and needs low computational effort. The fractality measures have a high number of parameters that need to be adjusted prior to analysis and therefore forfeit comparability, while entropy measures require a higher computational effort and more parameters to adjust compared to LZC. Comparison of a channel with brain activity and a control channel in neonatal recordings showed significant differences in most complexity metrics. This clear difference can be seen as proof of concept for the usability of complexity metrics in fMEG. For fetal data, this comparison produced less clear results which can be related to leftover maternal signals included in the control channel. Further work is necessary to conclusively interpret results from the analysis of fetal recordings. Yet this study shows that complexity metrics can be used for fMEG data on early consciousness and the evaluation gives a guidance for future work. The inconsistency of results from different metrics highlights the challenges of working with complexity metrics as neural correlates of consciousness, as well as the caution one should apply to interpret them.

Increasing evidence links disorders of consciousness (DOC) with disruptions in functional connectivity between distant brain areas. However, to which extent the balance of brain network segregation and integration is modified in DOC patients remains unclear. Using high-density electroencephalography (EEG), the objective of our study was to characterize the local and global topological changes of DOC patients' functional brain networks.Resting state high-density-EEG data were collected and analyzed from 82 participants: 61 DOC patients recovering from coma with various levels of consciousness (EMCS (n = 6), MCS+ (n = 29), MCS- (n = 17) and UWS (n = 9)), and 21 healthy subjects (i.e., controls). Functional brain networks in five different EEG frequency bands and the broadband signal were estimated using an EEG connectivity approach at the source level. Graph theory-based analyses were used to evaluate their relationship with decreasing levels of consciousness as well as group differences between healthy volunteers and DOC patient groups.Results showed that networks in DOC patients are characterized by impaired global information processing (network integration) and increased local information processing (network segregation) as compared to controls. The large-scale functional brain networks had integration decreasing with lower level of consciousness. Keywords: Disorders of consciousness, High-density electroencephalography, Functional brain networks, Unresponsive wakefulness syndrome, Minimally conscious state

High-frequency oscillations (HFO) have been suggested as biomarkers of epileptic tissues. While visual marking of these short and small oscillations is tedious and time-consuming, automatic HFO detectors have not yet met a large consensus. Even though detectors have been shown to perform well when validated against visual marking, the large number of false detections due to their lack of robustness hinder their clinical application. In this study, we developed a validation framework based on realistic and controlled simulations to quantify precisely the assets and weaknesses of current detectors. We constructed a dictionary of synthesized elements-HFOs and epileptic spikes-from different patients and brain areas by extracting these elements from the original data using discrete wavelet transform coefficients. These elements were then added to their corresponding simulated background activity (preserving patient- and region- specific spectra). We tested five existing detectors against this benchmark. Compared to other studies confronting detectors, we did not only ranked them according their performance but we investigated the reasons leading to these results. Our simulations, thanks to their realism and their variability, enabled us to highlight unreported issues of current detectors: (1) the lack of robust estimation of the background activity, (2) the underestimated impact of the 1/f spectrum, and (3) the inadequate criteria defining an HFO. We believe that our benchmark framework could be a valuable tool to translate HFOs into a clinical environment.

Developing a clear understanding of the relationship between cerebral blood flow (CBF) response and neuronal activity is of significant importance because CBF increase is essential to the health of neurons, for instance through oxygen supply. This relationship can be investigated by analyzing multimodal (fMRI, PET, laser Doppler…) recordings. However, the important number of intermediate (non-observable) variables involved in the underlying neurovascular coupling makes the discovery of mechanisms all the more difficult from the sole multimodal data. We present a new computational model developed at the population scale (voxel) with physiologically relevant but simple equations to facilitate the interpretation of regional multimodal recordings. This model links neuronal activity to regional CBF dynamics through neuro-glio-vascular coupling. This coupling involves a population of glial cells called astrocytes via their role in neurotransmitter (glutamate and GABA) recycling and their impact on neighboring vessels. In epilepsy, neuronal networks generate epileptiform discharges, leading to variations in astrocytic and CBF dynamics. In this study, we took advantage of these large variations in neuronal activity magnitude to test the capacity of our model to reproduce experimental data. We compared simulations from our model with isolated epileptiform events, which were obtained in vivo by simultaneous local field potential and laser Doppler recordings in rats after local bicuculline injection. We showed a predominant neuronal contribution for low level discharges and a significant astrocytic contribution for higher level discharges. Besides, neuronal contribution to CBF was linear while astrocytic contribution was nonlinear. Results thus indicate that the relationship between neuronal activity and CBF magnitudes can be nonlinear for isolated events and that this nonlinearity is due to astrocytic activity, highlighting the importance of astrocytes in the interpretation of regional recordings.

The brain is a large-scale complex network often referred to as the "connectome". Exploring the dynamic behavior of the connectome is a challenging issue as both excellent time and space resolution is required. In this context Magneto/Electroencephalography (M/EEG) are effective neuroimaging techniques allowing for analysis of the dynamics of functional brain networks at scalp level and/or at reconstructed sources. However, a tool that can cover all the processing steps of identifying brain networks from M/EEG data is still missing. In this paper, we report a novel software package, called EEGNET, running under MATLAB (Math works, inc), and allowing for analysis and visualization of functional brain networks from M/EEG recordings. EEGNET is developed to analyze networks either at the level of scalp electrodes or at the level of reconstructed cortical sources. It includes i) Basic steps in preprocessing M/EEG signals, ii) the solution of the inverse problem to localize / reconstruct the cortical sources, iii) the computation of functional connectivity among signals collected at surface electrodes or/and time courses of reconstructed sources and iv) the computation of the network measures based on graph theory analysis. EEGNET is the unique tool that combines the M/EEG functional connectivity analysis and the computation of network measures derived from the graph theory. The first version of EEGNET is easy to use, flexible and user friendly. EEGNET is an open source tool and can be freely downloaded from this webpage: https://sites.google.com/site/eegnetworks/.

The recent past years have seen a noticeable increase of interest for electroencephalography (EEG) to analyze functional connectivity through brain sources reconstructed from scalp signals. Although considerable advances have been done both on the recording and analysis of EEG signals, a number of methodological questions are still open regarding the optimal way to process the data in order to identify brain networks. In this paper, we analyze the impact of three factors that intervene in this processing: i) the number of scalp electrodes, ii) the combination between the algorithm used to solve the EEG inverse problem and the algorithm used to measure the functional connectivity and iii) the frequency bands retained to estimate the functional connectivity among neocortical sources. Using High-Resolution (hr) EEG recordings in healthy volunteers, we evaluated these factors on evoked responses during picture recognition and naming task. The main reason for selection this task is that a solid literature background is available about involved brain networks (ground truth). From this a priori information, we propose a performance criterion based on the number of connections identified in the regions of interest (ROI) that belong to potentially activated networks. Our results show that the three studied factors have a dramatic impact on the final result (the identified network in the source space) as strong discrepancies were evidenced depending on the methods used. They also suggest that the combination of weighted Minimum Norm Estimator (wMNE) and the Phase Synchronization (PS) methods applied on High-Resolution EEG in beta/gamma bands provides the best performance in term of topological distance between the identified network and the expected network in the above-mentioned cognitive task.

Both biophysical and neurophysiological aspects need to be considered to assess the impact of electric fields induced by transcranial current stimulation (tCS) on the cerebral cortex and the subsequent effects occurring on scalp EEG. The objective of this work was to elaborate a global model allowing for the simulation of scalp EEG signals under tCS. In our integrated modeling approach, realistic meshes of the head tissues and of the stimulation electrodes were first built to map the generated electric field distribution on the cortical surface. Secondly, source activities at various cortical macro-regions were generated by means of a computational model of neuronal populations. The model parameters were adjusted so that populations generated an oscillating activity around 10 Hz resembling typical EEG alpha activity. In order to account for tCS effects and following current biophysical models, the calculated component of the electric field normal to the cortex was used to locally influence the activity of neuronal populations. Lastly, EEG under both spontaneous and tACS-stimulated (transcranial sinunoidal tCS from 4 to 16 Hz) brain activity was simulated at the level of scalp electrodes by solving the forward problem in the aforementioned realistic head model. Under the 10 Hz-tACS condition, a significant increase in alpha power occurred in simulated scalp EEG signals as compared to the no-stimulation condition. This increase involved most channels bilaterally, was more pronounced on posterior electrodes and was only significant for tACS frequencies from 8 to 12 Hz. The immediate effects of tACS in the model agreed with the post-tACS results previously reported in real subjects. Moreover, additional information was also brought by the model at other electrode positions or stimulation frequency. This suggests that our modeling approach can be used to compare, interpret and predict changes occurring on EEG with respect to parameters used in specific stimulation configurations.

Astrocytes are integral functional components of synapses, regulating transmission and plasticity. They have also been implicated in the pathogenesis of epilepsy, although their precise roles have not been comprehensively characterized. Astrocytes integrate activity from neighboring synapses by responding to neuronally released neurotransmitters such as glutamate and ATP. Strong activation of astrocytes mediated by these neurotransmitters can promote seizure-like activity by initiating a positive feedback loop that induces excessive neuronal discharge. Recent work has demonstrated that astrocytes express cannabinoid 1 (CB1) receptors, which are sensitive to endocannabinoids released by nearby pyramidal cells. In this study, we tested whether this mechanism also contributes to epileptiform activity. In a model of 4-aminopyridine induced epileptic-like activity in hippocampal slice cultures, we show that pharmacological blockade of astrocyte CB1 receptors did not modify the initiation, but significantly reduced the maintenance of epileptiform discharge. When communication in astrocytic networks was disrupted by chelating astrocytic calcium, this CB1 receptor-mediated modulation of epileptiform activity was no longer observed. Thus, endocannabinoid signaling from neurons to astrocytes represents an additional significant factor in the maintenance of epileptiform activity in the hippocampus.

In this study, we aimed to demonstrate whether spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal derived from resting state functional magnetic resonance imaging (fMRI) reflect spontaneous neuronal activity in pathological brain regions as well as in regions spared by epileptiform discharges. This is a crucial issue as coherent fluctuations of fMRI signals between remote brain areas are now widely used to define functional connectivity in physiology and in pathophysiology. We quantified functional connectivity using non-linear measures of cross-correlation between signals obtained from intracerebral EEG (iEEG) and resting-state functional MRI (fMRI) in 5 patients suffering from intractable temporal lobe epilepsy (TLE). Functional connectivity was quantified with both modalities in areas exhibiting different electrophysiological states (epileptic and non affected regions) during the interictal period. Functional connectivity as measured from the iEEG signal was higher in regions affected by electrical epileptiform abnormalities relative to non-affected areas, whereas an opposite pattern was found for functional connectivity measured from the BOLD signal. Significant negative correlations were found between the functional connectivities of iEEG and BOLD signal when considering all pairs of signals (theta, alpha, beta and broadband) and when considering pairs of signals in regions spared by epileptiform discharges (in broadband signal). This suggests differential effects of epileptic phenomena on electrophysiological and hemodynamic signals and/or an alteration of the neurovascular coupling secondary to pathological plasticity in TLE even in regions spared by epileptiform discharges. In addition, indices of directionality calculated from both modalities were consistent showing that the epileptogenic regions exert a significant influence onto the non epileptic areas during the interictal period. This study shows that functional connectivity measured by iEEG and BOLD signals give complementary but sometimes inconsistent information in TLE.

Epilepsy is a complex neurological disorder characterized by recurring seizures. In 30% of patients, seizures are insufficiently reduced by anti-epileptic drugs. In the case where seizures originate from a relatively circumscribed region of the brain, epilepsy is said to be partial and surgery can be indicated. The success of epilepsy surgery depends on the accurate localisation and delineation of the epileptogenic zone (which often involves several structures), responsible for seizures. It requires a comprehensive pre-surgical evaluation of patients that includes not only imaging data but also long-term monitoring of electrophysiological signals (scalp and intracerebral EEG). During the past decades, considerable effort has been devoted to the development of signal analysis techniques aimed at characterizing the functional connectivity among spatially-distributed regions over interictal (outside seizures) or ictal (during seizures) periods from EEG data. Most of these methods rely on the measurement of statistical couplings among signals recorded from distinct brain sites. However, methods differ with respect to underlying theoretical principles (mostly coming from the field of statistics or the field of nonlinear physics). The objectives of this paper are: i) to provide an brief overview of methods aimed at characterizing functional brain connectivity from electrophysiological data, ii) to provide concrete application examples in the context of drug-refractory partial epilepsies, and iii) to highlight some key points emerging from results obtained both on real intracerebral EEG signals and on signals simulated from physiologically-plausible models in which the underlying connectivity patterns are known a priori (ground truth).