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Objective. Electro/Magnetoencephalography (EEG/MEG) source-space network analysis is increasingly recognized as a powerful tool for tracking fast electrophysiological brain dynamics. However, an objective and quantitative evaluation of pipeline steps is challenging due to the lack of realistic ‘controlled’ data. Here, our aim is two-folded: (a) provide a quantitative assessment of the advantages and limitations of the analyzed techniques and (b) introduce (and share) a complete framework that can be used to optimize the entire pipeline of EEG/MEG source connectivity. Approach. We used a human brain computational model containing both physiologically based cellular GABAergic and Glutamatergic circuits coupled through Diffusion Tensor Imaging, to generate high-density EEG recordings. We designed a scenario of successive gamma-band oscillations in distinct cortical areas to emulate a virtual picture-naming task. We identified fast time-varying network states and quantified the performance of the key steps involved in the pipeline: (a) inverse models to reconstruct cortical-level sources, (b) functional connectivity measures to compute statistical interdependency between regional signals, and (c) dimensionality reduction methods to derive dominant brain network states (BNS). Main results. Using a systematic evaluation of the different decomposition techniques, results show significant variability among tested algorithms in terms of spatial and temporal accuracy. We outlined the spatial precision, the temporal sensitivity, and the global accuracy of the extracted BNS relative to each method. Our findings suggest a good performance of weighted minimum norm estimate/ Phase Locking Value combination to elucidate the appropriate functional networks and ICA techniques to derive relevant dynamic BNS. Significance. We suggest using such brain models to go further in the evaluation of the different steps and parameters involved in the EEG/MEG source-space network analysis. This can reduce the empirical selection of inverse model, connectivity measure, and dimensionality reduction method as some of the methods can have a considerable impact on the results and interpretation.

International audience; OBJECTIVE: This study was undertaken to investigate how gain of function (GOF) of slack channel due to a KCNT1 pathogenic variant induces abnormal neuronal cortical network activity and generates specific electroencephalographic (EEG) patterns of epilepsy in infancy with migrating focal seizures. METHODS: We used detailed microscopic computational models of neurons to explore the impact of GOF of slack channel (explicitly coded) on each subtype of neurons and on a cortical micronetwork. Then, we adapted a thalamocortical macroscopic model considering results obtained in detailed models and immature properties related to epileptic brain in infancy. Finally, we compared simulated EEGs resulting from the macroscopic model with interictal and ictal patterns of affected individuals using our previously reported EEG markers. RESULTS: The pathogenic variants of KCNT1 strongly decreased the firing rate properties of γ-aminobutyric acidergic (GABAergic) interneurons and, to a lesser extent, those of pyramidal cells. This change led to hyperexcitability with increased synchronization in a cortical micronetwork. At the macroscopic scale, introducing slack GOF effect resulted in epilepsy of infancy with migrating focal seizures (EIMFS) EEG interictal patterns. Increased excitation-to-inhibition ratio triggered seizure, but we had to add dynamic depolarizing GABA between somatostatin-positive interneurons and pyramidal cells to obtain migrating seizure. The simulated migrating seizures were close to EIMFS seizures, with similar values regarding the delay between the different ictal activities (one of the specific EEG markers of migrating focal seizures due to KCNT1 pathogenic variants). SIGNIFICANCE: This study illustrates the interest of biomathematical models to explore pathophysiological mechanisms bridging the gap between the functional effect of gene pathogenic variants and specific EEG phenotype. Such models can be complementary to in vitro cellular and animal models. This multiscale approach provides an in silico framework that can be further used to identify candidate innovative therapies.

Work in the last two decades has shown that neural mass models (NMM) can realistically reproduce and explain epileptic seizure transitions as recorded by electrophysiological methods (EEG, SEEG). In previous work, advances were achieved by increasing excitation and heuristically varying network inhibitory coupling parameters in the models. Based on these early studies, we provide a laminar NMM capable of realistically reproducing the electrical activity recorded by SEEG in the epileptogenic zone during interictal to ictal states. With the exception of the external noise input into the pyramidal cell population, the model dynamics are autonomous. By setting the system at a point close to bifurcation, seizure-like transitions are generated, including pre-ictal spikes, low voltage fast activity, and ictal rhythmic activity. A novel element in the model is a physiologically motivated algorithm for chloride dynamics: the gain of GABAergic post-synaptic potentials is modulated by the pathological accumulation of chloride in pyramidal cells due to high inhibitory input and/or dysfunctional chloride transport. In addition, in order to simulate SEEG signals for comparison with real seizure recordings, the NMM is embedded first in a layered model of the neocortex and then in a realistic physical model. We compare modeling results with data from four epilepsy patient cases. By including key pathophysiological mechanisms, the proposed framework captures succinctly the electrophysiological phenomenology observed in ictal states, paving the way for robust personalization methods based on NMMs.

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, 21 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 group-specific brain network states that were dominant during the task. 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, HC displayed a significant functional network state that involved typical CAC-related prefrontal and cingulate nodes (e.g., inferior frontal cortex). Both group- and subject-level analyses showed that this network was less present in PD to the benefit of other networks involving lateralized temporal and insular components. The presence of this prefrontal network was associated with decreased reaction time. In the gamma band, two networks (fronto-cingulate and fronto-temporal) followed one another in HC, while 3 partially overlapping networks that included fronto-temporal, fronto-occipital and cross-hemispheric temporal connections were found in PD. At the subject-level, differences between PD and HC were less marked. Altogether, this study showed that the functional brain networks observed during CAC and their temporal changes were different in PD patients as compared to HC, and that these differences partially relate to behavioral changes. This study also highlights that task-based dynamic functional connectivity is a promising approach in understanding the cognitive dysfunctions observed in PD and beyond.HighlightsCognitive action control is associated with dynamic functional networksPrefrontal and cingulate beta connectivity are prominent in healthy controlsPD patients have different dynamic networks in which prefrontal nodes are absentThe occurrence of prefrontal beta networks was associated with a decreased reaction timeFunctional networks in the gamma band were temporally organized in HC, but overlapping in PD patients

ObjectiveElectro/Magnetoencephalography (EEG/MEG) source-space network analysis is increasingly recognized as a powerful tool for tracking fast electrophysiological brain dynamics. However, an objective and quantitative evaluation of pipeline steps is challenging due to the lack of realistic ‘controlled’ data. Here, our aim is two-folded: 1) provide a quantitative assessment of the advantages and limitations of the analyzed techniques and 2) introduce (and share) a complete framework that can be used to optimize the entire pipeline of EEG/MEG source connectivity.ApproachWe used a human brain computational model containing both physiologically based cellular GABAergic and Glutamatergic circuits coupled through Diffusion Tensor Imaging, to generate high-density EEG recordings. We designed a scenario of successive gamma-band oscillations in distinct cortical areas to emulate a virtual picture-naming task. We identified fast time-varying network states and quantified the performance of the key steps involved in the pipeline: 1) inverse models to reconstruct cortical-level sources, 2) functional connectivity measures to compute statistical interdependency between regional signals, and 3) dimensionality reduction methods to derive dominant brain network states (BNS).Main ResultsUsing a systematic evaluation of the different decomposition techniques, results show significant variability among tested algorithms in terms of spatial and temporal accuracy. We outlined the spatial precision, the temporal sensitivity, and the global accuracy of the extracted BNS relative to each method. Our findings suggest a good performance of wMNE/PLV combination to elucidate the appropriate functional networks and ICA techniques to derive relevant dynamic brain network states.SignificanceWe suggest using such brain models to go further in the evaluation of the different steps and parameters involved in the EEG/MEG source-space network analysis. This can reduce the empirical selection of inverse model, connectivity measure, and dimensionality reduction method as some of the methods can have a considerable impact on the results and interpretation.

Objective. In partial epilepsies, interictal epileptiform discharges (IEDs) are paroxysmal events observed in epileptogenic zone (EZ) and non-epileptogenic zone (NEZ). IEDs’ generation and recurrence are subject to different hypotheses: they appear through glutamatergic and gamma-aminobutyric acidergic (GABAergic) processes; they may trigger seizures or prevent seizure propagation. This paper focuses on a specific class of IEDs, spike-waves (SWs), characterized by a short-duration spike followed by a longer duration wave, both of the same polarity. Signal analysis and neurophysiological mathematical models are used to interpret puzzling IED generation. Approach. Interictal activity was recorded by intracranial stereo-electroencephalography (SEEG) electrodes in five different patients. SEEG experts identified the epileptic and non-epileptic zones in which IEDs were detected. After quantifying spatial and temporal features of the detected IEDs, the most significant features for classifying epileptic and non-epileptic zones were determined. A neurophysiologically-plausible mathematical model was then introduced to simulate the IEDs and understand the underlying differences observed in epileptic and non-epileptic zone IEDs. Main results. Two classes of SWs were identified according to subtle differences in morphology and timing of the spike and wave component. Results showed that type-1 SWs were generated in epileptogenic regions also involved at seizure onset, while type-2 SWs were produced in the propagation or non-involved areas. The modeling study indicated that synaptic kinetics, cortical organization, and network interactions determined the morphology of the simulated SEEG signals. Modeling results suggested that the IED morphologies were linked to the degree of preserved inhibition. Significance. This work contributes to the understanding of different mechanisms generating IEDs in epileptic networks. The combination of signal analysis and computational models provides an efficient framework for exploring IEDs in partial epilepsies and classifying EZ and NEZ.

International audience; Objective - We aimed to characterize epilepsy of infancy with migrating focal seizures (EIMFS), a rare, severe early onset developmental epilepsy related to KCNT1 mutation, and to define specific electroencephalography (EEG) markers using EEG quantitative analysis. The ultimate goal would be to improve early diagnosis and to better understand seizure onset and propagation of EIMFS as compared to other early onset developmental epilepsy. Methods - EEG of 7 EIMFS patients with KCNT1 mutations (115 seizures) and 17 patients with other early onset epilepsies (30 seizures) was included in this study. After detection of seizure onset and termination, spatiotemporal characteristics were quantified. Seizure propagation dynamics were analyzed using chronograms and phase coherence. Results - In patients with EIMFS, seizures started and were localized predominantly in temporal and occipital areas, and evolved with a stable frequency (4-10 Hz). Inter- and intrahemispheric migrations were present in 60% of EIMFS seizures with high intraindividual reproducibility of temporospatial dynamics. Interhemispheric migrating seizures spread in 71% from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures involved mainly frontotemporal, temporal, and occipital channels. Causality links were present between ictal activities detected under different channels during migrating seizures. Finally, time delay index (based on delays between the different ictal onsets) and phase correlation index (based on coherence of ictal activities) allowed discrimination of EIMFS and non-EIMFS seizures with a specificity of 91.2% and a sensitivity of 84.4%. Significance - We showed that the migrating pattern in EIMFS is not a random process, as suggested previously, and that it is a particular propagation pattern that follows the classical propagation pathways. It is notable that this study reveals specific EEG markers (time delay and phase correlation) accessible to visual evaluation, which will improve EIMFS diagnosis.

Objective. Fast ripples (FRs) have received considerable attention in the last decade since they represent an electrophysiological biomarker of the epileptogenic zone (EZ). However, the real dynamics underlying the occurrence, amplitude, and time-frequency content of FRs generation during epileptogenesis are still not well understood. This work aims at characterizing and explaining the evolution of these features. Approach. Intracortical electroencephalographic signals recorded in a kainate mouse model of temporal lobe epilepsy were processed in order to compute specific FR features. Then realistic physiologically based computational modeling was employed to explore the different elements that can explain the mechanisms of epileptogenesis and simulate the recorded FR in the early and late latent period. Main results. Results indicated that continuous changes of FR features are mainly portrayed by the epileptic (pathological) tissue size and synaptic properties. Furthermore, the microelectrodes characteristics were found to dramatically affect the observability and spectral/temporal content of FRs. Consequently, FRs evolution seems to mirror the continuous pathophysiological mechanism changes that occur during epileptogenesis as long as the microelectrode properties are taken into account. Significance. Our study suggests that FRs can account for the pathophysiological changes which might explain the EZ generation and evolution and can contribute in the treatment plan of pharmaco-resistant epilepsies.

Motor, sensory and cognitive functions rely on dynamic reshaping of functional brain networks. Tracking these rapid changes is crucial to understand information processing in the brain, but challenging due to the random selection of methods and the limited evaluation studies. Using Magnetoencephalography (MEG) combined with Source Separation (SS) methods, we present an integrated framework to track fast dynamics of electrophysiological brain networks. We evaluate nine SS methods applied to three independent MEG databases (N=95) during motor and memory tasks. We report differences between these methods at the group and subject level. We show that the independent component analysis (ICA)-based methods and especially those exploring high order statistics are the most efficient, in terms of spatiotemporal accuracy and subject-level analysis. We seek to help researchers in choosing objectively the appropriate methodology when tracking fast reconfiguration of functional brain networks, due to its enormous benefits in cognitive and clinical neuroscience.

International audience; Transcranial Direct brain stimulation (tDCS) is commonly used in order to modulate cortical networks activity during physiological processes through the application of weak electrical fields with scalp electrodes. Cathodal stimulation has been shown to decrease brain excitability in the context of epilepsy, with variable success. However, the cellular mechanisms responsible for the acute and the long-lasting effect of tDCS remain elusive. Using a novel approach of computational modeling that combines detailed but functionally integrated neurons we built a physiologically-based thalamocortical column. This model comprises 10,000 individual neurons made of pyramidal cells, and 3 types of gamma-aminobutyric acid (GABA) -ergic cells (VIP, PV, and SST) respecting the anatomy, layers, projection, connectivity and neurites orientation. Simulating realistic electric fields in term of intensity, main results showed that 1) tDCS effects are best explained by modulation of the presynaptic probability of release 2) tDCS affects the dynamic of cortical network only if a sufficient number of neurons are modulated 3)VIP GABAergic interneurons of the superficial layer of the cortex are especially affected by tDCS 4) Long lasting effect depends on glutamatergic synaptic plasticity.

Objective In this study we aim to identify the key (patho)physiological mechanisms and biophysical factors which impact the observability and spectral features of High Frequency Oscillations (HFOs). Methods In order to accurately replicate HFOs we developed virtual-brain/virtual-electrode simulation environment combining novel neurophysiological models of neuronal populations with biophysical models for the source/sensor relationship. Both (patho)physiological mechanisms (synaptic transmission, depolarizing GABAA effect, hyperexcitability) and physical factors (geometry of extended cortical sources, size and position of electrodes) were taken into account. Simulated HFOs were compared to real HFOs extracted from intracerebral recordings of 2 patients. Results Our results revealed that HFO pathological activity is being generated by feed-forward activation of cortical interneurons that produce fast depolarizing GABAergic post-synaptic potentials (PSPs) onto pyramidal cells. Out of phase patterns of depolarizing GABAergic PSPs explained the shape, entropy and spatiotemporal features of real human HFOs. Conclusions The terminology “high-frequency oscillation” (HFO) might be misleading as the fast ripple component (200–600 Hz) is more likely a “high-frequency activity” (HFA), the origin of which is independent from any oscillatory process. Significance New insights regarding the origins and observability of HFOs along depth-EEG electrodes were gained in terms of spatial extent and 3D geometry of neuronal sources.

International audience; Estimating functional connectivity (FC) has become an increasingly powerful tool for understanding our brain and investigating healthy and abnormal brain functions. Most previous studies assume temporal stationarity, such as correlation and data-driven decompositions computed across the whole duration of the acquisition. However, emerging evidence revealed the presence of temporal variability of FC, leading to increasing interest in estimating the dynamic Functional Connectivity (dFC). In this context, several approaches have been proposed in order to extract the relevant brain networks fluctuating over time. Still, a clear comparative study among the existing methods is needed. Thus, we aimed here to compare three dimensionality reduction techniques, specifically Independent Component Analysis (ICA), Principle Component Analysis (PCA) and generalized Canonical Correlation Analysis (gCCA), on two Magnetoencephalography (MEG) datasets recorded during motor and memory tasks. First, source connectivity combined with a sliding window approach was used in order to reconstruct the dynamic brain networks at the cortical level. Then, for each algorithm, we extracted the significant patterns of brain network connections with their associated time variation. Results show characteristic properties of each method in terms of computation time, reproducibility and potentiality in extracting the top dominant networks. © 2019 IEEE.

International audience; Epilepsy of infancy with migrating focal seizures was first described in 1995. Fifteen years later, KCNT1 gene mutations were identified as the major disease-causing gene of this disease. Currently, the data on epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations are heterogeneous and many questions remain unanswered including the prognosis and the long-term outcome especially regarding epilepsy, neurological and developmental status and the presence of microcephaly. The aim of this study was to assess data from patients with epilepsy in infancy with migrating focal seizures with KCNT1 mutations to refine the phenotype spectrum and the outcome. We used mind maps based on medical reports of children followed in the network of the French reference centre for rare epilepsies and we developed family surveys to assess the long-term outcome. Seventeen patients were included [age median (25th-75th percentile) 4 (2-15) years, sex ratio 1.4, length of follow-up 4 (2-15) years]. Seventy-one per cent started at 6 (1-52) days with sporadic motor seizures (n = 12), increasing up to a stormy phase with long lasting migrating seizures at 57 (30-89) days. The others entered this stormy phase directly at 1 (1-23) day. Ten patients entered a consecutive phase at 1.3 (1-2.8) years where seizures persisted at least daily (n = 8), but presented different semiology brief and hypertonic with a nocturnal (n = 6) and clustered (n = 6) aspects. Suppression interictal patterns were identified on the EEG in 71% of patients (n = 12) sometimes from the first EEG (n = 6). Three patients received quinidine without reported efficacy. Long-term outcome was poor with neurological sequelae and active epilepsy except for one patient who had an early and long-lasting seizure-free period. Extracerebral symptoms probably linked with KCNT1 mutation were present, including arteriovenous fistula, dilated cardiomyopathy and precocious puberty. Eight patients (47%) had died at 3 (1.5-15.4) years including three from suspected sudden unexpected death in epilepsy. Refining the electro-clinical characteristics and the temporal sequence of epilepsy in infancy with migrating focal seizures should help diagnosis of this epilepsy. A better knowledge of the outcome allows one to advise families and to define the appropriate follow-up and therapies. Extracerebral involvement should be investigated, in particular the cardiac system, as it may be involved in the high prevalence of sudden unexpected death in epilepsy in these cases.

International audience; Objective - Among electrophysiological signals, local field potentials (LFPs) are extensively used to study brain activity, either in vivo or in vitro. LFPs are recorded with extracellular electrodes implanted in brain tissue. They reflect intermingled excitatory and inhibitory processes in neuronal assemblies. In cortical structures, LFPs mainly originate from the summation of post-synaptic potentials (PSPs), either excitatory (ePSPs) or inhibitory (iPSPs) generated at the level of pyramidal cells. The challenging issue, addressed in this paper, is to estimate, from a single extracellularly-recorded signal, both ePSP and iPSP components of the LFP. Approach - The proposed method is based on a model-based reverse engineering approach in which the measured LFP is fed into a physiologically-grounded neural mass model (mesoscopic level) to estimate the synaptic activity of a sub-population of pyramidal cells interacting with local GABAergic interneurons. Main results - The method was first validated using simulated LFPs for which excitatory and inhibitory components are known a priori and can thus serve as a ground truth. It was then evaluated on in vivo data (PTZ-induced seizures, rat; PTZ-induced excitability increase, mouse; epileptiform discharges, mouse) and on in clinico data (human seizures recorded with depth-EEG electrodes). Significance - Under these various conditions, results showed that the proposed reverse engineering method provides a reliable estimation of the average excitatory and inhibitory post-synaptic potentials originating of the measured LFPs. They also indicated that the method allows for monitoring of the excitation/inhibition ratio. The method has potential for multiple applications in neuroscience, typically when a dynamical tracking of local excitability changes is required.

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

International audience; 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.

International audience; OBJECTIVE:We aimed at providing an accurate estimation of human brain tissue electrical conductivity in clinico, using local, low-intensity pulsed stimulation.METHODS:Using the quasi-static approximation of Maxwell equations, we derived an analytical model of the electric field generated by intracerebral stereoelectroencephalography (SEEG) electrodes. We coupled this electric field model with a model of the electrode-electrolyte interface to provide an explicit, analytical expression of brain tissue conductivity based on the recorded brain tissue response to pulse stimulation.RESULTS:We validated our biophysical model using i) saline solutions calibrated in electrical conductivity, ii) rat brain tissue, and iii) electrophysiological data recorded in clinico from two epileptic patients during sEEG.CONCLUSION:This new model-based method offers a fast and reliable estimation of brain tissue electrical conductivity, by accounting for contributions from the electrode-electrolyte interface.SIGNIFICANCE:This method outperforms standard bioimpedance measurements since it provides absolute (as opposed to relative) changes in brain tissue conductivity. Application for diagnosis is envisioned since conductivity values strongly differ when estimated in the healthy vs. hyperexcitable brain tissue.

Signal processing methods may constitute a substantial complement to visual analysis of SEEG signals in providing quantified information on signals (e.g. morphological characteristics) and in computing meaningful quantities that are not accessible to visual inspection (e.g. spectral properties or synchrony). In addition, and complementary to signal processing, computational neuroscience aims at developing models of epileptogenic networks and ultimately explaining some mechanisms involved in the generation of epileptiform activity. This chapter reviews a number of signal processing methods (time–frequency analysis, epileptogenicity index, and nonlinear correlation analysis) and computational models (at micro- and mesoscopic levels). The methods and models described illustrate the insight that can be gained about the information conveyed by SEEG signals recorded from epileptogenic networks observed during interictal (spikes and high-frequency oscillations) and ictal (fast-onset discharges) periods. Provided examples show that appropriate processing/modelling methods applied to electrophysiological signals can considerably improve the interpretation of SEEG recordings.

While electrical stimulation of brain tissue has been thoroughly investigated over the last decades, ongoing questions remain regarding the neurophysiological effects of low-level electric fields (on the order of 1 V/m) on brain activity. Electric fields at such levels are, for example, induced by transcranial direct/alternating current stimulation (tDCS/tACS). Action potentials can be indeed elicited when applied (supra-threshold) electric fields are in the 10–100 V/m range, while lower (subthreshold) electric fields result in more limited and subtler membrane polarization effects. In this review, we address the question of the mechanisms underlying the immediate effects (also referred to as acute, concurrent or short-term) and the lasting effects (also referred to as long-term or aftereffects) of low-level electric fields on brain tissue. We review recent evidence at the in vitro and in vivo (animal and human) level, and also present mechanistic insights gained from in silico models, which are still few but have received increased attention over the recent past years. We highlight the convergent evidence towards potential mechanisms, and also discuss discrepancies between in vitro studies and human tDCS/tACS studies that require further investigation to bridge the gap between the single-cell and large-scale network level. Possible novel avenues of research are discussed.

International audience

International audience; Objective. Emerging evidence shows that the modular organization of the human brain allows for better and efficient cognitive performance. Many of these cognitive functions are very fast and occur in a sub-second time scale such as the visual object recognition. Approach. Here, we investigate brain network modularity while controlling stimuli meaningfulness and measuring a participant's reaction time. We particularly raised two questions: i) does the dynamic brain network modularity change during the recognition of meaningful and meaningless visual images? And (ii) is there a correlation between network modularity and the reaction time of the participants?To tackle these issues, we collected dense-electroencephalography (EEG, 256 channels) data from 20 healthy human subjects performing a cognitive task consisting of naming meaningful (tools, animals...) and meaningless (scrambled) images. Functional brain networks in both categories were estimated at the sub-second time scale using the EEG source connectivity method. By using multislice modularity algorithms, we tracked the reconfiguration of functional networks during the recognition of both meaningful and meaningless images. Main results. Results showed a difference in the module's characteristics of both conditions in term of integration (interactions between modules) and occurrence (probability on average of any two brain regions to fall in the same module during the task). Integration and occurrence were greater for meaningless than for meaningful images. Our findings revealed also that the occurrence within the right frontal regions and the left occipito-temporal can help to predict the ability of the brain to rapidly recognize and name visual stimuli. Significance. We speculate that these observations are applicable not only to other fast cognitive functions but also to detect fast disconnections that can occur in some brain disorders.

Among electrophysiological signals, Local Field Potentials (LFPs) are extensively used to study brain activity, either in vivo or in vitro. LFPs are recorded with extracellular electrodes implanted in brain tissue. They reflect intermingled excitatory and inhibitory processes in neuronal assemblies. In cortical structures, LFPs mainly originate from the summation of post-synaptic potentials (PSPs), either excitatory (ePSPs) and inhibitory (iPSPs) generated at the level of pyramidal cells. The challenging issue, addressed in this paper, is to estimate, from a single extracellularly-recorded signal, both ePSP and iPSP components of the LFP. The proposed method is based on a model-based reverse engineering approach in which the measured LFP is fed into a physiologically-grounded neural mass model (mesoscopic level) in order to estimate the synaptic activity of a sub-population of pyramidal cells interacting with local GABAergic interneurons. The method was first validated using simulated LFPs for which excitatory and inhibitory components are known a priori and can thus serve as a ground truth. It was then evaluated on in vivo data (PTZ-induced seizures, rat; PTZ-induced excitability increase, mouse; epileptiform discharges, mouse) and on in clinico data (human seizures recorded with depth-EEG electrodes). Under these various conditions, results showed that the proposed reverse engineering method provides a reliable estimation of the average excitatory and inhibitory post-synaptic potentials at the origin of the measured LFPs. They also indicated that the method allows for monitoring of the excitation/inhibition ratio. The method has potential for multiple applications in neuroscience, typically when a time tracking of local excitability changes is required.

Pathological high-frequency oscillations (HFOs, 200–600 Hz) observed in depth-EEG and on scalp EEG recordings are recognized to be potentially valuable biomarkers of the epileptogenic zone responsible for generating seizures. Many research studies have been dedicated to detect, classify, simulate and understand the underlying mechanisms responsible for their generation. However, broadly classifying the HFOs into classes of wide frequency bands may negatively impact the quality of information carried by these electrophysiological biomarkers. In this paper, we perform a comparative study of various signal processing methods for estimating the dominant frequency of HFOs. The novelty is to make use of a physiologically-plausible computational model in which the HFO frequency can be tuned a priori. Results indicate that non-parametric methods best estimate the frequency of the low-amplitude fast oscillations characteristic of HFOs.

Network modularity is a key feature for efficient information processing in the human brain. This information processing is however dynamic and networks can reconfigure at very short time period, few hundreds of millisecond. This requires neuroimaging techniques with sufficient time resolution. Here we use the dense electroencephalography, EEG, source connectivity methods to identify cortical networks with excellent time resolution, in the order of millisecond. We identify functional networks during picture naming task. Two categories of visual stimuli were presented, meaningful (tools, animals) and meaningless (scrambled) objects. In this paper, we report the reconfiguration of brain network modularity for meaningful and meaningless objects. Results showed mainly that networks of meaningful objects were more modular than those of meaningless objects. Networks of the ventral visual pathway were activated in both cases. However a strong occipitotemporal functional connectivity appeared for meaningful object but not for meaningless object. We believe that this approach will give new insights into the dynamic behavior of the brain networks during fast information processing., Comment: The 3rd Middle East Conference on Biomedical Engineering (MECBME'16)

International audience; High Frequency Oscillations (HFOs) are a potential biomarker of epileptogenic regions. They have been extensively investigated in terms of automatic detection, classification and feature extraction. However, the mechanisms governing the generation of HFOs as well as the observability conditions on clinical intracranial macroelectrodes remain elusive. In this paper, we propose a novel physiologically-relevant macroscopic model for accurate simulation of HFOs as invasively recorded in epileptic patients. This model accounts for both the temporal and spatial properties of the cortical patch at the origin of epileptiform activity. Indeed, neuronal populations are combined with a 3D geometrical representation to simulate an extended epileptic source. Then, by solving the forward problem, the contributions of neuronal population signals are projected onto intracerebral electrode contacts. The obtained signals are qualitatively and quantitatively compared to real HFOs, and a relationship is drawn between macroscopic model parameters such as synchronization and spatial extent on the one hand, and HFO features such as the wave and fast ripple (200-600 Hz) components, on the other hand. © 2016 IEEE.

Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1➔I1). The firing rate of interneurons was adapted to mimic the genetic alteration of voltage gated sodium channels found in DS patients, SCN1A(+/-). We implemented the "dynamic depolarizing GABAA" mediated post-synaptic potential in the model, as some studies reported that the chloride reversal potential can switch from negative to more positive value depending on interneuron activity. The "shunting inhibition" promoted by GABAA receptor activation was also implemented. We found that increasing the proportion of depolarizing GABAA mediated IPSP (I1➔I1 and I1➔P) only (i.e., other parameters left unchanged) was sufficient to sequentially switch the EEG activity from background to (1) interictal isolated polymorphic epileptic spikes, (2) fast onset activity, (3) seizure like activity and (4) seizure termination. The interictal and ictal EEG patterns observed in 4 DS patients were reproduced by the model via tuning the amount of depolarizing GABAA postsynaptic potential. Finally, we implemented the modes of action of benzodiazepines and stiripentol, two drugs recommended in DS. Both drugs blocked seizure-like activity, partially and dose-dependently when applied separately, completely and with a synergic effect when combined, as has been observed in DS patients. This computational modeling study constitutes an innovative approach to better define the role of depolarizing GABA in infantile onset epilepsy and opens the way for new therapeutic hypotheses, especially in Dravet syndrome.

International audience; 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 epilepti-form 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.

Objective: In partial epilepsies, interictal epileptic spikes (IESs) and fast ripples (FRs) represent clinically relevant biomarkers characteristic of epileptogenic networks. However, their specific significance and the pathophysiological changes leading to either FRs or IESs remain elusive. The objective of this study was to analyze the conditions in which hyperexcitable networks can generate either IESs or FRs and to reveal shared or distinct mechanisms that underlie both types of events. Methods: This study is the first to comparatively analyze mechanisms that induce either IESs or FRs using an approach that combines computational modeling and experimental data (in vivo and in vitro). A detailed CA1 hippocampal network model is introduced. A parameter sensitivity analysis was conducted to determine which model parameters (cell related and network related) allow the most accurate simulation of FRs and IESs. Results: Our model indicates that although FRs and IESs share certain common mechanisms (shifted gamma-aminobutyric acid [GABA]A reversal potential, altered synaptic transmission), there are also critical differences in terms of number of pyramidal cells involved (small vs large), spatial distribution of hyperexcitable pyramidal cells (clustered vs uniform), and firing patterns (weakly vs highly synchronized). In vitro experiments verified that subtle changes in GABAergic and glutamatergic transmission favor either FRs or IESs, as predicted by the model. Interpretation: This study provides insights into the interpretation of 2 interictal markers observed in intracerebral electroencephalographic data. Depending on the degree and spatiotemporal features of hyperexcitability, not only IESs or FRs are generated but also transitions between both types of events. ANN NEUROL 2012

International audience; In this paper, a neural mass model is proposed to analyze some mechanisms underlying the generation of fast oscillations (80 Hz and beyond) at the onset of seizures. This model includes one sub-population of pyramidal cells and one sub-population of interneurons targeting the perisomatic region of pyramidal cells where fast GABAergic currents are mediated. We identified some conditions for which the model can reproduce the features of high-frequency, chirp-like (from approximately 100 to approximately 70 Hz) signatures observed in real depth-EEG signals recorded in epileptic patients at seizure onset ("fast onset activity"). These conditions included appropriate alterations in (i) the strengths of GABAergic and glutamatergic connections, and (ii) the amplitude of average EPSPs/IPSPs. Results revealed that a subtle balance between excitatory and inhibitory feedbacks is required in the model for reproducing a 'realistic' fast activity, i.e., showing a reduction of frequency with a simultaneous increase in amplitude, as actually observed in epileptogenic cerebral cortex. Results also demonstrated that the number of scenarios (variation, in time, of model parameters) leading to chirp-like signatures was rather limited. First, to produce high-frequency output signals, the model should operate in a "resonance" region, at the frontier between a stable and an unstable region. Second both EPSP and IPSP amplitudes should decrease with time in order to obey the frequency/amplitude constraint. These scenarios obtained through a mathematical analysis of the model show how some alteration in the structure of neural networks can lead to dysfunction. They also provide insights into potentially important mechanisms for high-frequency epileptic activity generation.

Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiological, cellular and molecular mechanisms inducing post-ischemic plasticity of NMDA receptors, focusing on the sensitive CA1 pyramidal neurons in the hippocampus as compared to the relatively resistant neighboring CA3 neurons. Both a change in the equilibrium between protein tyrosine kinases/phosphatases and an increased density of surface NMDA receptors in response to ischemia may explain the selective vulnerability of specific cell types. Implications for the treatment of stroke and reasons for the failures of human clinical trials utilizing NMDA receptor antagonists are also discussed.

International audience; Background: Neurological disorders are often characterized by an excessive and prolonged imbalance between neural excitatory and inhibitory processes. An ubiquitous finding among these disorders is the disrupted function of inhibitory GABAergic interneurons. Objective: The objective is to propose a novel stimulation procedure able to evaluate the efficacy of inhibition imposed by GABAergic interneurons onto pyramidal cells from evoked responses observed in local field potentials (LFPs). Methods: Using a computational modeling approach combined with in vivo and in vitro electrophysiological recordings, we analyzed the impact of electrical extracellular, local, bipolar stimulation (ELBS) on brain tissue. We implemented the ELBS effects in a neuronal population model in which we can tune the excitation-inhibition ratio and we investigated stimulation-related parameters. Computer simulations led to sharp predictions regarding: i) the shape of evoked responses as observed in local field potentials, ii) the type of cells (pyramidal neurons and interneurons) contributing to these field responses and iii) the optimal tuning of stimulation parameters (intensity and frequency) to evoke meaningful responses. These predictions were tested in vivo (mouse). Neurobiological mechanisms were assessed in vitro (hippocampal slices). Results: Appropriately-tuned ELBS allows for preferential activation of GABAergic interneurons. A quantitative neural network excitability index (NNEI) is proposed. It is computed from stimulation-induced responses as reflected in local field potentials. NNEI was used in four patients with focal epilepsy. Results show that it can readily reveal hyperexcitable brain regions. Conclusion: Well-tuned ELBS and NNEI can be used to locally probe brain regions and quantify the (hyper)excitability of the underlying brain tissue. (C) 2016 Elsevier Inc. All rights reserved.