Phase clustering in transcranial magnetic stimulation-evoked EEG responses in genetic generalized epilepsy and migraine.

BACKGROUND: Epilepsy and migraine are paroxysmal neurological conditions associated with disturbances of cortical excitability. No useful biomarkers to monitor disease activity in these conditions are available. Phase clustering was previously described in electroencephalographic (EEG) responses to photic stimulation and may be a potential epilepsy biomarker. OBJECTIVE: The objective of this study was to investigate EEG phase clustering in response to transcranial magnetic stimulation (TMS), compare it with photic stimulation in controls, and explore its potential as a biomarker of genetic generalized epilepsy or migraine with aura. METHODS: People with (possible) juvenile myoclonic epilepsy (JME), migraine with aura, and healthy controls underwent single-pulse TMS with concomitant EEG recording during the interictal period. We compared phase clustering after TMS with photic stimulation across the groups using permutation-based testing. RESULTS: We included eight people with (possible) JME (five off medication, three on), 10 with migraine with aura, and 37 controls. The TMS and photic phase clustering spectra showed significant differences between those with epilepsy without medication and controls. Two phase clustering-based indices successfully captured these differences between groups. One participant was tested multiple times. In this case, the phase clustering-based indices were inversely correlated with the dose of antiepileptic medication. Phase clustering did not differ between people with migraine and controls. CONCLUSION: We present methods to quantify phase clustering using TMS-EEG and show its potential value as a measure of brain network activity in genetic generalized epilepsy. Our results suggest that the higher propensity to phase clustering is not shared between genetic generalized epilepsy and migraine.

Dynamics of convulsive seizure termination and postictal generalized EEG suppression.

It is not fully understood how seizures terminate and why some seizures are followed by a period of complete brain activity suppression, postictal generalized EEG suppression. This is clinically relevant as there is a potential association between postictal generalized EEG suppression, cardiorespiratory arrest and sudden death following a seizure. We combined human encephalographic seizure data with data of a computational model of seizures to elucidate the neuronal network dynamics underlying seizure termination and the postictal generalized EEG suppression state. A multi-unit computational neural mass model of epileptic seizure termination and postictal recovery was developed. The model provided three predictions that were validated in EEG recordings of 48 convulsive seizures from 48 subjects with refractory focal epilepsy (20 females, age range 15-61 years). The duration of ictal and postictal generalized EEG suppression periods in human EEG followed a gamma probability distribution indicative of a deterministic process (shape parameter 2.6 and 1.5, respectively) as predicted by the model. In the model and in humans, the time between two clonic bursts increased exponentially from the start of the clonic phase of the seizure. The terminal interclonic interval, calculated using the projected terminal value of the log-linear fit of the clonic frequency decrease was correlated with the presence and duration of postictal suppression. The projected terminal interclonic interval explained 41% of the variation in postictal generalized EEG suppression duration (P < 0.02). Conversely, postictal generalized EEG suppression duration explained 34% of the variation in the last interclonic interval duration. Our findings suggest that postictal generalized EEG suppression is a separate brain state and that seizure termination is a plastic and autonomous process, reflected in increased duration of interclonic intervals that determine the duration of postictal generalized EEG suppression.

Automated Video Detection of Epileptic Convulsion Slowing as a Precursor for Post-Seizure Neuronal Collapse.

Automated monitoring and alerting for adverse events in people with epilepsy can provide higher security and quality of life for those who suffer from this debilitating condition. Recently, we found a relation between clonic slowing at the end of a convulsive seizure (CS) and the occurrence and duration of a subsequent period of postictal generalized EEG suppression (PGES). Prolonged periods of PGES can be predicted by the amount of progressive increase of interclonic intervals (ICIs) during the seizure. The purpose of the present study is to develop an automated, remote video sensing-based algorithm for real-time detection of significant clonic slowing that can be used to alert for PGES. This may help preventing sudden unexpected death in epilepsy (SUDEP). The technique is based on our previously published optical flow video sequence processing paradigm that was applied for automated detection of major motor seizures. Here, we introduce an integral Radon-like transformation on the time-frequency wavelet spectrum to detect log-linear frequency changes during the seizure. We validate the automated detection and quantification of the ICI increase by comparison to the results from manually processed electroencephalography (EEG) traces as "gold standard". We studied 48 cases of convulsive seizures for which synchronized EEG-video recordings were available. In most cases, the spectral ridges obtained from Gabor-wavelet transformations of the optical flow group velocities were in close proximity to the ICI traces detected manually from EEG data during the seizure. The quantification of the slowing-down effect measured by the dominant angle in the Radon transformed spectrum was significantly correlated with the exponential ICI increase factors obtained from manual detection. If this effect is validated as a reliable precursor of PGES periods that lead to or increase the probability of SUDEP, the proposed method would provide an efficient alerting device.

Which insights have we gained from the kindling and post-status epilepticus models?

Experimental animal epilepsy research got a big boost since the discovery that daily mild and short (seconds) tetanic stimulations in selected brain regions led to seizures with increasing duration and severity. This model that was developed by Goddard (1967) became known as the kindling model for epileptogenesis and has become a widely used model for temporal lobe epilepsy with complex partial seizures. During the late ninety-eighties the number of publications related to electrical kindling reached its maximum. However, since the kindling procedure is rather labor intensive and animals only develop spontaneous seizures (epilepsy) after hundreds of stimulations, research has shifted toward models in which the animals exhibit spontaneous seizures after a relatively short latent period. This led to post-status epilepticus (SE) models in which animals experience SE after injection of pharmacological compounds (e.g. kainate or pilocarpine) or via electrical stimulation of (limbic) brain regions. These post-SE models are the most widely used models in epilepsy research today. However, not all aspects of mesial temporal lobe epilepsy (MTLE) are reproduced and the widespread brain damage is often a caricature of the situation in the patient. Therefore, there is a need for models that can better replicate the disease. Kindling, although already a classic model, can still offer valid clues in this context. In this paper, we review different aspects of the kindling model with emphasis on experiments in the rat. Next, we review characteristic properties of the post-SE models and compare the neuropathological, electrophysiological and molecular differences between kindling and post-SE epilepsy models. Finally, we shortly discuss the advantages and disadvantages of these models.

Epileptic neuronal networks: methods of identification and clinical relevance.

The main objective of this paper is to examine evidence for the concept that epileptic activity should be envisaged in terms of functional connectivity and dynamics of neuronal networks. Basic concepts regarding structure and dynamics of neuronal networks are briefly described. Particular attention is given to approaches that are derived, or related, to the concept of causality, as formulated by Granger. Linear and non-linear methodologies aiming at characterizing the dynamics of neuronal networks applied to EEG/MEG and combined EEG/fMRI signals in epilepsy are critically reviewed. The relevance of functional dynamical analysis of neuronal networks with respect to clinical queries in focal cortical dysplasias, temporal lobe epilepsies, and "generalized" epilepsies is emphasized. In the light of the concepts of epileptic neuronal networks, and recent experimental findings, the dichotomic classification in focal and generalized epilepsy is re-evaluated. It is proposed that so-called "generalized epilepsies," such as absence seizures, are actually fast spreading epilepsies, the onset of which can be tracked down to particular neuronal networks using appropriate network analysis. Finally new approaches to delineate epileptogenic networks are discussed.

High frequency spectral components after secobarbital: the contribution of muscular origin--a study with MEG/EEG.

OBJECTIVES: Previously we found that benzodiazepines not only provoke beta-activity in the EEG, but also higher frequency activity. Knowing the origin of this high frequency activity is crucial if localisation of epileptogenic brain tissue is the query. We attempt to differentiate cerebral from muscular origin of such activity. METHODS: We postulate that EEG and MEG have similar sensitivity to brain activity, but different sensitivity to muscle activity, and compare co-recorded EEG and MEG signals in a group of five patients who had received short-lasting barbiturates to induce sleep. We performed principal components analysis over time and subtract the results for MEG from the EEG to see where the frequency spectra differ. RESULTS: The EEG showed activity in the gamma bands up to 270Hz for all patients; the MEG significantly less. We find no differences in the lower frequency bands. Topographically the differences localized over the frontotemporal regions. CONCLUSIONS: In the EEG benzodiazepines and/or barbiturates are not only associated with frequencies in the beta band, but also with wide range gamma activity. The latter seems to be of muscular origin. SIGNIFICANCE: Our study suggests that gamma activity in such measurements may not be cerebral in origin. MEG is less susceptible to contamination from muscle activity than the EEG.

Mechanisms of physiological and epileptic HFO generation.

High frequency oscillations (HFO) have a variety of characteristics: band-limited or broad-band, transient burst-like phenomenon or steady-state. HFOs may be encountered under physiological or under pathological conditions (pHFO). Here we review the underlying mechanisms of oscillations, at the level of cells and networks, investigated in a variety of experimental in vitro and in vivo models. Diverse mechanisms are described, from intrinsic membrane oscillations to network processes involving different types of synaptic interactions, gap junctions and ephaptic coupling. HFOs with similar frequency ranges can differ considerably in their physiological mechanisms. The fact that in most cases the combination of intrinsic neuronal membrane oscillations and synaptic circuits are necessary to sustain network oscillations is emphasized. Evidence for pathological HFOs, particularly fast ripples, in experimental models of epilepsy and in human epileptic patients is scrutinized. The underlying mechanisms of fast ripples are examined both in the light of animal observations, in vivo and in vitro, and in epileptic patients, with emphasis on single cell dynamics. Experimental observations and computational modeling have led to hypotheses for these mechanisms, several of which are considered here, namely the role of out-of-phase firing in neuronal clusters, the importance of strong excitatory AMPA-synaptic currents and recurrent inhibitory connectivity in combination with the fast time scales of IPSPs, ephaptic coupling and the contribution of interneuronal coupling through gap junctions. The statistical behaviour of fast ripple events can provide useful information on the underlying mechanism and can help to further improve classification of the diverse forms of HFOs.

Does conscious intention to perform a motor act depend on slow prefrontal (de)oxyhemoglobin oscillations in the resting brain?

Characteristically within the resting brain there are slow fluctuations (around 0.1Hz) of EEG and NIRS-(de)oxyhemoglobin ([deoxy-Hb], [oxy-Hb]) signals. An interesting question is whether such slow oscillations can be related to the intention to perform a motor act. To obtain an answer we analyzed continuous blood pressure (BP), heart rate (HR), prefrontal [oxy-Hb], [deoxy-Hb] and EEG signals over sensorimotor areas in 10 healthy subjects during 5min of rest and during 10min of voluntary finger movements. Analyses of prefrontal [oxy-Hb]/[deoxy-Hb] oscillations around 0.1Hz and central EEG band power changes in the beta (alpha) band revealed that the positive [oxy-Hb] peaks preceded the central EEG beta (alpha) power peak by 3.6±0.9s in the majority of subjects. A similar relationship between prefrontal [oxy-Hb] and central EEG beta power was found during voluntary movements whereby the post movement beta power increase (beta rebound) is known to coexist with a decreased excitability of cortico-spinal neurons. Therefore, we speculate that the beta power increase ∼3s after slow fluctuating [oxy-Hb] peaks during rest is indicative for a slow excitability change of central motor cortex neurons. This work provides the first evidence that initiation of finger movements at free will in relatively constant intervals around 10s could be temporally related to slow oscillations of prefrontal [oxy-Hb] and autonomic blood pressure in the resting brain.

TMS studies of preictal cortical excitability change.

The transition between the interictal and ictal states may be characterised in terms of the dynamics of a complex system. Seizures may emerge because of a change in system parameters, but these parameters may be invisible to passive observation. Therefore, a number of investigators have developed methods to probe the system using stimulation; these probing stimuli may reveal important hidden parameters. Here we describe studies from two sets of investigators working independently, which have shown that motor responses to transcranial magnetic brain stimulation (TMS) differ between the interictal state remote from any seizure, and a period of hours immediately prior to a seizure. We place these studies in the context of the known physiology of motor responses to TMS and discuss how actively probing the state of brain excitability may open new windows on its dynamics.

Transition to seizure in photosensitive epilepsy.

Photosensitive epilepsy (PSE) offers a highly reproducible model to investigate whether changes in neuronal activity preceding the transition to an epileptic photoparoxysmal response (PPR) may be detected. We investigated this possibility in patients with idiopathic PSE using MEG, as well as normal controls and non-photosensitive epileptic patients of the same age group. Spectral analysis of the MEG signals recorded during intermittent light stimulation revealed relevant information in the phase spectrum. To quantify this effect, we introduced a second order response feature of the stimulus-triggered visual response preceding the PPR: the phase clustering index, which measures how close the phases of successive periods are grouped for each frequency component for all periods of the stimuli applied. We found that an enhancement of phase synchrony in the gamma-band (30-120Hz), harmonically related to the frequency of stimulation, preceded the stimulation trials that evolved into PPRs, and differed significantly from that encountered in trials not followed by PPR or in control subjects. Thus this index can be considered a valuable index of the pro-ictal transition to seizures in photosensitive epilepsy.

An electro-encephalogram beta gap after induction with diazepam: a localization method in epileptogenic lesions.

OBJECTIVE: We clinically tested a quantitative EEG method to localize abnormal variations in benzodiazepine-induced fast rhythms to localize focal epileptogenic lesions, assuming altered quality/quantity of GABA receptors in the lesions. METHODS: During a 64-channel-EEG (sampled at 1 kHz) recording benzodiazepines were administered to five patients with localization related epilepsy associated with an MRI visible focal lesion. We determined the post-injection dominant spectral modulation using Gabor wavelets and analysed the symmetry of spatial distribution. This was compared to the localization of the lesion on the MRI scan. RESULTS: The principal component was found in the beta/gamma band. In all patients one region of decreased change was associated with the lesional hemisphere, and overlapped with the site of the lesion in four. Three patients underwent surgery: interictal corticographic findings concurred with the area of decreased benzodiazepine response. CONCLUSIONS: This simple method localized abnormal function associated with epileptogenic lesions. Further methodological validation is now justified. Final clinical validation must be done in MRI-negative cases as well. SIGNIFICANCE: This research may lead to techniques for non-invasive easy localization of epileptogenic tissue that is not visible on a structural MRI scan.

Dynamics of evoked local field potentials in the hippocampus of epileptic rats with spontaneous seizures.

A change in neuronal network excitability within the hippocampus is one of the hallmarks of temporal lobe epilepsy (TLE). In the dentate gyrus (DG), however, neuronal loss and mossy fiber sprouting are associated with enhanced inhibition rather than progressive hyperexcitability. The aim of this study was to investigate how alterations in excitability take place in association with spontaneous seizures expressed in the DG before, during, and after a seizure. For this purpose, we used freely moving rats that had developed spontaneous seizures after a kainate-induced status epilepticus (SE). Continuous EEG was recorded in the DG during several days along with local field potentials (LFPs) that were evoked every 15-30 s by applying paired-pulse stimuli to the angular bundle. Input-output relations showed increased paired pulse depression in epileptic compared with control rats, suggesting a rather strong inhibition in the DG during the interictal state. A characteristic pattern of changes in intrinsic excitability was observed during the ictal period: an increase in the population spike (PS) amplitude, mostly during the early phase of a seizure and often followed by a decrease of the main evoked potential amplitude. The paired-pulse extracellular postsynaptic potential (fEPSP) ratio increased during the seizure and did slowly recover to preictal levels after the seizure ended. Although clear changes in excitability occurred during and after seizure activity, changes of LFP parameters were more subtle before seizure onset; a significant reduction of LFP and PS amplitudes was observed that started 1-2 min in advance in approximately 33% of the cases; in approximately 18%, an increase of LFP/PS amplitude was observed; in the other cases, no significant change was observed. Taken together, these results provide evidence that, in this experimental model, DG physiology is more likely to follow the already ongoing seizure activity rather than to contribute to its generation.

The impact of EEG/MEG signal processing and modeling in the diagnostic and management of epilepsy.

This overview covers recent advances in the field of EEG/MEG signal processing and modeling in epilepsy regarding both interictal and ictal phenomena. In the first part, the main methods used in the analysis of interictal EEG/MEG epileptiform spikes are presented and discussed. Source and volume conductor models are passed in review, namely the equivalent dipole source concept, the requirements for adequate time and spatial sampling, the question of how to validate source solutions, particularly by comparing solutions obtained using scalp and intracranial EEG signals, EEG & MEG data, or EEG simultaneously recorded with fMRI (BOLD signals). In the second part, methods used for the characterization of seizures are considered, namely dipolar modeling of spikes at seizure onset, decomposition of seizure EEG signals into sets of orthogonal spatio-temporal components, and also methods (linear and nonlinear) of estimating seizure propagation. In the third part, the crucial issue of how the transition between interictal and seizure activity takes place is examined. In particular the vicissitudes of the efforts along the road to seizure prediction are shortly reviewed. It is argued that this question can be reduced to the problem of estimating the excitability state of neuronal populations in the course of time as a seizure approaches. The value of active probing methods in contrast with passive analytical methods is emphasized. In the fourth part modeling aspects are considered in the light of two special kinds of epilepsies, absences characterized by spike-and-wave discharges and mesial temporal lobe epilepsy. These two types correspond to different scenarios regarding the transition to epileptic seizures, namely the former is a case of a jump transition and the latter is a typical case of gradual transition. In conclusion, the necessity of developing comprehensive computational models of epileptic seizures is emphasized.

Dynamic changes of proteases and protease inhibitors revealed by microarray analysis in CA3 and entorhinal cortex during epileptogenesis in the rat.

We investigated expression of genes involved in the proteolytic process during epileptogenesis in a rat model of temporal lobe epilepsy (TLE). In a previous microarray study we found prominent activation of this process, which reached highest expression during the acute and latent phase (1 week after SE) in CA3 and entorhinal cortex (EC). Detailed analysis shows differences in dynamics of the changes of several protease genes such as cathepsins, caspases, matrix metalloproteinases, and plasminogen activators. Most genes were acutely upregulated while others were mainly activated during the latent phase. Interestingly several proteolytic genes were still elevated in the chronic epileptic phase. Various protease inhibitors followed a similar time course. The identification of changes in the activation of genes involved in proteolysis at critical phases during epileptogenesis could point to potential time specific targets for intervention. The fact that several proteolytic genes were still activated in the chronic epileptic phase makes them interesting candidates to modify and slow down seizure progression.

GABAergic mechanisms in absence epilepsy: a computational model of absence epilepsy simulating spike and wave discharges after vigabatrin in WAG/Rij rats.

In this study, the effects of vigabatrin on spike-and-wave discharges (SWDs) were measured in WAG/Rij rats, an animal model of absence epilepsy. Vigabatrin was used with the aim of enhancing GABAergic neurotransmission, and in this way to investigate the role of this process in the properties of SWDs. The study was carried out both in the rat, in vivo, and also using a computational model, in order to test different mechanisms that may account for the changes in SWDs after vigabatrin. The model parameters, representing GABA levels, were changed according to the known, and assumed, mechanism of action of the drug. The results show that the computational model can most adequately simulate the data obtained in vivo on the assumption that the enhancement of GABAergic neurotransmission due to application of vigabatrin is most pronounced at the level of the thalamic relay nuclei (TC cells). Furthermore, vigabatrin was shown to affect both the SWD starting and stopping mechanisms, as reflected by hazard rates. Based on these results, we suggest that GABAergic neurotransmission in TC cells is actively involved in the SWD termination.

Is colour modulation an independent factor in human visual photosensitivity?

Considering that the role of colour in photosensitive epilepsy (PSE) remains unclear, we designed a study to determine the potential of different colours, colour combinations and white light to trigger photoparoxysmal responses (PPRs) under stringent controlled conditions. After assessing their photosensitivity to stroboscopic white light and black and white patterns, we studied 43 consecutive PSE patients (mean age 19 years, 34 women), using a specially designed colour stimulator. Stimuli included: pulse trains between 10 and 30 Hz of white light and of all primary colours, and also isoluminant alternating time-sequences of colours. Illuminance was kept constant at 100 lux. A progressive stepwise increase of the modulation-depth (MD) of the stimuli was used to determine PPRs threshold. Whereas all the 43 patients were found to be sensitive during the stroboscopic and pattern protocol, only 25 showed PPRs (Waltz's score >2) at least in one session when studied with the colour stimulator. Coloured stimuli elicited PPRs in all these patients, whereas white light did so only in 17 patients. Of the primary colours, red elicited more PPRs (54 in 22 patients) and at a lower MD (max Z-score 0.93 at 10 Hz). Of the alternating sequences, the red-blue was the most provocative stimulus, especially below 30 Hz (100% of patients, max Z-score: 1.65 at 15 Hz). Blue-green was the least provocative stimulus, since it elicited only seven PPRs in seven (28%) patients (max Z-score 0.44 at 10 Hz). Sensitivity to alternating colours was not correlated to sensitivity to individual colours. We conclude that colour sensitivity follows two different mechanisms: one, dependent on colour modulation, plays a role at lower frequencies (<30 Hz). Another, dependent on single-colour light intensity modulation correlates to white light sensitivity and is activated at higher frequencies. Our results suggest that the prescription of spectacles with coloured lenses, tailored to the patient, can be an effective preventative measure against visually induced seizures.

Synaptic responses in superficial layers of medial entorhinal cortex from rats with kainate-induced epilepsy.

Mesial temporal lobe epilepsy patients often display shrinkage of the entorhinal cortex, which has been attributed to neuronal loss in medial entorhinal cortex layer III (MEC-III). MEC-III neuronal loss is reproduced in chronic epileptic rats after kainate-induced (KA) status epilepticus. Here we examined, in vitro, functional changes in superficial entorhinal cortex layers. Alterations in superficial layer circuitry were suggested by showing that presubiculum, parasubiculum and deep MEC stimulation evoked 100-300 Hz field potential transients and prolonged EPSPs (superimposed on IPSPs) in superficial MEC which were partially blocked by APV (in contrast to control) and fully blocked by CNQX. Contrary to controls, bicuculline (5 and 30 microM) had minor effects on evoked field potentials in KA rats. GAD65/67 in situ hybridization revealed preserved interneurons in MEC-III. In conclusion, hyperexcitability in superficial MEC neurons is not due to loss of GABAergic interneurons and probably results from alterations in synaptic connectivity within superficial MEC.

Electrically evoked GABA release in rat hippocampus CA1 region and its changes during kindling epileptogenesis.

Previous findings on changes in K+-induced GABA release from hippocampal slices during kindling epileptogenesis were reinvestigated using physiological electrical stimulation. For that purpose, a procedure was developed enabling neurochemical monitoring of GABA release locally in the CA1 region of rat hippocampal slices upon tetanic stimulation of Schaffer-collateral fibers. In the presence of a GABA reuptake blocker, subsequent application of short (3 s) pulses of 50-Hz stimuli induced a local transient increase in GABA release. In slices from fully kindled animals, 24 h after the last generalized seizure, tetanically stimulated GABA release was increased in comparison to control slices. In slices from long-term kindled animals, 4-5 weeks after the last seizure, tetanically stimulated GABA release had returned to control levels. Application of the broad low-affinity GABAB receptor antagonist saclofen increased the tetanically stimulated GABA release in control slices, but had no effect in fully kindled slices. In slices from long-term kindled animals, however, saclofen enhanced GABA release similarly as in control slices. We conclude that the transient increase in tetanus-induced GABA release during kindling epileptogenesis is seizure-related, and probably caused by temporarily impaired presynaptic GABAB receptors. The possible relevance of this finding for GABA transmission in epilepsy is discussed.

Event-related neural activities: what about phase?

The main topic of this overview is an analysis of the concepts of phase and synchrony, as used in neurophysiology, in their various meanings. A number of notions related to the concepts of phase and synchrony, which are incorporated in contemporary neurophysiology, particularly in the domain of neuro-cognitive physiology are discussed. These notions need a critical examination, since their use sometimes is not clear, or it may even be ambiguous. We present some of these concepts, namely (a) (des)synchronization, (b) phase resetting, (c) phase synchrony and phase/time delays, and (d) phase clustering within one signal, while discussing what type of neuronal activities may underlie these EEG phenomena.