Mechanisms Of Seizure Generation Research Articles

Capturing the power of seizures: an empirical mode decomposition analysis of epileptic activity in the mouse hippocampus.

Various methods have been used to determine the frequency components of seizures in scalp electroencephalography (EEG) and in intracortical recordings. Most of these methods rely on subjective or trial-and-error criteria for choosing the appropriate bandwidth for filtering the EEG or local field potential (LFP) signals to establish the frequency components that contribute most to the initiation and maintenance of seizure activity. The empirical mode decomposition (EMD) with the Hilbert-Huang transform is an unbiased method to decompose a time and frequency variant signal into its component non-stationary frequencies. The resulting components, i.e., the intrinsic mode functions (IMFs) objectively reflect the various non-stationary frequencies making up the original signal. We employed the EMD method to analyze the frequency components and relative power of spontaneous electrographic seizures recorded in the dentate gyri of mice during the epileptogenic period. Epilepsy was induced in mice following status epilepticus induced by suprahippocampal injection of kainic acid. The seizures were recorded as local field potentials (LFP) with electrodes implanted in the dentate gyrus. We analyzed recording segments that included a seizure (mean duration 28 s) and an equivalent time period both before and after the seizure. Each segment was divided into non-overlapping 1 s long epochs which were then analyzed to obtain their IMFs (usually 8-10), the center frequencies of the respective IMF and their spectral root-mean-squared (RMS) power. Our analysis yielded unbiased identification of the spectral components of seizures, and the relative power of these components during this pathological brain activity. During seizures, the power of the mid frequency components increased while the center frequency of the first IMF (with the highest frequency) dramatically decreased, providing mechanistic insights into how local seizures are generated. We expect this type of analysis to provide further insights into the mechanisms of seizure generation and potentially better seizure detection.

A Review of Epileptic Seizure Prediction: Physiological Mechanism and Data Based Attempts

Epilepsy is a chronic brain disorder and epileptic patients encounter recurrent seizures caused by abnormally synchronous electrical activity in parts of the brain. Over 50 million people spread across the world have epilepsy amongst whom approximately 30% suffer from refractory epilepsy which cannot be controlled by existing treatment protocols. For all epileptic sufferers, the thought that their next seizure could come at any time is agonizing and traumatic. However, if seizures could be predicted reliably, associated dangers and inconveniences will be greatly mitigated. Although the epileptic seizure prediction challenge has been tackled headlong by researchers through different modelling methods the problem of prediction has not yet been satisfactorily solved. In this paper, a systematic literature review of prominent epileptic seizure prediction attempts was carried out. We focus majorly on the two predominant classes of modelling attempts used: physiological mechanism and data based. The review underscores the richness and utility of the diverse modeling strategies as well as the gainful contribution of researchers in the field of epilepsy. It shows that meaningful progress has been made towards discovering the exact mechanism of seizure generation and realization of reliable and consistent seizure prediction algorithm

Electrophysiological Evidence for the Development of a Self-Sustained Large-Scale Epileptic Network in the Kainate Mouse Model of Temporal Lobe Epilepsy.

Most research on focal epilepsy focuses on mechanisms of seizure generation in the primary epileptic focus (EF). However, neurological deficits that are not directly linked to seizure activity and that may persist after focus removal are frequent. The recruitment of remote brain regions of an epileptic network (EN) is recognized as a possible cause, but a profound lack of experimental evidence exists concerning their recruitment and the type of pathological activities they exhibit. We studied the development of epileptic activities at the large-scale in male mice of the kainate model of unilateral temporal lobe epilepsy using high-density surface EEG and multiple-site intracortical recordings. We show that, along with focal spikes and fast ripples that remain localized to the injected hippocampus (i.e., the EF), a subpopulation of spikes that propagate across the brain progressively emerges even before the expression of seizures. The spatiotemporal propagation of these generalized spikes (GSs) is highly stable within and across animals, defining a large-scale EN comprising both hippocampal regions and frontal cortices. Interestingly, GSs are often concomitant with muscular twitches. In addition, while fast ripples are, as expected, highly frequent in the EF, they also emerge in remote cortical regions and in particular in frontal regions where GSs propagate. Finally, we demonstrate that these remote interictal activities are dependent on the focus in the early phase of the disease but continue to be expressed after focus silencing at later stages. Our results provide evidence that neuronal networks outside the initial focus are progressively altered during epileptogenesis.SIGNIFICANCE STATEMENT It has long been held that the epileptic focus is responsible for triggering seizures and driving interictal activities. However, focal epilepsies are associated with heterogeneous symptoms, calling into question the concept of a strictly focal disease. Using the mouse model of hippocampal sclerosis, this work demonstrates that focal epilepsy leads to the development of pathological activities specific to the epileptic condition, notably fast ripples, that appear outside of the primary epileptic focus. Whereas these activities are dependent on the focus early in the disease, focus silencing fails to control them in the chronic stage. Thus, dynamical changes specific to the epileptic condition are built up outside of the epileptic focus along with disease progression, which provides supporting evidence for network alterations in focal epilepsy.

Anticonvulsive effects of nifedipine and flunarizine on maximal electroshock seizures induced seizures

Background: Epilepsy is a common neurological disorder but the mechanism of seizure generation has been only partially unraveled. Currently available antiepileptics have a low therapeutic index and furthermore, provide satisfactory seizures control in only 60–70% of patients. Therefore, the present study was done to review the basic mechanism of seizures with special attention on voltage gated calcium channels and search for new antiepileptic in order to improve the efficacy of current therapies. Aims and Objective: The current study aimed to evaluate the anticonvulsant activity of calcium channel blockers. Materials and Methods: The animals were treated with Nifedipine (100 μg/100 g ip and 200 μg/100 g ip) and Flunarizine (5mg ⁄ kg ip and 10 mg⁄kg ip) and maximal electroshock seizures (MES) was induced by technoelectro convulsometer, 2 hrs after the administration of drugs, and duration of various phases were noted. Duration of tonic hind limb extension (THLE) was taken as index for antiepileptic activity. Result: Nifedipine and Flunarizine when administered in dose of 100 μg/100 g ip and 5 mg/kg respectively did not produce any changes in any phases of the MES induced seizure. But in dose of 200 μg/100 g ip and 10 mg/kg ip respectively, it significantly reduced the duration of THLE. Conclusion: Nifedipine and Flunarizine have a significant action against MES induced seizures suggesting an important role of CCBs as future, promising antiepileptic drug.

Recent advances in epilepsy management.

Recent advances in our understanding of seizure generation have resulted in modified recommendations for when seizure treatment should be initiated, revisions to our definition of status epilepticus, and new pharmacological and neuromodulatory therapies. The goal of this review is to provide the anesthesiologist with an overview of the advancements they are most likely to encounter while providing clinical care. There have been recent modifications to seizure definitions and treatment recommendations. These include the idea that treatment with antiepileptic therapy should be initiated after the first unprovoked seizure in individuals who are at high risk for another seizure, and that the idea that status epilepticus should be thought of as a two-phase process, related to an initial phase after which intervention should be started, and a second phase after which time risk of long-term sequelae is increased. Additionally, several new therapies have become available that have novel mechanisms of action, which are more efficacious and have fewer side-effects. As knowledge about mechanisms of seizure generation has improved, there has been a concurrent evolution in our thinking about seizure-related definitions, and indications for initiation of treatment. Several next generation drug therapies with more specific targets have also become available. Taken together, there have been significant improvements in care options.

Seizure-onset patterns in focal cortical dysplasia and neurodevelopmental tumors: Relationship with surgical prognosis and neuropathologic subtypes.

The study of intracerebral electroencephalography (EEG) seizure-onset patterns is crucial to accurately define the epileptogenic zone and guide successful surgical resection. It also raises important pathophysiologic issues concerning mechanisms of seizure generation. Until now, several seizure-onset patterns have been described using distinct recording methods (subdural, depth electrode), mostly in temporal lobe epilepsies or with heterogeneous neocortical lesions. We analyzed data from a cohort of 53 consecutive patients explored by stereoelectroencephalography (SEEG) and with pathologically confirmed malformation of cortical development (MCD; including focal cortical dysplasia [FCD] and neurodevelopmental tumors [NDTs]). We identified six seizure-onset patterns using visual and time-frequency analysis: low-voltage fast activity (LVFA); preictal spiking followed by LVFA; burst of polyspikes followed by LVFA; slow wave/DC shift followed by LVFA; theta/alpha sharp waves; and rhythmic spikes/spike-waves. We found a high prevalence of patterns that included LVFA (83%), indicating nevertheless that LVFA is not a constant characteristic of seizure onset. An association between seizure-onset patterns and histologic types was found (p = 001). The more prevalent patterns were as follows: (1) in FCD type I LVFA (23.1%) and slow wave/baseline shift followed by LVFA (15.4%); (2) in FCD type II burst of polyspikes followed by LVFA (31%), LVFA (27.6%), and preictal spiking followed by LVFA (27.6%); (3) in NDT, LVFA (54.5%). We found that a seizure-onset pattern that included LVFA was associated with favorable postsurgical outcome, but the completeness of the EZ resection was the sole independent predictive variable. Six different seizure-onset patterns can be described in FCD and NDT. Better postsurgical outcome is associated with patterns that incorporate LVFA.

Brain State Is a Major Factor in Preseizure Hippocampal Network Activity and Influences Success of Seizure Intervention.

Hippocampal single-unit activity is strongly shaped by behavioral brain state, yet this relationship has been largely ignored when studying activity dynamics before spontaneous seizures in medial temporal lobe epilepsy. In light of the increased attention on using single-unit activity for the prediction of seizure onset and closed-loop seizure intervention, we show a need for monitoring brain state to interpret correctly whether changes in neural activity before seizure onset is pathological or normal. Moreover, we also find that the brain state preceding a seizure determines the success of therapeutic interventions to curtail seizure duration. Together, these findings suggest that seizure prediction and intervention will be more successful if tailored for the specific brain states from which seizures emerge.

Decrease in CA3 inhibitory network activity during Theiler’s virus encephalitis

Viral infections of the central nervous system are often associated with seizures, and while patients usually recover from the infection and the seizures cease, there is an increased lifetime incidence of epilepsy. These viral infections can result in mesial temporal sclerosis, and, subsequently, a type of epilepsy that is difficult to treat. In previous work, we have shown that Theiler’s murine encephalomyelitis virus (TMEV) infections in C57B/6 mice, an animal model of virus-induced epilepsy, results in changes in excitatory currents of CA3 neurons both during the acute infection and two months later, at a time when seizure thresholds are reduced and when spontaneous seizures can occur. The changes in the excitatory system differ at these two time points, suggesting different mechanisms for seizure generation. In the present paper, we examine GABAergic mediated inhibition in CA3 pyramidal cells at these two time points following TMEV infection. We found that amplitudes of sIPSCs and mIPSCs were reduced during the acute infection, but recovered at the two-month time point. These observations are consistent with previous measurements of excitatory currents suggesting different mechanisms of seizure generation during the acute infection and during chronic epilepsy.

V3. Idiopathic generalized epilepsy shows widespread increased network connectivity

Introduction Idiopathic generalized epilepsy (IGE) is a subtype of epilepsy presumed to have a genetic etiology and characterized by generalized seizures, i.e. seizures starting and rapidly engaging distributed networks. Although routine magnetic resonance imaging is apparently normal, many studies have reported structural alterations in idiopathic generalized epilepsy patients using diffusion tensor imaging and voxel based morphometry. Changes were also reported in functional networks during generalized spike wave discharges. In this study we wanted to investigate the IGE brain networks during the discharge-free intervals using Magnetoencephalography (MEG). To study the characteristics of the network, we used a graph theoretical approach. Methods We recorded resting state MEG data from 13 (9 females, mean age 38.6 years) IGE patients and 19 (11 females, mean age 38.5 years) healthy controls. Epileptic discharges were identified and marked by a neurologist and excluded from the analysis. Source localization of the resting state activity was performed using dynamic imaging of coherent sources (DICS) beamforming. Connectivity was estimated between all sources in the gray matter using the imaginary part of coherence. Another low-resolution network was generated by averaging connections between sources grouped by anatomical labeling. Graph measures were calculated on both the high resolution and low resolution networks. Results Network connectivity was significantly increased in IGE patients in the high-resolution networks in beta1 ( p = 0.003) and beta2 ( p = 0.0003) bands as compared to controls. In the low-resolution networks, connectivity in beta1 and beta2 was significantly higher in patients than in control subjects ( p = 0.005 and p = 0.0003 respectively). The further analysis of nodal strength using cluster-based statistics yielded significant clusters in the beta1 and beta2 bands. In the beta1 band, three significant clusters were found with higher nodal strength in IGE patients than in controls ( p = 0.004, p = 0.011 and p = 0.029 respectively). In the beta2 band, four significant clusters were found ( p = 0.0004, p = 0.002, p = 0.005 and p = 0.034 respectively) (see Fig. 1 ). We found no significant clusters of higher connectivity in controls compared to IGE patients in any of the frequency bands. Using Network Based Statistics, we found significant subnetworks with higher connectivity in IGE patients. The differences were found in alpha, beta1 and beta2 bands (see Fig. 2 ). We did not find any significant correlation between global connectivity and the age of participants. Conclusions Using graph theoretical network analysis, we found a widespread increase in connectivity in IGE patients compared to controls. These changes were more pronounced in the motor network and the mesio-frontal cortex. We did not, however, find any significant difference in clustering coefficient and characteristic path length which are measures that represent architectural differences in the network. Our findings suggest that an increased resting state connectivity in idiopathic generalized epilepsy could be a mechanism of seizure generation and represents a functional brain imaging endophenotype of the disease.

Microcircuits and their interactions in epilepsy: is the focus out of focus?

Epileptic seizures represent dysfunctional neural networks dominated by excessive and/or hypersynchronous activity. Recent progress in the field has outlined two concepts regarding mechanisms of seizure generation, or ictogenesis. First, all seizures, even those associated with what have historically been thought of as 'primary generalized' epilepsies, appear to originate in local microcircuits and then propagate from that initial ictogenic zone. Second, seizures propagate through cerebral networks and engage microcircuits in distal nodes, a process that can be weakened or even interrupted by suppressing activity in such nodes. We describe various microcircuit motifs, with a special emphasis on one that has been broadly implicated in several epilepsies: feed-forward inhibition. Furthermore, we discuss how, in the dynamic network in which seizures propagate, focusing on circuit 'choke points' remote from the initiation site might be as important as that of the initial dysfunction, the seizure 'focus'.

The inflammatory molecules IL-1β and HMGB1 can rapidly enhance focal seizure generation in a brain slice model of temporal lobe epilepsy.

Epilepsy is a neurological disorder characterized by a hyperexcitable brain tissue and unpredictable seizures, i.e., aberrant firing discharges in large neuronal populations. It is well established that proinflammatory cytokines, in addition to their canonical involvement in the immune response, have a crucial role in the mechanism of seizure generation. The purpose of the present study was to investigate the role of interleukin-1β (IL-1β) and high mobility group B1 (HMGB1) in the generation of seizure-like discharges using two models of focal epilepsy in a rat entorhinal cortex slice preparation. Seizure like-discharges were evoked by either slice perfusion with low Mg2+ and picrotoxin or with a double NMDA local stimulation in the presence of the proconvulsant 4-amino-pyridine. The effects of IL-1β or HMGB1 were evaluated by monitoring seizure discharge generation through laser scanning microscope imaging of Ca2+ signals from neurons and astrocytes. In the picrotoxin model, we revealed that both cytokines increased the mean frequency of spontaneous ictal-like discharges, whereas only IL-1β reduced the latency and prolonged the duration of the first ictal-like event. In the second model, a single NMDA pulse, per se ineffective, became successful when it was performed after IL-β or HMGB1 local applications. These findings demonstrate that both IL-1β and HMGB1 can rapidly lower focal ictal event threshold and strengthen the possibility that targeting these inflammatory pathways may represent an effective therapeutic strategy to prevent seizures.

Glutamate transporters control metabotropic glutamate receptors activation to prevent the genesis of paroxysmal burst in the developing hippocampus

Metabotropic glutamate receptors (mGluR) can control neuronal excitability by modulating several ionic channels. In hippocampal pyramidal cells, groups I/II mGluR are located extrasynaptically, suggesting that their endogenous activation is dependent on the glutamate clearance rate and therefore on excitatory amino-acid transporters (EAAT) efficiency. Deficiency of glutamate uptake can generate seizures in rodents and has been suggested as a mechanism of seizure generation in some human epileptic syndromes. However, the cellular mechanisms linking EAAT dysfunction and pathological cortical activities remain elusive. Here, we investigate the possible role of mGluR on paroxysmal burst of multiple unit activities (MUA) generated in the CA1 region of developing hippocampal slices using an EAAT inhibitor, TBOA. These bursts are generated by a synaptic release of glutamate and involve extrasynaptic NMDA receptors (NMDAR) activated by transmitter spillover. Here, we show that postsynaptic mGluR (groups I/II) are tonically activated by the rise in ambient glutamate concentration after EAAT inhibition and strongly contribute to paroxysmal burst genesis. The inhibition of mGluR with broad spectrum antagonists or addition of a glutamate scavenger strongly reduced the occurrence of paroxysmal burst and the frequency/number of MUA during the burst. Moreover, this endogenous activation of groups I/II mGluR leads to (i) the reduction of the slow afterhyperpolarization current (IsAHP), increasing the firing pattern of pyramidal cells, and (ii) the potentiation of extrasynaptic NMDAR-mediated responses, enabling glutamate spillover to generate a suprathreshold depolarization for several seconds. Our data show that an insufficient buffering of extracellular glutamate enables a cross talk between groups I/II mGluR and NMDAR, which, combined with a decrease of IsAHP, leads to the hyperexcitability of the hippocampal network, facilitating the genesis of epileptical-like activity in response to glutamate release. These findings highlight the importance of the control exerted by EAAT on mGluR.

Preictal changes in cerebral haemodynamics: Review of findings and insights from intracerebral EEG

The possibility of recording changes in brain signals occurring before epileptic seizures is of considerable interest, both as markers for seizure anticipation and as a window into the mechanisms of seizure generation. Several studies have reported preictal changes on electrophysiological traces. More recently, observations have been made of changes occurring on haemodynamic signals before interictal events or before seizures, often without concurrent changes observed on electrophysiology. We present here a critical review of these findings, in optical imaging, SPECT and fMRI, followed by a discussion based on data from intracerebral EEG.

New Antiepileptic Drugs: Molecular Targets

In the past 20 years, a number of new antiepileptic drugs (AEDs) have been introduced and other molecules are in development, some of which are advantageous in terms of pharmacokinetics, tolerability and potential for drug interactions. These drugs are regarded as second generation compared to older agents such as barbiturates, phenytoin, carbamazepine, ethosuximide and valproic acid. Although some of these second generation compounds may be advantageous in terms of kinetics, tolerability and potential for drug interactions, all of them still target voltage-gated channels or GABA-mediated inhibition, predominantly, without any real improvement in epilepsy therapy. Studies on mechanisms of seizure generation and propagation have identified new potential targets for AEDs. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies. In this review the molecular targets for new AEDs are discussed, providing further suggestions on how future research can be improved.

Neuropathologic quiz

Epilepsy is a common neurological disease but the mechanism of seizure generation has been only partially unraveled. Furthermore, almost 30% of epileptic patients are resistant to pharmacological treatment. Therefore, elucidation of the basic mechanism of seizures and search for new antiepileptics in order to treat the drug-resistant form of epilepsy and to improve the efficacy of current therapies seem justified. The aim of this overview is a brief presentation of some new concepts and research directions in pathogenesis and pharmacotherapy of epilepsy. Development of ideas on the mechanisms of seizures and antiepileptic drugs reflects the progress in our understanding of the central nervous system physiology, particularly of neurotransmission. Hyperactivity of excitatory amino acid systems, insufficient GABAA receptor-mediated neurotransmission, and disturbances in intrinsic properties of neuronal membranes are still regarded as the most important mechanisms of seizures. New data add to the complexity of GABA-glutamate interaction showing both excitatory and inhibitory role of GABA and glutamatergic neurons in the central nervous system. Moreover, besides synaptic NMDA and GABAA receptors, also extrasynaptic receptors for the amino acid transmitters have been recently implicated in the pathomechanism of epilepsy. Changes in expression, polymorphisms, lost- or gain-function mutations as well as cellular energetic imbalance can contribute to the disturbed function of the ligand- and voltage-dependent sodium, potassium, chloride and calcium channels, resulting in epileptiform activity. Voltage-dependent sodium and calcium channel blockers, and GABA mimetics are the most clinically useful groups of antiepileptic drugs and the newest research in this field is focused on more selective and subtle regulations of their molecular targets. Of interest is an emerging role of extrasynaptic GABAA receptors, various kinds of potassium ion channels, hyperpolarization-activated cyclic nucleotide gated (HCN) channels, acid-sensing ion channels, and gap junctions in the regulation of neuronal excitability and seizures. Iono- and metabotropic glutamate receptors used to be viewed as an attractive target for new anticonvulsants, however, opinions are now less enthusiastic, since their competitive and non-competitive antagonists possess undesired side effects. Positive or negative allosteric modulators of glutamate receptors with fewer side-effects can be more promising. The introduction of new compounds acting through novel pharmacological mechanisms gives hope that the proportion of patients with uncontrolled epilepsy will substantially decrease. However, this may be possible if molecular background of the pharmacoresistance in epilepsy is deciphered.