Types Of Epileptiform Activity Research Articles

Bursts with High and Low Load of Epileptiform Spikes Show Context-Dependent Correlations in Epileptic Mice.

Hypersynchronous network activity is the defining hallmark of epilepsy and manifests in a wide spectrum of phenomena, of which electrographic activity during seizures is only one extreme. The aim of this study was to differentiate between different types of epileptiform activity (EA) patterns and investigate their temporal succession and interactions. We analyzed local field potentials (LFPs) from freely behaving male mice that had received an intrahippocampal kainate injection to model mesial temporal lobe epilepsy (MTLE). Epileptiform spikes occurred in distinct bursts. Using machine learning, we derived a scale reflecting the spike load of bursts and three main burst categories that we labeled high-load, medium-load, and low-load bursts. We found that bursts of these categories were non-randomly distributed in time. High-load bursts formed clusters and were typically surrounded by transition phases with increased rates of medium-load and low-load bursts. In apparent contradiction to this, increased rates of low-load bursts were also associated with longer background phases, i.e., periods lacking high-load bursting. Furthermore, the rate of low-load bursts was more strongly correlated with the duration of background phases than the overall rate of epileptiform spikes. Our findings are consistent with the hypothesis that low-level EA could promote network stability but could also participate in transitions towards major epileptiform events, depending on the current state of the network.

Region-specific differences and areal interactions underlying transitions in epileptiform activity.

Key points Local neocortical and hippocampal territories show different and sterotypical patterns of acutely evolving, epileptiform activity.Neocortical and entorhinal networks show tonic–clonic‐like events, but the main hippocampal territories do not, unless it is relayed from the other areas.Transitions in the pattern of locally recorded epileptiform activity can be indicative of a shift in the source of pathological activity, and may spread through both synaptic and non‐synaptic means.Hippocampal epileptiform activity is promoted by 4‐aminopyridine and inhibited by GABAB receptor agonists, and appears far more sensitive to these drugs than neocortical activity.These signature features of local epileptiform activity can provide useful insight into the primary source of ictal activity, aiding both experimental and clinical investigation. Understanding the nature of epileptic state transitions remains a major goal for epilepsy research. Simple in vitro models offer unique experimental opportunities that we exploit to show that such transitions can arise from shifts in the ictal source of the activity. These transitions reflect the fact that cortical territories differ both in the type of epileptiform activity they can sustain and in their susceptibility to drug manipulation. In the zero‐Mg2+ model, the earliest epileptiform activity is restricted to neocortical and entorhinal networks. Hippocampal bursting only starts much later, and triggers a marked transition in neo‐/entorhinal cortical activity. Thereafter, the hippocampal activity acts as a pacemaker, entraining the other territories to their discharge pattern. This entrainment persists following transection of the major axonal pathways between hippocampus and cortex, indicating that it can be mediated through a non‐synaptic route. Neuronal discharges are associated with large rises in extracellular [K+], but we show that these are very localized, and therefore are not the means of entraining distant cortical areas. We conclude instead that the entrainment occurs through weak field effects distant from the pacemaker, but which are highly effective at recruiting other brain territories that are already hyperexcitable. The hippocampal epileptiform activity appears unusually susceptible to drugs that impact on K+ conductances. These findings demonstrate that the local circuitry gives rise to stereotypical epileptic activity patterns, but these are also influenced by both synaptic and non‐synaptic long‐range effects. Our results have important implications for our understanding of epileptic propagation and anti‐epileptic drug action.

Bioelectrical Activity in the Sleep–Waking Cycle in Rats after Pilocarpine-Induced Status Epilepticus

Chronic recording of electrograms of the somatosensory, auditory, and visual cortex, the hippocampus, and the caudate nucleus in Krushinskii–Molodkina and Wistar rats was used to study bioelectrical activity in the sleep–waking cycle during the month following pilocarpine-induced status epilepticus. The processes of normalization of behavior and the organization of sleep and waking were completed in animals over the three days following status epilepticus. From day 2 to day 4 after administration of pilocarpine, electrograms of the study structures in all rats at all stages of the sleep–waking cycle showed epileptiform activity in the form of sharp waves, multiple peaks, and peak-wave discharges. Interhemisphere asymmetry in the manifestations of paroxysmal activity was seen in some cases. Spontaneous epileptiform activity on the EEG, in the form of single or grouped peak-wave discharges, was recorded in rats only on the background of waking and slow-wave sleep. The simultaneous presence of different types of epileptiform activity on EEG patterns and the duration of paroxysms on the EEG during the post-status period indicated that exposure to pilocarpine can induce the formation of multiple foci of epileptogenesis in the rat brain, with production of stable paroxysmal syndrome, which has clear similarity with the clinical picture of nonconvulsive status epilepticus in humans.

Enhanced interlaminar excitation or reduced superficial layer inhibition in neocortex generates different spike-and-wave-like electrographic events in vitro.

Acute in vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike-and-wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalized and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden, and apparent anatomical origin (thalamic, neocortical, or both), but any relationship between this heterogeneity and underlying pathology remains elusive. In this study we demonstrate that physiological delta-frequency rhythms act as an effective substrate to permit modeling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modeled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals, whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies.NEW & NOTEWORTHY Spike-and-wave-type discharges (SpW) are a common feature in many epilepsies. Their electrographic manifestation is highly varied, as are available genetic clues to associated underlying pathology. Using computational and in vitro models, we demonstrate that distinct subtypes of SpW are generated by lamina-selective disinhibition or enhanced interlaminar excitation. These subtypes could be detected in at least some noninvasive patient recordings, suggesting more detailed analysis of SpW may be useful in determining clinical pathology.

Two Types of Epileptiform Activity Induced in Rats by Repeated Injections of Subconvulsive Picrotoxin Doses

Seizure activity in rats was induced by picrotoxin i.p. injected every 30 min for 4 h in subconvulsive doses (0.9 mg/kg in the first and 0.7 mg/kg in subsequent injections). Such picrotoxin-evoked epileptiform activity (EA) could be divided into two types, with the development of exclusively peak-wave (P-W) complexes (68.4%) and with generation of regular cortical peaks and only separate short P-W discharges (31.6%). In animals with EA of the first type, we observed the gradual development of clonic seizures of increasing intensities. In some rats of this group after the final (ninth) injection of picrotoxin, dramatic clonico-tonic seizures were observed. In animals with EA of the second type, the duration of P-W discharges after final injections of picrotoxin was shorter than in rats without generation of cortical peaks; these discharges were accompanied by clonic seizures of smaller intensity.

LP31: EEG and MEG source localization of the epileptogenic foci in tuberous sclerosis complex: a pediatric case report

LP31: EEG and MEG source localization of the epileptogenic foci in tuberous sclerosis complex: a pediatric case report

Significance of centro-temporal spikes on the EEG.

In a prospectively studied group of 43 children with centro-temporal spikes on the EEG, only 26 had the classical epileptic syndrome related to this EEG abnormality. Ten patients never had epileptic manifestations. In the other seven cases two types of epileptiform activity were encountered: in addition to the centro-temporal spikes generalized spike-and-wave complexes or--in other patients--occipital epileptiform phenomena occurred. In these cases the clinical signs and symptoms correlated best with the non-Rolandic EEG abnormalities. Some patients had only a few centro-temporal spikes during the recording of the EEG; in others this epileptiform activity was almost continuously present. This quantitative difference had no clinical correlation. Centro-temporal spikes should probably be looked upon as an (epi)phenomenon of cerebral disfunction with a wide range of clinical and electroencephalographic expressions.

Postnatal development of a new type of epileptiform activity in the rat hippocampus

Long-term application of Cs + (5 mM) induces an epileptiform field potential (Cs-FP) in area CA1 of the rat hippocampus, which is independent of N-methyl- d-aspartate (NMDA) and non-NMDA glutamate receptors and γ-aminobutyric acid (GABA) A receptors. To gain insight into possible mechanisms for the induction of the Cs-FP, we investigated the postnatal development of the response. In brain slices prepared from rats at different ages, the Cs-FP was evoked by stimulation of the Schaffer-collateral–commisural pathway. We found that expression of this potential was clearly dependent on the postnatal age. Thus, the Cs-FP was completely absent at 1 week of age. By 2 weeks, a reduced form of the response was observed, whereas slices taken from 3-week-old rats, displayed full Cs-FP, which were indistinguishable in size and shape from the adult form. In the presence of 4-aminopyridine, potentials resembling the Cs-FP were evoked. These potentials showed a similar age-dependency as the Cs-FP. The Na +/K + pump inhibitor dihydroouabain (DHO), when present during wash-in of Cs +, gave a partial block of the Cs-FP in adult slices. This effect was not seen when DHO was applied after development of the Cs-FP. The data indicate that the processes necessary for expression of the Cs-PF are absent at birth and develop during the second postnatal week. We propose that the Cs-FP depends on Cs + entry into presynaptic neurons, and that the Na +/K + pump contributes to this transport of Cs +. The observed age-dependency could therefore, in part, reflect the delayed development of the Na +/K + pump.

Modification of Epileptiform Discharges in Neocortical Neurons Following Glutamate Uptake Inhibition

Sodium-dependent high-affinity glutamate transporters regulate synaptic glutamate levels to maintain low ambient levels of glutamate and prevent excitotoxicity. Most studies using pharmacological inhibition of glutamate transport to examine the involvement of glutamate transporters in regulating synaptic activity have examined small synaptic currents. Using in vitro brain slices, we investigated the effects of uptake inhibition on two types of epileptiform activity, bicuculline-induced paroxysmal activity, and epileptiform responses in the freeze-lesion epilepsy model. In layer II/III pyramidal cells of the prefrontal cortex, inhibiting uptake with low concentrations of DL-threo-ss-benzyloxyaspartic acid (TBOA) (20 or 30 microM) prolonged bicuculline-induced epileptiform activity. At higher concentrations, TBOA (150 or 300 microM) caused a transient enhancement of epileptiform discharges that was followed by a decrease. In the freeze-lesion model, inhibiting uptake also increased the amplitude and response area of evoked activity. The prolongation of epileptiform activity exhibited by the inhibition of glutamate uptake (TBOA 20 or 30 microM) is attributed to an increase in the level of glutamate extracellularly during uptake blockade, resulting in sustained activation of glutamate receptors. The decrease in epileptiform activity at higher TBOA concentration could be due to glutamate receptor desensitization or loss of excitability due to a depolarization block. The present results suggest that decreases in glutamate uptake can be proconvulsant in the two models of epilepsy examined.

Decrease in Synaptic Transmission Can Reverse the Propagation Direction of Epileptiform Activity in Hippocampus In Vivo

Most types of epileptiform activity with synaptic transmission have been shown to propagate from the CA3 to CA1 region in hippocampus. However, nonsynaptic epileptiform activity induced in vitro is known to propagate slowly from the caudal end of CA1 toward CA2/CA3. Understanding the propagation modes of epileptiform activity, and their causality is important to revealing the underlying mechanisms of epilepsy and developing new treatments. In this paper, the effect of the synaptic transmission suppression on the propagation of epilepsy in vivo was investigated by using multiple-channel recording probes in CA1. Nonsynaptic epileptiform activity was induced by calcium chelator EGTA with varied concentrations of potassium. For comparison, disinhibition synaptic epileptiform activity was induced by picrotoxin (PTX) with or without partial suppression of excitatory synaptic transmission. The propagation velocity was calculated by measuring the time delay between two electrodes separated by a known distance. The results show that in vivo nonsynaptic epileptiform activity propagates with a direction and velocity comparable to those observed in in vitro preparations. The direction of propagation for nonsynaptic activity is reversed from the PTX-induced synaptic activity. A reversal in propagation direction and change in velocity were also observed dynamically during the process of synaptic transmission suppression. Even a partial suppression of synaptic transmission was sufficient to significantly change the propagation direction and velocity of epileptiform activity. These results suggest the possibility that the measurement of propagation can provide important information about the synaptic mechanism underlying epileptic activity.

Glutamate receptor involvement in dentate granule cell epileptiform activity evoked by mossy fiber stimulation

In many persons with temporal lobe epilepsy, dentate granule cells form an interconnected synaptic network. This recurrent mossy fiber circuit mediates reverberating excitation that may facilitate seizure propagation by synchronizing granule cell discharge. The involvement of specific glutamate receptors in granule cell epileptiform activity evoked by stimulating the mossy fibers was investigated with use of rat hippocampal slices superfused with bicuculline, with or without increasing [K +] o to 6 mM. The occurrence of short-latency mossy fiber-evoked granule cell epileptiform activity in slices from pilocarpine-treated rats correlated with the presence and extent of recurrent mossy fiber growth. Blockade of AMPA receptors nearly abolished the orthodromic component of the response; subsequent antagonism of kainate receptors as well appeared to have no further action. Antagonism of NMDA receptors reduced the duration of epileptiform discharge, but increased the amplitude of population spikes within the evoked burst. Thus AMPA and NMDA, but perhaps not kainate, receptors play an important role in this type of epileptiform activity. Activation of type II metabotropic glutamate receptors, which inhibits the release of glutamate from mossy fiber boutons, reduced the magnitude of epileptiform discharge. This action was reversed by a partial agonist of these receptors. However, neither an agonist nor an antagonist of type III metabotropic glutamate receptors significantly altered the response. Considering the importance of synchronous granule cell discharge for seizure propagation from the entorhinal cortex to the hippocampus, agonists of type II metabotropic glutamate receptors may be useful in suppressing such discharge both experimentally and clinically.

Abnormal responses to perforant path stimulation in the dentate gyrus of slices from rats with kainate-induced epilepsy and mossy fiber reorganization.

Previous electrophysiological studies have demonstrated that in a subset of hippocampal slices from tissue resected from patients with mesial temporal lobe epilepsy, perforant path stimulation can elicit prolonged negative field-potential shifts in the dentate granule cell layer (Masukawa et al., 1989. Brain Res. 493, 168-174; Isokawa and Fried, 1996. Neuroscience 72, 31-37). In this investigation, hippocampal slices were prepared from rats: (1) 2-4 days following kainate treatment, when little or no reorganization of the mossy fibers would be present and (2) 3-13 months after kainate treatment, when mossy fiber reorganization would have occurred. In saline-treated controls, perforant path stimulation typically evoked a single population spike. In contrast, perforant path stimulation could evoke 3-12 population spikes in nearly all slices from kainate-injected rats 2-4 days and 3-13 months after treatment. The majority of slices from kainate-injected rats 3-13 months after treatment had qualitatively similar responses to perforant path stimulation as that observed in slices from kainate-injected rats 2-4 days after treatment. However, in 17% of the slices from kainate-treated rats 3-13 months after treatment (29% of rats), the multiple population spikes were followed by a prolonged negative field-potential shift (duration: 140 ms-1.5 s) with variable superimposed population spike activity. This type of epileptiform activity was only observed in slices with robust Timm's staining in the inner molecular layer and similar responses could also be evoked in these slices with hilar stimulation. Furthermore, pharmacological depression of inhibition by adding the GABA(A) receptor antagonist bicuculline unmasked hilar-evoked prolonged negative field-potential shifts in most slices from kainate-treated rats 3-13 months following treatment, and these slices had robust Timm's staining in the inner molecular layer. Such events were not observed in slices from saline-treated controls or kainate-injected rats 2-4 days after treatment. In conclusion, the prolonged negative field-potential shifts evoked to perforant path stimulation in normal ACSF were associated with mossy fiber reorganization, but the relative contribution of altered inhibition, increased synaptic excitation, or even non-synaptic mechanisms is unknown.

A serotonin-1A receptor agonist and an N-methyl- d-aspartate receptor antagonist oppose each others effects in a genetic rat epilepsy model

The WAG/RIJ rats exhibit spontaneously occurring spike-wave discharges (SWD) accompanied by behavioural phenomena, with characteristics similar to the human absence type epilepsy. To study the mechanisms involved in this type of epileptiform activity we investigated the effects of the serotonin-1A (5-HT 1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the N-methyl- d-aspartate (NMDA) receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801). Intracerebroventricular (i.c.v.) injection of 8-OH-DPAT caused marked, dose dependent increase, MK-801 a decrease in the cumulative duration and number of spike-wave discharges. Pretreatment with MK-801 (10 μg/rat i.c.v.) abolished the increase caused by 8-OH-DPAT (20 μg/rat i.c.v.), but the decrease in SWD to MK-801 was counterbalanced by 8-OH-DPAT. These data provide evidence for an interaction of glutamatergic and serotonergic mechanisms in the triggering and maintenance of epileptic activity in this genetic model of absence epilepsy.

Serotonin blocks different patterns of low Mg2+-induced epileptiform activity in rat entorhinal cortex, but not hippocampus.

Low Mg2+-induced epileptiform activity in the entorhinal cortex is characterized by an initial expression of seizure-like events followed by late recurrent discharges. Both these forms of activity as well as the transition between them were blocked by serotonin. In contrast, serotonin had little effect upon the epileptiform activity in areas CA3 and CA1 of the hippocampus. Both forms of epileptiform activity in the entorhinal cortex are sensitive to N-methyl-D-aspartate receptor antagonists and it is shown here that serotonin blocked both types of epileptiform activity through an effective concentration-dependent reduction of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials in deep layer entorhinal cortex cells. Serotonin also prolonged or even prevented the transition between the two types of epileptiform activity and we suggest that this may be through activation of the Na+/K+-ATPase. The resistance of epileptiform activity in CA1 and CA3 to serotonin was most likely related to the inability of serotonin to reduce Schaffer collateral-evoked excitatory postsynaptic potentials. Given the strong serotonergic inputs to both the hippocampus and entorhinal cortex, the differential sensitivity of the two regions to serotonin suggests functional differences. In addition since the late recurrent discharges in the entorhinal cortex are resistant to all clinically used anticonvulsants, serotonin may open new avenues for the development of novel anticonvulsant compounds.

Effects of methysticin on three different models of seizure like events studied in rat hippocampal and entorhinal cortex slices.

Methysticin is one of the constituents of Piper methysticum which possesses anticonvulsant and neuroprotective properties. Its effects on different in vitro seizure models were tested using extracellular recordings in rat temporal cortex slices containing the hippocampus and the entorhinal cortex. Elevating [K+]0 induced seizure-like events with tonic and clonic electrographic phases in area CA1. Lowering [Ca2+]0 caused recurrent seizure like episodes with large negative field potential shifts. Lowering Mg2+ induced short recurrent discharges in area CA3 and CA1 while ictaform events lasting for many seconds were induced in the subiculum, entorhinal and temporal neocortex. In the hippocampus the activity stayed stable over a number of hours. In contrast, the ictaform events in the subiculum, entorhinal and temporal cortex changed their characteristics after one to two hours to late recurrent discharges. In a concentration-range from 10 to 100 microM methysticin reversibly blocked all these types of epileptiform activity. Decreases in [Ca2+]0 and associated slow field potentials evoked by repetitive stimulation of the stratum radiatum or the alveus remained almost unaffected by methysticin. A paired pulse stimulus paradigm used to test for effects of methysticin on synaptically evoked transient field potentials in normal medium revealed interference with mechanisms involved in frequency potentiation. While responses to alvear stimulation were largely unaffected, the responses to a paired pulse stimulus to stratum radiatum were depressed over the whole range of tested stimulus intervals. The findings suggest that methysticin has effects on different patterns of epileptiform activity possibly by interfering with processes responsible for frequency potentiation.

Ictal epileptiform events induced by removal of extracellular magnesium in slices of entorhinal cortex are blocked by baclofen

Most manipulations employed to elicit epileptiform activity in brain slices result in brief, interictal-like events. In slices of the rat entorhinal cortex perfusion with a magnesium-depleted medium elicits prolonged seizure events which are more reminiscent of ictal activity. The interictal events in brain slice models are blocked by baclofen, but there is an indication from one study (H. S. Swartzwelder, D. V. Lewis, W. W. Anderson, and W. A. Wilson, 1987, Brain Res. 410: 362-366) that ictal events may not be affected by this drug. The present study examined the effects of baclofen on ictal events recorded in entorhinal cortex slices in magnesium-free medium. Simultaneous studies of effects of baclofen on interictal responses in the hippocampal region of the same slices were made on many occasions. The results show that both types of epileptiform activity are suppressed with a similar facility by baclofen.

Seizure-like discharges induced by lowering [Mg 2+] 0 in the human epileptogenic neocortex maintained in vitro

Seizure-like discharges were observed in slices of human epileptogenic neocortex maintained in vitro when [Mg 2+] 0 was lowered near to zero. This type of epileptiform activity: (1) could occur spontaneously or following extracellular focal stimuli; (2) resembled the electrographic pattern associated with tonic-clonic seizures; (3) was accompanied by increases in [K +] 0 (maximally 6.2 mM from a baseline of 3.25 mM) and decreases in [Ca 2+] 0 (maximally 0.23 mM from a baseline of 1.8 mM). Application of the selective antagonist of N-methyl- d-aspartate (NMDA) receptors, dl-2-amino-5-phosphonovalerate, supressed in a reversible manner both spontaneous and stimulus-induced seizure-like discharges, suggesting that NMDA-activated conductances are important for the genesis of prolonged epileptiform discharges generated by human epileptogenic neocortical slices.

Induction of epileptiform activity in hippocampal slices by trains of electrical stimuli

In this paper we present an in vitro model of epileptogenesis based on electrical stimulation rather than pharmacological or ionic manipulations. Hippocampal slices given a series trains similar to those used in kindling ezhibited 3 types of epileptiform activity in CA3: (1) afterdischarges immediately following the trains; (2) spontaneous bursts of multiple population spikes; and (3) bursts triggered by single stimuli. The afterdischarges and spontaneous bursts may be comparable to those seen in vivo during kindling; also, the progression of these features in this model was similar to their progression during kindlilng. All epileptiform activities were long-lasting, persisting for up to 3.5 h following the last train. This stimulus train-induced population bursting should be valuable as an acute model of hippocampal epileptogenesis, and may also help elucidate hippocampal participation in the kindling process.

Evidence for late development of inhibition in area CA1 of the rat hippocampus

Development of recurrent inhibition in area CA1 of the rat hippocampus was monitored by a paired-pulse stimulation test. Inhibition of the second response was never observed before postnatal day six. In addition, a type of epileptiform activity, referred to as spontaneous unison firing, was observed frequently, only on postnatal days 4 and 5. Together these observations suggest that the inhibitory interneuronal network of area CA1 becomes effective on about postnatal day 6.