B.M. Bouwman

Dynamics of epileptic phenomena determined from statistics of ictal transitions

In this paper, we investigate the dynamical scenarios of transitions between normal and paroxysmal state in epilepsy. We assume that some epileptic neural network are bistable i.e., they feature two operational states, ictal and interictal that co-exist. The transitions between these two states may occur according to a Poisson process, a random walk process or as a result of deterministic time-dependent mechanisms. We analyze data from animal models of absence epilepsy, human epilepsies and in vitro models. The distributions of durations of ictal and interictal epochs are fitted with a gamma distribution. On the basis of qualitative features of the fits, we identify the dynamical processes that may have generated the underlying data. The analysis showed that the following hold. 1) The dynamics of ictal epochs differ from those of interictal states. 2) Seizure initiation can be accounted for by a random walk process while seizure termination is often mediated by deterministic mechanisms. 3) In certain cases, the transitions between ictal and interictal states can be modeled by a Poisson process operating in a bistable network. These results imply that exact prediction of seizure occurrence is not possible but termination of an ictal state by appropriate counter stimulation might be feasible.

The effects of vigabatrin on type II spike wave discharges in rats

The antiepileptic drug vigabatrin increases GABA concentrations by inhibiting GABA transaminase. The effects of vigabatrin on type II spike wave discharges (SWDs) in the electroencephalogram of ACI rats were studied in order to learn more about the effects of altering GABA concentration on SWDs. The incidence of type II SWDs increased after vigabatrin (60/h) as compared to saline treatment (3.7/h). This effect appeared with a halftime of 100 min. The duration of type II SWDs increased after vigabatrin (1.52 s) as compared to saline treatment (1.04 s), but the peak-frequency of the type II SWDs decreased after vigabatrin (5.6 Hz) as compared to saline treatment (7.5 Hz). Thus, vigabatrin alters the type II SWD morphology. These results are in agreement with predictions of Destexhes theoretical model, modulating both GABA(A) and GABA(B) conductances.

Effects of levetiracetam on spike and wave discharges in WAG/Rij rats.

Effects of the novel anti-epileptic drug levetiracetam (50 and 100 mg/kg) on spike and wave discharges (SWDs) of WAG/Rij rats were studied. Levetiracetam decreased the incidence, average duration, total duration and peak frequency of the SWDs. There was no difference between the two doses. These results agree with results obtained in Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Furthermore, the decrease of the SWD peak frequency might support the suggestions that levetiracetam might have a GABAergic mechanism of action.

The relationship between hippocampal EEG theta activity and locomotor behaviour in freely moving rats: effects of vigabatrin.

The relationship between hippocampal electroencephalogram (EEG) theta activity and locomotor speed in both spontaneous and forced walking conditions was studied in rats after vigabatrin injection (500 mg/kg i.p.). Vigabatrin increased the percentage of time that rats spent being immobile. During spontaneous walking in the open field, the speed of locomotion was increased by vigabatrin, while theta peak frequency was decreased. Vigabatrin also reduced the theta peak frequency during forced (speed controlled) walking. There was only a weak positive correlation (r=0.22) between theta peak frequency and locomotor speed for the saline condition. Furthermore, vigabatrin abolishes the weak relationship between speed of locomotion and theta peak frequency. Vigabatrin and saline did not differ in the slope of the regression line, but showed different offset points at the theta peak frequency axis. Thus, other factors than speed of locomotion seem to be involved in determination of the theta peak frequency.

The effects of vigabatrin on spike and wave discharges in WAG/Rij rats.

The effects of vigabatrin, which increases GABA concentrations by inhibiting GABA transaminase, on spike and wave discharges (SWDs) in the electroencephalogram of WAG/Rij rats were studied. Vigabatrin increased the incidence and duration of the SWDs, suggesting a quantitative GABA(A)ergic involvement in the mechanism(s) underlying the starting and stopping of an ongoing SWD. Also, vigabatrin decreased the SWD peak frequency, suggesting an important role of GABA(B) in the mechanism(s) underlying the peak frequency of the SWDs. Vigabatrin gradually changed the course of the hazard rates of the SWD durations, suggesting a qualitative GABAergic role in the mechanism(s) underlying the stopping of an ongoing SWD.

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.

Starting and stopping mechanisms of absence epileptic seizures are revealed by hazard functions.

We show that the hazard function provides useful information about the starting and the stopping mechanisms of absence epileptic seizures. The hazard function quantifies changes in the probability that an event (respectively, the starting and the stopping of a seizure) occurs in some small time interval given that it has not occurred yet. It informs us about changes in the concentration of endogenous substances that modulate the neuronal signalling properties of (parts of) the brain. In a pharmacological experiment, we used the hazard function to study the effect of a GABA-transaminase inhibitor (vigabatrin) on the starting and the stopping mechanisms of absence epileptic seizures in a genetic rat model of absence epilepsy (the WAG/Rij rat). This experiment showed that a high GABA level changed the stopping mechanism of the absence epileptic seizures, creating much better conditions for very long seizures to develop. With respect to the starting mechanism, it was found that both with a high and a low GABA level, there was evidence for a recovery mechanism that decreases the probability that a new seizure starts. Initially, this probability is larger with a high GABA level, but gradually it converges to the same constant baseline probability as in the condition with a low GABA level.