Properties of the convulsive threshold determined by direct cortical stimulation in rats

doi:10.1016/0920-1211(92)90031-N

Epilepsy Research

Volume 12, Issue 2, July 1992, Pages 111-120

https://doi.org/10.1016/0920-1211(92)90031-N Get rights and content

Abstract

The threshold for convulsions in rats can be determined by applying ramp-shaped pulse trains directly to the cerebral cortex in rats, which provides a convenient model for investigating anticonvulsant drug effects. This study was undertaken to extend a previous study on the properties of this model. Analysis of the cortical EEG, recorded from two motor areas and one somatosensory area, showed that the start of clonic forepaw movement, marking the convulsive threshold, is preceded by the appearance of sharp negative spikes at the electrodes in the two motor areas. There was a strong linear relation between the clinically determined threshold and the EEG derived threshold (r = 0.93, slope 0.99, SD 0.04), confirming the validity of the clonic movement threshold as an objective and accurate measure. Examination of the seizure patterns seen with various degrees of suprathreshold stimulation led to the distinction between a threshold for localized and for generalized seizure activity (TLS and TGS respectively). Carbamazepine selectively and strongly increased the TGS, whereas it only slightly affected the TLS, indicating that cortical stimulation can be used to select drugs that specifically prevent seizure spread, for which carbamazepine is a prototype. It was found that the TLS was not affected by testing at intervals as short as 1 min, provided that no self-sustained seizures were induced. However, if the TGS was passed, the TLS was increased substantially for at least 10 min, while complete recovery could take several hours. The intensity of stimulation, rather than seizure duration, appeared to be the determinant for the TLS increase. There was no seasonal influence or effect of stimulation electrode depth. There may be a minor effect of experience in using the test. It was concluded that the observed variability was mainly an intrinsic property of the individual animal.

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Electrical stimulation of local brain regions or whole brain electroshocks can produce seizures. The most well-known in vivo seizure models are the self-sustained status epilepticus models (SSSE), and the cortical stimulation model (CSM). The SSSE models can be used to study the mechanism that may explain why seizures become self-sustained, and why SE becomes intractable. This model is also typically used as chronic model for temporal lobe epilepsy. The CSM model can be used for repeated antiepileptic drug (AED) effect measurements. Because in this model the threshold for local seizure generation does not change over repeated stimulations, the number of animals needed to test dose-effect relations can be reduced. Electroshock models can be used to test efficacy of potential antiepileptic drugs. The most well-known whole brain electrical stimulation models are the maximal electroshock model (MES) and the 6 Hz psychomotor seizure model, both mainly in rodents. Even at the present time, these models are still the most widely used high-throughput drug screening models.
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Surgical implantation of microwire electrode arrays was performed as previously described for use with cortical stimulation (CS) model of focal motor seizures (Nelson et al., 2010). In short, five, male, inbred Sprague Dawley rats were used with a CS model, where it has been shown that repeated cortical stimulations result in measurable epileptiform afterdischarge (EAD) with a high reliability of clinical seizure initiation (Voskuyl et al., 1989, 1992; Della Paschoa et al., 1997; Krupp and Loscher, 1998; Mares et al., 2002; Mares and Kubova, 2006; Nelson et al., 2010), as measured by a modified Racine scale (Racine, 1972, 1975). Electrode arrays were implanted in the primary motor/somatosensory cortical (M1/S1HL) region of the right hemisphere (AP: 0 mm; ML: +1.5 mm), according to Paxinos and Watson (2005).
A modified cortical stimulation model was used to investigate the effects of varying the synchronicity and periodicity of electrical stimuli delivered to multiple pairs of electrodes on seizure initiation. In this model, electrical stimulation of the motor cortex of rats, along four pairs of a microwire electrode array, results in an observable seizure with quantifiable electrographic duration and behavioural severity. Periodic stimuli had a constant inter-stimulus intervals across the two-second stimulus duration, whilst synchronous stimuli consisted of singular biphasic, bipolar pulses delivered to the four pairs of electrodes at precisely the same time for the entire two second stimulation period. In this way four combinations of stimulation were possible; periodic/synchronous (P/S), periodic/asynchronous (P/As), aperiodic/synchronous (Ap/S) and aperiodic/asynchronous (Ap/As). All stimulation types were designed with equal pulse width, current intensity and mean frequency of stimulation (60 Hz), standardizing net charge transfer. It was expected that the periodicity of the stimulus would be the primary determinant of seizure initiation and therefore severity and electrographic duration. However, the results showed that significant differences in both severity and duration only occurred when the synchronicity was altered. For periodic stimuli, synchronous delivery increased median seizure duration from 5 s to 13 s and increased median Racine severity from 1 to 3. In the aperiodic case, synchronous stimulus delivery increased median duration from 5.5 s to 11 s and resulted in seizures of median severity 3 vs. 0 in the asynchronous case. These findings may have implications for the design of future neurostimulation waveform designs as higher numbers of electrodes and stimulator output channels become available in next generation implants.
Seizure severity and duration in the cortical stimulation model of experimental epilepsy in rats: A longitudinal study
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The aim of this study was to determine the current intensities necessary to elicit three levels of varying EEG and behavioural phenomena with electrical stimulation, and also to determine the consistency of the EEG and behavioural components of the triggered seizures over time. Electrical stimulation of the primary motor/somatosensory cortex was performed in 16 adult rats with multichannel microwire electrode arrays. Stimulation was delivered at a frequency of 60 Hz (1 ms pulse width), for 2 s duration, as biphasic rectangular pulses over four of the eight available electrode pairs. Current intensity thresholds for interruption of normal behaviour, epileptiform afterdischarge (EAD) longer than 5 s and motor seizures with Racine severity greater than 3 were not correlated to time post-surgery. The Racine threshold was shown to be negatively correlated to the EAD duration and Racine severity of seizures elicited in the following sessions. Seizures were reliably generated in rats through cortical stimulation with microwire electrode arrays and these seizures were not shown to be subject to any kindling type effects up to 53 days post-implantation. Both the electrographic duration and behavioural severity of stimulated seizures remained, on average, constant during this experimental period. Approximately one-third of stimulations did not cause observable motor seizures and of those that did result in seizures, forelimb clonus was the most common manifestation and the mean EAD duration was 18.5 s. No damage beyond that caused by surgical implantation of electrodes was observed in the histological analyses of stimulated and non-stimulated tissue. The consistency, duration and severity of seizures within this timeframe make this cortical stimulation model suitable for investigations into novel therapeutic interventions for epilepsy that require a known seizure focus.
Seizure elements and seizure element transitions during tonic-clonic seizure activity in the synapsin I/II double knockout mouse: A neuroethological description
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These findings are consistent with the suggestion that elaborate running seizures reflect brainstem activity [24–26]. Moreover, these findings are consistent with the observations of truncus-dominated and myoclony-like activity in seizures evoked by kindling [27], direct electrical stimulation [28], and kainate [29] or pilocarpine [30] application to forebrain structures where the seizures presumably reflect primarily activity in cortex and cortically related structures. Chains of events similar to those suggested by our findings in the Syn-DKO mouse have been proposed to underlie the seizures of the EL mouse [31].
Inactivation of genes for the synaptic terminal proteins synapsin I and synapsin II leads to development of epileptic seizures in mice (Syn-DKO mice) in which no other behavioral abnormalities or any gross anatomical brain deformities have been reported. In humans, mutated synapsin I is associated with epilepsy. Thus, the Syn-DKO mouse might model human seizure development. Here we describe a neuroethological analysis of behavioral elements and relationships between these elements during seizures in Syn-DKO mice. The seizure elements belong to one of three clusters each characterized by specific patterns of activity: truncus-dominated elements, myoclonic elements, and running-fit activity. The first two clusters, constituting the majority of seizural activity, evolve quite differently during ongoing seizure activity. Whereas truncus-dominated elements unfold in a strict sequence, the myoclonic elements wax and wane more independently, once myoclonic activity has started. These differences may point to neurobiological mechanisms relevant to both rodent and human epilepsies.
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Cortical epileptic afterdischarges in immature rats are differently influenced by NMDA receptor antagonists
2005, European Journal of Pharmacology
Epileptic afterdischarges elicited by stimulation of sensorimotor cortex were chosen to test anticonvulsant effects of NMDA receptor antagonists in developing rats (12, 18 and 25 days old) with implanted electrodes. Afterdischarges were elicited four times with 10-min intervals in the experiments with dizocilpine and 20 min with the other two drugs. Dizocilpine (0.5 or 1 mg/kg), CGP 40116 (0.1, 0.5 or 1 mg/kg) or 2-amino-7-phosphonoheptanoic acid (AP7, 30 or 60 mg/kg) was injected intraperitoneally between the first and second stimulation. Intensity of movements accompanying stimulation was diminished regularly only by CGP 40116. Duration of afterdischarges was reduced and intensity of clonic seizures was decreased by CGP 40116 in all age groups; dizocilpine exhibited similar action in 25- and 18-day-old rats, AP7 only in 25-day-old animals. Anticonvulsant action of the three NMDA antagonists exhibited different developmental profiles in our model; this difference might be due to developmental changes of NMDA receptors.

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Properties of the convulsive threshold determined by direct cortical stimulation in rats

Abstract

Brain Res. Rev.

Brain Res.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

Electroenceph. Clin. Neurophysiol.

Epilepsy Res.