Cerebellar contribution to absence epilepsy.

The new aggregate data analyses revealed the earlier missing role of cerebellum long-term electrical stimulation in the absence epilepsy. Neurophysiologic data gained by authors favor that cerebellar serial deep brain stimulation (DBS) (100 Hz) causes the transformation of penicillin-induced cortical focal discharges into prolonged 3,5-3,75 sec oscillations resembling spike-wave discharges (SWD) in cats. Such SWDs were not organized in the form of bursts and persisted continuously after stimulation. Therefore, the appearance of prolonged periods of SWD is regarded as a tonic cerebellar influence upon pacemaker of SWD and might be caused by the long-lasting DBS-induced increase of GABA-ergic extrasynaptic inhibition in the forebrain networks. The absence seizure facilitation caused by cerebellar DBS was discussed with the reviewed data on optogenetic stimulation, neuronal activity of cerebellar structures, and imaging data.

Diazepam and electrical stimulation of paleocerebellar cortex inhibits seizures in pentylenetetrazol­kindled rats.

The cerebellum is a potent anti­epileptic target for deep brain stimulation in patients with drug­resistant epilepsy. The effects of such stimulation, however, may also favor seizure activity. Our goal was to investigate the effect of cerebellar electrical stimulation (ES) alone and in combination with the anti­epileptic drug diazepam (DIA) on seizure outcome. We used a rat model of pentylenetetrazol kindling, which is characterized by seizures followed by deteriorations in central benzodiazepine­GABAA (BDZ­GABAA) receptors. We tested the effects of ES alone and in combination with DIA (0.1 and 1.0 mg/kg) on seizures. Our data demonstrated: 20 ES trials can prevent the recurrence of clonic­tonic kindled seizures, administration of either DIA­0.1 or ES (5 trials) alone is ineffective on seizures, and combining DIA­0.1 and 5 ES or DIA­1.0 and 5 ES caused an additive effect, prolonged the latency to seizure onset, and prevented recurrence of clonic­tonic seizures. We also observed that ES alone produced either facilitation or inhibition of seizures on EEG. In contrast, the same ES inhibited EEG seizures when delivered after a combination of DIA­1.0 and 5 ES and ultimately prevented the facilitation of the discharges. Lastly, we demonstrated that seizure suppression is intensified when cortical ES is performed after DIA administration. Our data supported the hypothesis that both BDZ­GABAA receptor activity along with cerebellar output comprise the potential mechanisms underlying the peculiar effects of deep brain stimulation in the cerebellum on seizures.

Anxiolytic and antidepressive effects of electric stimulation of the paleocerebellar cortex in pentylenetetrazol kindled rats.

Anxiety and depression are component of interictal behavioral deteriorations that occur as a consequence of kindling, a procedure to induce chronic epilepsy. The aim of this study was to evaluate the possible effects of electrical stimulation (ES) of paleocerebellar cortex on anxiety and depressive-like behavior in a PTZ kindled epilepsy model. Kindling was induced via pentylenetetrazol (PTZ) (25.0 mg/kg IP daily) during three weeks. Locomotion in open field, elevated plus-maze (EPM) and Porsolt forced swimming test have been used for the assessment of anxiety and depression-like behavior. ES (100 Hz) has been delivered to V-VII lobules of vermal cortex of kindled rats. ES of paleocerebellum reversed kindling-induced reduction of crossings of central squares, increased rearings, and decreased the number of defecations in open field. The duration that kindled animals spent in the open arms of the EPM increased in post- ES period, and the number of enterings into the closed arms of the EPM decreased. The duration of the immobility response in the swimming test in kindled rats was reduced after ESs of paleocerebellum. In all: ES of paleocerebellar structures suppressed anxious and depressive-like behavior in PTZ-kindled rats.

Influence of transcranial magnetic stimulation on spike-wave discharges in a genetic model of absence epilepsy.

Transcranial magnetic stimulation (TMS) impulses, (0.5 Hz, 3 impulses) were presented at threshold intensity to male WAG/Rij rats. One group received stimuli, which involved motor responses of hindlimbs, rats of the second group received sham stimulation. Electrocorticograms (ECoG) were recorded before and up to 2 hr from the moment of transcranial magnetic stimulation. It was established that such stimulation engendered a reduction of spike-wave discharge (SWD) bursts duration. This effect was most pronounced in 30 min from the moment of cessation of stimulation, when a decrease of 31.4% was noted in comparison with sham-stimulated control group. The number of bursts of spike-wave discharges was reduced, but did not reach significant difference when compared both with pre-stimulative base-line level and with sham-stimulated control rats. Bursts of spike-wave discharges restored up to pre-stimulative level in 90-150 minutes from the moment of cessation of transcranial stimulation. It can be concluded that transcranical magnetic stimulation possessed an ability to engender short-time suppression of bursts of spike-wave discharges in WAG/Rij rats.

Are there different mechanisms of synchronization in the course of spike-wave discharges (SWDs) burst development in WAG/Rij rats?

In WAG/Rij rats the pair linear correlation r was calculated for bipolar recordings in fronto-temporal, fronto-occipital and occipito-temporal zones of both hemispheres as well as in paleocerebellar cortex (culmen). It was shown that development of SWD bursts resulted in interhemispheric decreases of correlation between the right occipito-temporal cortical region on one side, and left fronto-temporal on the contralateral side. Towards the end of SWD, we found an increased interhemispheric correlation between left fronto-temporal and right fronto-occipital cortical zones, as well as, between both fronto-temporal zones. Paleocerebellum correlates at a weak to moderate level during different periods of SWD burst generation.

Causes and consequences of pathogenic processes in evolution: implications from experimental epilepsy in animals.

Examples from experimental epilepsy in animals are used to illustrate the view that a crucial role of the transfer of mechanisms from compensatory into pathogenic (e.g. lethal ones in the course of a disease), is played by the power of pathologic stimuli. In the genesis of epilepsy it is suggested that a critical increase of endogenous factors may underlie the conversion of the absence form of epilepsy into a generalized self-supporting form. The ability to precipitate endogenous self-augmenting mechanisms of diseases may have increased in the course of evolution. The lethal result of a serious pathogenic process leads to the suggestion that organisms cope with the disease by dying. This prevents spreading of the putative infectious disease within the population. This mechanism of disease aggravation could play a role in the survival of the species and in further evolutionary progress. This may explain why certain species may have survived in evolution and supports the theory of synthetic evolution.

TNF-alpha in cerebral cortex and cerebellum is affected by amygdalar kindling but not by stimulation of cerebellum.

One group of male Wistar rats was kindled by electrical stimulation (ES) of the amygdala, one group was sham operated, while other rats were stimulated in the paleocortex of the cerebellum. The kindled generalized clonictonic seizures were followed by a net increase of the tumor necrosis factor-alpha (TNF-alpha) content both in the cerebral cortex (from 34.7 +/- 6.0 to 76.7 +/- 6.9 pg/mg of wet brain tissue) and cerebellum (from 106.6 +/- 17.7 to 193.8 +/- 29.8 pg/mg of wet tissue) in comparison with the data from sham-operated animals. This effect was observed 24 h after the induction of the last kindled seizures. ES of the cerebellum (100 Hz) was not followed by any changes in TNF-alpha content in the cortex and cerebellum. Moreover, kindling was not followed by any changes in thiol/disulfide system, but ES of the paleocerebellum induced an increase in free thiol groups in the cortical tissue. It can be concluded that the increase in TNF-alpha content is specific for the kindling process and that the antiepileptic effects of cerebellar ES might be realized via an intensification of antioxidative processes in the neural tissue.