The Effects Of Low Frequency Stimulation In Deep Brain Regions On Seizures Induced By Amygdaloid Kindling

A significant proportion of epileptic patients have pharmacoresistant epilepsy. Among various seizure phenotypes,temporal lobe epilepsy is the most common in adults.The incident of intractable epilepsy is very high in temporal lobe epilepsy. Current treatments for intractable epilepsy are far from satisfactory.Deep brain stimulation(DBS)is emerging as a new approach for treatment of pharmacoresistant epilepsy,including temporal lobe epilepsy.DBS employing high frequency stimulation(HFS)is administered in several regions to control seizures,with mixed successes.However,HFS inhibits the normal function of the stimulation target and may cause tissue injury,and may even aggravate seizures.Low frequency stimulation(1-3 Hz,LFS)results in strong and long-lasting inhibition of seizure activity induced by kindling.LFS lacks the tetanizing property of higher frequencies(like 5 Hz),which can trigger kindling seizures.So far,LFS has usually been delivered to the epileptic focus(or kindling focus)in previous studies. Recently,our lab reported that LFS(1 Hz)of central piriform cortex markedly inhibits both acquisition and expression of amygdaloid kindled seizures in rats.This was the first demonstration that a brain region other than the epileptic focus can be used as the target of LFS to produce an anticonvulsant effect.However,there is concern that prolonged and direct stimulation of structures in the limbic system may have cognitive and emotional side effects(Gloor et al.,1982;Meletti et al.,2006). Furthermore,whether LFS in regions other than epileptic foci or central piriform cortex can induce inhibition of kindling seizures is less clear.Several lines of evidence suggested that the cerebellar fastigial nucleus(FN)is closely linked to seizure susceptibility and cerebral excitability.The FN has ample connections with a wide range of brain areas,include:the amygdala,temporal cortex, hippocampus,mediodorsal thalamic nucleus,parafascicular thalamic nucleus,ventral medial thalamic nucleus,vestibular nucleus.Our present study concentrates on the effects of LFS in the FN on amygdaloid kindling seizures,which is a classical model of temporal lobe epilepsy.1.Low frequency stimulation of the FN inhibits amygdaloid kindling acquisition in ratsStimulation at 1Hz(15min train of 0.1 ms pulses,100μA),but not at 3Hz,in the ipsilateral FN immediately after the daily kindling stimulus(1s train of 1ms pulses at 60Hz and 100-300μA)significantly inhibited the seizure stage and afterdischarge duration in kindling acquisition.Neither 1 Hz nor 3 Hz stimulation of the contralateral FH had any significant effect.It is interesting that delaying delivery (immediately after the cessation of afterdischarge)of LFS in the ipsilateral FN accelerated the rate of kindling acquisition compared to controls.Additionally,Lesion of ipsilateral FN abolished the inhibitory function of the FN stimulation at 1Hz on seizure acquisition.Our study suggests that LFS of targets outside the limbic system, such as the FN,has a significant antiepileptogenic action,and the effects of LFS depend on the frequency and timing of stimulation.In addition,the antiepileptic function of the FN stimulation is mediated by the intrinsic neurons of the FN.2.Pathways involved in the antiepileptogenic function of LFS in the FNTo elucidate of the pathways involved in the antiepileptogenic function of LFS in the FN,we evaluated the effect of LFS of the FN in animals with a lesion in bilateral vestibular nuclear(VN),ventral medial thalamic nucleus(VM), parafascicular thalamic nucleus(PF),ventral hippocampus(VHP)or dorsal hippocampus(DHP),respectively.Lesions of these brain regions were induced by ibotenic acid.Ten days later,the animals with lesion or sham received daily kindling stimulus in the amygdala(1s train of 1ms pulses at 60Hz and 100-300μA).Shortly after the kindling stimulation,they were subjected to LFS of the FN(15 min train of 0.1ms pulses at 1Hz,100μA).Lesions of the VN,PF,VM or DHP produced no appreciable effect on the protective effect induced by LFS of the FN.However,a lesion of VHP significantly reversed the effect of LFS of the FN.Our preliminary data suggest that the FN-VHP pathway is involved in the antiepileptogenic function of LFS in the FN.3.The effects of mediodorsal thalamic stimulation on amygdaloid kindling seizures and other seizure modelsThe mediodorsal thalamic nucleus(MD)has dense direct connections with the FN.Since inhibition of the MD significantly suppressed limbic seizures.Lesion of the MD is not a suitable method for evaluating the FN-MD pathway in the antiepileptic function of LFS in the FN.In this study,we directly delivered LFS in the MD,and evaluate its effect on amygdaloid kindling seizures.Additionally,effects of HFS of the MD were observed;the effects of MD stimulation on generalized seizures were also appraised.Both LFS(0.1 ms pulses at 1 Hz,100μA)and HFS(0.1 ms pulses at 100 Hz,100-200μA)of the MD did not significantly changed seizure development induced by amygdaloid kindling.LFS of the MD did not cause apparent adverse effect while HFS did.HFS of the MD at 100 Hz induced afterdischarge at a threshold intensity of 630±61μA(500-850μA,n=5).On the other hand,HFS of the ipsilateral or bilateral MD at 100 Hz decreased the seizures stage,the number of convulsive episodes and seizure duration in acute pentylenetetrazole-induced seizures.Bilateral MD stimulation at 100 Hz or 1 Hz did not change the seizure severity in maximal electroshock-induced seizures.Our findings do not support involvement of the FN-MD pathways in the antiepileptogenic function of LFS in the FN.The effect of LFS is brain region-dependent.HFS of the MD suppressed generalized seizure of cortical origin probably by utilizing a mechanism which is distinct from that underlying LFS.In conclusion,our study demonstrates that LFS of targets outside the limbic system,such as the FN,has a significant antiepileptogenic action;and the effects of LFS depend on the frequency and timing of stimulation.This antiepileptogenic action is mediated by intrinsic FN neurons and through FN-VHP pathway.LFS of the MD,a region with ample connections with the FN,has no significant effect on amygdaloid kindling seizures.The effect of LFS on seizure activity depends on the stimulation target.