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Low-frequency stimulation (LFS) has been considered as an option for the treatment of intractable epilepsy. However, previous data showed that LFS of certain brain regions only exerts its effect within a very narrow therapeutic time window, which lasts from seconds to tens of seconds, thus restricting its clinical application. The present study was designed to determine whether there exists a target with a wider therapeutic window for LFS treatment. Therefore, evoked seizures in the rat were induced by amygdala kindling and spontaneous seizures were induced by pilocarpine. The effects of different modes of LFS at the subiculum on the progression and severity of evoked seizures and the frequency of spontaneous seizure were evaluated. We found that (i) LFS at 1 Hz delivered to the subiculum before and immediately after the kindling stimulations, or after the cessation of afterdischarge (afterdischarge duration, ADD) decreased the seizure stages and shortened the ADD both in seizure acquisition and expression in amygdaloid-kindled seizures. In addition, even LFS delivered after duration of double the ADD prolonged the kindling progression. (ii) LFS delivered at 1 Hz, but not 0.5, 3 or 130 Hz, immediately after the cessation of kindling stimulations retarded the progression of kindling seizures. (iii) Pilocarpine-induced spontaneous seizures were completely inhibited by 1 Hz LFS. Thus, these results demonstrated that LFS of the subiculum has a wide therapeutic time-window for temporal lobe epilepsy treatment in rats, suggesting that the subiculum may be a promising and suitable target for clinical application.

Histamine plays a suppressive role in seizure. The tuberomammillary nucleus (TM) is the only locus of histaminergic neurons in the brain. To determine whether deep brain stimulation (DBS) of the TM provides protection against seizures, we tested the effects of low-frequency stimulation (LFS, 1 Hz), high frequency stimulation (HFS, 100 Hz), and electrolytic lesions of the TM on seizures generated by amygdaloid kindling, pentylenetetrazol (PTZ) and maximal electroshock (MES) in rats. LFS of TM accelerated the progression of behavioral seizure stage and increased the mean afterdischarge duration (ADD) during acquisition of amygdaloid-kindling seizures, but had no considerable anticonvulsive effect in fully kindled animals. It augmented the MES-induced seizures as well, but had no appreciable effects on PTZ-kindled seizures. In addition, both HFS and bilateral lesions of the TM exacerbated the progression of amygdaloid-kindling seizures. These results suggest that specific negative sites for DBS exist in the brain, such as the TM. This study indicates that it is crucial to choose a suitable target for DBS in the clinical treatment of epilepsy.

Low-frequency stimulation (LFS) has been considered as a new option for the treatment of intractable epilepsy. The present study was designed to determine whether LFS of the kindling focus given at different time points after seizures exert different roles on kindling seizures. Our results showed that: (i) In kindling animals, LFS delivered immediately after cessation of the kindling stimulus inhibited the seizure stage during kindling acquisition, whereas LFS delivered after the cessation of afterdischarge accelerated the kindling progression to stages 1 and 2. (ii) In fully kindled animals, when using the generalized seizure threshold current as the kindling stimulus, immediate LFS decreased the incidence of generalized seizures and the average seizure stage as well as shortened the cumulative generalized seizure duration (GSD). However, delayed LFS prolonged the cumulative GSD and afterdischarge duration. Our study indicates that there is a time-dependent aspect of LFS treatment, and immediate LFS has anti-epileptogenic action.

Low-frequency stimulation (LFS) of the kindling focus or the piriform cortex inhibits kindling epileptogenesis, but whether LFS of brain targets outside the limbic system has anticonvulsive actions remain unknown. The current study was designed to investigate the effect of LFS of the cerebellar fastigial nucleus (FN) on seizure progression induced by amygdaloid kindling. Stimulation at 1 Hz (15-min train of 0.1-ms pulses, 100 μA), but not at 3 Hz, in the ipsilateral FN immediately after the daily kindling stimulus (1-s train of 1-ms pulses at 60 Hz and 100–300 μA) 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. Our study suggests that LFS of targets outside the limbic system, such as the FN, may have a significant anti-epileptogenic action, and the effects of LFS depend on the frequency and timing of stimulation.