Abstract
The cerebellum is a potent anti‑epileptic target for deep brain stimulation in patients with drug‑resistant 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 anti‑epileptic drug diazepam (DIA) on seizure outcome. We used a rat model of pentylenetetrazol kindling, which is characterized by seizures followed by deteriorations in central benzodiazepine‑GABAA (BDZ‑GABAA) 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 clonic‑tonic kindled seizures, administration of either DIA‑0.1 or ES (5 trials) alone is ineffective on seizures, and combining DIA‑0.1 and 5 ES or DIA‑1.0 and 5 ES caused an additive effect, prolonged the latency to seizure onset, and prevented recurrence of clonic‑tonic 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 DIA‑1.0 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 BDZ‑GABAA receptor activity along with cerebellar output comprise the potential mechanisms underlying the peculiar effects of deep brain stimulation in the cerebellum on seizures.
Highlights
Epilepsy is a neurological disease characterized by the emergence of spontaneous recurrent seizures lead‐ ing to long‐term disability or death (Fisher et al, 2014)
Kindling development was demonstrated by an initial phase of “minor” epileptiform manifestations characterized as absence‐like seizures observed after 2 to 7 PTZ administrations
We have established that electrical stimulation (ES) (100 Hz, 20 trials of ES) of the paleocerebellar cortex prevented generalized clonic‐tonic seizure seizures induced by a testing dose of PTZ (30.0 mg/kg) in PTZ‐kindled rats
Summary
Epilepsy is a neurological disease characterized by the emergence of spontaneous recurrent seizures lead‐ ing to long‐term disability or death (Fisher et al, 2014). The remaining population of patients with epilepsy are resistant to anti‐epileptic drugs and require alternative therapeutic approaches (Kim et al, 2017). Cerebellar nuclei and paleocortex are known as an‐ ti‐convulsive targets for electrical stimulation (ES) (Re‐ imer et al, 1967; Ojemann 1980; Velasco et al, 2005; Da‐ vis, 2009; Fountas et al, 2010; Fisher and Velasco, 2014; Klinger and Mittal, 2016; Kim et al, 2017; Sprengers et al, 2017).
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