Mesial temporal lobe epilepsy (MTLE) is a common medically refractory neurological disease. Deep brain electrical stimulation (DBS) of grey matter has been used for MTLE with limited success. However, stimulation of a white matter tract connecting the hippocampi, the ventral hippocampal commissure (VHC), with low frequencies that simulate interictal discharges has shown promising results, with seizure reduction greater than 98% in bilateral hippocampi during stimulation and greater than 50% seizure reduction in bilateral hippocampi after treatment. A major hurdle to the implementation and optimization of this treatment is that the mechanisms of seizure reduction by low frequency electrical stimulation (LFS) are not known. The goal of this study is to understand how commissural fibre tract stimulation reduces bilateral hippocampal epileptic activity in an in vitro slice preparation containing bilateral hippocampi connected by the VHC. It is our hypothesis that electrical stimuli induce hyperpolarization lasting hundreds of milliseconds following each pulse which reduces spontaneous epileptic activity during each inter-stimulus interval (ISI). Stimulus-induced long-lasting-hyperpolarization (LLH) can be mediated by GABAB inhibitory post-synaptic potentials (IPSPs) or slow after-hyperpolarization (sAHP). To test the role of LLH in effective bilateral seizure reduction by fibre tract stimulation, we measured stimulus-induced hyperpolarization during LFS of the VHC using electrophysiology techniques. Antagonism of the GABAB IPSP and/or sAHP diminished stimulus-induced hyperpolarization concurrently with LFS efficacy (greater than 50% reduction). Blocking both the GABAB IPSP and sAHP simultaneously eliminated the effect of electrical stimulation on seizure reduction entirely. These data show that LFS of the VHC is an effective protocol for bilateral hippocampal seizure reduction and that its efficacy relies on the induction of long-lasting hyperpolarization mediated through GABAB IPSPs and sAHP. Based on this study, optimization of the timing of LFS and LFS-induced-LLH may lead to improved outcomes from DBS treatments for human epilepsy.
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机译:颞叶颞叶癫痫(MTLE)是一种常见的医学难治性神经系统疾病。灰质的深部脑电刺激(DBS)已用于MTLE,但效果有限。然而,低频模拟海马间质放电的连接海马,腹侧海马连合(VHC)的白质束刺激显示出令人鼓舞的结果,在刺激过程中双侧海马的癫痫发作减少大于98%,癫痫发作大于50%治疗后双侧海马减少。实施和优化这种治疗方法的主要障碍是通过低频电刺激(LFS)减少癫痫发作的机制尚不清楚。这项研究的目的是了解在通过VHC连接的包含双侧海马体的体外切片制剂中,连合纤维束刺激如何降低双侧海马体癫痫活性。我们的假设是,电刺激会在每个脉冲后持续持续数百毫秒的超极化,从而降低每个刺激间间隔(ISI)的自发性癫痫活动。刺激诱导的持久超极化(LLH)可以通过GABAB抑制的突触后电位(IPSPs)或缓慢的超极化后(sAHP)介导。为了测试LLH在通过纤维束刺激有效减少双边癫痫发作中的作用,我们使用电生理学技术在VHC的LFS期间测量了刺激诱导的超极化。 GABA B IPSP和/或sAHP的拮抗作用可降低刺激诱导的超极化,同时降低LFS功效(降低幅度超过50%)。同时阻断GABAB IPSP和sAHP可以完全消除电刺激对减少癫痫发作的影响。这些数据表明,VHC的LFS是减少双侧海马癫痫发作的有效方案,其功效依赖于诱导通过GABAB IPSP和sAHP介导的持久性超极化。根据这项研究,优化LFS和LFS诱导的LLH的时机可能会改善DBS对人类癫痫的治疗效果。
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