低频率深部脑刺激对大鼠电点燃癫痫的干预作用及其机制研究
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摘要
癫痫是神经科常见突发性脑功能紊乱综合征,一旦发病往往相伴终身,其反复发作容易引发意外更会逐渐损害患者认知功能。由于发病机制尚不清楚,药物及手术等临床方法治疗癫痫效果有限。约30%的癫痫患者(颞叶癫痫患者最为常见)会对抗癫痫药物耐受,成为难治性癫痫。外科手术切除灶点不但适用患者人群较少而且对脑组织造成较大损伤。如何防治难治性癫痫发病一直是临床癫痫治疗的重大难题。
低频率电刺激(low frequency stimulation, LFS)具有可逆性、可调性和微创性等优点,为难治性癫痫治疗提供新的选择。LFS癫痫灶点及灶点外靶点可以有效抑制病人和实验动物的癫痫发作。但是由于机制不清,LFS对癫痫的治疗尚有很多不明确的地方和不少相互矛盾的报道,限制了其临床应用；刺激靶点脑区及参数的优化还值得进一步研究。内嗅皮层(entorhinal cortex, EC)是信息进入海马的门户,是LFS治疗颞叶癫痫的潜在靶点。此外,近来临床开发出一种依据患者脑电变化反馈性给予电刺激的闭环刺激模式(closed-loop),相对于以往程序化定时定量的开环模式(open-loop)可能具有更小的副作用。然而,新的技术带来了新的问题：闭环刺激模式检测脑电变化会带来刺激延时,这可能会影响LFS的抗癫痫作用。课题组前期在大鼠杏仁核点燃癫痫模型中已经发现LFS小脑顶核和杏仁核的抗癫痫作用可能受癫痫发作状态的影响,提示LFS可能更适用于closed-loop模式。因此,我们首先观察了LFS EC是否具有抗癫痫作用并且评价了刺激延时对其抗癫痫作用的影响。
另一方面,癫痫环路的概念逐渐被人们接受和关注,癫痫网络既包括灶点及周边网络也涉及一些遥远的脑区结构。LFS直接作用癫痫灶点(如点燃灶点)及其他环路关键节点的作用目前都还不清楚。海马齿状回(dentate gyrus, DG)区域是颞叶癫痫环路的关键节点,被认为是癫痫形成和传播的关键区域之一。在颞叶癫痫患者及动物模型中,海马DG区抑制性中间神经元大量丢失,而大量存活的颗粒细胞表现出异常的兴奋性、分布和轴突苔藓纤维出芽。课题组的前期研究发现,在杏仁核点燃癫痫的形成过程伴随着DG区星形胶质细胞内与谷氨酸代谢相关的关键酶——谷氨酰胺合成酶(glutamine synthetase)的一过性增加,并且在形成过程中关键时间点选择性抑制其活性可以有效抑制癫痫形成,提示DG区在癫痫发病中的关键作用。解剖学上,DG区主要接受EC直接投射(perforant pathway, PP通路),DG区颗粒细胞被认为对来自EC传入进行调节过滤。更有意思的是,DG区颗粒细胞的兴奋性、结构功能及神经再生等都会受EC的调节。LFS EC有可能通过调节DG区神经活动干预癫痫的产生和传播。
因此,本课题进一步观察了LFS对杏仁核点燃灶点直接作用并意外发现了灶点LFS的极性特异性效应；同时我还在麻醉状态的颞叶癫痫模型中观察了LFSEC对DG区的神经元活动和痫样放电的作用,对LFS EC抗癫痫作用的环路机制进行了初步的探讨。模式。同时,我们还在AD过程中发现LFS作用的有效“治疗时间窗”,提示时间延时可能是临床LFS closed-loop模式应用的关键。
第二部分低频率电刺激杏仁核对大鼠杏仁核电点燃癫痫极性依赖性效应
电极极性与点燃刺激相同的双极LFS能有效抑制大鼠杏仁核电点燃癫痫形成过程,而电极极性与点燃刺激相反的双极LFS没有明显抗癫痫作用。正极而非负极的单极LFS能有效抑制大鼠杏仁核电点燃癫痫形成过程和大发作。双极LFS抗癫痫作用略强于单极LFS。进一步研究发现,LFS的正电极(无论是双极还是单极)降低杏仁核灶点的EEG能量,而LFS的负电极增加了杏仁核灶点的EEG能量。最主要EEG能量变化频段为0.5-4Hz的delta波段。Delta波段能量在杏仁核点燃癫痫形成过程中特异性上升。这些的结果直接证明癫痫电点燃灶点LFS存在极性特异性,并且其机制可能与LFS正负极对杏仁核活性尤其是Delta波段的活性存在不同的作用有关。因此,电极极性特别是正电极可能是影响LFS抗癫痫作用的另一个关键因素。
第三部分低频率电刺激内嗅皮层抗癫痫作用的潜在环路机制初步研究
在乌拉坦麻醉大鼠在体实验中我们发现：(1)单个脉冲刺激EC和PP通路会短暂抑制DG区神经元放电；Hz LFS EC能显著减低DG区神经元放电频率,并随着时间增加抑制效果加强。(2)预给15min LFS EC可以抑制DG区最大齿状回兴奋(Maximal dentate activation, MDA),包括延长MDA潜时,抑制ADD和MDA持续时间；MDA诱导同时给予LFS EC主要影响MDA的潜时而对MDA持续时间和后放电没有明显影响；(3)MDA诱导后给予LFS不但没有抑制作用反而延长MDA和后放电持续时间,并且可能调控AD节律。这些结果证明LFS EC可能可以干预复杂局灶性TLE发作,提示其抗癫痫作用机制可能通过抑制DG神经元放电,并且再一次证实“时间窗”对LFS的重要性。DG区神经元可能是临床干预复杂局灶TLE的潜在靶点。此外,对侧CA3诱导DG MDA后,再给予同侧EC LFS刺激可以调控DG区AD频率,提示一次癫痫发作的起始和发作节律的调节有可能通过三个甚至多个独立的脑区(诱发区如对侧CA3、调控区如EC区和放电区如DG区)共同完成,这为癫痫灶点网络提供了一定的实验证据。
总之,本课题发现LFS EC及癫痫灶点可以有效抑制癫痫形成过程和大发作；LFS EC干预癫痫发作存在“时间窗”效应,其机制可能与LFS EC调节DG区神经元发放有关；在灶点给予LFS时,电极极性,特别是阳极电流,对于LFS的抗癫痫作用的发挥非常重要,其机制可能与LFS正负极对灶点delta节律的不同调节作用有关；最后,我们还发现对侧CA3诱导DG区MDA后,LFS EC可以调控DG区AD频率,提示三个独立的脑区有可能不同分工地完成一次癫痫发作,这为癫痫灶点网络提供了较为直接的证据。
因此,本论文的研究结果阐明了LFS抗癫痫的作用及部分机制,初步解析了癫痫发生灶点网络特征,为将来LFS临床应用治疗癫痫提供了重要的实验依据。
Epilepsy is a common chronic neurological disorder and usually lifelong. Recurrent epileptic seizures may lead to accidents and cognitive impairment. Due to the lack of understanding of the complex pathogenesis of epilepsy, clinical treatment of epilepsy is not satisfactory so far. Approximately30%of patients (more in patients with temporal lobe epilepsy, TLE) continue to have seizures and develop intractable epilepsy even a variety of antiepileptic drugs are currently available. Although surgery may be considered as an option in some patients with intractable epilepsy, many are not appropriate candidates for surgery. Therefore, treatment of intractable epilepsy is a major problem for clinical antiepileptic practice.
Low-frequency stimulation (LFS,1-3Hz) targeting deep brain region is emerging as a new option for the treatment of intractable epilepsy with the advantages of reversiblity, adjustability and minimally invasive surgery. LFS of epileptic focus and some other brain areas can suppress seizures in patients and experimental animals. However, because of the complex mechanisms underlying LFS treatment for epilepsy, the optimal strategy for LFS remains unclear. Moreover, contradictory reports regarding the effects of LFS on epilepsy limited the clinical application of LFS. To find suitable stimulation targets and modes are important for LFS treatment of epilepsy. The entorhinal cortex (EC) serves as a gateway to the hippocampus and might be a promising target for LFS to treat epilepsy. On the other hand, closed-loop is a novel clinic mode for LFS which means that the stimulation is delivered in response to the electroencephalographic (EEG) activity. Comparing with open-loop mode in which stimulation delivery follows preset programming, closed-loop may minimize the side effects of LFS. However, new technology has brought new problems:the closed-loop mode inevitably has seconds delay for detecting the seizure and giving the stimulation, and such delay may influence the anticonvulsive effects of LFS. Recently, we reported LFS delivered daily immediately after the kindling stimulation inhibits amygdaloid-kindling seizures, while LFS after the cessation of afterdischarge (AD) has no effect or even augments epileptic activities, suggesting it may be reasonable to deliver LFS in the closed-loop mode. Therefore, we first evaluated whether delayed LFS of EC has antiepileptic effect, which is important for the clinical use of LFS in closed-loop mode.
Recently, the epileptic networks have been increasingly accepted and aroused wide concern. Epileptic networks include both the seizure focus and the remote brain structures outside of the focus. The effects of LFS on seizure focus (such as kindling focus) and other critical areas of the epileptic networks are poorly known. The dentate gyrus (DG) of hippocampus has been considered as a critical part of epilepsy circuits. Loss of inhibitory interneurons and many granule cell survived with hyper-excitability, abnormal dispersion and mossy fiber sprouting were found in the dentate gyrus both in animal models and patients with TLE. Our unpublished data found a transient increase of glutamine synthetase in the ipsilateral DG during amygdaloid kindling acquisition, and inhibition of GS in the ipsilateral DG to an adequate degree at the appropriate time retards kindling acquisition in the rat. Anatomically, DG granule cells mainly receive direct projections from EC, the perforant pathway (PP), and may filter the inputs from EC. Furthermore, the excitability, structures and regeneration of granule cells can be regulated by the inputs from EC. Thus, LFS EC may interfere with epilepsy by affecting the granule cells of DG.
Therefore, we further observed the effect of focal LFS on the EEG activity of the kindling focus and accidently found a polarity-specific effect of LFS; we also investigate the effect of LFS of the EC on neuronal activities and epileptic discharges of DG in maximal dentate activation (MDA) seizure model in rats.
1Therapeutic time window of low-frequency stimulation at entorhinal cortex for amygdaloid-kindling seizures in rats
LFS at the EC immediately or4seconds after kindling stimulation exhibited a strong anticonvulsive effect and4seconds-delayed LFS exhibited better effect than immediate LFS on both kindling and kindled seizures. However, LFS delivered after the cessation of AD or10seconds after the kindling stimulation augmented the epileptic activity in kindling progression. In addition, the immediate and4seconds-delayed LFS groups showed less decrease in AD threshold and more increase in the current intensity difference between AD threshold and'generalized seizure threshold. These results provide direct evidence that LFS of the EC can control temporal lobe epilepsy, and confirmed that there is a "time window" in AD duration for LFS therapy, indicating the time delay of closed-loop may be the key factor to LFS clinical treatment and optimization of stimulation timing is crucial.
2Polarity-dependent effect of low-frequency stimulation on amygdaloid kindling in rats
Bipolar LFS in the same direction of polarity as the kindling stimulation but not in the reverse direction retarded kindling acquisition. And anodal rather than cathodal monopolar LFS inhibited kindling acquisition and kindled seizures. Bipolar LFS showed a stronger anti-epileptic effect than monopolar LFS. Furthermore, anode of LFS (both bipolar and monopolar) deceased, while cathode of LFS increased the power of EEG of the amygdala in normal and kindled rats; the main changes in power of LFP frequency bands were in the delta (0.5-4Hz) band, which was specifically increased during kindling acquisition.Our results provide the first evidence that the effect of LFS at kindling focus is polarity-dependent, which may be due to the different effects of the anode and cathode of LFS on the activity of amygdala, especially on the delta band oscillation. It is likely that the electrode polarity is a key factor affecting the clinical effect of LFS on epilepsy.
3Preliminary study on potential circuit mechanism of the antiepileptic effect of low-frequency stimulation at the entorhinal cortex in urethane-anesthetized rats
In urethane-anesthetized rats, we found that:(1) a single pulse stimulation of the EC and PP pathway induced100-300ms inhibition in neuronal firing in the ipsilateral DG; LFS (15min) of the EC reduced the ipsilateral firing rate of DG neurons with an accumulation effect.(2) pre-treatment with LFS of the ipsilateral EC inhibited MDA induced by kindling stimulation at the contralateral CA3, demonstrated by increased MDA latency, decreased MDA duration and AD duration (ADD); LFS delivered together with kindling stimulation only increased the MDA latency but had no effect on MDA duration and ADD; however, LFS delivered after kindling stimulation prolonged MDA duration and ADD, and even regulated AD frequency. Thus, our results suggest LFS at the EC may control the complex focal TLE, possibly through inhibiting the neuronal activity in the DG, and the timing of LFS onset may be important for using LFS at the EC to treat epilepsy. The DG neurons may be one therapeutic target for clinical treatment of complex focal TLE. We also found the frequency of ADs in the DG, induced by kindling stimulation of the contralateral CA3, can be reglated by LFS of the ipsilateral EC. These results suggest that a seizure may be accomplished by three individual brain regions (the inducing region:the contralateral CA3; the frequency regulating region:the ipsilateral EC; and the discharge region:the ipsilateral DG).
In conclusion, we found LFS of the EC and kindling focus inhibit epileptogenesis and epileptic seizures. The antiepileptic effect of LFS of the EC exhibits the "time-window" phenomenon, and inhibition of DG neuronal firing may be involved in the antiepileptic mechanisms. LFS at the kinlding focus shows a polarity dependent property, which may be due to the different effects of the anode and cathode of LFS on the delta band oscillation, suggesting the electrode polarity, especially polarity for anode current, is a key factor affecting the clinical effect of LFS on epilepsy. In addition, we also found kindling stimulation at the contralateral CA3induces ADs at DG, while LFS EC can regulate the AD frequency, suggesting that a seizure may be carried out by three individual brain regions (the inducing region:the contralateral CA3; the frequency regulating region:the ipsilateral EC; and the discharge region:the ipsilateral DG), which provides direct evidence for the network hypothesis of epilepsy.
Therefore, the present study reveales some important characteristics and mechanisms for LFS interfering with kindling seizures, and also preliminarily found a focal network characteristic of TLE. These results provide an important experimental basis for clinical application of LFS treatment of epilepsy.
低频率电刺激(low frequency stimulation, LFS)具有可逆性、可调性和微创性等优点,为难治性癫痫治疗提供新的选择。LFS癫痫灶点及灶点外靶点可以有效抑制病人和实验动物的癫痫发作。但是由于机制不清,LFS对癫痫的治疗尚有很多不明确的地方和不少相互矛盾的报道,限制了其临床应用；刺激靶点脑区及参数的优化还值得进一步研究。内嗅皮层(entorhinal cortex, EC)是信息进入海马的门户,是LFS治疗颞叶癫痫的潜在靶点。此外,近来临床开发出一种依据患者脑电变化反馈性给予电刺激的闭环刺激模式(closed-loop),相对于以往程序化定时定量的开环模式(open-loop)可能具有更小的副作用。然而,新的技术带来了新的问题：闭环刺激模式检测脑电变化会带来刺激延时,这可能会影响LFS的抗癫痫作用。课题组前期在大鼠杏仁核点燃癫痫模型中已经发现LFS小脑顶核和杏仁核的抗癫痫作用可能受癫痫发作状态的影响,提示LFS可能更适用于closed-loop模式。因此,我们首先观察了LFS EC是否具有抗癫痫作用并且评价了刺激延时对其抗癫痫作用的影响。
另一方面,癫痫环路的概念逐渐被人们接受和关注,癫痫网络既包括灶点及周边网络也涉及一些遥远的脑区结构。LFS直接作用癫痫灶点(如点燃灶点)及其他环路关键节点的作用目前都还不清楚。海马齿状回(dentate gyrus, DG)区域是颞叶癫痫环路的关键节点,被认为是癫痫形成和传播的关键区域之一。在颞叶癫痫患者及动物模型中,海马DG区抑制性中间神经元大量丢失,而大量存活的颗粒细胞表现出异常的兴奋性、分布和轴突苔藓纤维出芽。课题组的前期研究发现,在杏仁核点燃癫痫的形成过程伴随着DG区星形胶质细胞内与谷氨酸代谢相关的关键酶——谷氨酰胺合成酶(glutamine synthetase)的一过性增加,并且在形成过程中关键时间点选择性抑制其活性可以有效抑制癫痫形成,提示DG区在癫痫发病中的关键作用。解剖学上,DG区主要接受EC直接投射(perforant pathway, PP通路),DG区颗粒细胞被认为对来自EC传入进行调节过滤。更有意思的是,DG区颗粒细胞的兴奋性、结构功能及神经再生等都会受EC的调节。LFS EC有可能通过调节DG区神经活动干预癫痫的产生和传播。
因此,本课题进一步观察了LFS对杏仁核点燃灶点直接作用并意外发现了灶点LFS的极性特异性效应；同时我还在麻醉状态的颞叶癫痫模型中观察了LFSEC对DG区的神经元活动和痫样放电的作用,对LFS EC抗癫痫作用的环路机制进行了初步的探讨。模式。同时,我们还在AD过程中发现LFS作用的有效“治疗时间窗”,提示时间延时可能是临床LFS closed-loop模式应用的关键。
第二部分低频率电刺激杏仁核对大鼠杏仁核电点燃癫痫极性依赖性效应
电极极性与点燃刺激相同的双极LFS能有效抑制大鼠杏仁核电点燃癫痫形成过程,而电极极性与点燃刺激相反的双极LFS没有明显抗癫痫作用。正极而非负极的单极LFS能有效抑制大鼠杏仁核电点燃癫痫形成过程和大发作。双极LFS抗癫痫作用略强于单极LFS。进一步研究发现,LFS的正电极(无论是双极还是单极)降低杏仁核灶点的EEG能量,而LFS的负电极增加了杏仁核灶点的EEG能量。最主要EEG能量变化频段为0.5-4Hz的delta波段。Delta波段能量在杏仁核点燃癫痫形成过程中特异性上升。这些的结果直接证明癫痫电点燃灶点LFS存在极性特异性,并且其机制可能与LFS正负极对杏仁核活性尤其是Delta波段的活性存在不同的作用有关。因此,电极极性特别是正电极可能是影响LFS抗癫痫作用的另一个关键因素。
第三部分低频率电刺激内嗅皮层抗癫痫作用的潜在环路机制初步研究
在乌拉坦麻醉大鼠在体实验中我们发现：(1)单个脉冲刺激EC和PP通路会短暂抑制DG区神经元放电；Hz LFS EC能显著减低DG区神经元放电频率,并随着时间增加抑制效果加强。(2)预给15min LFS EC可以抑制DG区最大齿状回兴奋(Maximal dentate activation, MDA),包括延长MDA潜时,抑制ADD和MDA持续时间；MDA诱导同时给予LFS EC主要影响MDA的潜时而对MDA持续时间和后放电没有明显影响；(3)MDA诱导后给予LFS不但没有抑制作用反而延长MDA和后放电持续时间,并且可能调控AD节律。这些结果证明LFS EC可能可以干预复杂局灶性TLE发作,提示其抗癫痫作用机制可能通过抑制DG神经元放电,并且再一次证实“时间窗”对LFS的重要性。DG区神经元可能是临床干预复杂局灶TLE的潜在靶点。此外,对侧CA3诱导DG MDA后,再给予同侧EC LFS刺激可以调控DG区AD频率,提示一次癫痫发作的起始和发作节律的调节有可能通过三个甚至多个独立的脑区(诱发区如对侧CA3、调控区如EC区和放电区如DG区)共同完成,这为癫痫灶点网络提供了一定的实验证据。
总之,本课题发现LFS EC及癫痫灶点可以有效抑制癫痫形成过程和大发作；LFS EC干预癫痫发作存在“时间窗”效应,其机制可能与LFS EC调节DG区神经元发放有关；在灶点给予LFS时,电极极性,特别是阳极电流,对于LFS的抗癫痫作用的发挥非常重要,其机制可能与LFS正负极对灶点delta节律的不同调节作用有关；最后,我们还发现对侧CA3诱导DG区MDA后,LFS EC可以调控DG区AD频率,提示三个独立的脑区有可能不同分工地完成一次癫痫发作,这为癫痫灶点网络提供了较为直接的证据。
因此,本论文的研究结果阐明了LFS抗癫痫的作用及部分机制,初步解析了癫痫发生灶点网络特征,为将来LFS临床应用治疗癫痫提供了重要的实验依据。
Epilepsy is a common chronic neurological disorder and usually lifelong. Recurrent epileptic seizures may lead to accidents and cognitive impairment. Due to the lack of understanding of the complex pathogenesis of epilepsy, clinical treatment of epilepsy is not satisfactory so far. Approximately30%of patients (more in patients with temporal lobe epilepsy, TLE) continue to have seizures and develop intractable epilepsy even a variety of antiepileptic drugs are currently available. Although surgery may be considered as an option in some patients with intractable epilepsy, many are not appropriate candidates for surgery. Therefore, treatment of intractable epilepsy is a major problem for clinical antiepileptic practice.
Low-frequency stimulation (LFS,1-3Hz) targeting deep brain region is emerging as a new option for the treatment of intractable epilepsy with the advantages of reversiblity, adjustability and minimally invasive surgery. LFS of epileptic focus and some other brain areas can suppress seizures in patients and experimental animals. However, because of the complex mechanisms underlying LFS treatment for epilepsy, the optimal strategy for LFS remains unclear. Moreover, contradictory reports regarding the effects of LFS on epilepsy limited the clinical application of LFS. To find suitable stimulation targets and modes are important for LFS treatment of epilepsy. The entorhinal cortex (EC) serves as a gateway to the hippocampus and might be a promising target for LFS to treat epilepsy. On the other hand, closed-loop is a novel clinic mode for LFS which means that the stimulation is delivered in response to the electroencephalographic (EEG) activity. Comparing with open-loop mode in which stimulation delivery follows preset programming, closed-loop may minimize the side effects of LFS. However, new technology has brought new problems:the closed-loop mode inevitably has seconds delay for detecting the seizure and giving the stimulation, and such delay may influence the anticonvulsive effects of LFS. Recently, we reported LFS delivered daily immediately after the kindling stimulation inhibits amygdaloid-kindling seizures, while LFS after the cessation of afterdischarge (AD) has no effect or even augments epileptic activities, suggesting it may be reasonable to deliver LFS in the closed-loop mode. Therefore, we first evaluated whether delayed LFS of EC has antiepileptic effect, which is important for the clinical use of LFS in closed-loop mode.
Recently, the epileptic networks have been increasingly accepted and aroused wide concern. Epileptic networks include both the seizure focus and the remote brain structures outside of the focus. The effects of LFS on seizure focus (such as kindling focus) and other critical areas of the epileptic networks are poorly known. The dentate gyrus (DG) of hippocampus has been considered as a critical part of epilepsy circuits. Loss of inhibitory interneurons and many granule cell survived with hyper-excitability, abnormal dispersion and mossy fiber sprouting were found in the dentate gyrus both in animal models and patients with TLE. Our unpublished data found a transient increase of glutamine synthetase in the ipsilateral DG during amygdaloid kindling acquisition, and inhibition of GS in the ipsilateral DG to an adequate degree at the appropriate time retards kindling acquisition in the rat. Anatomically, DG granule cells mainly receive direct projections from EC, the perforant pathway (PP), and may filter the inputs from EC. Furthermore, the excitability, structures and regeneration of granule cells can be regulated by the inputs from EC. Thus, LFS EC may interfere with epilepsy by affecting the granule cells of DG.
Therefore, we further observed the effect of focal LFS on the EEG activity of the kindling focus and accidently found a polarity-specific effect of LFS; we also investigate the effect of LFS of the EC on neuronal activities and epileptic discharges of DG in maximal dentate activation (MDA) seizure model in rats.
1Therapeutic time window of low-frequency stimulation at entorhinal cortex for amygdaloid-kindling seizures in rats
LFS at the EC immediately or4seconds after kindling stimulation exhibited a strong anticonvulsive effect and4seconds-delayed LFS exhibited better effect than immediate LFS on both kindling and kindled seizures. However, LFS delivered after the cessation of AD or10seconds after the kindling stimulation augmented the epileptic activity in kindling progression. In addition, the immediate and4seconds-delayed LFS groups showed less decrease in AD threshold and more increase in the current intensity difference between AD threshold and'generalized seizure threshold. These results provide direct evidence that LFS of the EC can control temporal lobe epilepsy, and confirmed that there is a "time window" in AD duration for LFS therapy, indicating the time delay of closed-loop may be the key factor to LFS clinical treatment and optimization of stimulation timing is crucial.
2Polarity-dependent effect of low-frequency stimulation on amygdaloid kindling in rats
Bipolar LFS in the same direction of polarity as the kindling stimulation but not in the reverse direction retarded kindling acquisition. And anodal rather than cathodal monopolar LFS inhibited kindling acquisition and kindled seizures. Bipolar LFS showed a stronger anti-epileptic effect than monopolar LFS. Furthermore, anode of LFS (both bipolar and monopolar) deceased, while cathode of LFS increased the power of EEG of the amygdala in normal and kindled rats; the main changes in power of LFP frequency bands were in the delta (0.5-4Hz) band, which was specifically increased during kindling acquisition.Our results provide the first evidence that the effect of LFS at kindling focus is polarity-dependent, which may be due to the different effects of the anode and cathode of LFS on the activity of amygdala, especially on the delta band oscillation. It is likely that the electrode polarity is a key factor affecting the clinical effect of LFS on epilepsy.
3Preliminary study on potential circuit mechanism of the antiepileptic effect of low-frequency stimulation at the entorhinal cortex in urethane-anesthetized rats
In urethane-anesthetized rats, we found that:(1) a single pulse stimulation of the EC and PP pathway induced100-300ms inhibition in neuronal firing in the ipsilateral DG; LFS (15min) of the EC reduced the ipsilateral firing rate of DG neurons with an accumulation effect.(2) pre-treatment with LFS of the ipsilateral EC inhibited MDA induced by kindling stimulation at the contralateral CA3, demonstrated by increased MDA latency, decreased MDA duration and AD duration (ADD); LFS delivered together with kindling stimulation only increased the MDA latency but had no effect on MDA duration and ADD; however, LFS delivered after kindling stimulation prolonged MDA duration and ADD, and even regulated AD frequency. Thus, our results suggest LFS at the EC may control the complex focal TLE, possibly through inhibiting the neuronal activity in the DG, and the timing of LFS onset may be important for using LFS at the EC to treat epilepsy. The DG neurons may be one therapeutic target for clinical treatment of complex focal TLE. We also found the frequency of ADs in the DG, induced by kindling stimulation of the contralateral CA3, can be reglated by LFS of the ipsilateral EC. These results suggest that a seizure may be accomplished by three individual brain regions (the inducing region:the contralateral CA3; the frequency regulating region:the ipsilateral EC; and the discharge region:the ipsilateral DG).
In conclusion, we found LFS of the EC and kindling focus inhibit epileptogenesis and epileptic seizures. The antiepileptic effect of LFS of the EC exhibits the "time-window" phenomenon, and inhibition of DG neuronal firing may be involved in the antiepileptic mechanisms. LFS at the kinlding focus shows a polarity dependent property, which may be due to the different effects of the anode and cathode of LFS on the delta band oscillation, suggesting the electrode polarity, especially polarity for anode current, is a key factor affecting the clinical effect of LFS on epilepsy. In addition, we also found kindling stimulation at the contralateral CA3induces ADs at DG, while LFS EC can regulate the AD frequency, suggesting that a seizure may be carried out by three individual brain regions (the inducing region:the contralateral CA3; the frequency regulating region:the ipsilateral EC; and the discharge region:the ipsilateral DG), which provides direct evidence for the network hypothesis of epilepsy.
Therefore, the present study reveales some important characteristics and mechanisms for LFS interfering with kindling seizures, and also preliminarily found a focal network characteristic of TLE. These results provide an important experimental basis for clinical application of LFS treatment of epilepsy.
引文
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