Bragin A, Wilson C L, Engel J
Department of Neurology, UCLA School of Medicine, Los Angeles, California 90095-1769, USA.
Epilepsia. 2000;41 Suppl 6:S144-52. doi: 10.1111/j.1528-1157.2000.tb01573.x.
The "silent period" is a characteristic of human localization-related symptomatic epilepsy. In mesial temporal lobe epilepsy (MTLE), it follows an initial precipitating injury, and in animal models of MTLE in which brain damage is artificially created, there is also a prolonged interval between injury and the onset of spontaneous seizures. The neuronal reorganization responsible for epileptogenesis presumably takes place during this silent interval; however, the functional correlates of this process are poorly understood. We have previously described high-frequency (250 to 500 Hz) oscillations, called fast ripples (FR), in the hippocampus and entorhinal cortex (EC) of intrahippocampal kainic acid (KA)-injected rats and patients with MTLE that are confined to the region of spontaneous seizure generation. We have proposed, therefore, that FR reflect the mechanisms responsible for epileptogenesis. If this is the case, they should appear during the process of epileptogenesis, before the appearance of spontaneous seizures. The purpose of the present study was to record continuously from rats after KA injection to compare the temporal development of FR with spontaneous seizures. Additional goals were to determine in these rats after spontaneous seizures begin (a) the volume of tissue in which FR can be recorded in hippocampus and EC, (b) the multiple-unit and field potential correlates of FR oscillations, and (c) whether there is an association of FR with mossy fiber sprouting.
After unilateral KA injection in the posterior hippocampus, interictal field epileptic activity and single-unit activity were recorded from freely moving animals using multiple-contact microelectrodes in dentate gyrus (DG) and EC. One group of animals underwent continuous recording to determine the time of onset of both FR oscillations and spontaneous seizures. A second group was implanted after behavioral seizures began to measure the area within which FR could be recorded as well as their unit and field potential correlates. The neo-Timm method was used to reveal mossy fiber sprouting, and gray value analysis was used to measure the intensity of sprouting in the inner molecular layer of DG.
In KA-injected rats, FR were observed in hippocampal areas adjacent to the lesion and in the ipsilateral EC 11 to 14 days after injection, whereas spontaneous behavioral seizures occurred 2 to 4 months after injection. Analysis of depth profiles of interictal FR in the DG and EC showed that they were generated in local areas with a volume of about 1.0 mm3, and unit recordings indicated that they reflected fields of hypersynchronous action potentials. FR were found in areas of DG with more intensive mossy fiber sprouting. However, the correspondence was not absolute.
The electrophysiological and anatomical data are consistent with the participation of FR oscillations, within small neuronal assemblies, in the development of chronic epileptogenesis. It is hypothesized that small clusters of pathologically interconnected neurons develop after focal hippocampal injury and that these clusters are capable of generating powerful hypersynchronous bursts of action potentials, which initiate epileptogenesis via a kindling effect. As the silent period progresses, a network of such clusters is formed that allows the development of discharges that spread throughout the limbic system. When this network engages brain areas that control motor activity, clinical seizures occur and the silent period ends.
“静息期”是人类与定位相关症状性癫痫的一个特征。在颞叶内侧癫痫（MTLE）中，它出现在最初的促发损伤之后，并且在人为造成脑损伤的MTLE动物模型中，损伤与自发性癫痫发作开始之间也存在较长的间隔期。推测负责癫痫发生的神经元重组可能在此静息期发生；然而，这一过程的功能关联仍知之甚少。我们之前曾描述过，在海马内注射 kainic 酸（KA）的大鼠以及 MTLE 患者的海马和内嗅皮质（EC）中，存在高频（250至500Hz）振荡，称为快速涟漪（FR），且局限于自发性癫痫发作产生的区域。因此，我们提出FR反映了癫痫发生的机制。如果是这样，它们应该在癫痫发生过程中、自发性癫痫发作出现之前出现。本研究的目的是在KA注射后对大鼠进行连续记录，以比较FR与自发性癫痫发作的时间发展。其他目标是确定在这些大鼠自发性癫痫发作开始后：（a）海马和EC中可记录到FR的组织体积；（b）FR振荡的多单位和场电位关联；（c）FR与苔藓纤维出芽之间是否存在关联。
在单侧后海马注射KA后，使用多触点微电极在齿状回（DG）和EC中记录自由活动动物的发作间期场癫痫活动和单单位活动。一组动物进行连续记录以确定FR振荡和自发性癫痫发作开始的时间。第二组在行为性癫痫发作开始后植入，以测量可记录到FR的区域以及它们的单位和场电位关联。采用新Timm法显示苔藓纤维出芽，并使用灰度值分析测量DG内分子层出芽的强度。
在注射KA的大鼠中，注射后11至14天在损伤附近的海马区域和同侧EC中观察到FR，而自发性行为性癫痫发作在注射后2至4个月出现。对DG和EC中发作间期FR的深度分布分析表明，它们在体积约为1.0mm³的局部区域产生，单单位记录表明它们反映了超同步动作电位场。在苔藓纤维出芽更密集的DG区域发现了FR。然而，这种对应关系并非绝对。
电生理和解剖学数据与FR振荡在小神经元集合中参与慢性癫痫发生发展的观点一致。据推测，局灶性海马损伤后会形成一小群病理上相互连接的神经元，这些神经元能够产生强大的超同步动作电位爆发，通过点燃效应引发癫痫发生。随着静息期的进展，会形成这样的神经元群网络，从而使放电能够在整个边缘系统传播。当这个网络涉及控制运动活动的脑区时，就会发生临床癫痫发作，静息期结束。
