Divisions of Neurology and Pediatric Neurology, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.
Epilepsia. 2011 Mar;52(3):531-40. doi: 10.1111/j.1528-1167.2010.02942.x. Epub 2011 Jan 26.
Human hypothalamic hamartomas (HHs) are associated with gelastic seizures, intrinsically epileptogenic, and notoriously refractory to medical therapy. We previously reported that the L-type calcium channel antagonist nifedipine blocks spontaneous firing and γ-aminobutyric acid (GABA)(A)-induced depolarization of single cells in HH tissue slices. In this study, we examined whether blocking L-type calcium channels attenuates emergent activity of HH neuronal networks.
A high-density multielectrode array was used to record extracellular signals from surgically resected HH tissue slices. High-frequency oscillations (HFOs, ripples and fast ripples), field potentials, and multiunit activity (MUA) were studied (1) under normal and provoked [4-aminopyridine (4-AP)] conditions; and (2) following nifedipine treatment.
Spontaneous activity occurred during normal artificial cerebrospinal fluid (aCSF) conditions. Nifedipine reduced the total number and duration of HFOs, abolished the association of HFOs with field potentials, and increased the inter-HFO burst intervals. Notably, the number of active regions was decreased by 45 ± 9% (mean ± SEM) after nifedipine treatment. When considering electrodes that detected activity, nifedipine increased MUA in 58% of electrodes and reduced the number of field potentials in 67% of electrodes. Provocation with 4-AP increased the number of events and, as the number of electrodes that detected activity increased 248 ± 62%, promoted tissue-wide propagation of activity. During provocation with 4-AP, nifedipine effectively reduced HFOs, the association of HFOs with field potentials, field potentials, MUA, and the number of active regions, and limited propagation.
This is the first study to report (1) the presence of HFOs in human subcortical epileptic brain tissue in vitro; (2) the modulation of "pathologic" high-frequency oscillations (i.e., fast ripples) in human epileptic tissue by L-type calcium channel blockers; and (3) the modulation of network physiology and synchrony of emergent activity in human epileptic tissue following blockade of L-type calcium channels. Attenuation of activity in HH tissue during normal and provoked conditions supports a potential therapeutic usefulness of L-type calcium channel blockers in epileptic patients with HH.
人类下丘脑错构瘤（HH）与发笑性癫痫发作有关，具有内在致痫性，并且对药物治疗明显有抗性。我们之前曾报道过，L 型钙通道拮抗剂硝苯地平可阻断 HH 组织切片中单细胞的自发性放电和γ-氨基丁酸（GABA）（A）诱导的去极化。在这项研究中，我们检查了阻断 L 型钙通道是否会减轻 HH 神经元网络的突发活动。
使用高密度多电极阵列从手术切除的 HH 组织切片中记录细胞外信号。研究了在正常和激发[4-氨基吡啶（4-AP）]条件下：（1）高频振荡（HFOs，锐波和快锐波）、场电位和多单位活动（MUA）；（2）在硝苯地平处理后。
在正常人工脑脊液（aCSF）条件下会发生自发性活动。硝苯地平减少了 HFO 的总数和持续时间，消除了 HFO 与场电位的关联，并增加了 HFO 爆发之间的间隔。值得注意的是，硝苯地平处理后，活跃区域的数量减少了 45 ± 9%（平均值 ± SEM）。当考虑到检测到活动的电极时，硝苯地平增加了 58%电极的 MUA，并减少了 67%电极的场电位数量。用 4-AP 激发增加了事件的数量，并且由于检测到活动的电极数量增加了 248 ± 62%，促进了活动的全组织传播。在使用 4-AP 激发时，硝苯地平可有效减少 HFO、HFO 与场电位的关联、场电位、MUA 和活跃区域的数量，并限制传播。
这是第一项报道（1）在人类皮质下癫痫脑组织中存在 HFOs 的研究；（2）L 型钙通道阻滞剂对人类癫痫组织中“病理性”高频振荡（即快锐波）的调节；（3）阻断 L 型钙通道后，人类癫痫组织中突发活动的网络生理学和同步性的调节。在正常和激发条件下 HH 组织活性的减弱支持 L 型钙通道阻滞剂在具有 HH 的癫痫患者中具有潜在的治疗用途。
