Ziai Wendy C, Sherman David L, Bhardwaj Anish, Zhang Ning, Keyl Penelope M, Mirski Marek A
Division of Neurosciences Critical Care, the John's Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Epilepsia. 2005 Jun;46(6):878-88. doi: 10.1111/j.1528-1167.2005.49304.x.
Anterior thalamic nucleus (AN) deep brain stimulation (DBS) is effective in raising EEG and clonic seizure threshold in experimental models. Little is known about the specific properties of DBS that afford its anticonvulsant effect. We sought to test the hypothesis that experimental seizures and the anticonvulsant action of AN DBS alter the underlying regional neurochemistry of AN, specifically with facilitation of the serotonergic system to local electrical stimulation.
Halothane-anesthetized adult Sprague-Dawley male rats underwent stereotactically guided bilateral placement of bipolar stimulating steel electrodes and dialysis probes-guide cannulae in AN and posterior thalamus (PT), and placement of four epidural EEG screw electrodes 48 h before experiments. Both stimulated (AN DBS) and nonstimulated (NO DBS) animals (n=7 per group) were infused with i.v. pentylenetetrazol (PTZ, 5.5 mg/kg/min). Simultaneous thalamic and cortical EEG were recorded, and microdialysis samples were collected from AN and PT in 20-min epochs. AN stimulation was delivered (150 microA; 0.1-ms pulse duration) 40 min before and continued during PTZ infusion.
Bilateral AN stimulation delayed the onset of EEG seizures compared with controls: 82+/-8 vs. 58+/-5 min (p=0.02). PTZ infusion alone, or together with stimulation, resulted in a steady increase in norepinephrine (NE), but not dopamine, at AN and PT sites (p<0.001). Although extracellular serotonin was measured at very low levels, the metabolite, 5-hydroxyindoleacetic acid (5-HIAA) increased selectively in AN after stimulation and during preconvulsant infusion of PTZ (p<0.001), returning to baseline after the first generalized seizure.
These data suggest that PTZ and DBS together enhance the nonselective release of NE in thalamic nuclei while specifically stimulating AN-localized serotonin. Low serotonin levels at baseline and during STIM alone or PTZ infusion may indicate efficient reuptake systems for serotonin, with 5-HIAA serving as a surrogate marker for serotonergic activity. Modulation of the AN-specific serotonergic activity may be critical in altering PTZ seizure threshold and be an important neurotransmitter system underlying the efficacy of AN DBS.
丘脑前核（AN）深部脑刺激（DBS）在实验模型中可有效提高脑电图（EEG）和阵挛性癫痫阈值。关于DBS产生抗惊厥作用的具体特性知之甚少。我们试图验证以下假设：实验性癫痫发作和AN DBS的抗惊厥作用会改变AN潜在的局部神经化学，特别是促进血清素能系统对局部电刺激的反应。
用氟烷麻醉的成年雄性Sprague-Dawley大鼠在立体定向引导下，在双侧丘脑前核和丘脑后核（PT）植入双极刺激钢电极和透析探针引导套管，并在实验前48小时放置四个硬膜外EEG螺旋电极。刺激组（AN DBS）和非刺激组（NO DBS）动物（每组n = 7）静脉注射戊四氮（PTZ，5.5mg/kg/min）。同时记录丘脑和皮层的脑电图，并以20分钟为间隔从AN和PT采集微透析样本。在PTZ输注前40分钟开始进行AN刺激（150微安；0.1毫秒脉冲持续时间），并在PTZ输注期间持续刺激。
与对照组相比，双侧AN刺激延迟了EEG癫痫发作的开始：82±8分钟对58±5分钟（p = 0.02）。单独输注PTZ或与刺激一起输注，导致AN和PT部位去甲肾上腺素（NE）持续增加，但多巴胺没有增加（p<0.001）。尽管细胞外血清素的测量水平非常低，但在刺激后和PTZ惊厥前输注期间，代谢物5-羟吲哚乙酸（5-HIAA）在AN中选择性增加（p<0.001），在首次全身性癫痫发作后恢复到基线水平。
这些数据表明，PTZ和DBS共同增强了丘脑核中NE的非选择性释放，同时特异性刺激了AN局部的血清素。在基线时以及单独刺激或输注PTZ期间血清素水平较低，可能表明血清素的再摄取系统有效，5-HIAA可作为血清素能活性的替代标志物。调节AN特异性血清素能活性可能对改变PTZ癫痫阈值至关重要，并且是AN DBS疗效的重要神经递质系统。
