Kommajosyula Srinivasa P, Randall Marcus E, Brozoski Thomas J, Odintsov Boris M, Faingold Carl L
Department of Pharmacology, Southern Illinois University School of Medicine, P.O. Box 19629, Springfield, IL 62794-9629, United States.
Department of Surgery/Otolaryngology, Southern Illinois University School of Medicine, P.O. Box 19629, Springfield, IL 62794-9629, United States.
Epilepsy Res. 2017 Sep;135:87-94. doi: 10.1016/j.eplepsyres.2017.05.011. Epub 2017 May 25.
Sudden unexpected death in epilepsy (SUDEP) is a major concern for patients with epilepsy. In most witnessed cases of SUDEP generalized seizures and respiratory failure preceded death, and pre-mortem neuroimaging studies in SUDEP patients observed changes in specific subcortical structures. Our study examined the role of subcortical structures in the DBA/1 mouse model of SUDEP using manganese-enhanced magnetic resonance imaging (MEMRI). These mice exhibit acoustically-evoked generalized seizures leading to seizure-induced respiratory arrest (S-IRA) that results in sudden death unless resuscitation is rapidly instituted. MEMRI data in the DBA/1 mouse brain immediately after acoustically-induced S-IRA were compared to data in C57 (control) mice that were exposed to the same acoustic stimulus that did not trigger seizures. The animals were anesthetized and decapitated immediately after seizure in DBA/1 mice and after an equivalent time in control mice. Comparative T1 weighted MEMRI images were evaluated using a 14T MRI scanner and quantified. We observed significant increases in activity in DBA/1 mice as compared to controls at previously-implicated auditory (superior olivary complex) and sensorimotor-limbic [periaqueductal gray (PAG) and amygdala] networks and also in structures in the respiratory network. The activity at certain raphe nuclei was also increased, suggesting activation of serotonergic mechanisms. These data are consistent with previous findings that enhancing the action of serotonin prevents S-IRA in this SUDEP model. Increased activity in the PAG and the respiratory and raphe nuclei suggest that compensatory mechanisms for apnea may have been activated by S-IRA, but they were not sufficient to prevent death. The present findings indicate that changes induced by S-IRA in specific subcortical structures in DBA/1 mice are consistent with human SUDEP findings. Understanding the changes in brain activity during seizure-induced death in animals may lead to improved approaches directed at prevention of human SUDEP.
癫痫猝死（SUDEP）是癫痫患者的一个主要担忧。在大多数有目击的SUDEP病例中，全身性癫痫发作和呼吸衰竭先于死亡，并且对SUDEP患者的死前神经影像学研究观察到特定皮质下结构的变化。我们的研究使用锰增强磁共振成像（MEMRI）在SUDEP的DBA/1小鼠模型中研究了皮质下结构的作用。这些小鼠表现出由声音诱发的全身性癫痫发作，导致癫痫诱发的呼吸骤停（S-IRA），除非迅速进行复苏，否则会导致猝死。将声音诱发S-IRA后立即获得的DBA/1小鼠脑内的MEMRI数据与暴露于相同未触发癫痫发作的声音刺激的C57（对照）小鼠的数据进行比较。在DBA/1小鼠癫痫发作后以及对照小鼠同等时间后，立即将动物麻醉并断头。使用14T MRI扫描仪评估并量化比较性T1加权MEMRI图像。我们观察到，与对照组相比，DBA/1小鼠中先前涉及的听觉（上橄榄复合体）和感觉运动-边缘系统[导水管周围灰质（PAG）和杏仁核]网络以及呼吸网络中的结构的活性显著增加。某些中缝核的活性也增加，提示血清素能机制被激活。这些数据与先前的研究结果一致，即在该SUDEP模型中增强血清素的作用可预防S-IRA。PAG、呼吸核和中缝核活性增加表明，呼吸暂停的代偿机制可能已被S-IRA激活，但不足以防止死亡。目前的研究结果表明，S-IRA在DBA/1小鼠特定皮质下结构中引起的变化与人类SUDEP的研究结果一致。了解动物癫痫诱发死亡期间脑活动的变化可能会带来针对预防人类SUDEP的改进方法。
