Interdisciplinary Graduate Program in Neuroscience, Iowa City, IA, USA.
Iowa Neuroscience Institute, Iowa City, IA, USA.
J Physiol. 2021 Mar;599(6):1885-1899. doi: 10.1113/JP280856. Epub 2021 Feb 18.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature death in patients with refractory epilepsy. SUDEP typically occurs during the night, although the reason for this is unclear. We found that, in normally entrained mice, time-of-day alters vulnerability to seizure-induced death. We found that, in free-running mice, circadian phase alters the vulnerability to seizure-induced death. These findings suggest that circadian rhythmicity may be responsible for the increased night-time prevalence of SUDEP ABSTRACT: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP typically occurs during the night following a seizure. Many aspects of mammalian physiology are regulated by circadian rhythms in ways that might make seizures occuring during the night more dangerous. Using two mouse models of seizure-induced death, we demonstrate that time-of-day and circadian rhythms alter vulnerability to seizure-induced death. We exposed normally entrained DBA/1 mice to a potentially seizure-inducing acoustic stimulus at different times of day and compared the characteristics and outcomes of the seizures. Time-of-day did not alter the probability of a seizure but it did alter the probability of seizure-induced death. To determine whether circadian rhythms alter vulnerability to seizure-induced death, we induced maximal electroshock seizures in free-running C57BL/6J mice at different circadian time points at the same time as measuring breathing via whole body plethysmography. Circadian phase did not affect seizure severity but it did alter postictal respiratory outcomes and the probability of seizure-induced death. By contrast to our expectations, in entrained and free-running mice, vulnerability to seizure-induced death was greatest during the night and subjective night, respectively. These findings suggest that circadian rhythmicity may be responsible for the increased night-time prevalence of SUDEP and that the underlying mechanism is phase conserved between nocturnal and diurnal mammals. All of the seizures in the present study were induced during wakefulness, indicating that the effect of time point on vulnerability to seizure-induced death was not the result of sleep. Understanding why SUDEP occurs more frequently during the night may inform future preventative countermeasures.
癫痫猝死症（SUDEP）是抗药性癫痫患者过早死亡的主要原因。尽管原因尚不清楚，但 SUDEP 通常发生在夜间。我们发现，在正常节律的小鼠中，时间会改变癫痫发作导致死亡的易感性。我们发现，在自由运行的小鼠中，昼夜节律会改变癫痫发作导致死亡的易感性。这些发现表明，昼夜节律可能是导致夜间 SUDEP 发病率增加的原因。
癫痫猝死症（SUDEP）是癫痫相关死亡的主要原因。SUDEP 通常发生在癫痫发作后的夜间。许多哺乳动物的生理机能都受到昼夜节律的调节，这可能使夜间发生的癫痫发作更具危险性。使用两种癫痫发作导致死亡的小鼠模型，我们证明了时间和昼夜节律会改变癫痫发作导致死亡的易感性。我们在不同的时间点对正常节律的 DBA/1 小鼠施加潜在的致痫性声音刺激，并比较了癫痫发作的特征和结果。时间不会改变癫痫发作的概率，但会改变癫痫发作导致死亡的概率。为了确定昼夜节律是否会改变癫痫发作导致死亡的易感性，我们在自由运行的 C57BL/6J 小鼠中诱导最大电休克发作，同时通过全身 plethysmography 测量呼吸，在不同的昼夜时间点进行。昼夜节律相位不影响癫痫发作的严重程度，但会改变发作后的呼吸结果和癫痫发作导致死亡的概率。与我们的预期相反，在节律和自由运行的小鼠中，癫痫发作导致死亡的易感性在夜间和主观夜间分别最大。这些发现表明，昼夜节律可能是导致夜间 SUDEP 发病率增加的原因，并且夜间和日间哺乳动物之间的潜在机制是相位保守的。本研究中的所有癫痫发作都是在觉醒期间诱导的，这表明时间点对癫痫发作导致死亡的易感性的影响不是睡眠的结果。了解为什么 SUDEP 更频繁地发生在夜间可能为未来的预防措施提供信息。
