Seizure-associated central apnea in a rat model: Evidence for resetting the respiratory rhythm and activation of the diving reflex.
Seizure-associated central apnea in a rat model: Evidence for resetting the respiratory rhythm and activation of the diving reflex.
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DOI：
10.1016/j.nbd.2017.01.008
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发表时间：
2017-05
影响因子：
6.1
通讯作者：
Stewart M
中科院分区：
文献类型：
--
作者：
Villiere SM;Nakase K;Kollmar R;Silverman J;Sundaram K;Stewart M
呼吸紊乱，包括不规则的呼吸急促和中枢性或阻塞性呼吸暂停，可能是癫痫患者和动物模型中癫痫发作活动的后果。癫痫相关的中枢性呼吸暂停期（定义为体积描记术期间快速发作和无气流偏移的>1 s的时间段）表明癫痫发作扩散到脑干呼吸区以扰乱呼吸。我们试图将乌拉坦麻醉大鼠并给予静脉注射红藻氨酸以诱导反复发作的癫痫发作相关中枢性呼吸暂停发作作为癫痫发作对呼吸节律影响的指标。我们测量了中枢性呼吸暂停期的开始和结束，以确定开始-结束关系是否是以下因素的结果：1）呼吸节律的重置，2）呼吸节律的短暂暂停，从呼吸暂停期结束时的暂停点恢复，3）呼吸行为的短暂抑制与呼吸暂停前呼吸模式的持续预测的呼吸暂停偏移，或4）随机重新进入呼吸循环。用连续ECG、EEG和体积描记法监测动物。7只患有多次呼吸暂停发作的大鼠在癫痫发作期间记录了190次中枢呼吸暂停发作（1.04至36.18 s，平均值：3.2 ± 3.7 s）。大多数呼吸暂停发作发生在呼气期间（125/161次呼吸暂停发作，78%）。在呼气或吸气中，呼吸暂停发作往往发生在周期的后期，即在峰值和呼气结束（82/125，66%）或吸气结束（34/36，94%）之间。呼吸暂停期偏移在早期和晚期呼气（27%，34%）和吸气（16%，23%）之间分布更均匀。呼吸暂停发作时的呼吸阶段和相应的偏移阶段之间的差异变化很大，即使在个别动物。每次中枢性呼吸暂停发作与发作时EEG或ECG记录中的高频事件相关。与平线体积描记图无关的高频事件显示每只动物的体积描记图模式恒定，表明呼吸节律明显重置。然而，呼吸节律在约1秒后变得高度可变，这是补偿相位不可预测的原因。呼吸节律重置与气流停止的分离也表明中枢性呼吸暂停期涉及脑干区域的激活，这些脑干区域服务于潜水反射以消除呼吸运动的表达。这一结论得到了心率下降作为呼吸暂停持续时间的函数的支持。我们的结论是，潜水相关的中枢性呼吸暂停发作与1）呼吸节律的重置，和2）激活脑干区域的潜水反射抑制呼吸行为。这些结论的意义在于，癫痫发作对脑干回路影响的这些细节代表了评估癫痫发作扩散和潜在的癫痫发作模式细分的指标。
Respiratory derangements, including irregular, tachypnic breathing and central or obstructive apnea can be consequences of seizure activity in epilepsy patients and animal models. Periods of seizure-associated central apnea, defined as periods >1 s with rapid onset and offset of no airflow during plethysmography, suggest that seizures spread to brainstem respiratory regions to disrupt breathing. We sought to characterize seizure-associated central apneic episodes as an indicator of seizure impact on the respiratory rhythm in rats anesthetized with urethane and given parenteral kainic acid to induce recurring seizures. We measured central apneic period onsets and offsets to determine if onset-offset relations were a consequence of 1) a reset of the respiratory rhythm, 2) a transient pausing of the respiratory rhythm, resuming from the pause point at the end of the apneic period, 3) a transient suppression of respiratory behavior with apnea offset predicted by a continuation of the breathing pattern preceding apnea, or 4) a random re-entry into the respiratory cycle. Animals were monitored with continuous ECG, EEG, and plethysmography. One hundred ninety central apnea episodes (1.04 to 36.18 s, mean: 3.2 ± 3.7 s) were recorded during seizure activity from 7 rats with multiple apneic episodes. The majority of apneic period onsets occurred during expiration (125/161 apneic episodes, 78%). In either expiration or inspiration, apneic onsets tended to occur late in the cycle, i.e. between the time of the peak and end of expiration (82/125, 66%) or inspiration (34/36, 94%). Apneic period offsets were more uniformly distributed between early and late expiration (27%, 34%) and inspiration (16%, 23%). Differences between the respiratory phase at the onset of apnea and the corresponding offset phase varied widely, even within individual animals. Each central apneic episode was associated with a high frequency event in EEG or ECG records at onset. High frequency events that were not associated with flatline plethysmographs revealed a constant plethysmograph pattern within each animal, suggesting a clear reset of the respiratory rhythm. The respiratory rhythm became highly variable after about 1 s, however, accounting for the unpredictability of the offset phase. The dissociation of respiratory rhythm reset from the cessation of airflow also suggested that central apneic periods involved activation of brainstem regions serving the diving reflex to eliminate the expression of respiratory movements. This conclusion was supported by the decreased heart rate as a function of apnea duration. We conclude that seizure-associated central apnea episodes are associated with 1) a reset of the respiratory rhythm, and 2) activation of brainstem regions serving the diving reflex to suppress respiratory behavior. The significance of these conclusions is that these details of seizure impact on brainstem circuitry represent metrics for assessing seizure spread and potentially subclassifying seizure patterns.
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