Circadian analysis of peripheral and brain samples in epilepsy patients

项目摘要 大脑和身体中发生的几乎每一个过程都遵循24小时的周期。此外，不良健康 诸如心脏病发作、中风和癫痫发作等事件往往发生在一天中的特定时间。癫痫发作通常会 一种节律模式，但这种模式可能会因患者而异。如果我们能确定 预测癫痫发作可能发生的因素，那么这就允许适当的治疗时机， 治疗效果最好，副作用最少。事实上，有几个团体已经开始应用这种时间疗法 作为一种个性化的方法来预测和治疗包括癫痫发作在内的许多疾病。睡眠/清醒时 活动测量是一天中最佳用药时间的粗略预测，它们受到 各种环境因素，并不总是符合内源性节律。外周标记物的使用 血液或尿液中的浓度可以用于微调计时方法，因为它们在临床上很容易获得。 事实上，研究人员现在已经能够准确地预测主时钟的相位， 视交叉上核（SCN），使用少至1-2个血液样品。此外，更好地理解阶段 外周标记物、SCN相位和大脑部分中的分子节律之间的关系， 经验癫痫发作，将有助于不仅在管理的时间疗法，而且在我们的理解 为什么大脑会在一天中的特定时间发作在这项研究中，我们有难得的机会 在一天的同一时间从男性和女性身上获取人脑组织、血液和尿液样本， 接受手术切除治疗癫痫发作的青少年和年轻成人（约25例受试者）。在 此外，在手术前，我们将收集睡眠/觉醒数据、行为数据、认知评估、评估 癫痫发作模式和精神评估这将使我们能够第一次衡量成绩单， 在一天中的同一时间，来自多个外周和脑样品的具有已知节律的代谢物 相同的个体，为我们提供了有关外周样本中的相位标记如何与 癫痫发生的大脑区域的标记物。我们还将能够确定这些分子和 代谢测量与睡眠/觉醒测量以及各种临床特征、癫痫发作模式和 健康和疾病组织之间的差异，特别注意任何性别和发育 差异这些数据将为未来的机理研究提供信息，以了解癫痫发作为什么会在一天中的特定时间发生， 优化外周样本的使用，以作为最合适的治疗时机的生物标志物。

PROJECT SUMMARY Nearly every process that occurs in the brain and the body follows a 24 hour cycle. Moreover, adverse health events such as heart attacks, stroke and seizures tend to occur at particular times of day. Seizures often follow a rhythmic pattern, but this pattern can be very different from patient to patient. If one can determine the circadian factors that predict that a seizure is likely to occur, then this allows proper timing of treatments to provide the most therapeutic impact with fewest side effects. Indeed, several groups are starting to apply this chronotherapy as a personalized approach to predict and treat a number of disorders including seizures. While sleep/wake activity measures are a gross predictor of the optimal time of day for medication, they are confounded by a variety of environmental factors and do not always align with endogenous rhythms. The use of peripheral markers in blood or urine could serve to fine tune chronotherapeutic approaches as they are easily obtained in the clinic. Indeed, researchers have now been able to accurately predict the phase of the master clock in the suprachiasmatic nucleus (SCN) using as little as 1-2 blood samples. Moreover, better understanding of phase relationships between peripheral markers, SCN phase, and molecular rhythms in parts of the brain that experience seizures, would help not only in the administration of chronotherapy, but also in our understanding of why the brain might experience a seizure at a particular time of day. In this study, we have the rare opportunity to obtain human brain tissue, blood, and urine samples at the same time of day from male and female adolescents and young adults (~25 subjects) undergoing surgical resection for the treatment of seizures. In addition, prior to surgery, we will collect sleep/wake data, behavioral data, cognitive assessments, assessments of seizure patterns and psychiatric evaluations. This will allow us for the first time to measure transcripts and metabolites with known rhythms across multiple peripheral and brain samples at the same time of day from the same individuals, giving us precise data regarding how markers of phase in the peripheral samples align with markers in brain regions in which seizures occur. We will also be able to determine how these molecular and metabolic measures align with sleep/wake measures and various clinical features, seizure patterns, and differences between healthy and disease tissue, paying particular attention to any sex and developmental differences. This data will inform future mechanistic studies of why seizures occur at particular times of day, and optimize the use of peripheral samples to serve as biomarkers for the most appropriate timing for treatment.