Circadian analysis of peripheral and brain samples in epilepsy patients

项目总结 大脑和身体中发生的几乎每一个过程都有一个24小时的周期。此外，对健康不利 心脏病发作、中风和癫痫等事件往往发生在一天中的特定时间段。癫痫发作通常伴随着 这是一种有节奏的模式，但这种模式可能会因患者而异。如果一个人能确定昼夜节律 预测癫痫可能发生的因素，那么这就允许适当的治疗时机来提供 治疗效果最好，副作用最少。事实上，有几个团体开始应用这种计时疗法。 作为一种个性化的方法来预测和治疗一些疾病，包括癫痫发作。在睡眠/清醒时 活动测量是一天中最佳用药时间的粗略预测指标，它们被一种 环境因素多种多样，并不总是与内生节奏一致。外周标记的使用 在血液或尿液中可以用来微调时间治疗方法，因为它们很容易在临床上获得。 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)只需1-2个血样。此外，更好地理解了阶段 外周标志物、SCN时相与脑内部分脑区分子节律的关系 体验癫痫发作，不仅有助于时间疗法的实施，而且有助于我们理解 为什么大脑在一天中的特定时间会经历癫痫发作。在这项研究中，我们有难得的机会 在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 青少年和青壮年(约25名受试者)接受手术切除治疗癫痫。在……里面 此外，在手术前，我们将收集睡眠/清醒数据、行为数据、认知评估、评估 癫痫发作模式和精神病学评估。这将使我们能够首次测量成绩单和 具有已知节律的代谢物在一天中同一时间在多个外周和大脑样本中 相同的个体，为我们提供了关于外周样本中的相位标记如何与 癫痫发作时大脑区域的标志物。我们还将能够确定这些分子和 代谢指标与睡眠/清醒指标以及各种临床特征、癫痫发作模式和 健康组织和疾病组织的区别，特别注意性别和发育 不同之处。这些数据将为未来的机制研究提供信息，了解为什么癫痫发作发生在一天中的特定时间，以及 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.