Development and application of signal analysis methods for preclinical and fundamental research in epilepsy

癫痫是一种以癫痫发作为特征的神经系统疾病，癫痫发作是突发性的过度神经元放电，有时伴有意识丧失。它是一种常见的神经系统疾病，影响着大约1%的世界人口，约占总医疗费用的0.5%。虽然在理解和用抗癫痫药物和手术治疗癫痫方面取得了进展，但大约30%的癫痫患者继续经历癫痫发作的破坏性影响，尽管做出了各种治疗努力。众所周知，癫痫发生(癫痫作为一种疾病的发展过程)和细胞分裂(个体癫痫发作的进展)的机制相当复杂和多样。与最终治疗特别相关的是弥合在分子和细胞水平上对疾病的精细详细了解与活着患者的临床成像数据之间的科学鸿沟。这种桥梁在很大程度上依赖于局部神经元活动和血管反应之间的耦合，这是用非侵入性成像技术观察到的。**近红外光谱(NIRS)就是这样一种成像技术。近红外光谱测量与神经活动相关的氧合和脱氧血红蛋白浓度的变化。与其他成像技术相比，它具有明显的优势，如长期监测、便携性、安全性和低成本，使其成为某些应用中唯一的成像竞争者。在过去的几年里，我们团队在将近红外光谱应用于癫痫的研究活动中发挥了主导作用。我们证明了NIRS足以检测到各种类型的癫痫发作，我们研究了癫痫棘波，量化了它们血流动力学反应的非线性。**由于我们发现NIRS在检测癫痫发作方面是有效的，我们建议开发这一实时监测技术，单独或结合脑电(EEG)，用于对患者的长期监测。这一努力最终可能导致在5至10年内开发出一种新的临床工具。该项目的一个部分是开发和验证利用近红外光谱(和脑电)检测癫痫发作的实时框架。为使这一努力取得成功，应在减少混淆方面取得进一步进展，因为在癫痫患者中观察到的反应模式非常复杂，反映在癫痫发作检测的假阳性率太高，目前难以在临床上得到强有力的应用。我们假设，动物模型可能是更好地理解这些模式的最佳策略，从而使在人类中的漫反射光学成像观察更可靠。在小鼠身上，我们将在用神经毒素诱导癫痫发作后进行先进的侵入性显微成像实验。他们将在稍后扩展到更现实的人类癫痫模型--中颞叶癫痫(MTLE)模型，并指出在我们的数据中，MTLE患者表现出特别神秘的近红外反应。利用光遗传技术，为了在毫秒级控制神经元尖峰，我们将测量当受到光遗传刺激扰动时神经元和血液对癫痫发作的反应，同时监测关键的生理变量，如心率、呼吸频率和外周血氧饱和度。然后，我们将使用复杂的信号处理工具，包括生物物理模型来理解这些观察到的行为。这将有助于将动物的微观理解与人类的宏观观察联系起来。最终结果将是一种临床工具，可以具体改善住院患者的护理和生活，这些患者有反复发作、中风和脑氧减饱和的风险。

Epilepsy is a neurological disorder characterized by epileptic seizures, which are sudden excessive neuronal discharges, sometimes accompanied by loss of consciousness. It is a common neurological disease, affecting approximately 1% of the world population and representing about 0.5% of total medical costs. While progress has been achieved in understanding and treating the epilepsies with anti-epileptic drugs and surgery, about 30% of epileptics continue to experience the devastating impact of seizures despite all efforts at treatment. It is well recognized that the mechanisms of epileptogenesis (the process of developing epilepsy as a disease) and of ictogenesis (the progression of individual seizures) are quite intricate and varied. Particularly relevant for eventual therapies is bridging the scientific gap between exquisitely detailed understanding of the disease at the molecular and cellular levels with clinical imaging data in living patients. Much of this bridge rests on the coupling between local neuronal activity and the vascular response that is observed with non-invasive imaging techniques.**One such imaging technique is near-infrared spectroscopy (NIRS). NIRS measures changes in oxygenated and deoxygenated hemoglobin concentrations associated with neural activity. It offers distinct advantages over other imaging techniques, such as long-term monitoring, portability, safety, and low cost, making it the only imaging contender in some applications. Over the past few years, our group has taken a lead role in the research activity applying NIRS to epilepsy. We demonstrated that NIRS is adequate to detect various kinds of seizures and we studied epileptic spikes, quantifying the nonlinearity of their hemodynamic response. * *Since we found that NIRS was effective at detecting seizures, we propose here to develop this real-time monitoring technology, by itself or in combination with electroencephalography (EEG), for long-term monitoring of patients. This effort could eventually lead to a new clinical tool over a 5 to 10 year horizon. One part of this project is the development and validation of a real-time framework for detecting seizures with NIRS (and EEG). For this effort to succeed, further progress should be made for reducing the confounding aspects due to the very complex response patterns observed in epileptic patients, reflected in false positive rates for seizure detection that are too high at present for a robust clinical application. We hypothesize that an animal model may be the best strategy to better understand these patterns so as to make the diffuse optical imaging observations in human more reliable. In mice, we will perform advanced and invasive microscopic imaging experiments after inducing epileptic seizures with a neurotoxin. They will be extended later to a more realistic model of human epilepsy, a mesio-temporal lobe epilepsy (MTLE) model, noting that in our data, MTLE patients exhibit especially cryptic NIRS responses. Using optogenetic technology, to control neuronal spiking at the millisecond time scales, we will measure the neuronal and the blood responses to seizures when perturbed by optogenetic stimulation, while monitoring key physiological variables such as heart rate, respiration rate and peripheral oxygen saturation. We will then use sophisticated signal processing tools including biophysical models to understand these observed behaviors. This will help bridge the microscopic understandings in animals with the macroscopic observations in humans. The final result will be a clinical tool that could concretely improve care and the lives of patients admitted to the hospital at risk for recurrent seizures, stroke and brain oxygen desaturation.