Optical Detection of the Pre-seizure State

描述(申请人提供)：可靠的手段，检测在“癫痫发作前状态”发生的变化，可作为癫痫发作预测的方法，癫痫研究的基准(NIH治疗癫痫会议，2000年和2007年)。我们的初步数据表明，在脑电检测到癫痫发作之前，癫痫发作前脑细胞外间隙(ECS)的收缩伴随着近红外(NIR)光散射的减少。本应用的目的是在临床相关的癫痫动物模型中确定癫痫前状态的光学特征。将追求三个具体目标：(1)检验癫痫发作前状态的光信号可以用来预测体外癫痫样活动的假设。我们的初步数据表明，在体外，光学相干断层扫描(OCT)产生的信号先于癫痫样活动。为此，我们将使用高分辨率微电极阵列(MEA)和OCT同步记录来表征在体外海马片癫痫样活动之前发生的光学变化。这些实验将完全确定癫痫发作前状态和体外癫痫样活动期间发生的光学变化。(2)验证癫痫发作前状态的光信号可用于体内预测急性癫痫发作的假设。我们的初步数据表明，OCT导出的反射强度在体内癫痫发作之前降低(Eberle等人，2012年)。为此，我们将通过OCT成像测试光学信号检测的能力，以 在已建立的全身性和局灶性急性皮质癫痫模型中检测癫痫发作前的活体状态。这些实验将验证不同癫痫模型中癫痫发作前光学变化的存在，并为用光学方法预测体内癫痫发作提供概念验证。(3)验证植入光纤近红外探头可用于检测癫痫动物癫痫发作前状态的假设。我们的初步数据表明，在体内急性癫痫发作之前，立体植入小鼠海马区的光纤显示出近红外反射率的降低。临床应用的黄金标准将是 可靠地检测到癫痫动物的自发性癫痫发作。因此，在这个目标中，我们将把我们的新型光纤近红外光谱检测系统应用于一个公认的慢性癫痫动物模型(海马内红藻氨酸模型)。光学的灵敏度、特异度和时程 将测定慢性自发性癫痫发作前和发作期间的近红外反射率变化。这些实验将为植入式光纤监测首次检测癫痫发作的有效性提供原理证明。我们的方法的创新之处在于：(I)关注光学散射的变化，而不是先前研究中的吸收变化；(Ii) 首次在体外和体内结合MEA和OCT技术；(Iii)首次使用新型光纤近红外探头测量体内癫痫发作前大脑深部结构的光学变化。这项研究具有重要意义，因为这些结果将阐明癫痫发作前状态的光学特征，并导致以前所未有的时空分辨率检测局灶性和全身性癫痫发作的方法。

DESCRIPTION (provided by applicant): Reliable means of detecting changes which occur during the "pre-seizure state" could serve as a method of seizure prediction, a benchmark in epilepsy research (NIH Curing Epilepsy Conferences, 2000 and 2007). Our preliminary data indicate pre-seizure constriction in brain extracellular space (ECS) accompanied by reduction in near-infrared (NIR) optical scattering prior to detection of seizure by electroencephalography (EEG). The objective in this application is to determine the optical characteristics of the pre-seizure state in clinically relevant animal models of epilepsy. Three specific aims will be pursued: (1) To test the hypothesis that optical signals of the pre-seizure state can be used to predict epileptiform activity in vitro. Our preliminary data indicate that optical coherence tomography (OCT)-derived signals precede epileptiform activity in vitro. In this Aim, we will characterize the optical changes that occur prior to epileptiform activity in vitro in the hippocampal slice using simultaneous high-resolution microelectrode array (MEA) and OCT recordings. These experiments will fully define the optical changes occurring during the pre-seizure state and during epileptiform activity in vitro. (2) To test the hypothesis that optical signals of the pre-seizure state can be used to predict acute seizures in vivo. Our preliminary data indicate that OCT-derived reflectance intensity decreases prior to seizures in vivo (Eberle et al., 2012). In this Aim, we will test the ability of optical signal detection via OCT imaging to detect the pre-seizure state in vivo in well-established models of generalized and focal acute cortical seizures. These experiments will validate the existence of pre-seizure optical changes in distinct seizure models and provide proof-of-concept for the prediction of seizure onset in vivo with optical methods. (3) To test the hypothesis that implanted fiberoptic NIR probes can be used to detect the pre-seizure state of epileptic animals. Our preliminary data indicate that fiberoptics stereotactically implanted in mouse hippocampus demonstrate reduction in NIR reflectance prior to acute seizures in vivo. The gold standard for clinical application would be to reliably detect a spontaneous seizure in an epileptic animal. Therefore, in this Aim we will apply our novel fiberoptic NIRS detection system to a well-established animal model of chronic epilepsy (intrahippocampal kainic acid model). Sensitivity, specificity, and time course of optical NIR reflectance changes before and during chronic spontaneous seizures will be determined. These experiments will provide proof-of-principle for the efficacy of implanted fiberoptic monitoring to detect epileptic seizures for the first time. Our approach is innovative in (i) focusing on optical scattering changes rather than absorption changes as in prior studies; (ii) the first combination of MEA and OCT technologies in vitro and in vivo; (iii) use of novel fiberoptic NIR probes to measure optical changes in deep brain structures prior to seizures in vivo for the first time. The proposed research is significant because the results will elucidate optical characteristics of the pre-seizure state and lead to methods to detect focal and generalized seizures with unprecedented spatiotemporal resolution.