Optical Detection of the Pre-seizure State

描述（由申请人提供）：检测“癫痫前状态”期间发生的变化的可靠方法可以作为癫痫发作预测的方法，是癫痫研究的基准（NIH治疗癫痫会议，2000年和2007年）。我们的初步数据表明，在脑电图（EEG）检测到癫痫发作之前，癫痫发作前的脑细胞外空间（ECS）收缩伴随着近红外（NIR）光散射的减少。本应用的目的是确定临床相关癫痫动物模型中癫痫发作前状态的光学特征。本研究将有三个具体目标：(1)验证癫痫前状态的光信号可用于体外预测癫痫样活动的假设。我们的初步数据表明，光学相干断层扫描（OCT）衍生的信号先于体外癫痫样活动。在本研究中，我们将使用同时高分辨率微电极阵列（MEA）和OCT记录来表征海马体切片在体外癫痫样活动之前发生的光学变化。这些实验将充分确定在体外癫痫发作前状态和癫痫样活动期间发生的光学变化。(2)验证癫痫发作前状态光信号在体内预测急性发作的假设。我们的初步数据表明，oct衍生的反射强度在体内癫痫发作前会降低（Eberle等人，2012）。在这篇文章中，我们将测试通过OCT成像来检测光信号的能力

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.