Mapping progressive loss of intracortical inhibition by TMS and EEG in posttraumatic epileptogenesis

 描述（由申请人提供）：脑损伤通常通过癫痫发生导致癫痫，癫痫发生是大脑转变为持久状态（癫痫）的过程，其特征是反复的无端癫痫发作。严重创伤性脑损伤（TBI）是年轻人癫痫发生的最常见例子，在20-50%的情况下导致癫痫。这一癫痫发作期提供了一个机会窗口，可以识别有癫痫发作风险的患者，并可以给予抗癫痫治疗。然而，没有可靠的癫痫发生的临床生物标志物来确定癫痫发生是否已经开始以及已经进展了多远。因此，所提出的实验的长期目标是使用大鼠致痫性TBI模型来开发安全、廉价和非侵入性的癫痫发生的电生理生物标志物，其基于通过经颅磁刺激（TMS）测量皮质兴奋性。作为次要目标，我们将测试 是否可以通过皮层脑电图获得类似的测量结果。我们最近开发的方法在大鼠局灶性运动皮层TMS，表明这些可靠地反映GABA介导的皮层抑制的幅度，并表明，这种抑制是抑郁的大鼠癫痫发作模型，包括模型的创伤后癫痫。在这里，我们建议使用大鼠侧位液压冲击（LFP）创伤后癫痫模型来测试（1）在癫痫发生过程中皮质抑制的丧失是否是渐进的，（2）损伤后皮质内抑制的丧失是否可以预测癫痫发作，以及（3）潜在可逆的细胞变化，如GABA能中间神经元的丧失是否是TMS衍生的皮质抑制丧失指标的基础。虽然所提出的实验仅限于TBI后癫痫发生的大鼠模型，但我们预计结果将为TMS作为其他形式癫痫发生生物标志物的研究提供信息。此外，由于我们将记录所有动物的EEG，我们将测试伽马频率EEG功率（也反映GABA介导的皮层抑制的完整性）是否可以作为癫痫发生生物标志物。由于TMS和EEG已经在人类中广泛使用，我们预计来自所提出的实验的有利数据将迅速转化为人类TBI的临床试验。

 DESCRIPTION (provided by applicant): Cerebral injury often leads to epilepsy via epileptogenesis, the process by which the brain is transformed into an enduring state (epilepsy) characterized by repeated unprovoked seizures. Severe traumatic brain injury (TBI) is the most common example of epiletogenesis in young adults, and leads to epilepsy in 20-50% of instances. This epileptogenic period provides a window of opportunity where patients at risk for developing seizures may be identified, and where anti-epileptogenic therapy may be administered. Yet, there is no reliable clinical biomarker for epileptogenesis to identify whether epileptogenesis has started and how far it has advanced. Accordingly, the long-term goal of the proposed experiments is to use a rat epileptogenic TBI model to develop a safe, inexpensive and noninvasive electrophysiologic biomarker of epileptogenesis that is based on measures of cortical excitability by transcranial magnetic stimulation (TMS). As a secondary goal, we will test if similar measures can be obtained by cortical EEG. We recently developed methods for focal motor cortex TMS in rats, demonstrated that these reliably reflect the magnitude of GABA-mediated cortical inhibition, and showed that such inhibition is depressed in rat seizure models, including a model of posttraumatic epilepsy. Here we propose to use the rat lateral fluid percussion (LFP) possttraumatic epilepsy model to test (1) whether the loss of cortical inhibition is progressive in time during epileptogenesis, (2) whether loss of intracortical inhibition after injury can predict seizure onset, and (3) whether potentially reversible cellular changes such as loss of GABA-ergic interneurons underlie the TMS-derived measures of cortical inhibition loss. Although the proposed experiments are limited to a rat model of post-TBI epileptogenesis, we anticipate that the results will inform studies of TMS as a biomarker in other forms of epileptogenesis. Further, as we will record EEG in all animals, we will test whether gamma frequency EEG power, which also reflects the integrity of GABA-mediated cortical inhibition, can serve as an epileptogenesis biomarker. Since TMS and EEG are already in wide human use, we anticipate that favorable data from the proposed experiments will be rapidly translated to clinical trials in human TBI.