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

通过 TMS 和 EEG 绘制创伤后癫痫发生过程中皮质内抑制的逐渐丧失

基本信息

批准号：
8888294
负责人：
Alexander Rotenberg
金额：
$ 36.92万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888294
关键词：
Acetylcysteine Adult Anatomy Animals Antiepileptogenic Antioxidants Biological Assay Biological Markers Biological Process Brain Brain Injuries Calcium-Binding Proteins Ceftriaxone Cells Cerebrum Cessation of life Clinical Clinical Trials Contralateral Data Depressed mood Detection Development Diagnostic Diagnostic Procedure Electroencephalography Epilepsy Epileptogenesis Frequencies Functional disorder Glutamates Goals Harvest Health Heterogeneity Human Individual Injury Interneurons Intervention Lateral Lead Limb structure Liquid substance Maps Measures Mediating Methods Modeling Motor Cortex Motor Evoked Potentials Muscle Neurologic Outcome Parvalbumins Pathologic Patients Percussion Physiologic pulse Post-Traumatic Epilepsy Process Protocols documentation Rattus Research Personnel Risk Seizures Skin Sorting - Cell Movement Stimulus Stress Tests Testing Time Tissues Transcranial magnetic stimulation Translating Traumatic Brain Injury Work base conditioning fluid percussion injury gamma-Aminobutyric Acid improved insight magnetic field new therapeutic target outcome forecast prevent prophylactic public health relevance research study response tool young adult

项目摘要

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.

描述（由适用提供）：脑损伤通常通过癫痫发生导致癫痫发作，该过程将大脑转化为持久状态（癫痫），其特征在于反复的无端癫痫发作。严重的脑损伤（TBI）是年轻人癫痫发生的最常见例子，并在20-50％的情况下导致癫痫发作。这个癫痫发作时期提供了一个机会之窗，可以鉴定出有癫痫发作风险的患者，并且可以进行抗癫痫疗法。然而，没有可靠的临床生物标志物用于癫痫生成，可以识别癫痫发生是否已经开始以及它已经发展了多远。根据所提出的实验的长期目标，是使用大鼠癫痫发生的TBI模型来开发癫痫生成的安全，廉价和无创的电生理生物学生物标志物，基于经颅磁刺激（TMS）对皮质兴奋性的测量。作为次要目标，我们将测试如果可以通过皮质脑电图获得类似的措施。我们最近开发了大鼠局灶性运动皮层TMS的方法，证明了这些方法可靠地反映了GABA介导的皮质抑制的大小，并表明在大鼠癫痫发作模型中，这种抑制作用降低，包括创伤后癫痫的模型。在这里，我们建议使用大鼠外侧液体敲击（LFP）后癫痫模型进行测试（1）（1）皮质抑制的丧失是否在癫痫发生期间是否在时间上逐步进行，（2）受伤后心脏抑制的丧失是否可以预测癫痫发作和（3）是否可以预测诸如可逆的细胞 - - - - （3）是否可以逆时针损失 - （3）皮质抑制损失的测量。尽管提出的实验仅限于TBI癫痫发生后的大鼠模型，但我们预计结果将为TMS的研究提供一些以其他形式的癫痫生成为生物标志物的研究。此外，正如我们将在所有动物中记录EEG一样，我们将测试伽马频率EEG功率是否也反映了GABA介导的皮质抑制的完整性，可以用作癫痫生成生物标志物。由于TMS和EEG已经广泛使用，因此我们预计提出的实验的有利数据将迅速转化为人类TBI的临床试验。