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

• 批准号: 9215704
• 负责人: Alexander Rotenberg
• 金额: $ 38.72万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/9215704
• 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; Electrophysiology (science); Epilepsy; Epileptogenesis; Frequencies; Functional disorder; Glutamates; Goals; Harvest; Health; Heterogeneity; Human; Individual; Injury; Interneurons; Intervention; Lateral; Lead; Limb structure; Liquid substance; 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; Stimulus; Stress Tests; Testing; Time; Tissues; Transcranial magnetic stimulation; Translating; Traumatic Brain Injury; base; clinical biomarkers; conditioning; experimental study; fluid percussion injury; gamma-Aminobutyric Acid; improved; insight; magnetic field; new therapeutic target; outcome forecast; prevent; prophylactic; public health relevance; response; tool; young adult

 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（由申请人提供）：脑损伤通常通过癫痫发生导致癫痫，在该过程中，大脑转变为以反复无端癫痫发作为特征的持久状态（癫痫），严重外伤性脑损伤（TBI）是最常见的例子。年轻人发生癫痫，20-50% 的情况下会导致癫痫。这个癫痫发生期为患者提供了发生癫痫的机会。然而，尚无可靠的癫痫发生临床生物标志物来确定癫痫发生是否已经开始以及进展程度。因此，所提出的实验的长期目标是。使用大鼠致癫痫性 TBI 模型开发一种安全、廉价且无创的癫痫发生电生理生物标志物，该标志物基于经颅磁刺激 (TMS) 的皮质兴奋性测量作为次要目标，我们将测试 如果可以通过皮质脑电图获得类似的测量结果，我们最近开发了大鼠局灶性运动皮层 TMS 的方法，证明这些方法可靠地反映了 GABA 介导的皮质抑制的程度，并表明这种抑制在大鼠癫痫模型中被抑制，包括在这里，我们建议使用大鼠侧向液体冲击（LFP）创伤后癫痫模型来测试（1）皮质抑制的丧失在癫痫发生过程中是否随时间进行。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（例如 GABA 能中间神经元的丧失）是否是 TMS 衍生的皮质抑制丧失测量的基础，尽管所提出的实验仅限于大鼠模型。关于 TBI 后癫痫发生的研究，我们预计该结果将为 TMS 作为其他形式癫痫发生的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脑电图，我们将测试伽马频率脑电图功率是否存在。也反映了 GABA 介导的皮质抑制的完整性，可以作为癫痫发生的生物标志物，因为 TMS 和 EEG 已经在人类中广泛使用，我们预计来自拟议实验的有利数据将迅速转化为人类 TBI 的临床试验。