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(申请人提供)：脑损伤通常通过癫痫发生导致癫痫，这是大脑转变为持久状态(癫痫)的过程，特征是反复无端癫痫发作。严重创伤性脑损伤(TBI)是青壮年最常见的后遗症，在20-50%的病例中会导致癫痫。这一致痫时期提供了一扇机会之窗，可以在其中识别有癫痫发作风险的患者，并在其中实施抗癫痫治疗。然而，目前还没有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到什么程度。因此，提出的实验的长期目标是使用大鼠致痫脑损伤模型来开发一种安全、廉价和非侵入性的癫痫发生的电生理生物标志物，该生物标志物基于经颅磁刺激(TMS)皮质兴奋性的测量。作为次要目标，我们将测试 如果皮质脑电也能得到类似的测量结果。我们最近开发了大鼠局灶性运动皮质TMS的方法，证明了这些方法可靠地反映了GABA介导的皮质抑制的程度，并表明这种抑制在大鼠癫痫模型中受到抑制，包括创伤后癫痫模型。在这里，我们建议使用大鼠外侧液压冲击(LFP)后创伤性癫痫模型来检验(1)在癫痫发生过程中皮质抑制的丧失是否是进行性的，(2)损伤后皮质内抑制的丧失是否可以预测癫痫的发生，(3)潜在的可逆细胞变化，如GABA能中间神经元的丧失是否是TMS派生的皮质抑制丧失的基础。虽然建议的实验仅限于脑外伤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的生物标志物的研究提供参考。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功率是否可以作为癫痫发生的生物标记物，该功率也反映了GABA介导的皮质抑制的完整性。由于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在人类脑外伤中的临床试验。