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.

Public Health Relevance

Traumatic brain injury (TBI) is the most common cause of acquired epilepsy in adults where it leads to epilepsy in 20-50% of instances. Yet after TBI, for a given patient, there is presently no diagnostic tool to predict whether he or she will be among those who develop post-traumatic epilepsy. We propose to obtain insight into the mechanisms of posttraumatic epilepsy and develop transcranial magnetic stimulation (TMS) as a safe and rapid biomarker, a sort of neurologic 'stress test,' which will enable clinicians and researchers t (1) identify whether the biological processes that lead to epilepsy have started after TBI, (2) forecast whether post- traumatic seizures are likely, and (3) identify whether prophylactic strategies aimed to restore normal brain function after TBI and prevent epilepsy onset are working.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS088583-05
Application #
9645679
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Churn, Severn Borden
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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