Post-Traumatic Epileptogenesis: Role of Neocortical-Hippocampal Interactions
Abstract
After severe traumatic brain injury (TBI), up to 20%-50% of patients may develop delayed seizures, or post-traumatic epilepsy (PTE), several months to several years after injury in a process called epileptogenesis. We have no effective therapies to prevent it. There is evidence that injury to a part of the brain called the temporal lobe increases one’s risk of PTE, yet most seizures that occur in PTE do not seem to originate from the temporal lobe, which is a common location for non-traumatic epileptic seizures to originate. Given the apparent discrepancy, this research proposal seeks to understand whether temporal lobe injury after TBI plays a role in the development of PTE even if few temporal lobe seizures result. The lateral fluid percussion injury (FPI) rat model of TBI parallels this seeming paradox in humans: FPI causes characteristic damage to a structure in the temporal lobe called the hippocampus, but leads to seizures coming predominantly from a different area of the brain, the overlying neocortex. Damage after FPI makes the hippocampus more excitable, exhibiting exaggerated responses to inputs, but whether this contributes to PTE is unknown. The hippocampus receives information from nearly all of the neocortex and is responsible for forming memories from that information. The hippocampus, in turn, communicates encoded memories back to the neocortex for long-term storage. The mechanisms by which this bidirectional communication occurs may be corrupted by the epileptogenic process. This study seeks to understand how the circuitry within the hippocampus may change over time after its initial injury following FPI and whether those changes can contribute to abnormal activity in the neocortex that ultimately leads to PTE. To do this, we will use the FPI rat model of TBI. In the first set of experiments, rats will undergo FPI and then will be implanted with electrodes in the hippocampus and the neocortex. We will monitor the rats for up to 24 weeks after FPI, looking for the evolution of abnormal signals recorded from the hippocampus and neocortex that suggest progressive hippocampal hyperexcitability and abnormal communication between these structures, as well as whether these abnormalities predict the development of PTE. In the second set of experiments, we will attempt to reverse the hyperexcitability of the hippocampus after injury by activating a particular set of cells called interneurons within the hippocampus (some of which are damaged after FPI) via delivery of light using a technique called optogenetics. We will test whether reducing the injury-induced hyperexcitability in the hippocampus can prevent, or attenuate, the development of PTE. The military population bears a disproportionate burden of PTE, occurring in up to 53% of cases of severe TBI, compared to 10%-20% in civilians. Delayed onset of PTE and associated cognitive and memory impairment after TBI leads to increased risk of death as well as further loss of functional independence, reduced quality of life, and increased economic burden. Effective preventative therapies (of which there are currently none) are urgently needed to improve function and quality of life after TBI, particularly in the military population. The immediate goal of this proposed research is to identify key changes in the circuitry of the hippocampus that contribute to the development of PTE. As an intermediate step for subsequent preclinical studies, strategies for identifying and reversing these key changes would then be developed and tested for effectiveness in reducing PTE. The long-term goal is two-fold: to define key hippocampus circuitry changes that both (1) predict development of PTE and thus help define the population of TBI patients that should receive preventative therapy, and (2) can be intervened upon as an effective therapy to prevent, or attenuate, the development of PTE. Modifying the function of brain circuits to treat disease using implantable stimulating electr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310363
Entities
People
- Paul Koch
Organizations
- United States Army
- Virginia Commonwealth University