Highlights of the Initiative
- Using its team science expertise and drawing on 2015 Department of Defense (DoD) funding, CURE Epilepsy brought together six teams to study diverse aspects of PTE. The goal of the ongoing initiative is to lay the groundwork for the development of future preventative therapies.
- Collectively, PTE Initiative teams have developed and characterized several different animal models of PTE, enhanced our understanding of the biological underpinnings of PTE, and identified several potential risk factors and potential biomarkers for PTE.
- So far, the PTE Initiative has produced 18 scientific abstracts, 10 conference presentations, seven peer-reviewed articles, four investigator’s workshops, and one data blitz presentation (a number that continues to grow).
- CURE Epilepsy has recently been awarded additional funding by the DoD Congressionally-Directed Medical Research Program (CDMRP) Epilepsy Research Program to provide similar infrastructure to a new team science award. This award will explore a subset of findings from the PTE Initiative and is estimated to begin in late 2023.
About the Initiative
So far, the Post Traumatic Initiative (PTE) has improved the way we are studying PTE in a laboratory setting and is shedding light on PTE in humans who are impacted by traumatic brain injury (TBI). It is also allowing us to understand biomarkers that could reveal who will develop PTE after TBI.
This multi-disciplinary program devotes significant resources towards research benefiting individuals affected by traumatic brain injury (TBI) and resulting post-traumatic epilepsy (PTE). CURE Epilepsy’s PTE Initiative features a multi-center, multi-investigator research team dedicated to improving ways to study PTE in a laboratory setting, developing biomarkers, and understanding risk factors to help us predict who will develop PTE following TBI. In this way, we are laying groundwork for the creation of novel therapies to prevent the development of PTE.
CURE Epilepsy’s PTE Initiative assembles thought leaders in the field to address questions with a peer-reviewed approach. An External Advisory Council also provides scientific and logistical oversight over the selected investigative team. As science drives the initiative, it adapts to make outcomes as impactful as possible, with the key aim of positively affecting the lives of those affected by TBI and PTE.
University of Pennsylvania Project
Primary Investigator: Dr. Victoria Johnson
Dr. Vicky Johnson and her team are focused on how possible detrimental changes following TBI, including chronic leakage of the blood-brain barrier (a cell barrier within blood vessels that blocks certain substances from passing into the brain from the rest of the body), neuronal degeneration (the deterioration and death of neurons) and gliosis (changes in important neuronal support cells in response to central nervous system damage), might lead to PTE. To characterize these, the team is using tissue from humans with traumatic brain injury as well as a unique large animal model of TBI. Thus far, the team findings suggest dysfunctional changes in certain cell types and pathways in the brain after TBI that may be associated with the development of PTE. The team is also studying how certain changes in brain activity following TBI may indicate the development of PTE.
University of Illinois, Chicago Project
Primary Investigator: Dr. Jeffrey Loeb
A major challenge to the study of PTE is that there are vast differences in the types of TBI that can lead to epilepsy, including blows to the head, blasts, and penetrating brain injuries. To better understand and prevent epilepsy following TBI, it is essential to understand common changes in the brain that might lead to PTE.
Dr. Jeffrey Loeb and his team have focused their efforts on studying subarachnoid hemorrhage, or bleeding in the space between the brain and the tissue surrounding the brain, a phenomenon that commonly occurs following a brain injury. In fact, in both animals and humans, subarachnoid hemorrhage occurs in almost all severe TBIs and is known to produce seizures. By examining patients with subarachnoid hemorrhage and an animal model of subarachnoid hemorrhage, the Loeb team is utilizing methods such as MRI and EEG to characterize the development ofPTE with the aim of understanding and predicting who is at risk for developing this condition and identifying potential treatment strategies. Additionally, the team is developing a web-based application to support the analysis and understanding of the way multiple factors, such as a person’s medical history or injury type, relate to the development of PTE.
Virginia Tech Project
Primary Investigator: Dr. Michelle Olson (primary investigator previously Dr. Harald Sontheimer)
Traumatic brain injury is the most common cause of acquired epilepsy. Despite our awareness that TBI can lead to PTE, prevention of PTE with antiseizure medications has been unsuccessful. One reason for the lack of success may be that current treatments do not address certain potential root causes of PTE, including abnormal changes in an important type of neuronal support cell, called an astrocyte, and disruption of the blood-brain barrier, a cell barrier that blocks toxic substances from passing into the brain from the rest of the body. These changes can occur after TBI and may increase the likelihood of seizures and PTE. Further hampering progress towards the development of treatments for PTE is a lack of adequate animal models to investigate the mechanisms behind this devastating disorder.]
In a project originally developed by Dr. Harald Sontheimer and now led by Dr. Michelle Olsen, the Virginia Tech team have identified the need for additional animal models of post-traumatic epilepsy and have spent time developing a newer mouse model of post-traumatic epilepsy alongside a more established model to investigate the ways in which TBI leads to PTE. Their approach focuses on carefully classifying how changes that occur in the number, structure, and location of neuronal support cells as well as changes in the blood-brain barrier might lead to the development of PTE, with the aim of identifying new targets at which to aim treatments. The team has also focused on analyzing changes in brain activity following TBI in these models, with preliminary evidence finding changes that may relate to the development of PTE.
Harvard Medical School Project
Primary Investigator: Dr. Kevin Staley
Currently, there is little understanding of why 20% of significant severe civilian closed-head injuries result in PTE, nor is there an understanding of why this type of epilepsy is so often resistant to treatment with currently available options. It is known that TBI can initiate changes in glial cells – a type of cell that provides essential support and insulation to neurons in the brain, a process that is also associated with PTE.
Completing his PTE Initiative work in 2022, Dr. Kevin Staley and his team focused their project on examining changes in the brain’s neuronal support system that occur after TBI. His team hypothesized that these changes might alter the balance between inhibitory and excitatory neurotransmission and contribute to the development of post-traumatic epilepsy. The team’s project worked to develop a novel large animal model of PTE and created innovative optical imaging equipment to view changes occurring within the brain of these animals that could increase the brain’s excitation, potentially leading to seizures. The team also studied biofluids from humans with severe traumatic brain injury to investigate the possibility of measuring changes in substances within these biofluids as an indicator of TBI.
Dr. Staley’s team recently received a Program Project Grant from the National Institute of Neurological Disorders and Stroke to continue the team’s investigation into the role of the extracellular matrix in PTE. Dr. Staley credits the funding his team received through the PTE Initiative as being critical for generating the substantial preliminary data and papers needed to demonstrate the feasibility of the proposed program project.
University of Florida Project
Primary Investigator: Dr. Kevin Wang
Dr. Kevin Wang and his team, are utilizing a mouse model of post-traumatic epilepsy characterized by the development of spontaneous seizures to study changes that occur in brain activity and chemical and molecular processes within important epilepsy-related areas of the brain. The team is comparing animals that develop PTE after traumatic brain injury to those that do not in an effort to uncover the unique processes that lead to PTE. Thus far, the team has focused on characterizing changes in proteomics (changes in proteins within the brain), metabolomics (changes in metabolites within the brain), and changes in microRNA (small RNA molecules that affect basic biological processes), with the goal of providing new potential areas upon which to target the development of treatments for PTE.
Mid-Atlantic Epilepsy and Sleep Center Project
Primary Investigator: Dr. Pavel Klein
PTE does not develop until weeks or years after a traumatic brain injury, offering a window of opportunity for preventative treatment. However, it is currently not possible to predict who will develop epilepsy following TBI, nor do any preventative measures exist. In fact, there are currently no clinical studies being conducted that seek to prevent the development of PTE, despite the availability of a number of approved drugs with antiepileptogenic properties. A major reason for the lack of clinical trials in this area is the relatively low rate and unpredictability of PTE among individuals with a TBI, making such studies large and costly.
Dr. Pavel Klein and his team are working to address the current inability to predict which individuals will develop PTE after traumatic brain injury by studying the development of PTE in a group of “high risk” individuals with severe TBI. Utilizing an extensive network of clinical sites within the US and Europe, the team is looking at genetic risk factors for PTE as well as searching for potential markers that can be measured in a person’s blood after TBI that would predict an increased risk of post-traumatic epilepsy development. By identifying ways to distinguish individuals most at risk of developing PTE, the team will pave the way for the creation of therapies to prevent its development in the first place.