The experimental model represents a critical platform for developing new medicines for military persons and civilians with traumatic brain injuries
When military soldiers go into combat, they put themselves at risk of a traumatic brain injury (TBI), which is caused by a bump, blow or jolt to the head. Explosions experienced during combat or training exercises can cause a soldier’s head to be hit or violently shaken and can even result in a concussion or closed head injury. About 69 million individuals worldwide are estimated to sustain a TBI each year.
TBI is also a major concern for athletes and first responders. Other populations that are affected by TBIs include older people, children, motor vehicle drivers and cyclists. TBI is among the leading causes of injury-related death and disability in many countries worldwide. An estimated 100 million people live with the challenges of a long-term TBI-related disability. With symptoms ranging from “mild” to “severe,” individuals who suffer from TBIs can develop a wide range of long-term consequences such as poor motor balance, depression, post-traumatic stress disorder (PTSD), dementia, epilepsy and premature death. Spontaneous recurrent seizures (SRS) may occur in the months or years following the injury, which is commonly referred to as post-traumatic epilepsy (PTE). Currently, there is no effective treatment or cure for PTE; therefore, there is a critical need to develop animal models to help further understand and assess the mechanisms and interventions related to TBI-induced epilepsy.
Dr Samba Reddy, a Professor at Texas A&M University College of Medicine, and team have created a novel experimental model that is able to successfully replicate the same SRS that occur in humans who develop TBI-induced epilepsy. Their findings were recently published in the journal Experimental Neurology. This research, funded by grants from the U.S. Department of Defense, can be used to test medical treatments to prevent seizures and other neuropsychiatric conditions in military personnel.
This is a game-changing model on many fronts, Dr Reddy said. “Without an effective brain injury model, you cannot study the consequences of brain injury. This research is so important because it is the first new-generation model of TBI epilepsy. This work has great clinical and military significance for identifying and advancing therapies for brain injury.”
PTE research involves a complex set of operations. In order to effectively study treatment options for PTE, it is critical for the model to accurately and consistently mimic the severity of the brain injury and the spontaneity of a seizure that occurs in humans. Reddy and Victoria Golub, PhD, postdoctoral research associate in Reddy’s lab and the first author of the paper, worked on this research project for five years. This is the first study to examine PTE at this level.
The researchers partnered with biomedical engineers to utilise a machine learning approach that conducted automatic analyses of the seizures from an electroencephalography (EEG) database. Through this, the team was able to identify multiple electrographic biomarkers of epileptogenic circuits—meaning that they were able to understand and recognize the behavior and signs of epileptogenesis. In their analyses, they found that high-frequency oscillations and discharges are preceded by seizures, which may serve as biomarkers for predicting seizure risk in the future.
“Presently, we have no treatment to interrupt the epileptogenic response after TBI. The latency period is critical because it represents a therapeutic window to test medical interventions. If such early brain plasticity can be halted by medicines, then this can completely prevent subsequent epilepsy and neuropsychiatric problems following a brain injury”, Dr Reddy added.
In addition to long-term EEG analysis, Dr Reddy’s team profiled a longitudinal change in the brain in two other major areas: brain tissue histology and behavioral patterns. Behaviorally, the test subjects showed sensory and behavioral functional deficits as well as long-term memory dysfunction—too often overlooked facets of the condition in humans that can negatively affect the quality of life and independent functioning.
“Collectively, this animal model effectively replicates and exhibits PTE as it is in the human condition. By creating neural cascades of epileptogenesis, this model opens avenues for screening strategies that can be used to block epileptogenesis and the development of epilepsy. We hope this research will help propel the field towards new medicines and treatment options for individuals suffering from this debilitating condition. We know that brain damage is irreversible, but we hope this model can help reduce or prevent neuropsychiatric comorbidities that occur as a result of TBI, especially in soldiers, athletes and civilians”, Dr Reddy added.
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