Led by Aristea S. Galanopoulou, MD, PhD, in collaboration with Solomon L. Moshé, MD, and Andrey M. Mazarati, MD, PhD, Montefiore Einstein investigators developed a more naturalistic model of traumatic brain injury (TBI) designed to isolate the impact of peri-trauma stress on epileptogenesis and post-traumatic outcomes, including post-traumatic stress disorder (PTSD). This breakthrough stems from the 2025 completion of a major U.S. Department of Defense (DoD)-funded project (W81XWH2210510) modeling how the trauma experience affects post-traumatic outcomes and epilepsy. By strategically modifying the lateral fluid percussion injury (LFPI) model, the research team successfully created a new moderate-to-severe brain trauma model that more accurately reflects real-world injury conditions.

The success of this work directly enabled Montefiore Einstein’s subsequent $1.2 million DoD award (HT9425-24-1-0134, 2024–2026), which is now focused on using this optimized model to identify and validate multimodal biomarkers—including protein, metabolic, electroencephalography (EEG), gut microbiome and behavioral signatures—of both early and late post-traumatic sequelae. By removing the confounding effects of anesthesia and better capturing early post-injury physiology, combined with the ability to account for antiseizure medications and both early and late seizures, this novel model may substantially enhance the translational value and clinical relevance of candidate biomarkers.

Traditional LFPI models rely on anesthesia during injury delivery. This step removes critical contextual elements and experiences present immediately before, during and shortly after TBI—factors essential in shaping long-term physical, emotional and cognitive outcomes, including PTSD. By eliminating anesthesia at the time of injury and introducing well-defined sensory cues surrounding the traumatic event, the Montefiore Einstein team developed an optimized, modified awake LFPI model with significantly reduced mortality, fewer experimental confounders and a more accurate representation of how peri-trauma stress contributes to epileptogenesis, post-traumatic stress responses and chronic neurological impairment.

This novel model recapitulates key features of human TBI, including neuropathological changes in the brain and the development of post-traumatic epilepsy (PTE). Preliminary findings suggest that peri-trauma experiences leave lasting memories in the rats, predisposing them to increased stress upon re-exposure to similar environmental factors, a discovery with important implications for understanding PTSD-linked pathways that elevate epilepsy risk.

The ongoing biomarker study aims to establish predictive biomarker panels that can stratify TBI patients by risk, differentiate injury trajectories, guide prophylactic antiseizure therapy and ultimately support the development of precision-guided interventions that may prevent or reduce the progression to PTE.

“By creating a more naturalistic and translationally relevant model of traumatic brain injury, we are uncovering insights that were not possible to observe using traditional models,” said Dr. Galanopoulou. “Our goal is to develop biomarker-guided strategies that can accurately identify who is at highest risk for post-traumatic epilepsy and inform early interventions that have the potential to change the trajectory of recovery.”

Together, these initiatives position Montefiore Einstein at the forefront of TBI and epilepsy research, driving forward a new generation of predictive, personalized and preventatively focused approaches to care. This work reflects Montefiore Einstein’s broader commitment to improving outcomes for individuals with TBI, especially those at heightened risk for PTE and long-term neurological complications.

Montefiore Einstein is ranked in the top 1% of all hospitals in the nation for neurology and neurosurgery according to U.S. News & World Report, and is home to one of the first Comprehensive Level 4 Epilepsy Centers, the highest designation from the National Association of Epilepsy Centers.