Neurophysiology of Post-Traumatic Epilepsy: Unraveling Epileptogenesis Signals (NEPTUNE)

Principal Investigator: AMORIM DE CERQUEIRA FILHO, EDILBERTO

Proposal Number: EP220036

Award Number: HT9425-23-1-0242

Period of Performance: 9/1/2023 - 8/31/2025

PUBLIC ABSTRACT

Focus Area:

(1) Markers and Mechanisms and (2) Innovative Research.

Objectives and Rationale:

Post-traumatic epilepsy (PTE) affects 20% of civilians and near half of military Service Members with severe traumatic brain injury (TBI). Seizures and other brain activity following acute injury are likely contributing to PTE in humans; however, the specific early changes in brain wave characteristics that emerge before epilepsy starts are unknown. In this Idea Development Award proposal, Dr. Amorim will test whether quantitative analysis of brain waves can help predict seizures within 7 days and PTE diagnosis 6 months after TBI.

The central hypothesis is that evolution in shapes and features of brain waveforms soon after TBI reflect the biology of epilepsy. Dr. Amorim already collected data from 85 patients with TBI who had electrodes placed on the brain’s surface to record seizures during life-saving TBI surgery, and he plans to recruit 60 additional patients. Effects of anti-seizure medications (ASM) given in the hospital will be connected to the brain wave data to determine which ASM better prevent early seizures and their association with PTE risk. Dr. Geoffrey Manley, Professor of Neurosurgery at the University of California, San Francisco (UCSF), and Dr. Lowenstein, Professor of Neurology at UCSF, are world-renowned leaders in the field of TBI and epilepsy who are committed to Dr. Amorim’s project and his career development. This project is expected to discover new knowledge about brain activity after TBI that may: (1) help future studies select patients most likely to benefit from interventions to prevent seizures and PTE and (2) help select the right medication for the right patient to prevent seizure recurrence and prevent side effects. This research opportunity will ideally position Dr. Amorim to lead studies to prevent PTE and advance treatments.

Applications and Benefits:

A successful project will expand our knowledge about PTE biology and guide the care of patients with TBI to (1) improve survival without disability from seizures or PTE and (2) improve selection and dosing of ASM.

- What populations will it help, and how will it help them?

This work will have immediate impact to patients and military Service Members with TBI who are at highest risk for PTE: patients with moderate to severe TBI or penetrating injuries. The overarching goal is to create patient-specific treatment strategies to avoid PTE from developing early on after TBI.

- What are the potential applications, benefits, and risks?

This study will support point-of-care applications for acute seizure diagnosis after TBI, early predictors of PTE, and individualized ASM use. Importantly, this information will support future studies testing interventions to prevent epilepsy in patients at highest risk. Participants in this study may benefit from epilepsy evaluation with experts in PTE. This study has limited risks as there are no interventions; however, it may involve a small risk of loss of privacy as patient information will be collected.

- What are the likely contributions of the proposed research project to advancing PTE research, patient care, and/or quality of life?

Understanding the specific biological changes in brain activity that predict epilepsy after TBI will help clinicians educate patients and families about epilepsy risk and select interventions for studies to stop acute seizures and PTE. Side effects from ASM are common in PTE; therefore, ASM selection to maximize effectiveness and prevent side effects could have a big impact in a patient’s quality of life.

Timeline:

We plan to complete this project in 24 months. We will enroll patients and pursue brain wave analysis for 18 months and complete the needed PTE follow-up by 24 months. In the last 6 months of the project, we plan to submit a proposal for a study in PTE prevention that uses brain wave responses to ASM within days from TBI to guide medication selection. If this new proposal is awarded, patients would be invited to participate in the study within 6-12 months after the completion of the Idea Development Award.

TECHNICAL ABSTRACT

Background:

Combat-related post-traumatic epilepsy (PTE) affects up to 25%-50% of Warfighters with moderate to severe traumatic brain injury (TBI) and is the most frequent cause of new-onset epilepsy in young adult civilians. Despite being a common and highly disabling complication of TBI, predicting who will develop PTE and selecting what anti-seizure medication (ASM) can prevent acute and late seizures is not possible with our current understanding of PTE neurophysiology. Critical barriers in making PTE a preventable and treatable disease are (1) the lack of tools able to identify biological targets for early-goal directed therapies and (2) unknown treatment-response biomarkers for selecting patients most likely to benefit from clinical trials for PTE prevention and control. Intracranial electrocorticography (ECoG) recordings have revolutionized epilepsy surgery and may provide new insights about the neurophysiological mechanisms of epileptogenesis contributing to acute seizures and PTE.

Hypothesis:

This project hypothesis is that spike activity and cerebral spreading depolarizations (CSD) captured using intracranial ECoG are mechanisms contributing to acute seizures and epileptogenesis after TBI.

Specific Aims:

Aim 1: Determine whether spike and CSD features increase seizure risk within 7 days from TBI. Aim 2: Determine whether acute spike and CSD burden predict PTE onset 6 months from TBI. Aim 3: Determine effects of ASM on acute seizures and PTE.

Study Design:

This study will take advantage of a retrospective cohort of 85 subjects who had intracranial ECoG recordings for seizure monitoring immediately after moderate to severe TBI. During the study period, we will prospectively enroll 60 additional subjects. We will interview survivors from both prospective and retrospective cohorts to determine PTE diagnosis using National Institute of Neurological Disorders and Stroke (NINDS) common data elements.

Intracranial Neuromonitoring: Brain monitoring involves 4-16 intracranial electrodes placed during TBI cranial surgery (strip) or through a transcranial bolt (depth), and recordings last up to 10 days. In addition to ECoG, patients routinely have intracranial pressure, cerebral blood flow, and brain oxygen monitoring together with surface electroencephalography (EEG). Clinical, laboratory, imaging, and medication data for all patients undergoing intracranial neuromonitoring will be acquired (already available for retrospective cohort).

Analytical Approach:

We will use computational methods to analyze full-band ECoG signals with a focus on spike and cerebral spreading depolarizations morphological, spectral, and connectivity features using signal processing and deep learning pipelines already in use by our group. We will use mixed effects and survival analysis to model PTE risk and individualized ASM treatment-response biomarkers.

Innovation:

Mechanism-driven approach to pharmacological target-mediated effects: Spikes and CSD are commonly seen in acute TBI, and this study will use intracranial ECoG recordings to quantitatively determine if these fast and slow brain rhythms are an epiphenomenon or a modifiable target for ASM interventions in patients with TBI.

Tool-driven approach to in-vivo biomarker discovery: a systems neuroscience toolbox applied to ECoG recordings in TBI enables both quantitative- and biological-driven approaches for PTE biomarker discovery.

Impact:

This project will uncover important insights about neurophysiological mechanisms of epileptogenesis in acute TBI with the unparalleled time-and local resolution of intracranial ECoG monitoring. By determining how these longitudinal trends evolve after TBI as well as their response to ASM before acute seizures and PTE emerges, this work will inform future studies focused on PTE prevention on how to incorporate this physiology to individualize and monitor response to therapies. We envision the adoption of intracranial monitoring as part of standard TBI acute care.