Seizure genesis in CNS oxygen toxicity: animal studies
Abstract
There is no consensus as to where seizures originate in the central nervous system (CNS) when breathing hyperbaric oxygen (HBO2), which is defined clinically as #CNS oxygen toxicity# (CNS-OT). CNS-OT presents as a series of abnormal cardiorespiratory responses followed by various nonconvulsive signs and symptoms (S/Sx) that culminate in generalized seizures and post-ictal neurogenic/cardiogenic pulmonary edema. The risk for developing CNS-OT is what limits all applications for breathing HBO2 in undersea and hyperbaric medicine#most importantly, USN divers who use rebreathers when diving. Currently, the maximum bottom time in 50-fsw is only 10-min to avoid the most susceptible diver suffering CNS-OT. Longer, safer dives are desired. The goal of this 6.2 research project is to identify the electrical signaling properties and locations of O2-sensitive neurons (#oxtox trigger neurons#) that initiate the early depolarizing signals that ultimately culminate, tens-of-min later, in generalized seizures (Sz), i.e., Sz genesis. Based on old brain lesioning experiments, the temporal pattern of abnormal cardiorespiratory responses activated (bradycardia, hyperventilation), and nonconvulsive S/Sx that often precede Sz (e.g., facial/lip twitching), we hypothesize that oxtox trigger neurons/nuclei are concentrated in subcortical regions that include brain stem cardiorespiratory centers and cranial nerve (CN) nuclei. Once #triggered#, brain stem oxtox trigger signals are relayed across amplifying brain stem and forebrain circuits, eventually culminating in the epileptiformbrain activity and detectable motor Sz, i.e., CNS-OT. We plan to test these hypotheses in Sprague-Dawley rats using electrophysiology and functional near infrared spectroscopy (fNIRS). Aim 1 test the O2-sensitivity of neurons in CO2-chemosensitive nuclei and CN nuclei. Aim 2 studies the temporal pattern of neural activation in subcortical regions vs. higher motor centers using deep intracerebral electrode telemetry to measure local field potentials in freely behaving rats during exposure to HBO2#CO2. Aim 3 studies the temporal pattern of neuro-hemodynamic changes (cerebral blood volume, tissue oxygenation) using fNIRS along the caudo-rostral neuroaxis of unanesthetized rats during exposure to HBO2#CO2. Answering these fundamental questions will help future ONR-DoD performers to specifically target #oxtox trigger neurons and synapses##the most vulnerable O2-sensitive populations of neurons and synapses in the mammalian brain#for investigating new, untested mitigation strategies to delay and prevent Sz genesis in basic undersea medical research and clinical trials. Historically, therapies targeting specific brain nuclei, neural circuits, and cell populations have proven useful in treating various neurological disorders, most notably, drug resistant epilepsy. Likewise, targeted therapies such as transcranial ultrasound neurostimulation have proven highly beneficial for epilepsy. Could such targeted strategies be used against the most O2-sensitive, HBO2-vulnerable brain stem regions to improve a diver#s resistance during HBO2 exposures? Interventions like this,and targeted neuropharmaceuticals, cannot be studied in animal and human models of CNS-OT, and ultimately transitioned to the Fleet, until the brain#s oxtox trigger zones are identified. That is the goal of this project.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 24, 2023
- Source ID
- N000142312717
Entities
People
- Jay B. Dean
Organizations
- Office of Naval Research
- United States Navy
- University of South Florida