Electroencephalographic (EEG) seizures and background abnormalities in a rat model of neonatal hypoxic-ischemic encephalopathy

An important clinical problem that has not been adequately addressed in animal models is the rapid and reliable detection of cerebral dysfunction and brain damage. The use of continuous electroencephalographic (EEG) monitoring has the potential to address this unmet medical need, but for technical reasons translational research with animal models of neonatal hypoxic-ischemic encephalopathy (HIE) has lagged behind clinical research on human neonates in this area. Previously, large animal models, such as sheep/lambs were required to study the quantitative features of EEG in animal models of neonatal brain injury. In this study, we (1) developed and adapted a miniature wireless EEG system for use in rat pups as young as postnatal day 6 (P6); (2) compared seizures and EEG background in two animal models of acute neonatal seizures (hypoxia with seizures but no obvious neuronal death; and, hypoxia-ischemia with seizures and catastrophic brain damage); and (3) quantitatively analyzed electrographic seizures and background EEG abnormalities during the subacute period in these rat-pup models (i.e., hours to days after hypoxia alone and HIE). We showed that the miniature telemetry system allowed repeated recordings of electrographic activity during and at different times after the insult in individual animals; these recordings had high signal-to-noise ratio and low number of artifacts, which in turn allowed quantitative analyses of both the electrographic seizures and ! iv! changes in the background EEG. The recordings during the two insults (i.e., hypoxia alone and HIE) showed that the acute hypoxic environment was the driving force for the electrographic seizures in both models, but that brain damage was associated with a progressive suppression of both the ongoing seizures and the background EEG. During the subacute period, however, rat pups that had experienced hypoxia alone showed no seizures and displayed a background EEG virtually identical to sham-control animals. The rat pups with a catastrophic lesion and HIE consistently had suppression of the background EEG (and some showed electrographic seizures during the intermittent recordings). Most important, quantitative analyses with Fast Fourier Transforms from brief periods of EEG recording (i.e., as short as 1 min) could rapidly and reliably detect those animals that were experiencing HIE. Our findings may translate to the human neonatal population at risk for HIE.