Pathologic electrographic changes after experimental traumatic brain injury

Abstract

Summary Objective To investigate possible electroencephalography (EEG) correlates of epileptogenesis after traumatic brain injury (TBI) using the fluid percussion model. Methods Experiments were conducted on adult 2- to 4-month-old male Sprague-Dawley rats. Two groups of animals were studied: (1) the TBI group with depth and screw electrodes implanted immediately after the fluid percussion injury (FPI) procedure, and (2) a naive age-matched control group with the same electrode implantation montage. Pairs of tungsten microelectrodes (50 µm outer diameter) and screw electrodes were implanted in neocortex inside the TBI core, areas adjacent to TBI, and remote areas. EEG activity, recorded on the day of FPI, and continuously for 2 weeks, was analyzed for possible electrographic biomarkers of epileptogenesis. Video-EEG monitoring was also performed continuously in the TBI group to capture electrographic and behavioral seizures until the caps came off (28–189 days), and for 1 week, at 2, 3, and 6 months of age, in the control group. Results Pathologic high-frequency oscillations (pHFOs) with a central frequency between 100 and 600 Hz, were recorded from microelectrodes, beginning during the first two post-FPI weeks, in 7 of 12 animals in the TBI group (58%) and never in the controls. pHFOs only occurred in cortical areas within or adjacent to the TBI core. These were associated with synchronous multiunit discharges and popSpikes, duration 15–40 msec. Repetitive pHFOs and EEG spikes (rHFOSs) formed paroxysmal activity, with a unique arcuate pattern, in the frequency band 10–16 Hz in the same areas as isolated pHFOs, and these events were also recorded by screw electrodes. Although loss of caps prevented long-term recordings from all rats, pHFOs and rHFOSs occurred during the first 2 weeks in all four animals that later developed seizures, and none of the rats without these events developed late seizures. Significance pHFOs, similar to those associated with epileptogenesis in the status rat model of epilepsy, may also reflect epileptogenesis after FPI. rHFOSs could be noninvasive biomarkers of epileptogenesis.

Update on the mechanisms and roles of high‐frequency oscillations in seizures and epileptic disorders

“…74 They found that a complex of repetitive HFOs superimposed on arcuate-shaped 10–16 Hz activity. These repetitive HFOs reflected population spikes with hypersynchronous multi-unit firing, and were only found in those FPI rats that later developed seizures.…”

“…72; 73 In FPI rats, a microelectrode and cortical screws recorded pathological HFOs (100–600 Hz) in cortical areas adjacent to or within the injury core during the first two weeks following injury. 74 Moreover, pathological HFOs have been reported to occur in almost 60% of FPI rats, but in none of the control rats. In FPI rats that had completed long-term monitoring, pathological HFOs were found in only those rats that later developed post-traumatic seizures, but were not observed in rats that did not develop late seizures.…”

“…In FPI rats that had completed long-term monitoring, pathological HFOs were found in only those rats that later developed post-traumatic seizures, but were not observed in rats that did not develop late seizures. 74 …”

Nonictal EEG biomarkers for diagnosis and treatment

“…Reports from the animal literature have suggested 3 additional changes in routine noninvasive EEG that appear to correlate with epileptogenesis or ictogenesis. In the fluid percussion TBI rat model, arcuate‐shaped discharges can be recorded with skull screws adjacent to the injury, which appear to predict which animals will eventually develop PTE . Microelectrode recordings demonstrate that these arcuate events reflect the presence of pHFOs (Fig.…”

“…In the latter study, whereas interictal spikes increase postictally when seizure threshold is high, pHFOs do not increase, but they do increase after medication reduction when seizure threshold is reduced, demonstrating that pHFOs more reliably indicate the degree of epileptogenicity than interictal spikes . Animal studies have demonstrated that pHFOs occur early after 2 epileptogenic insults, intrahippocampal kainic acid injection and fluid percussion TBI, and reliably predict animals that will go on to have spontaneous seizures. pHFOs have yet to be confirmed as reliable biomarkers of epileptogenesis in patients.…”