Progressive, Seizure-Like, Spike-Wave Discharges Are Common in Both Injured and Uninjured Sprague-Dawley Rats: Implications for the Fluid Percussion Injury Model of Post-Traumatic Epilepsy

Abstract

Variable-duration oscillations and repetitive, high-voltage spikes have been recorded in the electrocorticogram (ECoG) of rats weeks and months after fluid percussion injury (FPI), a model of traumatic brain injury. These ECoG events, which have many similarities to spike-wave-discharges (SWDs) and absence seizures, have been proposed to represent nonconvulsive seizures characteristic of posttraumatic epilepsy (PTE). The present study quantified features of SWD episodes in rats at different time points after moderate to severe FPI, and compared them with age-matched control rats. Control and FPI-injured rats at 1 year of age displayed large-amplitude and frequent SWD events at frontal and parietal recording sites. At 3-6 months, SWDs were shorter in duration and less frequent; extremely brief SWDs (i.e., "larval") were detected as early as 1 month. The onset of the SWDs was nearly always synchronous across electrodes and of larger amplitude in frontal regions. A sensory stimulus, such as a click, immediately and consistently stopped the occurrence of the SWDs. SWDs were consistently accompanied by behavioral arrest. All features of SWDs in control and experimental (FPI) rats were indistinguishable. None of the FPI-treated rats developed nonconvulsive or convulsive seizures that could be distinguished electrographically or behaviorally from SWDs. Because SWDs have features similar to genetic absence seizures, these results challenge the hypothesis that SWDs after FPI reflect PTE.

Voluntary Control of Epileptiform Spike–Wave Discharges in Awake Rats

“…We recently reported that epochs of SWDs and associated immobility are indistinguishable between FPI and sham-injured rats (Rodgers et al, 2015). We concluded that since their occurrence did not require prior injury, they must reflect heritable seizures typically reported in rats inbred for SWDs over multiple generations and used as genetic models of absence epilepsy for decades.…”

“…Whether SWDs reflect PTE has been challenged by evidence of an equal prevalence in age-matched uninjured rats (Pearce et al, 2014;Rodgers et al, 2015). We recently reported that epochs of SWDs and associated immobility are indistinguishable between FPI and sham-injured rats (Rodgers et al, 2015).…”

“…Older rats were used because they typically display more SWDs than younger rats (Rodgers et al, 2015). Rats were housed under standard laboratory conditions in a temperature-controlled and relative humidity-controlled (i.e., 20 Ϯ 1°C and 60%, respectively) environment with a normal 12 h light/dark cycle (lights on 7:00 A.M. to 7:00 P.M.).…”

“…Three hallmarks characterize typical human absence (petit mal) seizures: (1) a distinct heritability or clear genetic component, (2) a clinical manifestation of sudden and brief but profound impairment of consciousness with behavioral arrest (i.e., absence), and (3) a concomitant appearance of classic, large-amplitude, 3 Hz, paroxysmal SWDs in the EEG. While established inbred rodent models of human absence epilepsy approximate these hallmarks, our observations of SWDs were in outbred Sprague Dawley rats (SD rats; Rodgers et al, 2015). Episodes of SWDs and associated immobility reported in most outbred strains suggest that rats used in behavioral and preclinical studies have frequent seizures that could seriously confound results of many types of studies, particularly if undetected.…”

“…If SWDs and associated immobil-ity are consistently epileptic, it is of concern because frequent SWDs (many per hour) are also observed in many healthy adult outbred strains of laboratory rats used in behavioral neuroscience research and preclinical studies of epilepsy (Vergnes et al, 1982;Kaplan, 1985;Buzsaki et al, 1990;Kelly, 2004;Shaw, 2004;Pearce et al, 2014) where unrecognized seizures could present a significant confound. However, the role of SWDs in rat epilepsy is a matter of continuing debate (Kaplan, 1985;Wiest and Nicolelis, 2003;Kelly, 2004;Shaw, 2004;D'Ambrosio and Miller, 2010;Dudek and Bertram, 2010;Rodgers et al, 2015).…”