Voluntary Control of Epileptiform Spike–Wave Discharges in Awake Rats

Abstract

Genetically inherited absence epilepsy in humans is typically characterized by brief (seconds) spontaneous seizures, which involve spike-wave discharges (SWDs) in the EEG and interruption of consciousness and ongoing behavior. Genetic (inbred) models of this disorder in rats have been used to examine mechanisms, comorbidities, and antiabsence drugs. SWDs have also been proposed as models of complex partial seizures (CPSs) following traumatic brain injury (post-traumatic epilepsy). However, the ictal characteristics of these rat models, including SWDs and associated immobility, are also prevalent in healthy outbred laboratory rats. We therefore hypothesized that SWDs are not always associated with classically defined absence seizures or CPSs. To test this hypothesis, we used operant conditioning in male rats to determine whether outbred strains, Sprague Dawley and Long-Evans, and/or the inbred WAG/Rij strain (a rat model of heritable human absence epilepsy) could exercise voluntary control over these epileptiform events. We discovered that both inbred and outbred rats could shorten the duration of SWDs to obtain a reward. These results indicate that SWD and associated immobility in rats may not reflect the obvious cognitive/behavioral interruption classically associated with absence seizures or CPSs in humans. One interpretation of these results is that human absence seizures and perhaps CPSs could permit a far greater degree of cognitive capacity than often assumed and might be brought under voluntary control in some cases. However, these results also suggest that SWDs and associated immobility may be nonepileptic in healthy outbred rats and reflect instead voluntary rodent behavior unrelated to genetic manipulation or to brain trauma.

Spontaneous Recurrent Absence Seizure-like Events in Wild-Caught Rats

“…Fourier analysis also reveals that SWDs in wild rats are distinguished from other EEG waveforms by the quasiperiodic spike-wave morphology, with the repeating spike resulting in spectral harmonics at multiples of the fundamental frequency. This particular characteristic was also present in our WAG/Rij, outbred BN, and LE rats, and in other inbred and outbred rats (Shaw, 2004(Shaw, , 2007Meeren et al, 2009;Sitnikova et al, 2009;Taylor et al, 2017). It so uniquely identifies SWDs in GAERS rats that harmonic analysis by itself has been effectively used for automated detection of SWDs (Van Hese et al, 2003, 2009).…”

“…ETX ETX has a powerful attenuating effect on SWDs in inbred rat models of absence epilepsy (Terzioglu et al, 2006;Shaw, 2007;Taylor et al, 2017). Our results indicate that SWDs in wild rats share a similar pharmacosensitivity to ETX seen in both inbred and outbred rat strains.…”

“…2) to extract all recorded bursts in a given animal (described in Materials and Methods). SWD bursts in our wild rats displayed a distinct frequency spectrum (common to SWDs reported for most outbred and inbred rats) due to the quasiperiodic waveform, with a fixed fundamental frequency peak in the range of 7-10 Hz, and peaks at whole harmonics of this fundamental frequency (Van Hese et al, 2003, 2009Shaw, 2004;Sitnikova et al, 2009;Rodgers et al, 2015;Taylor et al, 2017). Figure 3A (blue trace) shows an example of spectral analysis in a wild rat, averaged across all SWD bursts, with a fundamental frequency of 7.5 Hz and prominent harmonic peaks at ϳ15 and 22.5 Hz.…”

“…Supervised pattern recognition of SWDs. Similar to our previous studies (Rodgers et al, 2015;Taylor et al, 2017), automated detection was used to quantify SWD events in the ECoG data. For a given rat, SWDs were visually identified, the peaks of 30 -50 spikes were digitally marked, and 1 s samples surrounding each peak were extracted (see Fig.…”

“…Whether or not SWD/immobility reflects absence seizures in outbred rats has a long history of controversy (Kaplan, 1985;Wiest and Nicolelis, 2003;Shaw, 2004;Pearce et al, 2014). We recently found that Sprague Dawley and Long-Evans (LE) rats displayed frequent SWD/immobility events that appeared to be absence-like seizures very similar to inbred WAG/Rij absence epilepsy rats (Taylor et al, 2017). We concluded that, although these events could model mild absence epilepsy with only partial attenuation of consciousness, they may instead be a form of modifiable behavior.…”