Abstracts

Rationale: Existing literature on human epilepsy shows a complex and bidirectional relationship between sleep and seizures. This includes an increased likelihood of seizures following unstable sleep patterns, particularly relative to the loss of REM, as well as seizure-frequency-associated sleep fragmentation. To further understand the development of this relationship via chronic recording, we have examined the sleep-wake physiology of mice induced into spontaneous seizure via the intra-amygdala kainic acid (IAKA) model of epilepsy through the course of the epileptogenic period.


Methods: Mice (9-31 weeks old, N = 63) were implanted with fronto-parietal subdural EEG screw electrodes, bilateral perforant path depth electrodes, a cerebellar reference screw electrode, a right frontal ground screw electrode, and nuchal EMG paddles. Following a 3 day tether habituation period, these mice were recorded for one week of baseline, then a 0.3 μg of kainic acid in 200 nL of saline was injected into the basolateral amygdala (BLA) to induce status epilepticus. The mice were then chronically recorded for 3 weeks to evaluate their sleep and epileptiform phenotypes. Epileptiform activity was analyzed via both manual seizure identification and Racine scoring, in addition to interictal epileptiform discharge (IED) detection. Pre- and post-IAKA sleep state duration and sleep fragmentation measures were assessed at both 20- and 4-second epoch lengths using our team’s Sleep Wake and the Ictal State Classifier (SWISC).


Results: The IAKA-treated animals show disrupted sleep homeostasis including increased wakefulness over controls and reductions in non-REM and REM sleep. These alterations in sleep amount lead to accrued sleep debt over time, and are not due to circadian alteration. Sleep loss is also accompanied by sleep fragmentation, with increased distinct occurrences and shorter average bout length of sleep bouts in the IAKA-treated mice.

These sleep characteristics are also not accounted for by seizure events alone, as the accrual of sleep debt does not correlate directly with seizure event timing. We also find increased detection of IEDs both during wake and sleep.

We sought to produce a model to predict the sleep fragmentation index for a given mouse, as approximated by average sleep bout length, using hippocampal IED rates, average Racine seizure grade, and seizure counts during and after status epilepticus. Using this analysis, the contribution of IED count to the predictive model outweighs that of the seizure measures, suggesting IED phenomena as a potential mechanistic target for sleep disruption in our model.




Conclusions: Using our chronic recordings of intra-amygdala kainic acid model mice, we have shown a relationship between IED occurrence and sleep loss, as well as sleep fragmentation. This validates the kainic acid model as a model of epilepsy-associated sleep fragmentation, agrees with existing human literature regarding the effects of IEDs on sleep states, and highlights specific epileptiform activity for further mechanistic analysis of the epilepsy and sleep disruption phenomenon.

Funding: CURE Epilepsy Award (NPP)

NIH R21NS122011 (NPP)

NIH K08NS105929 (NPP)