Abstracts

This abstract has been invited to present during the Basic Science Poster Highlights poster session

Rationale: Epilepsy affects over three million people in the U.S. alone, with many patients reporting a relationship between seizure timing and sleep-wake patterns. People with epilepsy have a much higher incidence of sleep disorder, sleep loss can increase the risk of seizures, sleep problems may worsen other comorbidities of epilepsy, and sudden unexpected death in epilepsy typical occurs in sleep.  As a first step in understanding the mechanisms of this strong relationship between sleep and epilepsy, we sought to characterize these relationships in chronic recordings in a good model of medial temporal lobe epilepsy._x000D_
Methods: Mice were implanted with a pre-configured head plate equipped with hippocampal electrodes, a microinjection cannula targeting the amygdala, and dural screws and EMG electrodes for sleep scoring. After recovery, video-EEG was recorded for one week (baseline), before imtraamygdala kainate injection and three further weeks of continuous recording. Mice were then perfused for histological analysis. Data was analyzed off-line manually and by use of a deep learning classifier.

Results: There was a significant reduction in sleep in the mice injected with intraamygdala kainic acid, with an overall 10.4% increase in time awake (ANOVA p= 0.0085, n= 10,10), 9.7% decrease in non-REM sleep (p = 0.0072), 1.6% decrease in REM sleep (p = 0.03) and 0.8% of the total time was spent in the ictal or post-ictal state in IAKA mice. Seizures most occurred during wakefulness (58.6%), with next most common state being non-REM sleep (26.2%), REM sleep (9.0%), and the post-ictal state (6.2%). Seizures were over-represented in both REM sleep and the post-ictal state as IAKA mice spent only 5% and 6% of recording time in each state, respectively. Histopathological patterns were consistent with human types I and III hippocampal sclerosis. There were significant correlations between seizure count and basolateral amygdala damage (τ_b=0.30, p=0.011), CA3 damage (τ_b= 0.49, p=4.022E-05), and hilus damage (τ_b= 0.48, p= 3.364E-04).

Conclusions: These findings mirror documented human sleep disorders in epilepsy, with prominent insomnia and sleep disruption, in addition to recapitulating human histopathology. These data suggest that the post-ictal, REM, and awake states represent the highest relative risk of seizures, a novel finding given that there may be a high risk of SUDEP during REM sleep. Studies continue with circuit-based manipulations aiming to normalize sleep and examine the effect on cognition and seizure frequency._x000D_
Funding: Research reported in this publication was supported by CURE Epilepsy under award 708617 and subsequently by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award numbers R21NS122011 and K08NS105929.