Abstracts

Rationale: Recent studies have uncovered a circadian rhythmicity in Interictal Epileptic Activity (IEA) in humans and rats. IEAs are more likely during the sleep phase of the circadian rhythm, but the mechanisms that underlie this phenomenon are unknown. We set out to examine the association between behavioral state (sleep/wake) and IEA probability in order to determine if it is due to dynamic changes in network excitability and, if so, to account for this effect when evaluating therapeutic interventions. Methods: We measured epileptiform population discharge probability in chronically implanted transgenic mice using a novel approach, optogenetic dose-response curves. We have previously demonstrated that the optogenetic population discharge (oPD) is analogous to the IEA and produces the same network wide electrophysiological signatures as spontaneous discharges in seizure exposed mice. Our chronic preparation consists of an optrode above area CA1 of Thy1-ChR2 (line 18) mice and 7 individually placed microwires in hippocampal and peri-hippocampal structures to monitor the network wide propagation of optogenetic stimulation. A range of light intensities was presented in randomized order, occasionally producing all-or-none high amplitude oPDs. The conditional probability of oPD given each light intensity was calculated and fit with the Boltzmann equation to determine an I50, or the light intensity at which oPDs occur 50% of the time. This metric, the I50, can be used to precisely track network excitability in freely moving mice. Results: Long-term (8hr) oPDT recordings (20 intensity levels, 5 sec intervals) revealed a strong effect of behavioral state on the oPDT, with sleep states associated with higher excitability (lower oPDTs, mean I50 = 12.21 levels [11.30 - 13.12],) than active wakefulness (mean I50 = 14.18 levels [13.40 - 14.97]), p = 0.0045, n = 6. Behavioral state was quantified using the hippocampal theta/LIA ratio, as well as manually scored video-EEG recordings. Conclusions: This result has two consequences: first, it confirms the findings of earlier studies showing that sleep states are more permissive to IEA and seizure; second, it suggests a strategy by which behavioral state can be used to segment oPDT data, further improving the precision of the technique when assessing the efficacy of potential therapeutic interventions for epilepsy. Support: R01AA016852 and the Tab Williams Family Fund. Funding: No funding