Abstracts

Rationale: Neuromodulation therapies, including electrical stimulation, are a promising avenue for treating pharmacoresistant epilepsy. We have previously used Bayesian optimization to show that electrical stimulation of the cerebellar vermis can - with the correct stimulation parameters – inhibit hippocampal seizures (Stieve et al. Brain, 2022). Our current research seeks to understand i) if effective cerebellar stimulation requires an on-demand intervention, or if an open-loop strategy can also be effective, and ii) if stimulation remains effective when delivered chronically. To address these questions, we are examining four different stimulation conditions over the course of 8 weeks of intervention: 1) on-demand stimulation, 2) yoked stimulation, 3) open-loop stimulation, and 4) no stimulation.

Methods: To generate chronically epileptic mice, we are using the intrahippocampal kainic acid mouse model of temporal lobe epilepsy (TLE). In this model, focal kainic acid injection reproduces key features of human hippocampal sclerosis, with spontaneous recurrent electrographic seizures emerging from the damaged hippocampus several weeks after injection. On-demand animals receive cerebellar-directed electrical stimulation (vermis lobule 4/5) selectively at the time of detected seizures recorded in the hippocampal local field potential. Yoked animals receive stimulation at the same time as the on-demand animal, irrespective of their seizure state. This paradigm allows for comparison between animals receiving the same pattern of stimulation, while evaluating the specific impact of aligning stimulation to seizure state. Open-loop animals receive stimulation at a fixed time interval. No-stimulation control animals receive no intervention.

Results: Preliminary results suggest that beneficial impacts of on-demand cerebellar stimulation largely persist with chronic intervention: during the first week of on-demand intervention, 79-98% of detected seizures terminate within 3 seconds of on-demand stimulation; during the final week, 65-97% of detected seizures are terminated (across n=3 animals). This supports the continued effectiveness of on-demand cerebellar stimulation. In comparison, control animals receiving no stimulation had, if anything, longer seizures at the end of 8-weeks compared to baseline (23.5% ± 14.6% increase, n=4 animals), suggesting a progression of the epilepsy phenotype without intervention. Yoked and open-loop animals are currently being analyzed.


Conclusions: Our encouraging preliminary findings suggest that on-demand stimulation of the cerebellum remains effective over a chronic time period.

Funding: NIH R01-NS112518, University of Minnesota MnDRIVE Brain Conditions Initiative, University of Minnesota McKnight Presidential Fellowship