Krook-Magnuson, C. | Search bioRxiv

bioRxiv2021

Optimization of closed-loop electrical stimulation enables robust cerebellar-directed seizure control

Additional treatment options for temporal lobe epilepsy are needed, and potential interventions targeting the cerebellum are of interest. Previous animal work has shown strong inhibition of hippocampal seizures through on-demand optogenetic manipulation of the cerebellum. However, decades of work examining electrical stimulation - a more immediately translatable approach - targeting the cerebellum has produced very mixed results. We were therefore interested in exploring the impact that stimulation parameters may have on seizure outcomes. Using a mouse model of temporal lobe epilepsy, we conducted on-demand electrical stimulation of the cerebellar cortex, and varied stimulation charge, frequency, and pulse width, resulting in over a thousand different potential combinations of settings. To explore this parameter space in an efficient, data-driven, manner, we utilized Bayesian optimization with Gaussian process regression, implemented in Matlab with an Expected Improvement Plus acquisition function. We examined two different fitting conditions and two different electrode orientations. Following the optimization process, we conducted additional on-demand experiments to test the effectiveness of selected settings. Across all animals, we found that Bayesian optimization allowed identification of effective intervention settings. Additionally, generally similar optimal settings were identified across animals, suggesting that personalized optimization may not always be necessary. While optimal settings were consistently effective, stimulation with settings predicted from the Gaussian process regression to be ineffective failed to provide seizure control. Taken together, our results provide a blueprint for exploration of a large parameter space for seizure control, and illustrate that robust inhibition of seizures can be achieved with electrical stimulation of the cerebellum, but only if the correct stimulation parameters are used.

neuroscience↗

bioRxiv2019

Selective loss of the GABAAα1 subunit from Purkinje cells is sufficient to induce a tremor phenotype

BackgroundIncreased circuit level insights into Essential tremor, the most prevalent movement disorder, are needed. Previously, an Essential Tremor-like phenotype was noted in animals with a global knockout of the GABAA1 subunit. However, global knockout of the GABAA1 subunit has limitations, including potential early mortality and limited circuit level insights into the tremor.\n\nMethodsGiven the hypothesized role of the cerebellum in tremor, including Essential Tremor, we used transgenic mice to selectively knock out the GABAA1 subunit from cerebellar Purkinje cells. As previous work suggested background strain may influence phenotype in this model, we used two different background strains (a Black6 and a Mixed background). We examined the resulting phenotype regarding impacts on inhibitory postsynaptic currents, survival rates, gross motor abilities, and expression of tremor.\n\nResultsWe found that GABAA-mediated synaptic currents are abolished in Purkinje cells from Purkinje cell specific knockout mice, while GABAA-mediated inhibition to cerebellar molecular layer interneurons remains intact. Selective loss of GABAA1 from Purkinje cells did not produce gross motor deficits, as measured by the accelerating rotarod, nor did it result in decreased survival rates. However, a tremor phenotype was apparent, regardless of sex or background strain. This tremor mimicked the tremor seen in animals with a global knockout of the GABAA1 subunit, and, like Essential Tremor in patients, was responsive to ethanol.\n\nConclusionsThese findings indicate that reduced inhibition to Purkinje cells is sufficient to induce a tremor phenotype, highlighting the importance of the cerebellum, inhibition, and Purkinje cells, in tremor.

neuroscience↗