Spatial and Amplitude Dynamics of Neurostimulation: Insights from the Acute Intrahippocampal Kainate Seizure Mouse Model

ObjectiveNeurostimulation is an emerging treatment for patients with medically refractory epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model. MethodsWe performed high-throughput testing of high-frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of temporal lobe epilepsy. We evaluated combinations of six anatomic targets and three stimulus amplitudes. ResultsWe found that the spike-suppressive effects of high-frequency neurostimulation are highly dependent on the stimulation amplitude and location, with higher amplitude stimulation being significantly more effective. Epileptiform spiking activity was significantly reduced with ipsilateral 250 A stimulation of the CA1 and CA3 hippocampal regions with 21.5% and 22.2% reductions, respectively. In contrast, we found that spiking frequency and amplitude significantly increased with stimulation of the ventral hippocampal commissure. We further found spatial differences with broader effects from CA1 versus CA3 stimulation. SignificanceThese findings demonstrate that the effects of therapeutic neurostimulation in an acute hippocampal seizure model are highly dependent on the location of stimulation and stimulus amplitude. We provide a platform to optimize the anti-seizure effects of neurostimulation, and demonstrate that an exploration of the large electrical parameter and location space can improve current modalities for treating epilepsy. Key PointsO_LIEvaluated spatial and temporal parameters of neurostimulation in a mouse model of acute seizures C_LIO_LIBrief bursts of high-frequency (100 Hz) stimulation effectively interrupted epileptiform activity. C_LIO_LIThe suppressive effect was highly dependent on stimulation amplitude and was maximal at the ipsilateral CA1 and CA3 regions. C_LIO_LIPro-excitatory effects were identified with high-amplitude high-frequency stimulation at the ventral hippocampal commissure and contralateral CA1. C_LI