Foutz Thomas J, Rensing Nicholas, Han Lirong, Durand Dominique M, Wong Michael
bioRxiv. 2023 Mar 9:2023.03.07.531440. doi: 10.1101/2023.03.07.531440.
Neurostimulation 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.
We 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.
We 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 μA 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.
These 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.
Evaluated spatial and temporal parameters of neurostimulation in a mouse model of acute seizuresBrief bursts of high-frequency (100 Hz) stimulation effectively interrupted epileptiform activity.The suppressive effect was highly dependent on stimulation amplitude and was maximal at the ipsilateral CA1 and CA3 regions.Pro-excitatory effects were identified with high-amplitude high-frequency stimulation at the ventral hippocampal commissure and contralateral CA1.
神经刺激是一种用于治疗药物难治性癫痫患者的新兴疗法，用于抑制、预防和终止癫痫发作活动。不幸的是，植入后尽管遵循了最佳临床实践，但大多数患者即使经过多年的经验性优化仍会持续发作。本研究的目的是确定神经刺激在急性海马癫痫模型中抑制癫痫样活动的最佳空间和幅度特性。
我们在颞叶癫痫的急性海马内注射 kainic 酸小鼠模型中进行了高频局灶性脑刺激的高通量测试。我们评估了六个解剖靶点和三种刺激幅度的组合。
我们发现高频神经刺激的棘波抑制作用高度依赖于刺激幅度和位置，较高幅度的刺激明显更有效。同侧 250 μA 刺激海马 CA1 和 CA3 区域时，癫痫样棘波活动分别显著降低了 21.5% 和 22.2%。相比之下，我们发现刺激腹侧海马连合时，棘波频率和幅度显著增加。我们还发现 CA1 与 CA3 刺激的空间差异，CA1 刺激的影响更广泛。
这些发现表明，在急性海马癫痫模型中，治疗性神经刺激的效果高度依赖于刺激的位置和刺激幅度。我们提供了一个优化神经刺激抗癫痫效果的平台，并证明探索大的电参数和位置空间可以改善目前治疗癫痫的方式。
在急性癫痫小鼠模型中评估神经刺激的空间和时间参数高频（100 Hz）刺激的短暂脉冲有效中断了癫痫样活动。抑制作用高度依赖于刺激幅度，在同侧 CA1 和 CA3 区域最大。在腹侧海马连合和对侧 CA1 进行高幅度高频刺激时发现了促兴奋作用。
