Izadi Ali, Schedlbauer Amber, Ondek Katelynn, Disse Gregory, Ekstrom Arne D, Cowen Stephen L, Shahlaie Kiarash, Gurkoff Gene G
Department of Neurological Surgery, University of California, Davis, Sacramento, CA, United States.
Center for Neuroscience, University of California, Davis, Davis, CA, United States.
Front Neurol. 2021 Sep 7;12:708957. doi: 10.3389/fneur.2021.708957. eCollection 2021.
Over one-third of patients with temporal lobe epilepsy are refractory to medication. In addition, anti-epileptic drugs often exacerbate cognitive comorbidities. Neuromodulation is an FDA treatment for refractory epilepsy, but patients often wait >20 years for a surgical referral for resection or neuromodulation. Using a rodent model, we test the hypothesis that 2 weeks of theta stimulation of the medial septum acutely following exposure to pilocarpine will alter the course of epileptogenesis resulting in persistent behavioral improvements. Electrodes were implanted in the medial septum, dorsal and ventral hippocampus, and the pre-frontal cortex of pilocarpine-treated rats. Rats received 30 min/day of 7.7 Hz or theta burst frequency on days 4-16 post-pilocarpine, prior to the development of spontaneous seizures. Seizure threshold, spikes, and oscillatory activity, as well as spatial and object-based learning, were assessed in the weeks following stimulation. Non-stimulated pilocarpine animals exhibited significantly decreased seizure threshold, increased spikes, and cognitive impairments as compared to vehicle controls. Furthermore, decreased ventral hippocampal power (6-10 Hz) correlated with both the development of spikes and impaired cognition. Measures of spikes, seizure threshold, and cognitive performance in both acute 7.7 Hz and theta burst stimulated animals were statistically similar to vehicle controls when tested during the chronic phase of epilepsy, weeks after stimulation was terminated. These data indicate that modulation of the septohippocampal circuit early after pilocarpine treatment alters the progression of epileptic activity, resulting in elevated seizure thresholds, fewer spikes, and improved cognitive outcome. Results from this study support that septal theta stimulation has the potential to serve in combination or as an alternative to high frequency thalamic stimulation in refractory cases and that further research into early intervention is critical.
超过三分之一的颞叶癫痫患者对药物治疗无效。此外，抗癫痫药物常常会加剧认知共病。神经调节是美国食品药品监督管理局（FDA）批准的治疗难治性癫痫的方法，但患者通常要等待20多年才能获得手术转诊以进行切除或神经调节治疗。我们使用啮齿动物模型来检验以下假设：在接触毛果芸香碱后立即对内侧隔区进行2周的θ波刺激，将改变癫痫发生的进程，从而带来持续的行为改善。将电极植入接受毛果芸香碱治疗的大鼠的内侧隔区、背侧和腹侧海马以及前额叶皮质。在毛果芸香碱处理后的第4至16天，大鼠在自发癫痫发作出现之前，每天接受30分钟的7.7赫兹或θ波爆发频率刺激。在刺激后的几周内评估癫痫发作阈值、棘波和振荡活动，以及基于空间和物体的学习能力。与溶剂对照组相比，未接受刺激的毛果芸香碱处理动物的癫痫发作阈值显著降低，棘波增加，且存在认知障碍。此外，腹侧海马功率降低（6 - 10赫兹）与棘波的出现和认知障碍均相关。在癫痫慢性期（刺激终止数周后）进行测试时，急性接受7.7赫兹和θ波爆发刺激的动物的棘波、癫痫发作阈值和认知表现指标在统计学上与溶剂对照组相似。这些数据表明，在毛果芸香碱治疗后早期对隔海马回路进行调节可改变癫痫活动的进程，从而提高癫痫发作阈值、减少棘波并改善认知结果。本研究结果支持，在难治性病例中，隔区θ波刺激有可能与高频丘脑刺激联合使用或作为其替代方法，并且对早期干预的进一步研究至关重要。
