Lee Darrin J, Izadi Ali, Melnik Mikhail, Seidl Stacey, Echeverri Angela, Shahlaie Kiarash, Gurkoff Gene G
Department of Neurological Surgery, UC Davis School of Medicine, 4860 Y Street, Suite 3740, Sacramento, CA 95817, United States.
Department of Neurological Surgery, UC Davis School of Medicine, 4860 Y Street, Suite 3740, Sacramento, CA 95817, United States; Center for Neuroscience, University of California, 1544 Newton Court, Davis, CA 95618, United States.
Epilepsy Res. 2017 Feb;130:53-63. doi: 10.1016/j.eplepsyres.2017.01.005. Epub 2017 Jan 17.
Temporal lobe epilepsy often leads to hippocampal sclerosis and persistent cognitive deficits, including difficulty with learning and memory. Hippocampal theta oscillations are critical in optimizing hippocampal function and facilitating plasticity. We hypothesized that pilocarpine-induced status epilepticus would disrupt oscillations and behavioral performance and that electrical neuromodulation to entrain theta would improve cognition specifically in injured rats. Rats received a pilocarpine (n=30) or saline injection (n=27) and unilateral bi-polar electrodes were implanted into the medial septum and hippocampus the following day. Hippocampal and septal theta were recorded in a Plexiglas box over the first week following implantation. Control and pilocarpine-treated rats were split into stimulation (continuous 7.7Hz, 80μA, 1ms pulse width) and non-stimulation groups for behavioral analysis. Continuous stimulation was initiated one-minute prior to and throughout an object exploration task (post-injury day seven) and again for each of six trials on the Barnes maze (post-injury days 12-14). There was a significant reduction in hippocampal theta power (p<0.05) and percentage of time oscillating in theta (p<0.05). In addition there was a significant decrease in object exploration in rats post-pilocarpine (p<0.05) and an impairment in spatial learning. Specifically, pilocarpine-treated rats were more likely to use random search strategies (p<0.001) and had an increase in latency to find the hidden platform (p<0.05) on the Barnes maze. Stimulation of the medial septum at 7.7Hz in pilocarpine-treated rats resulted in performance similar to shams in both the object recognition and Barnes maze tasks. Stimulation of sham rats resulted in impaired object exploration (p<0.05) with no difference in Barnes maze latency or strategy. In conclusion, pilocarpine-induced seizures diminished hippocampal oscillations and impaired performance in both an object exploration and a spatial memory task in pilocarpine-treated rats. Theta stimulation at 7.7Hz improved behavioral outcome on the Barnes maze task; this improvement in function was not related to a general cognitive enhancement, as shams did not benefit from stimulation. Therefore, stimulation of the medial septum represents an exciting target to improve behavioral outcome in patients with epilepsy.
颞叶癫痫常导致海马硬化和持续性认知缺陷，包括学习和记忆困难。海马θ振荡对于优化海马功能和促进可塑性至关重要。我们假设毛果芸香碱诱导的癫痫持续状态会扰乱振荡和行为表现，并且通过电神经调节来夹带θ波将特别改善受损大鼠的认知。大鼠接受毛果芸香碱注射（n = 30）或生理盐水注射（n = 27），并于次日将单侧双极电极植入内侧隔区和海马体。在植入后的第一周，在有机玻璃箱中记录海马和隔区的θ波。将对照和毛果芸香碱处理的大鼠分为刺激组（连续7.7Hz，80μA，1ms脉冲宽度）和非刺激组进行行为分析。在物体探索任务（损伤后第7天）开始前1分钟及整个过程中以及在巴恩斯迷宫的六个试验中的每一个试验中（损伤后第12 - 14天）开始连续刺激。海马θ波功率（p < 0.05）和θ波振荡时间百分比（p < 0.05）显著降低。此外，毛果芸香碱处理后的大鼠物体探索能力显著下降（p < 0.05），空间学习能力受损。具体而言，毛果芸香碱处理的大鼠更有可能采用随机搜索策略（p < 0.001），并且在巴恩斯迷宫上找到隐藏平台的潜伏期增加（p < 0.05）。在毛果芸香碱处理的大鼠中以7.7Hz刺激内侧隔区导致在物体识别和巴恩斯迷宫任务中的表现与假手术组相似。刺激假手术组大鼠导致物体探索能力受损（p < 0.05），在巴恩斯迷宫潜伏期或策略上无差异。总之，毛果芸香碱诱导的癫痫发作减少了毛果芸香碱处理的大鼠在物体探索和空间记忆任务中的海马振荡并损害了表现。7.7Hz的θ波刺激改善了巴恩斯迷宫任务的行为结果；这种功能改善与一般认知增强无关，因为假手术组未从刺激中受益。因此，刺激内侧隔区是改善癫痫患者行为结果的一个令人兴奋的靶点。
