变间隔的脉冲改变高频刺激对于脑神经元的作用

通常采用恒定电脉冲间隔的高频刺激(high-frequency stimulation,HFS),进行深部脑刺激治疗帕金森氏症等运动障碍疾病.为了开发适用于不同脑疾病治疗的新刺激模式,近年来脉冲间隔(inter-pulse-interval,IPI)变化的变频刺激模式受到关注.已有研究表明,即使具有相同的平均电脉冲频率,变频刺激与恒频刺激的治疗效果也不同.我们推测,变频刺激的短小IPI变化就足以改变HFS对于神经元的作用.为了验证此推测,本文在大鼠海马CA1区锥体神经元的输入轴突纤维上交替施加恒频刺激(100或133 Hz,即IPI=10 ms或7.5 ms)和随机变频刺激(100～200 Hz,即IPI=5～10 ms,平均频率为133 Hz),记录并分析刺激下游神经元群体的诱发电位,用于定量评价神经元对于恒频和变频刺激的响应.实验结果表明,持续的恒频刺激使得神经元的响应从最初的同步发放形成的群峰电位(population spike,PS)转变为非同步的动作电位发放(即单元锋电位).但是,当刺激切换为变频模式时,却又可以诱发神经元群体同步产生动作电位,重新形成PS波.并且,变频刺激诱发的PS幅值和神经元发放的同步程度可达基线的单脉冲刺激诱发波的水平.但是,PS的发生率只有脉冲刺激频率的7%左右,表明在持续的变频刺激时,多个脉冲累积的作用才能诱发这种同步的神经元发放.而且PS的出现与前导IPI的长度之间存在一定关系.神经元的轴突和突触等结构对于高频刺激的非线性响应可能是变频刺激诱发同步活动的原因.这些结果表明,变频刺激序列中短小的间隔变化可以产生与恒定间隔不同的调控作用.本文的结果对于揭示脑刺激的作用机制,促进新型刺激模式的开发及其在不同类型脑疾病治疗中的应用具有重要意义.

The Altering Effect of High Frequency Stimulation on Brain Neurons With Small Changes in The Lengths of Inter-Pulse-Intervals

Deep brain stimulation has been used to treat movement disorders such as Parkinson diseases by utilizing high-frequency stimulations (HFS) of electrical pulses with constant inter-pulse-intervals (IPI). To develop new stimulation paradigms for treating more brain diseases, HFS with varying IPI (i.e., varying-frequency) has been investigated. Previous studies have shown that the efficacy obtained by varying-frequency is different from that obtained by constant-frequency even with a same mean frequency. We hypothesized that small changes in IPI during HFS could substantially change the effect of HFS on neurons. To test this hypothesis, HFS sequences with constant IPI (IPI = 10 or 7.5 ms for a frequency of 100 or 133 Hz ) and varying IPI (IPI = 5-10 ms with a mean frequency of 133 Hz) were alternately applied at afferent axon fibers of pyramidal cells in rat hippocampal CA1 region. The evoked potentials of downstream neurons were recorded and analyzed to quantitatively evaluate the neuronal responses to stimulations with constant IPI and varying IPI. The results showed that during persistent stimulation with constant IPI, the responses of downstream neurons changed from initial synchronized firing of population spikes (PS) into non-synchronized firing (i.e., unit spikes). However, once the stimulation switched to the sequence with varying IPI, synchronized firing reappeared with large PS events. Additionally, the amplitude of PS and the synchronization degree of firing induced by varying IPI were similar to those induced by single pulses at baseline. However, the incidence of PS was only ~7% of the pulse frequency, indicating a cumulative action of multiple pulses for generating such synchronized firing of neurons by stimulations with varying IPI. In addition, the appearance of PS was related to the length of proceeding IPI. Presumably, nonlinear responses of neuronal axons and synapses to high-frequency stimulation might cause the synchronized activity induced by varying-frequency. These results indicate that tiny differences in intervals of varying-frequency stimulation may generate a modulation effect on neurons very different from that of constant-frequency stimulation. The present study shows important results for revealing the mechanisms of brain stimulation and for advancing the development of new stimulation paradigms to treat various brain diseases.