Feng Zhouyan, Ma Weijian, Wang Zhaoxiang, Qiu Chen, Hu Hanhan
Key Lab of Biomedical Engineering for Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China.
Front Neurosci. 2019 Jan 31;13:36. doi: 10.3389/fnins.2019.00036. eCollection 2019.
Deep brain stimulation (DBS) traditionally utilizes electrical pulse sequences with a constant frequency, i.e., constant inter-pulse-interval (IPI), to treat certain brain disorders in clinic. Stimulation sequences with varying frequency have been investigated recently to improve the efficacy of existing DBS therapy and to develop new treatments. However, the effects of such sequences are inconclusive. The present study tests the hypothesis that stimulations with varying IPI can generate neuronal activity markedly different from the activity induced by stimulations with constant IPI. And, the crucial factor causing the distinction is the relative differences in IPI lengths rather than the absolute lengths of IPI nor the average lengths of IPI. In rat experiments , responses of neuronal populations to applied stimulation sequences were collected during stimulations with both constant IPI (control) and random IPI. The stimulations were applied in the efferent fibers antidromically (in alveus) or in the afferent fibers orthodromically (in Schaffer collaterals) of pyramidal cells, the principal cells of hippocampal CA1 region. Amplitudes and areas of population spike (PS) waveforms were used to evaluate the neuronal responses induced by different stimulation paradigms. During the periods of both antidromic and orthodromic high-frequency stimulation (HFS), the HFS with random IPI induced synchronous neuronal firing with large PS even if the lengths of random IPI were limited to a small range of 5-10 ms, corresponding to a frequency range 100-200 Hz. The large PS events did not appear during control stimulations with a constant frequency at 100, 200, or 130 Hz (i.e., the mean frequency of HFS with random IPI uniformly distributed within 5-10 ms). Presumably, nonlinear dynamics in neuronal responses to random IPI might cause the generation of synchronous firing under the situation without any long pauses in HFS sequences. The results indicate that stimulations with random IPI can generate salient impulses to brain tissues and modulate the synchronization of neuronal activity, thereby providing potential stimulation paradigms for extending DBS therapy in treating more brain diseases, such as disorders of consciousness and vegetative states.
传统上，深部脑刺激（DBS）利用具有恒定频率（即恒定脉冲间期，IPI）的电脉冲序列来治疗临床上的某些脑部疾病。最近，人们对具有变化频率的刺激序列进行了研究，以提高现有DBS疗法的疗效并开发新的治疗方法。然而，此类序列的效果尚无定论。本研究检验了这样一个假设，即具有变化IPI的刺激能够产生与由具有恒定IPI的刺激所诱导的活动明显不同的神经元活动。而且，造成这种差异的关键因素是IPI长度的相对差异，而非IPI的绝对长度，也不是IPI的平均长度。在大鼠实验中，在使用恒定IPI（对照）和随机IPI进行刺激期间，收集了神经元群体对施加的刺激序列的反应。刺激分别逆向施加于锥体细胞（海马CA1区的主要细胞）的传出纤维（在齿状回）或正向施加于传入纤维（在海马体的Schaffer侧支）。群体峰电位（PS）波形的幅度和面积用于评估不同刺激模式所诱导的神经元反应。在逆向和正向高频刺激（HFS）期间，即使随机IPI的长度被限制在5 - 10毫秒的小范围内（对应于100 - 200赫兹的频率范围），具有随机IPI的HFS也会诱导出具有大PS的同步神经元放电。在100、200或130赫兹的恒定频率对照刺激期间（即随机IPI的平均频率均匀分布在5 - 10毫秒内的HFS），未出现大PS事件。据推测，神经元对随机IPI反应中的非线性动力学可能导致在HFS序列中没有任何长停顿的情况下产生同步放电。结果表明，具有随机IPI的刺激能够向脑组织产生显著的冲动并调节神经元活动的同步性，从而为扩展DBS疗法以治疗更多脑部疾病（如意识障碍和植物状态）提供潜在的刺激模式。
