Investigating The Modulation Effects Of High-frequency Pulse Stimulations With Different Patterns On The Activity Of Neuronal Population

In clinic,deep brain stimulation(DBS)has achieved good results in the treatment of neurological diseases such as Parkinson's disease,epilepsy and obsessive-compulsive disorder by continuously applying high-frequency electrical pulse stimulation(HFS)at a constant frequency However,there are also many patients whose symptoms do not get the desired effect through this constant frequency HFS;and the treatment of many other brain diseases also urgently needs new stimulation patterns.Among them,changing the stimulation frequency(i.e.the inter-pulse interval,IPI)is an important direction.In this paper,we mainly studied the different effects of HFS with varying IPI and constant IPI on the neuronal population and the underlying mechanisms,including neuronal responses caused by the direct effect of electrical stimulation without synaptic involvement,and responses of post-synaptic neurons involved in synaptic transmission in the downstream.The results are of great significance for the development of new DBS stimulation patterns.In this paper,HFS with different patterns were applied in Alveus(efferent fiber tracts,antidromically)and Schaffer collaterals(afferent fiber tracts,orthodromically)of hippocampal CA1 region in adult male rats,respectively.The antidromically-evoked population spike(APS)and orthodromically-evoked population spike(OPS)were analyzed to study the responses of CA1 neuronal population to HFS.The main results are as follows(1)The excitatory effect of HFS with varying IPI is stronger than constant IPIWith a similar mean frequency,antidromic high-frequency stimulation(AHFS)with constant IPI only induce small regular APS,while AHFS with varying IPI could induce larger APS.Moreover,when AHFS with constant IPI induced small regular APS,larger APS could still be induced after switching to varying IPI.During orthodromic high-frequency stimulation(OHFS),more OPS were induced by OHFS with varying IPI than constant IPI.When OHFS with constant IPI induced the desynchronized firing of CA1 neurons,large OPS were re-induced after switched to varying IPI.These results indicate that HFS with varying IPI has a stronger excitatory effect on neurons and could induce more neurons firing synchronously.(2)HFS with varying IPI can recruit more neurons to fire synchronously by rearranging the activation time of neuronsIn the experiment of AHFS with the alternation of constant IPI and varying IPI,even if all IPIs were shorter than constant IPI,AHFS with varying IPI could still induce larger APS than constant IPI.And during the period of AHFS with varying IPI,the amplitude of the current APS was related to the length of the preceding two IPIs(denoted as IPI1 and IPI2).The stimulus after shorter IPI2 can scarcely recruit any neurons to fire,so that the stimulus after longer IPI1 can recruit more neurons to fire synchronously,and thereby inducing larger APS.(3)Synapses transmission could amplify the excitatory effect of HFS with varying IPI on downstream neuronsBy comparing the PS induced by OHFS and AHFS with varying IPI,it was found that the amplitude and area of OPS were significantly larger than APS,which suggests OHFS with varying IPI could induce more neurons to fire synchronously.In addition,the power spectrum analysis found that the synaptic activities increased significantly during OHFS with varying IPI,indicating that the excitation induced by stimuli during varying IPI had a cumulative effect in the synaptic transmission process.This cumulative effect reduced the firing rate of OPS and amplified the excitatory effect on neurons thereby inducing large OPSIn summary,this dissertation found:Unlike regularly firing induced by HFS with constant IPI,HFS with varying IPI could intermittently recruit more neurons to fire synchronously by rearranging the activation time of neurons,and the synchronization effect was more obvious in the case of synapse participation.These findings provide a new idea for revealing the mechanism of the difference between the effects of HFS with constant and varying IPI,and the more synchronous effect of HFS with varying IPI may be protentialy used in the treatment of other neurological diseases caused by excessive inhibition.