Investigating The Modulation Effects Of Axonal High-Frequency Electrical Stimulation On Neuronal Activity

Deep brain stimulation(DBS)is effective for treating neurological disorders in clinic.However,the mechanisms of action of high-frequency stimulation(HFS)which is DBS commonly used have not yet been elucidated.The following crucial points were need to be addressed:Whether the effect of HFS on the downstream neurons is excitatory or inhibitory?Whether the neurons change their firing patterns during HFS?How does stimulation frequency,temporal patterns and duration of stimulation affect the effects of HFS?The answers of these questions are vitally important for understanding the mechanism of action of DBS and providing important evidence for optimizing DBS stimulation parameters.In order to answer these questions,we applied HFS with different parameters in the Schaffer collaterals of hippocampal CA1 region in adult male Sprague Dawley rats.The field potentials and spikes recorded in the downstream regions during HFS were analyzed to investigate the effects of HFS on the downstream neuronal population and individuals,as well as the effect of stimulation frequency(50～200 Hz),temporal patterns(regular or irregular inter pulse interval)and duration of stimulation(1～10 min)on the effects of HFS.Furthermore,the possible mechanism underlying these responses were discussed.The main results of this dissertation were summarized as follows:(1)HFS had excitatory effects on both pyramidal neurons and interneurons in the downstream regionThe increased firing rate of action potential of neurons in the downstream region during HFS as well as the silent periods immediately following the end of HFS,indicated the excitatory effect of HFS on downstream neurons.However,the excitability of stimulation pulse during HFS was weaker than that at the baseline recording before HFS.Additionally,the higher the stimulation frequency,the lower the excitability of the electrical pulses on downstream neurons.The reason for these results may be that the partial block of axonal conduction induced by HFS reduced the probability of each axon being activated by stimulation pulse and the degree of axonal conduction block increased with the stimulation frequency increased.(2)HFS established new asynchronous firing pattern in the downstream regionThe inter-spike intervals(ISI)histogram of spikes indicated that the original firing pattern of both pyramidal neurons and inteneurons in downstream was replaced by a new stimuli-modulated pattern during HFS.The original inputs from the upstream CA3 neurons to the CA1 region was blocked by HFS completely by the axon conduction block induced by HFS.Additionally,the intermittent excitement of HFS pulses could modulate the firing of action potential of downstream neurons thereby establishing stimulus-related firing pattern.The results of peri-stimulus time histogram(PSTH)of both multiple unit activity(MUA)and single unit activity(SUA)during HFS,as well as the ratio of synchronous firing between pairs of neurons,indicated that the firing of neurons in CA1 region during HFS was asynchronous.(3)Effects of stimulation pattern and duration on asynchronous excitatory effects induced by HFSThe synchronous firing of both pyramidal neurons and interneurons induced by stimulation pulses with irregular inter pulse interval(IPI)during HFS indicated that the irregular IPI increased synchronization of excitatory effects of stimulation pulses on downstream neurons.The firing rate and PSTH of both pyramidal neurons and interneurons during 10-minutes long HFS indicated the asynchronous excitatory effects of regular HFS with higher stimulation frequency on the downstream neurons could be maintained for long time.In summary,the main new found of this dissertation was that HFS with higher stimulation frequency(100～200 Hz)and regular IPI could establish asynchronous firing pattern in the neurons in CA1 region and block the physiological projection signal on the axons.These finding provides a novel explanation for how DBS could inhibit the pathological synchronous firing in the target region and block the transmission of pathological signals in different brain regions.However,stimulation with too low frequency or with irregular IPI had synchronous excitatory effects on target neurons,which may be unfavorable for inhibiting the synchronous firing of neurons in epilepsy and Parkinson’s diseases.However,it can be used to develop new stimulation models to treat other neurological diseases caused by excessive inhibition.These results provided new ideas for revealing the mechanism of action of HFS,provided important evidences for optimizing DBS stimulation parameters in clinical.