| Deep brain stimulation(DBS)has achieved good results in the treatment of neurological movement disorders,such as Parkinson’s disease.It has also shown bright prospects in the treatment of other neurological diseases.Commonly,DBS employs high frequency stimulations(HFS)of electrical pulses with its stimulation patterns monotonous.To improve DBS efficacy and expand its applications,investigations on the temporal patterns and stimulus waveforms of HFS are urgently needed due to their large design space.Moreover,the action mechanisms of HFS are not clear,which limits development of DBS.In order to intensively study the effects of HFS patterns and elucidate their mechanisms,this paper applied axonal(Alveus)electrical stimulation in rat hippocampal CA1 region in vivo along with computational model of neurons.Neural signals were recorded and analyzed,including the antidromic population spike(APS),unit spikes,membrane potantials(V_m)and the inactivation variable(h＿Na)of sodium channels on neuronal membrane.The stimulation parameters of temporal patterns and pulse waveforms were changed and adjusted,to study the direct modulation effects and possible mechanisms of various stimulations on neuronal activity,so as to provide bases for the development of novel stimulation patterns obtaining diverse effects of brain neuromodulation.The main work and results are summarized as follows:(1)The arrangement of inter-pulse interval significantly affects stimulation effectsIn order to understand the effect and mechanism of inter-pulse intervals(IPIs)during HFS,this paper applied animal experiments and simulation models,to investigate the neuronal response to the pulse sequences with different IPI arrangements.The results of the rat experiments showed that during HFS of constant frequency and gradient frequency,the stimulation pulses stably induced small APSs,and the amount of evoked neuronal firing(indicated by APS amplitude)was positively related to the preceding IPI.However,during HFS with IPI randomly varying in 5–10 ms,stimulation pulses could evoke larger APSs or did not evoke an APS,and the evoked APS was correlated to its preceding two IPIs.The simulation results showed that during HFS with IPI randomly varying,successive firing of action potentials led to the increase of the potassium concentration outside the axonal membrane([K~+]_o),resulting in intermittent inactivation of sodium channels on neuronal membrane.Random varying of IPI caused the irregular recovery time of sodium channels,consequently,each neuron exhibited irregular intermittent firing patterns,with a certain probability of synchronous firing(evoking large APS)or synchronous not firing(not evoking APS).Some specific IPI episodes can facalitate the synchronous neuronal firing evoked by the pulses.This study innovatively exploits the nonlinear change process of ion channels on neuronal membrane during HFS,to explain the complex neuronal responses evoked by stimulations of different IPI sequences observed in rat experiments in vivo,which provides new information for understanding the role and mechanism of temporal patterns of HFS.(2)Design sequences to achieve preset responses of neuronal populationSince different neuronal responses can be achieved by changing IPIs in real time,and the neuronal responses are correlated with the preceding IPIs,then the IPI sequences of HFS can be designed according to the desired neuronal responses.Based on this new idea,this paper established a mathematical linear model to describe the relationship between the APS amplitude and its preceding two IPIs.Use the mathematical model to develop an algorithm,and the corresponding IPI sequences of HFS were designed according to the preset neuronal responses,which were then applied in animal experiments.The results obtained in the experiments using the designed HFS were similar to the preset neuronal responses.This study first proposed a quantitative method for designing HFS sequences based on the direct neuronal response,which provides a new strategy for designing stimulation sequences to achieve the desired stimulation effects.(3)The effect of anodic phase in biphasic pulse is intensity-dependentTo reduce the risk of tissue damage and electrode corrosion,DBS typically employs charge-balanced biphasic pulses.In the biphasic pulse,the anodic phase used for balancing charge is generally thought to reverse the depolarization effect of the preceding cathodic phase,thereby weakening the effect of electrical stimulation on neuronal activation.However,the anodic pulse itself can activate neurons through a"virtual cathode"effect.Based on that,it can be speculated that the anodic phase of biphasic pulse may facilitate the activation of neurons,especially when a population of neurons are stimulated.To test the hypothesis,the effects of cathodic pulse,anodic pulse and biphasic pulse stimulations with pulse intensities of 0.1–2.0 m A were compared.Results from rat experiments in vivo showed that with a small stimulation intensity(less than 0.4 m A),the anodic phase of the biphasic pulse inhibited the activation of neurons.However,with a large stimulation intensity(greater than 0.9 m A),the anodic phase facilitated the neuronal activation.Simulation results showed that the cathodic pulse with a large intensity caused hyperpolarization block in axons very close to the stimulating electrode,which blocked the conduction of action potentials.The anodic phase of biphasic pulse can reverse the hyperpolarization effect,thus facilitating the activation of axons and conduction of action potentials.This study firstly applied a wide range of stimulation intensity in experiments in vivo,to investigate the effects of pulses on neuronal populations with different pulse polarities,and revealed the activation effects of the anodic phase in biphasic pulse,which provides important information for designing pulse waveforms of electrical nerve stimulation in vivo.(4)Alternate stimulation of monophasic cathodic and anodic pulses can activate neuronal subpopulations separatelyThe activation effect of the anodic phase suggests that the anodic pulses can be used to activate neurons in HFS to improve the efficiency of electrical energy,such as using HFS of alternate monophasic(cathodic and anodic)pulses(termed alternate monophasic HFS).With the same stimulation frequency,the energy consumption of alternate monophasic HFS is only half that of HFS with biphasic pulse(termed biphasic HFS).Therefore,this paper firstly compared the effects of alternate monophasic HFS and biphasic HFS in rat experiments,and then investigated the roles of pulse frequency,interval,intensity,width and electrode depth in stimulations.The experimental results showed that alternate monophasic HFS can activate neurons more efficiently than biphasic HFS.Both the alternate monophasic HFS and biphasic HFS did not cause any irreversible damage to the stimulated neurons.In addition,the cathodic and anodic pulses of alternating monophasic pulses can activate different subpopulations of neurons.By changing the pulse parameters and electrode depth of HFS,the proportion of neurons activated by the two types of pulses can be regulated,thus the neuronal activity in different regions can be flexibly modulated.The results of this study provide guidance for designing more efficient stimulation sequences and provide new ideas for realizing flexible modulation of neurons in different regions.In conclusion,this paper used electrical axonal stimulation in rat hippocampus in vivo together with the computational neuron model to study the roles of temporal patterns and pulse waveforms of HFS,and clarified their action mechanisms.A mathematical linear model was constructed to design HFS sequences obtaining desired neuronal responses.These results provide new ideas for optimizing HFS parameters and designing novel HFS sequences,which is of great significance for improving DBS efficacy and expanding its applications. |
PDF Full Text Request