Design Of Electrical Stimulation Paradigms With Time-varying Parameters And Its Application To Deep Brain Stimulation

Deep brain stimulation(DBS)has good development potential in treating various nervous system diseases clinically.Typical DBS normally uses diphasic pulse high frequency stimulation(HFS)with constant parameters.However,the changes of pulse frequency and intensity have important influence on the effects of HFS.Development of a new stimulation paradigm with time-varying parameters is helpful to further explore the mechanism of DBS and optimize the stimulation effects.Neurons have dynamic responses to HFS.For instance,HFS with constant parameters induces abnormal synchronous action potential of population of neurons at the onset of HFS,which has a risk of inducing epilepsy and damaging brain tissue.In order to avoid the strong interaction(also known as "onset response")at the onset of HFS,this dissertation designed a stimulation paradigm with time-varying intensity and frequency applied to DBS,which based on the previous experience of avoiding onset responses by stimulating peripheral nerves with time-varying intensity and frequency.On the other hand,this dissertation also designed a stimulation paradigm with random inter-pulse-interval(IPI)in order to explore the influence of different IPI on DBS effects.The main work of this dissertation includes two parts:(1)Designing and implementing the stimulation systems with time-varying parameters.By using LabVIEW software,this dissertation designed and implemented the stimulation paradigms with time-varying intensity and frequency,as well with random IPI.Then,by combining an NI data acquisition card and an analog stimulation isolator,the stimulation systems with time-varying parameters for animal experiment study was developed.(2)Conducting animal experiments to test the effects of the new stimulation paradigms with time-varying parameters.Applying the novel HFS paradigms to efferent fibers Alveus in pyramidal layer of rat hippocampal CA1 region,to excite the pyramidal neurons antidromically.Accessing the stimulation effects and neuronal responses with the amplitude of the antidromically-evoked population spike(APS).The experimental results of HFS with time-varying intensity and frequency indicated the ramp-up intensity at the onset of HFS could avoid onset responses.Decelerating the variation of stimulation intensity or elevating the stimulation frequency both enhanced the effects of avoiding onset responses.In order to avoid large APS events while achieving axon block faster,this dissertation used a stimulation paradigm which composed of three sub-sequences sequentially:a sub-sequence with an elevated frequency and ramped intensity(linear incline);a sub-sequence with attenuating frequency from high frequency to typical frequency;and a remaining period with typical constant intensity and frequency,to obtain a stable stimulation effects during the whole HFS.This kind of HFS did not induce abnormal synchronous action potential of population of neurons,avoiding the onset responses.It could maintain partially conduction block of axon and stable regular firing of population of neurons during the stimulation process.In addition,the experimental results of random IPI HFS indicated that APS induced by each pulse had a positive correlation with the length of IPI which is before the pulse.Therefore,the firing intension of neurons could be modulated following the changes of IPI in real-time,and the process was reversible.In conclusion,the two DBS paradigms with time-varying parameters in this dissertation have positive impact and referential significance in exploring the mechanism of DBS,reducing the risks of HFS on brain tissue,avoiding side effects of typical DBS,modulating axonal conduction block and developing safer and controllable new DBS paradigms.It will also provide a new direction for future DBS research.Because the hippocampus is one of the target areas for DBS to treat epilepsy and Alzheimer's disease,the animal experiment researches of rat hippocampus in this dissertation have important significance on treating epilepsy and Alzheimer's disease by using DBS more effectively and more safely.