Investigation Of The Neuronal Responses And Mechanisms Underlying Axonal High Frequency Stimulation In Rat Hippocampal Region

Deep brain stimulation (DBS) is a hot spot in neural engineering research. The high frequency stimulation (HFS) of DBS has achieved remarkable results on treating brain diseases like epilepsy and Parkinson’s disease (PD). However, the mechanisms are still under debate.Since the axonal fiber is prone to be activated by the stimulation and it plays an important role in information conduction, the excitation of DBS pulses is likely to generate at the axon and conduct through the axonal fibers to excite the upstream and downstream areas, thereby leading to changes of neural populations in these areas. Therefore, the responses of axons might be an important mechanism of DBS.This dissertation designed in-vivo experiments and a simulation model to investigate the responses of axons and neural populations and the possible mechanisms underlying these responses, and it is vitally important for understanding the effects and mechanisms of DBS.The main results were summarized as follows:(1) HFS induced axonal conduction block in hippocampal CA1 regionWe delivered HFS pulses to the input and output axonal fibers in hippocampal CA1 region in vivo to study the responses of axons during HFS. According to our results, the orthodromically-and antidromically-evoked population spikes (OPS and APS) attenuated rapidly, whereas the multiple unit activity in downstream area increased. Further in-vivo experiment indicated that the attenuations of population spikes were the results of the HFS-induced axonal conduction block, and this block is not complete, the attenuated excitation of stimulation pulses might still be conducted to downstream area to increase the neuronal firings.(2) The extension of refractory period might be the mechanism underlying the HFS-induced axonal conduction blockWe explored the APS during and after antidormic HFS in hippocampal CA1 region. Results indicated that, the decreased APS during HFS could recover to large amplitude in a short period (-20 ms) after HFS, indicating the fast recovery stage of axonal conduction. Further investigation elucidated that these changes were associated with the extension of neuronal refractory period during HFS. The HFS pulses extended the refractory period of neurons from-1 ms to> 10 ms, and this is likely to be one of the important mechanisms underlying the block during HFS.(3) The potassium accumulation might induce the extension of refractory periodWe built a computational model of the myelinated axon with accumulation of potassium in hippocampal CA1 region to investigate the relationship between the axonal block and the ion concentration inside and outside the neuronal membranes. Results showed that, substantial accumulation of the potassium in sub-myelin areas of axons evoked the sustained depolarization of axonal membrane potential during HFS, thereby extended the refractory period of axons to 15-20 ms and then evoked axonal conduction block.(4) Axonal HFS modulated the neural population activity in downstream areaWe applied HFS to the input pathway of CA1 region and studied the LFP rhythmic activity in pyramidal layer (Pyr.layer) and stratum radiatum (S.rad) before, during and after HFS. We found that the axonal HFS could modulate the neural population activity in downstream areas by decreasing the energy and synchronization of lower frequency components and increasing the energy of the higher frequency component of LFP.In conclusion, this dissertation not only provided new in-vivo evidence to HFS-induced axonal conduction block and axonal HFS-induced modulation of neural population activity, but also utilized simulation modeling studies to elucidate that the accumulation of potassium resulting in the extension of refractory period was a possible mechanism of the block. In addition, we also suggested that the partially axonal conduction block and the residual excitation of stimulation pulses might be the mechanisms of the modulation of neural population activity during HFS. These results provide new ideas to the researches regarding the mechanisms of DBS and provide references to new clinical applications of DBS.