Effects Of Repetitive Transcranial Magnetic Stimulation On Rat Models Of Epilepsy And Cerebral Glucose Metabolism

Repetitive transcranial magnetic stimulation(rTMS) is a method for noninvasive focal cortical stimulation that enables changes in the excitability of different cortical areas.Many characteristics of TMS such as coil form,position,frequency and intensity of the stimulus are important for the effect of rTMS on cortical excitability.In general, low-frequency rTMS(≤1 Hz) decreases cortical excitability,whereas frequencies above 5 Hz exert the inverse effect,causing its enhancement.rTMS can disrupt neuronal function and,thus,can interfere with ongoing seizures.Additionally, low-frequency rTMS can lead to lasting reductions in cortical excitability.Focal epilepsies are ideal for the application of rTMS due to a epileptogenic zone of increased excitability.In human,different studies with rTMS have shown more marked effects on neocortical epilepsies on the convexity of the brain than on mesial temporal lobe epilepsies.The precise effects of low rTMS on mesial temporal lobe epilepsy remain unknown.Animal studies showed low rTMS could effectively suppress status epilepticus in rat models of temporal lobe epilepsy,however,whether this can also suppress epileptogenesis is unclear.In the other hand,preconditioning with low rTMS can suppress acute seizure induced by pentylenetetrazol(PTZ) in rats,nevertheless,the effects of low rTMS on seizure development of PTZ kindling have not been investigated yet.In spite of rTMS effectiveness,its precise mechanism of action has not yet been established.Long-term potentiation and long-term depression-like mechnasims have been mainly postulated as responsible for rTMS effects.However,the mechanism may be not so simple,since the effects of rTMS can spread to distant sites,even at the sites of stimulaton a mixture of neural populations are activated.Traditional technologies in neuroscience are used to investigate functional changes in a specific brain area,whereas PET technology provides the opportunity to monitor metabolism in the whole brain including deep subcortical areas.The level of glucose utilization correlates with the degree of neuronal activity.The impact of rTMS on cerebral glucose metabolim in rats, which reflect the effects for rTMS on neural activity,can be mapped by using microPET.The rat brain is much smaller than the human's,so the effects for rTMS might be quite different between rats and human.So far,it has not been studied yet.Therefore,this study mainly focuses on the effects of rTMS on rat models of epilepsy and cerebral glucose metabolism.Part 1 Effects of rTMS on rat models of temporal lobe epilepsy and generalized epilepsy.Preconditioning with low rTMS(1Hz,100%motor threshold,15mins) significantly prolonged the latencies for myoclonic jerks induced by PTZ and epileptiform discharge on EEG,lowered the degree of seizure;and it also significant suppressed the development of PTZ kindling.Preconditioning with low-frequency low-intensity rTMS(1Hz,50%motor threshold,15mins) had no effect on seizure induced by PTZ.Precondition with low-frequency high-intensity rTMS(1Hz, 200%motor threshold,15mins) significantly lowered the degree of seizure,but had no effect on the latencies.Preconditioning with high-frequency rTMS(20Hz,100%motor threshold,3s,intertrains 57s,15 trains) not only significantly shortened the latency for myoclonic jerks,but also increased the degree of seizure.Sham stimulation(1Hz, 100%motor threshold,15mins) had no effect on acute seizures and kindling of PTZ. No significant changes in aterial blood pressure,heart rates and breath rates were found after rTMS.High-frequency stimulation caused irritability in some rats. Compared to control and sham stimulation,low rTMS(1Hz,100%motor threshold, 15mins,5days) which started 48h after status epilepticus induced by pilocarpine may postponed the occurrence of spontaneous recurrent seizures and lower the mean degree of seizure.Our results indicate the effects of rTMS on acute seizure induced by PTZ were dependent on frequency and intensity.Preconditioning with low rTMS(1Hz, 100%motor threshold,15mins) can safely and effectively suppress the development of PTZ kindling.In addition,the early treatment with low rTMS may inhibit epileptogenesis induced by pilocarpine.Part 2 Effects of rTMS on cerebral glucose metabolism in rats:a FDG-microPET study.Low-frequency rTMS(1Hz,100%motor threshold,15mins) and high-frequency rTMS(20Hz,100%motor threshold,3s,intertrains 57s,15 trains) were applied in rats during FDG uptake in order to observe glucose metabolic changes during stimulation. We found either low-frequency or high-frequency rTMS significantly reduced the mean glucose metabolism rate of whole brain.More obvious hypometabolism were found in forebrain areas(the prefrontal,sensorimotor cortices,the hippocampus, thalamus) during high-frequency stimulation than low-frequency stimulation.In order to observe glucose metabolic changes after rTMS,FDG were injected immediately after rTMS.We found that after effects of low-frequence rTMS reduced the regional normalized cerebral metabolic rate for glucose(nCMRglc) values in forebrain ROIs,whereas after effects of high -frequency rTMS increased the nCMRglc values in forebrain ROI.The nCMRglc values in brainstem was increased after either low-frequency or high-frequency rTMS.The mean glucose metabolism of whole brain didn't change,comparing to baseline.No significant metabolic change was found in sham group.Our results indicate the impacts of rTMS on glucose metabolism in rat brain were dependent on frequency,and rTMS can activate the remote brain areas.In conclusion,we found the effects of preconditioning with rTMS on seizure susceptibility were dependent on frequency and intensity.Preconditioning with Low-frequency rTMS(1Hz,100%motor threshold,15mins) can decreases seizure susceptibility,safely and effectively suppress the development of PTZ kindling.We also observed the early delivery of low-frequency rTMS after status epilepticus induced by pilocarpine may suppress epileptogenesis.In addition,the impacts of rTMS on glucose metabolism in rat brain were dependent on frequency,and rTMS can activate the remote brain areas.