The Effects Of The Continuous Theta Burst Stimulation On Meningeal Lymphatic Vessels

Background and ObjectiveMeningeal lymphatic vessels(m LVs),directly relating to cerebrospinal fluid-interstitial fluid(CSF-ISF)circulation,locate in the dura mater of the brain and can drain molecules from cerebrospinal fluid to the cervical lymph nodes.With the discovery of m LVs,their roles in the clearance of substance metabolism in the brain have been widely concerned.In the case of lymphatic structure damage,it often adversely affects the drainage of brain toxic molecules and immune cells,thus aggravating the development of brain metabolic disorders or brain injury.The improvement of lymphatic function in central nervous system may become a new direction in the treatment of some diseases connected with neurological disorders.Continuous theta burst stimulation(CTBS)is a noval stimulus mode of repetitive transcranial magnetic stimulation,which is often used in neuro-regulation and the treatment of common nervous system diseases.A study has shown that CTBS can promote the clearance of debris through CSF-ISF.Dysfunction of meningeal lymphatic pathway affects some neurological diseases,Alzheimer's disease(AD),ischemic stroke,encephalorrhagia and the like.m LVs closely relate to CSF-ISF,but it is not clear whether CTBS can regulate meningeal lymphatic pathway.Therefore,we observed the instantaneous effect of CTBS on m LVs,the movement of exogenous Amyloid-?(A?)in brain,and the long-dated effect of CTBS on meningeal lymphatic function and A? clearance in the brain in a mouse model of AD.Methods1.The changes of meningeal lymphatic diameters,the level of vascular endothelial growth factor-C(VEGF-C)in meninges and the drainage of lymphatic vessels after cisterna magna injection in a certain period of time were investigated in healthy male C57 mice when they had been performed with real or sham CTBS under natural condition.At the same time,the effect of CTBS on the diameters of meningeal lymphatic vessels was observed under the condition of drug inhibition of vascular endothelial growth factor receptor(VEGFR).2.Fluorescence-labeled A? was injected into the cisterna magna in healthy male C57 mice to observe the movement of A? starting from cerebrospinal fluid until 30,60 and 90 minutes.3.APP-PS1 mice were performed with CTBS for 2 weeks to observe the changes of meningeallymphatic vessels coverage,sprouts and A? deposition in meninges and brain parenchyma.Results1.Lymphatic dilated,VEGF-C increased,and meningeal lymphatic drainage accelerated after CTBS,and the effect of lymphatic augmentation induced by real CTBS was weakened after the inhibition of VEGFR.2.Exogenous A? accumulated adjacent to the lymphatic vessels.Within 0-90 minutes after entering the cerebrospinal fluid,the accumulation that neared superior sagittal sinus gradually increased,while that neared the transverse sinus increased at first and then decreased.3.The meningeal lymphatic vessels enlarged in size and sproutted,the A? deposition in meninges and brain parenchyma decreased as well after2-week CTBS.Conclusion1.CTBS can augment meningeal lymphatic vessels and promote lymphatic drainage by up-regulating the expression of VEGF-C.2.The meningeal lymphatic vessels indirectly participate in the metabolism of A?.The A? entering the cerebrospinal fluid first enriches near the transverse sinus and then turns to the superior sagittal sinus.3.Long-dated CTBS promotes meningeal lymphatic regeneration and A? clearance in the brain.