| Background Transcranial magnetic stimulator is a non-invasive method of stimulating the brain by generating magnetic field pulses through coils placed on the patient’s scalp,causing electrical currents(known as "vortex")through the skull and brain tissue,thus stimulating nerve cells to act as a non-invasive,safe treatment.At present,the most common clinical form of transcranial magnetic stimulator is repeated transcranial magnetic stimulation(r TMS),although its underlying physiological mechanism is not fully understood.Since Barker et al.first reported it in 1985,r TMS has had extensive and diverse success in regulating brain activity.The use of TMS has been successful in treating and recovering a growing number of neurological disorders,including drug addiction,depression,stroke,Alzheimer’s disease and Parkinson’s disease,among which the first TMS devices were approved by the U.S.Food and Drug Administration in 2008 to treat clinical depression.One of the main attractive features of TMS compared to early clinical methods of stimulating the brain is its non-invasive nature.All instruments are external and can stimulate different areas by changing the position of the coil and adjusting the intensity and frequency of the stimulation.Early neuroelectric stimulators require the implantation of large electrodes into the brain,and the risk of trauma were high,limiting the use of head electro-stimulators.However,the current in the brain tissue induced by r TMS is usually much weaker than the current provided by the use of direct electrical stimulation,which greatly reduced the therapeutic effect of TMS.Increasing the magnetic field of the r TMS device can produce stronger neuron stimulation,but can cause stronger scalp pain and limit the clinical use of r TMS.At present,there is little research on developing more incensed stimulation in TMS technology.But since TMS itself has fewer side effects and non-invasive nature,TMS is more likely to develop a better accepted,high-value targeted deep brain stimulation technology for clinical application.In addition,due to the commonality of magnetic stimulation and electrical stimulation,magnetic stimulation of the carotid sinus also has the potential to achieve a hypotensive effect,and there is room for research.Magnetic nanomaterials contain superparamagnetic,paramagnetic and permanently magnetic nanomaterials,which are typically represented by iron-based metal oxides.Superparamagnetic nanomaterials,depends on external magnetic field to achieve its magnetism,thus achieve its controllability.The most studied superparamagnetic nanomaterials are usually biomaterials with better biocompatibility and specific functional modification,which can reduce the biotoxicity of magnetic nanomaterials and improve their biological delivery capacity.In current reports,magnetic nanomaterials are usually injected directly into organisms,a highly invasive practice that is prone to infection and inflammation and is not suitable for treating benign diseases of the nervous system.The development of magnetic nanoparticles that can pass through the blood-brain barrier and can sense the magnetic field of the transcranial magnetic stimulator to enhance the effect of stimulating treatment is of great significance for reducing patient injury and improving the effectiveness of r TMS treatment.Objective1.Superparamagnetic nanomaterials with good biocapacity,with the help of external magnetic fields,to achieve the targeted delivery of magnetic nanomaterials in the brain,to explore the possibility of avoiding direct injection,and damage to the central nervous system.2.Explore the possibility of enhancing the role of r TMS with superparamagnetic nanomaterials to provide new ideas for clinical treatment.3.Based on the results of early animal experiments in the laboratory,explore the possibility of using transcranial magnetic stimulation to lower the blood pressure of the carotid sinus.Methods 1.Preparation of superparamagnetic nanoparticles modified with PEG and carboxylated chitosan were synthesized by the thermolysis method.2.DLS,XRD,SQUID,FTIR,MTT,transmission microscope were used to determine the physicochemical properties and biotoxicity of synthetic particles.3.The particles were further injected into the amnestied rat through the tail veins,with the head of the rat fixed with permanent magnets to assist the particles to get through the blood-brain barrier.Experiments such as TEM,elemental analysis,magnetic resonance imaging,etc.were used to verify the distribution of particles in the brains of rats.Later,with TMS assistance,a part of SPIONs + magnet treated rats were measured with GMT,MT,MEP and other motor-related indicators.The other part of rats were treated with TMS sequence and later remove their brain tissue.The brain tissues were analyzed with immunofluorescence,western blot test to detect c-fos protein expression,so as to detect the effect of electrical stimulation.4.Perform the right carotid sinus magnetic stimulation experiment on patients in prehypertension,observe the changes of the patient’s hemodynamic parameters such as SBP,MAP,HR,BRS,and detect the possibility of magnetic stimulation of the carotid sinus to lower blood pressure.Results1.Nanoparticles modified with PEG and carboxylated chitosan were synthesized.The nanoparticle has a spherical diameter of 11.10 ± 3.25 nm under the scanning electron microscope,and dynamic light scattering measurement determined that the average hydrodynamic diameter of the nanoparticles is 19.63 ± 0.81 nm.The surface zeta potential is-12 mv.There was no significant toxicity in the MTT cytotoxicity experiment.2.In the elemental analysis experiment,rats in the SPIONs + magnet group had an iron content of 345.0 ± 99.9 μg Fe per gram of tissue in the brain frontal cortical layer,much higher than 60.8 ± 15.4 μg Fe per gram of tissue in the control group.3.Under the transmission electron microscope,black particles with a particle size of 9-11 nm are seen in the rat brain cortex,which is consistent with the size of the magnetic nanoparticles synthesized in this experiment.And the ICP-OES experiment proved that the particles contain iron element.4.In the MRI biopsy,the SPIONs + magnet group showed that the black particles gathered in the cortex,which confirmed that the particles can pass through the blood-brain barrier.5.In the repeated transcranial magnetic stimulation instrument stimulation experiment,the mean amplitude of the maximum motor-evoked potential recorded in the SPIONs + magnet group was significantly higher than that of the control group(5.78 ± 2.54 vs.1.80 ± 1.55 m V,P = 0.015).6.In the M1 area of the rat cortical layer,immunofluorescence detected that the number density of c-fos positive cells in the SPIONs + magnet group was 3.44 times higher than that of the control group.In the Western-blot experiment detected that the expression of c-fos protein in the SPIONs + magnet group was also significantly increased compared to the control group,indicating that the SPIONs + magnet group had more discharged cells under transcranial magnetic stimulation.7.In the study of human carotid sinus stimulation,compared with treatment,MAP(F = 37.4,P < 0.001),SBP(F = 50.7,P < 0.001),HR(F = 7.7,P = 0.017),DBP(F = 33.8,P < 0.001)the change was significant.Conclusions 1.The particles we synthesized can cross the blood brain barrier of rat with the help of external magnetic field.2.Magnetic nanoparticles entering the cerebral cortical layer of rats with the aid of a magnetic field can enhance the stimulating effect of transcranial magnetic stimulation.3.The transcranial magnetic stimulator stimulates the human carotid sinus,which can reduce blood pressure to a certain extent in patients with prehypertension. |
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