BACKGROUND： Deep-brain stimulation has proven to be beneficial in the treatment of Parkinson＇s disease （PD） patients. OBJECTIVE： To investigate the effects of high-frequency stimulation （HFS） to the subthalamic...BACKGROUND： Deep-brain stimulation has proven to be beneficial in the treatment of Parkinson＇s disease （PD） patients. OBJECTIVE： To investigate the effects of high-frequency stimulation （HFS） to the subthalamic nucleus （STN） on neuronal apoptosis and apoptosis-related gene expression in the substantia nigra pars compacta, and to analyze the neuroprotective effect of HFS-STN. DESIGN, TIME AND SETTING： Neuronal morphology experiments were performed in the Beijing Neurosurgical Institute from May to December in 2005. MATERIALS： Forty healthy, adult, Sprague Dawley rats were used to establish a PD model with a unilateral microinjection of 6-hydroxydopamine into two target areas of the right medial forebrain bundle. 6-hydroxydopamine was purchased from Sigma （USA）; high-frequency electrical stimulator was produced by World Precision Instruments （USA）; Terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） kit was a product of Nanjing Jiancheng Technology Co., Ltd. （China）; and Bcl-2 and Bax protein assay kit were purchased from Wuhan Boster Bioengineering Co., Ltd. （China）. METHODS： Forty rats were randomly divided into three groups. The stimulation group （n = 15） received HFS-STN on the day of PD modeling. The PD model group （n = 15） was used to establish the PD model. The control group （n = 10） was injected with normal saline containing 0.2 g/L ascorbic acid into two areas of the right medial forebrain bundle. MAIN OUTCOME MEASURES： Survival of dopaminergic neurons in the substantia nigra pars compacta was determined using Nissl staining. Apoptosis of dopaminergic neurons was detected using TUNEL techniques. Expression of anti-apoptotic protein, Bcl-2, and pro-apoptotic protein, Bax, were assayed by immunohistochemistry. RESULTS： Following 6-hydroxydopamine injection, the number of substantia nigra pars compacta neurons was reduced in the stimulation and PD model groups, compared to the control group. At 2 and 4 weeks post-surgery, the grey value of Nissl stained images was significantly less in the PD model and stimulation groups （P 〈 0.05）, and the stimulation group exhibited greater grey values compared to the model group （P 〈 0.05）. At 2 and 4 weeks post-surgery, the number of apoptotic neurons was significantly less in the stimulation group compared to the model group （P 〈 0.05）. In addition, Bcl-2 and Bax expression, as well as the Bcl-2/Bax ratio, was much higher in the stimulation group compared to the model group （P 〈 0.05）. CONCLUSION： HFS-STN has a neuroprotective effect on dopaminergic neurons in the substantia nigra pars compacta of PD rats by promoting Bcl-2 expression, inhibiting Bax expression, and reducing the number of apoptotic dopaminergic neurons.展开更多
Degeneration and death of the neurons of the substantia nigra can cause a deficit in brain dopamine, leading to loss of movement control The subthalamic nucleus is a junction of basal ganglia neural circuit and can re...Degeneration and death of the neurons of the substantia nigra can cause a deficit in brain dopamine, leading to loss of movement control The subthalamic nucleus is a junction of basal ganglia neural circuit and can regulate the efferent information of basal ganglia and control motor activity. High-frequency stimulation of the subthalamic nucleus can alter dopamine levels as well as related factor expression in the corpus striatum and thereby improve the symptoms of Parkinson＇s disease.展开更多
Epilepsy is one of the most common serious neurological disorders. Pharmacoresistant epilepsy patients are poorly controlled or their seizures are refractory to drug treatment. Resective surgery is frequently a promis...Epilepsy is one of the most common serious neurological disorders. Pharmacoresistant epilepsy patients are poorly controlled or their seizures are refractory to drug treatment. Resective surgery is frequently a promising therapy in this population, however, not all the patients meet the eligibility criteria for the surgical treatment. Deep brain stimulation has been investigated in clinical studies and animal studies as an alternative treatment, but the optimal stimulation parameters remain an issue. The present study was designed to investigate the effect of unilateral high-frequency stimulation (HFS) of hippocampus on seizure development by using the hippocampal rapid kindling method (hRK) in rats, and compared the results with those of low-frequency stimulation previously published by our group. We used male Wistar rats implanted with electrodes in the ventral hippocampus. All rats underwent hRK (biphasic square wave pulses, 20 Hz for 10 seconds) during three consecutive days (twelve stimulations per day). The control group (hRK;n = 7) received only RK stimulus, while the treated group (HFS-hRK;n = 9) received also HFS (biphasic square wave pulses, 130 Hz for 30 seconds) immediately before the RK stimulus, during three consecutive days. At the end of behavioral testing 78% (p 0.01) of the animals receiving HFS treatment were still not fully kindled staying in stages 0 -III (p 0.01). HFS group needed a higher number of stimulations to achieve stage III (p 0.05) with respect to control group. However, no significant differences in the cumulative daily afterdischarge duration were observed. HFS did not present significant differences compared with LFS in any of studied parameters. The findings suggest that unilateral HFS applied on hippocampus effectively inhibited the epileptogenic process induced by hippocampal rapid kindling. According to the comparative results about hippocampal rapid kindled animals stimulated with HFS and LFS (5 Hz), we found no conclusive information on which treatment is most efficient.展开更多
BACKGROUND： Subthalamic nucleus-high frequency stimulation （STN-HFS） plays an important role in the treatment of Parkinson＇s disease, but the mechanisms underlying STN-HFS remain unclear. Some studies have demonst...BACKGROUND： Subthalamic nucleus-high frequency stimulation （STN-HFS） plays an important role in the treatment of Parkinson＇s disease, but the mechanisms underlying STN-HFS remain unclear. Some studies have demonstrated that STN stimulation inhibits the firing activity of substantia nigra pars reticulata neurons. OBJECTIVE： To investigate the effects of different-frequency STN stimulation and microiontophoresis of gamma-aminobutyric acid （GABA） and its antagonist, bicuculline, on spontaneous firing activity in a rat model of Parkinson＇s disease, and to analyze the action pathway of high frequency stimulation in firing activity inhibition of substantia nigra pars reticulata neurons. DESIGN, TIME AND SETTING： This neuroelectrophysiological, animal experiment was performed at the Electrophysiology Laboratory of Liaoning Medical University, China from March to August 2008. MATERIALS： 6-hydroxydopamine （6-OHDA） （Sigma, USA）, A320R isolated stimulus and DAM80 preamplifier （World Precision Instruments, USA）, 6400A microiontophoresis apparatus （Dagan, USA）, and Spike 2 biological signal acquisition system （CED, UK） were used in this study. METHODS： A total of 20 Sprague Dawley rats were used to establish a Parkinson＇s disease model via injection of 6-OHDA into the right striatum. Electrical stimulation （0.06-ms width, 0.4-mA intensity 20-200-Hz frequency, 5-second train duration） was delivered to the subthalamic nucleus. Peripheral channels were separately filled with GABA （pH 3.5, 0.2 mol/L）, bicuculline （pH 4.0, 0.01 mol/L）, and NaCI （pH 7.0, 3 mol/L）. The electrode was positioned with a WK-2 microelectrode propulsion device, and was slowly inserted into the substantia nigra pars reticulata to record spontaneous firing activity of substantia nigra pars reticulata neurons. MAIN OUTCOME MEASURES： The number and firing rate of substantia nigra pars reticulata neurons which were either inhibited or excited were measured. RESULTS： Substantia nigra pars reticulata neurons were inhibited by STN stimulation. The proportion of inhibited substantia nigra pars reticulata neurons increased with increasing stimulation frequency. GABA had a tonic inhibitory effect on substantia nigra pars reticulata neurons. Microiontophoresis of bicuculline suppressed the inhibitory effect of STN-HFS on 67% （4/6） of substantia nigra pars reticulata neurons. CONCLUSION： STN-HFS ameliorated abnormal activity in substantia nigra pars reticulata neurons via the inhibitory effect of GABA treatment in a rat model of Parkinson＇s disease.展开更多
Background The advent of brain stimulation techniques to treat movement disorders and psychiatric diseases has shown potential to decode the neural mechanism that underlies the cognitive process by modulating the inte...Background The advent of brain stimulation techniques to treat movement disorders and psychiatric diseases has shown potential to decode the neural mechanism that underlies the cognitive process by modulating the interrupted circuit.Here,the present investigation aimed at evaluating the influence of deep brain stimulation of the anterior nucleus thalamus （ANT-DBS） on memory.Methods Thirty-two rats were randomized into phosphate buffer saline （PBS） group （n=8,rats received PBS injections without implantation of electrodes into the ANT）,Alzheimer＇s dementia （AD） group （n=8,rats received Aβ1-40 injections without implantation of electrodes into the ANT）,ANT sham stimulation group （n=8,rats received Aβ1-40 injections with implantation of electrodes into the ANT but without stimulation） and ANT stimulation group （n=8,rats received Aβ1-40 injections with implantation of electrodes into the ANT and stimulation）.A Morris maze test was used for determining the effect of electrical stimulation on cognitive function in rats.The data were assessed statistically with one-way analysis of variance （ANOVA） followed by Tukey＇s tests for multiple post hoc comparisons.Results The data showed that in the training test,PBS group and AD group managed to learn the hidden-platform faster and faster while AD group needed a significantly longer time to reach the platform than PBS group （P ＜0.05）.Meanwhile,ANT stimulation group demonstrated a significantly shorter time to reach the platform （P ＜0.05） compared to the AD group,while there was no significant difference between the ANT sham stimulation group and the AD group （P ＞0.05）.On the probe test,the AD group spent less time （（10.15±2.34） seconds） in the target quadrant than the PBS group （（28.20±2.75） seconds） （P ＜0.05）.And the times of platform-traversing of the AD group （3.35±1.12） significantly decreased compared with the PBS group （8.69±2.87） （P ＜0.05）.However,the times of platform-traversing and the time spent in the target quadrant of the ANT stimulation group significantly increased compared to the AD group （P ＜0.05）,while times of platformtraversing or the time spent in the target quadrant was not significantly different between the ANT sham stimulation group and the AD group （P ＞0.05）.Conclusion Bilateral high-frequency stimulation of the ANT may be useful as a potential therapeutic modality for cognitive dysfunction in AD.展开更多
Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of kn...Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of knowledge about the underlying modes of action and optimal treatment modalities,a thorough translational investigation of noninvasive brain stimulation in preclinical animal models is urgently needed.Thus,we reviewed the current literature on the mechanistic underpinnings of noninvasive brain stimulation in models of central nervous system impairment,with a particular emphasis on traumatic brain injury and stroke.Due to the lack of translational models in most noninvasive brain stimulation techniques proposed,we found this review to the most relevant techniques used in humans,i.e.,transcranial magnetic stimulation and transcranial direct current stimulation.We searched the literature in Pub Med,encompassing the MEDLINE and PMC databases,for studies published between January 1,2020 and September 30,2024.Thirty-five studies were eligible.Transcranial magnetic stimulation and transcranial direct current stimulation demonstrated distinct strengths in augmenting rehabilitation post-stroke and traumatic brain injury,with emerging mechanistic evidence.Overall,we identified neuronal,inflammatory,microvascular,and apoptotic pathways highlighted in the literature.This review also highlights a lack of translational surrogate parameters to bridge the gap between preclinical findings and their clinical translation.展开更多
Although previous studies have demonstrated that transcranial focused ultrasound stimulation protects the ischemic brain,clear criteria for the stimulation time window and intensity are lacking.Electrical impedance to...Although previous studies have demonstrated that transcranial focused ultrasound stimulation protects the ischemic brain,clear criteria for the stimulation time window and intensity are lacking.Electrical impedance tomography enables real-time monitoring of changes in cerebral blood perfusion within the ischemic brain,but investigating the feasibility of using this method to assess post-stroke rehabilitation in vivo remains critical.In this study,ischemic stroke was induced in rats through middle cerebral artery occlusion surgery.Transcranial focused ultrasound stimulation was used to treat the rat model of ischemia,and electrical impedance tomography was used to measure impedance during both the acute stage of ischemia and the rehabilitation stage following the stimulation.Electrical impedance tomography results indicated that cerebral impedance increased after the onset of ischemia and decreased following transcranial focused ultrasound stimulation.Furthermore,the stimulation promoted motor function recovery,reduced cerebral infarction volume in the rat model of ischemic stroke,and induced the expression of brain-derived neurotrophic factor in the ischemic brain.Our results also revealed a significant correlation between the impedance of the ischemic brain post-intervention and improvements in behavioral scores and infarct volume.This study shows that daily administration of transcranial focused ultrasound stimulation for 20 minutes to the ischemic hemisphere 24 hours after cerebral ischemia enhanced motor recovery in a rat model of ischemia.Additionally,our findings indicate that electrical impedance tomography can serve as a valuable tool for quantitatively evaluating rehabilitation after ischemic stroke in vivo.These findings suggest the feasibility of using impedance data collected via electrical impedance tomography to clinically assess the effects of rehabilitatory interventions for patients with ischemic stroke.展开更多
Neuromodulation techniques effectively intervene in cognitive function,holding considerable scientific and practical value in fields such as aerospace,medicine,life sciences,and brain research.These techniques utilize...Neuromodulation techniques effectively intervene in cognitive function,holding considerable scientific and practical value in fields such as aerospace,medicine,life sciences,and brain research.These techniques utilize electrical stimulation to directly or indirectly target specific brain regions,modulating neural activity and influencing broader brain networks,thereby regulating cognitive function.Regulating cognitive function involves an understanding of aspects such as perception,learning and memory,attention,spatial cognition,and physical function.To enhance the application of cognitive regulation in the general population,this paper reviews recent publications from the Web of Science to assess the advancements and challenges of invasive and non-invasive stimulation methods in modulating cognitive functions.This review covers various neuromodulation techniques for cognitive intervention,including deep brain stimulation,vagus nerve stimulation,and invasive methods using microelectrode arrays.The non-invasive techniques discussed include transcranial magnetic stimulation,transcranial direct current stimulation,transcranial alternating current stimulation,transcutaneous electrical acupoint stimulation,and time interference stimulation for activating deep targets.Invasive stimulation methods,which are ideal for studying the pathogenesis of neurological diseases,tend to cause greater trauma and have been less researched in the context of cognitive function regulation.Non-invasive methods,particularly newer transcranial stimulation techniques,are gentler and more appropriate for regulating cognitive functions in the general population.These include transcutaneous acupoint electrical stimulation using acupoints and time interference methods for activating deep targets.This paper also discusses current technical challenges and potential future breakthroughs in neuromodulation technology.It is recommended that neuromodulation techniques be combined with neural detection methods to better assess their effects and improve the accuracy of non-invasive neuromodulation.Additionally,researching closed-loop feedback neuromodulation methods is identified as a promising direction for future development.展开更多
Brain lesions,such as those caused by stroke or traumatic brain injury(TBI),frequently result in persistent motor and cognitive impairments that significantly affect the individual patient's quality of life.Despit...Brain lesions,such as those caused by stroke or traumatic brain injury(TBI),frequently result in persistent motor and cognitive impairments that significantly affect the individual patient's quality of life.Despite differences in the mechanisms of injury,both conditions share a high prevalence of motor and cognitive impairments.These deficits show only limited natural recovery.展开更多
Alzheimer's disease is the most common type of cognitive disorder,and there is an urgent need to develop more effective,targeted and safer therapies for patients with this condition.Deep brain stimulation is an in...Alzheimer's disease is the most common type of cognitive disorder,and there is an urgent need to develop more effective,targeted and safer therapies for patients with this condition.Deep brain stimulation is an invasive surgical treatment that modulates abnormal neural activity by implanting electrodes into specific brain areas followed by electrical stimulation.As an emerging therapeutic approach,deep brain stimulation shows significant promise as a potential new therapy for Alzheimer's disease.Here,we review the potential mechanisms and therapeutic effects of deep brain stimulation in the treatment of Alzheimer's disease based on existing clinical and basic research.In clinical studies,the most commonly targeted sites include the fornix,the nucleus basalis of Meynert,and the ventral capsule/ventral striatum.Basic research has found that the most frequently targeted areas include the fornix,nucleus basalis of Meynert,hippocampus,entorhinal cortex,and rostral intralaminar thalamic nucleus.All of these individual targets exhibit therapeutic potential for patients with Alzheimer's disease and associated mechanisms of action have been investigated.Deep brain stimulation may exert therapeutic effects on Alzheimer's disease through various mechanisms,including reducing the deposition of amyloid-β,activation of the cholinergic system,increasing the levels of neurotrophic factors,enhancing synaptic activity and plasticity,promoting neurogenesis,and improving glucose metabolism.Currently,clinical trials investigating deep brain stimulation for Alzheimer's disease remain insufficient.In the future,it is essential to focus on translating preclinical mechanisms into clinical trials.Furthermore,consecutive follow-up studies are needed to evaluate the long-term safety and efficacy of deep brain stimulation for Alzheimer's disease,including cognitive function,neuropsychiatric symptoms,quality of life and changes in Alzheimer's disease biomarkers.Researchers must also prioritize the initiation of multi-center clinical trials of deep brain stimulation with large sample sizes and target earlier therapeutic windows,such as the prodromal and even the preclinical stages of Alzheimer's disease.Adopting these approaches will permit the efficient exploration of more effective and safer deep brain stimulation therapies for patients with Alzheimer's disease.展开更多
High-frequency spinal cord stimulation(HF-SCS) has been established as an effective therapy for neuropathic pain. However, the analgesic mechanisms involved in HF-SCS remain to be clarified. In our study, adult rat ne...High-frequency spinal cord stimulation(HF-SCS) has been established as an effective therapy for neuropathic pain. However, the analgesic mechanisms involved in HF-SCS remain to be clarified. In our study, adult rat neuropathic pain was induced by spinal nerve ligation. Two days after modeling, the rats were subjected to 4 hours of HF-SCS(motor threshold 50%, frequency 10,000 Hz, and pulse width 0.024 ms) in the dorsal horn of the spinal cord. The results revealed that the tactile allodynia of spinal nerve-injured rats was markedly alleviated by HFSCS, and the effects were sustained for 3 hours after the stimulation had ceased. HF-SCS restored lysosomal function, increased the levels of lysosome-associated membrane protein 2(LAMP2) and the mature form of cathepsin D(matu-CTSD), and alleviated the abnormally elevated levels of microtubule-associated protein 1 A/B-light chain 3(LC3)-II and sequestosome 1(P62) in spinal nerve-injured rats. HF-SCS also mostly restored the immunoreactivity of LAMP2, which was localized in neurons in the superficial layers of the spinal dorsal horn in spinal nerve-injured rats. In addition, intraperitoneal administration of 15 mg/kg chloroquine for 60 minutes reversed the expression of the aforementioned proteins and shortened the timing of the analgesic effects of HF-SCS. These findings suggest that HF-SCS may exhibit longlasting analgesic effects on neuropathic pain in rats through improving lysosomal dysfunction and alleviating autophagic flux. This study was approved by the Laboratory Animal Ethics Committee of China Medical University, Shenyang, China(approval No. 2017 PS196 K) on March 1, 2017.展开更多
BACKGROUND Cognitive impairments are core characteristics of schizophrenia,but are largely resistant to current treatments.Several recent studies have shown that highfrequency repetitive transcranial magnetic stimulat...BACKGROUND Cognitive impairments are core characteristics of schizophrenia,but are largely resistant to current treatments.Several recent studies have shown that highfrequency repetitive transcranial magnetic stimulation(rTMS)of the left dorsolateral prefrontal cortex(DLPFC)can reduce negative symptoms and improve certain cognitive deficits in schizophrenia patients.However,results are inconsistent across studies.AIM To examine if high-frequency rTMS of the DLPFC can improve visual memory deficits in patients with schizophrenia.METHODS Forty-seven chronic schizophrenia patients with severe negative symptoms on stable treatment regimens were randomly assigned to receive active rTMS to the DLPFC(n=25)or sham stimulation(n=22)on weekdays for four consecutive weeks.Patients performed the pattern recognition memory(PRM)task from the Cambridge Neuropsychological Test Automated Battery at baseline,at the end of rTMS treatment(week 4),and 4 wk after rTMS treatment(week 8).Clinical symptoms were also measured at these same time points using the Scale for the Assessment of Negative Symptoms(SANS)and the Positive and Negative Syndrome Scale(PANSS).RESULTS There were no significant differences in PRM performance metrics,SANS total score,SANS subscores,PANSS total score,and PANSS subscores between active and sham rTMS groups at the end of the 4-wk treatment period,but PRM performance metrics(percent correct and number correct)and changes in these metrics from baseline were significantly greater in the active rTMS group at week 8 compared to the sham group(all P<0.05).Active rTMS treatment also significantly reduced SANS score at week 8 compared to sham treatment.Moreover,the improvement in visual memory was correlated with the reduction in negative symptoms at week 8.In contrast,there were no between-group differences in PANSS total score and subscale scores at either week 4 or week 8(all P>0.05).CONCLUSION High-frequency transcranial magnetic stimulation improves visual memory and reduces negative symptoms in schizophrenia,but these effects are delayed,potentially due to the requirement for extensive neuroplastic changes within DLPFC networks.展开更多
Repetitive magnetic stimulation is effective for treating posttraumatic neuropathies following spinal or axonal injury.Neurotropin is a potential treatment for nerve injuries like demyelinating diseases.This study sou...Repetitive magnetic stimulation is effective for treating posttraumatic neuropathies following spinal or axonal injury.Neurotropin is a potential treatment for nerve injuries like demyelinating diseases.This study sought to observe the effects of high-frequency repetitive magnetic stimulation,neurotropin and their combined use in the treatment of peripheral nerve injury in 32 adult male Sprague-Dawley rats.To create a sciatic nerve injury model,a 10 mm-nerve segment of the left sciatic nerve was cut and rotated through 180°and each end restored continuously with interrupted sutures.The rats were randomly divided into four groups.The control group received only a reversed autograft in the left sciatic nerve with no treatment.In the high-frequency repetitive magnetic stimulation group,peripheral high-frequency repetitive magnetic stimulation treatment(20 Hz,20 min/d)was delivered for 10 consecutive days after auto-grafting.In the neurotropin group,neurotropin therapy(0.96 NU/kg per day)was administrated for 10 consecutive days after surgery.In the combined group,the combination of peripheral high-frequency repetitive magnetic stimulation(20 Hz,20 min/d)and neurotropin(0.96 NU/kg per day)was given for 10 consecutive days after the operation.The Basso-Beattie-Bresnahan locomotor rating scale was used to assess the behavioral recovery of the injured nerve.The sciatic functional index was used to evaluate the recovery of motor functions.Toluidine blue staining was performed to determine the number of myelinated fibers in the distal and proximal grafts.Immunohistochemistry staining was used to detect the length of axons marked by neurofilament 200.Our results reveal that the Basso-Beattie-Bresnahan locomotor rating scale scores,sciatic functional index,the number of myelinated fibers in distal and proximal grafts were higher and axon lengths were longer in the high-frequency repetitive magnetic stimulation,neurotropin and combined groups compared with the control group.These measures were not significantly different among the high-frequency repetitive magnetic stimulation,neurotropin and combined groups.Therefore,our results suggest that peripheral high-frequency repetitive magnetic stimulation or neurotropin can promote the repair of injured sciatic nerves,but their combined use seems to offer no significant advantage.This study was approved by the Animal Ethics Committee of the Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University,China on December 23,2014(approval No.2014keyan002-01).展开更多
Prolife ration of neural stem cells is crucial for promoting neuronal regeneration and repairing cerebral infarction damage.Transcranial magnetic stimulation(TMS)has recently emerged as a tool for inducing endogenous ...Prolife ration of neural stem cells is crucial for promoting neuronal regeneration and repairing cerebral infarction damage.Transcranial magnetic stimulation(TMS)has recently emerged as a tool for inducing endogenous neural stem cell regeneration,but its underlying mechanisms remain unclea r In this study,we found that repetitive TMS effectively promotes the proliferation of oxygen-glucose deprived neural stem cells.Additionally,repetitive TMS reduced the volume of cerebral infa rction in a rat model of ischemic stro ke caused by middle cerebral artery occlusion,im p roved rat cognitive function,and promoted the proliferation of neural stem cells in the ischemic penumbra.RNA-sequencing found that repetitive TMS activated the Wnt signaling pathway in the ischemic penumbra of rats with cerebral ischemia.Furthermore,PCR analysis revealed that repetitive TMS promoted AKT phosphorylation,leading to an increase in mRNA levels of cell cycle-related proteins such as Cdk2 and Cdk4.This effect was also associated with activation of the glycogen synthase kinase 3β/β-catenin signaling pathway,which ultimately promotes the prolife ration of neural stem cells.Subsequently,we validated the effect of repetitive TMS on AKT phosphorylation.We found that repetitive TMS promoted Ca2+influx into neural stem cells by activating the P2 calcium channel/calmodulin pathway,thereby promoting AKT phosphorylation and activating the glycogen synthase kinase 3β/β-catenin pathway.These findings indicate that repetitive TMS can promote the proliferation of endogenous neural stem cells through a Ca2+influx-dependent phosphorylated AKT/glycogen synthase kinase 3β/β-catenin signaling pathway.This study has produced pioneering res ults on the intrinsic mechanism of repetitive TMS to promote neural function recove ry after ischemic stro ke.These results provide a stro ng scientific foundation for the clinical application of repetitive TMS.Moreover,repetitive TMS treatment may not only be an efficient and potential approach to support neurogenesis for further therapeutic applications,but also provide an effective platform for the expansion of neural stem cells.展开更多
Repetitive transcranial magnetic stimulation （rTMS） has been utilized as a therapeutic tool for neurodegenerative disorders including Alzheimer＇s disease. However, the precise mechanisms of its clinical effects rem...Repetitive transcranial magnetic stimulation （rTMS） has been utilized as a therapeutic tool for neurodegenerative disorders including Alzheimer＇s disease. However, the precise mechanisms of its clinical effects remain unknown. β-amyloid （Aβ） exhibits direct neurotoxic effects and is closely related to neuronal degeneration in Alzheimer＇s disease. Therefore, it has been hypothesized that the neuroprotective effects of rTMS are related to the mechanisms of protection against Aβ neurotoxicity. Organotypic hippocampal slices were prepared from 8-day old, Sprague Dawley rats. The tissue slices were exposed to 100 μmol/L Al3142 since day 12 in vitro with and without high-frequency （20 Hz） magnetic stimulation. Magnetic stimulation efficacy was evaluated by measuring neuronal nuclei （NeuN） protein expression and by observing cultures following propidium iodide fluorescence staining and bromodeoxyuridine （BrdU） immunohistochemistry. Lactate dehydrogenase activity was detected in the culture media to evaluate hippocampal neuronal damage. Our results demonstrated that high-frequency magnetic stimulation significantly reversed the reduction of NeuN protein expression because of Aβ1-42 exposure （P 〈 0.05） and significantly reduced the number of damaged cells in the hippocampal slices （P 〈 0.05）. However, lactate dehydrogenase levels and anti-BrdU staining results did not reveal any statistical differences These findings indicate that high-frequency magnetic stimulation might have protective effect on hippocampal neurons from Aβ1-42 neurotoxicity.展开更多
Individuals with amnestic mild cognitive impairment(aMCI)have a high risk of developing Alzheimer’s disease.Although repetitive transcranial magnetic stimulation(rTMS)is considered a potentially effective treatment f...Individuals with amnestic mild cognitive impairment(aMCI)have a high risk of developing Alzheimer’s disease.Although repetitive transcranial magnetic stimulation(rTMS)is considered a potentially effective treatment for cognitive impairment in patients with aMCI,the neuroimaging mechanisms are poorly understood.Therefore,we performed a double-blind randomized sham-controlled trial in which rTMS was applied to the left dorsolateral prefrontal cortex of aMCI patients recruited from a community near the Third Hospital Affiliated to Sun Yat-sen University,China.Twenty-four patients with aMCI were randomly assigned to receive true rTMS(treatment group,n=12,6 men and 6 women;age 65.08±4.89 years)or sham stimulation(sham group,n=12,5 men and 7 women;age 64.67±4.77 years).rTMS parameters included a stimulation frequency of 10 Hz,stimulation duration of 2 seconds,stimulation interval of 8 seconds,20 repetitions at 80%of the motor threshold,and 400 pulses per session.rTMS/sham stimulation was performed five times per week over a period of 4 consecutive weeks.Our results showed that compared with baseline,Montreal Cognitive Assessment scores were significantly increased and the value of the amplitude of low-frequency fluctuation(ALFF)was significantly increased at the end of treatment and 1 month after treatment.Compared with the sham group,the ALFF values in the right inferior frontal gyrus,triangular part of the inferior frontal gyrus,right precuneus,left angular gyrus,and right supramarginal gyrus were significantly increased,and the ALFF values in the right superior frontal gyrus were significantly decreased in the treatment group.These findings suggest that high-frequency rTMS can effectively improve cognitive function in aMCI patients and alter spontaneous brain activity in cognitive-related brain areas.This study was approved by the Ethics Committee of Shenzhen Baoan Hospital of Southern Medical University,China(approval No.BYL20190901)on September 3,2019 and registered in the Chinese Clinical Trials Registry(registration No.ChiCTR1900028180)on December 14,2019.展开更多
Background Opiate addiction remains intractable in a large percentage of patients, and relapse is the biggest hurdle to recovery. Many studies have identified a central role of the nucleus accumbens （NAc） in addicti...Background Opiate addiction remains intractable in a large percentage of patients, and relapse is the biggest hurdle to recovery. Many studies have identified a central role of the nucleus accumbens （NAc） in addiction. Deep brain stimulation （DBS） has the advantages of being reversible, adjustable, and minimally invasive, and it has become a potential neurobiological intervention for addiction. The purpose of our study was to investigate whether high-frequency DBS in the NAc effectively attenuates the reinstatement of morphine seeking in morphine-primed rats. Methods A morphine-dependent group of rats was given increasing doses of morphine during conditioned place preference training. A control group of rats was given equal volumes of saline. After the establishment of this model, withdrawal syndromes were precipitated in these two groups by administering naloxone, and the differences in withdrawal symptoms between the groups were analyzed. Electrodes for DBS were implanted in the bilateral shell of the NAc in the experimental group. The rats were stimulated daily in the NAc for 5 hours per day over 30 days. Changes in the conditioned place preference test and withdrawal symptoms in the rats were investigated and place navigation studies were performed using the Morris water maze. The data were assessed statistically with one-way analysis of variance （ANOVA） followed by Tukey＇s tests for multiple post hoc comparisons. Results High-frequency stimulation of the bilateral NAc prevented the morphine-induced reinstatement of morphine seeking in the conditioned place preference test. The time spent in the white compartment by rats following 30 days of DBS （（268.25±25.07） seconds） was not significantly different compared with the time spent in the white compartment after relapse was induced by morphine administration （（303.29±34.22） seconds）. High-frequency stimulation of the bilateral NAc accelerated the innate decay of drug craving in morphine-dependent rats without significantly influencing learning and memory. Conclusion Bilateral high-frequency stimulation of the shell of the NAc may be useful as a novel therapeutic modality for the treatment of severe morphine addiction.展开更多
Brief-pulse stimulation at 50 Hz has been shown to terminate afterdischarges observed in epilepsy patients. However, the optimal pulse stimulation parameters for terminating cortical electrical stimulation-induced aft...Brief-pulse stimulation at 50 Hz has been shown to terminate afterdischarges observed in epilepsy patients. However, the optimal pulse stimulation parameters for terminating cortical electrical stimulation-induced afterdischarges remain unclear. In the present study, we examined the effects of different brief-pulse stimulation frequencies（5, 50 and 100 Hz） on cortical electrical stimulation-induced afterdischarges in 10 patients with refractory epilepsy. Results demonstrated that brief-pulse stimulation could terminate cortical electrical stimulation-induced afterdischarges in refractory epilepsy patients. In conclusion,（1） a brief-pulse stimulation was more effective when the afterdischarge did not extend to the surrounding brain area.（2） A higher brief-pulse stimulation frequency（especially 100 Hz） was more likely to terminate an afterdischarge.（3） A low current intensity of brief-pulse stimulation was more likely to terminate an afterdischarge.展开更多
A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigati...A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.展开更多
Transcutaneous electrical acupoint stimulation(TEAS)is a kind of physical therapy that use electric cur-rent through the electrodes placed on the surface of acupoints to produce clinical effects in the human body,whic...Transcutaneous electrical acupoint stimulation(TEAS)is a kind of physical therapy that use electric cur-rent through the electrodes placed on the surface of acupoints to produce clinical effects in the human body,which is characterized by less adverse reaction and convenient operation.It has been widely used in the treatment of various diseases.This review introduces six major clinical applications of TEAS,named analgesia,regulation of gastrointestinal function,improvement of reproductive function,enhancement of cognitive function,promotion of limb function recovery and relief of fatigue.Besides,TEAS has been ap-plied to the treatment of other chronic diseases such as hypertension and diabetes,achieving satisfactory clinical effects.However,two crucial challenges are encountered in the development of TEAS.One is the lack of standardization in the selection of parameters such as waveform,frequency,intensity and stimula-tion duration.The other is the limitation on the flexibility in the acupoint selection.This review analyzes key issues that need to be addressed in the current clinical application of TEAS,such as the selection of parameters and acupoints,and this review provides a certain reference value for optimizing regimens of TEAS and promoting its development and application.展开更多
基金Postdoctoral Science Foundation of China, No. 20070420399
文摘BACKGROUND： Deep-brain stimulation has proven to be beneficial in the treatment of Parkinson＇s disease （PD） patients. OBJECTIVE： To investigate the effects of high-frequency stimulation （HFS） to the subthalamic nucleus （STN） on neuronal apoptosis and apoptosis-related gene expression in the substantia nigra pars compacta, and to analyze the neuroprotective effect of HFS-STN. DESIGN, TIME AND SETTING： Neuronal morphology experiments were performed in the Beijing Neurosurgical Institute from May to December in 2005. MATERIALS： Forty healthy, adult, Sprague Dawley rats were used to establish a PD model with a unilateral microinjection of 6-hydroxydopamine into two target areas of the right medial forebrain bundle. 6-hydroxydopamine was purchased from Sigma （USA）; high-frequency electrical stimulator was produced by World Precision Instruments （USA）; Terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） kit was a product of Nanjing Jiancheng Technology Co., Ltd. （China）; and Bcl-2 and Bax protein assay kit were purchased from Wuhan Boster Bioengineering Co., Ltd. （China）. METHODS： Forty rats were randomly divided into three groups. The stimulation group （n = 15） received HFS-STN on the day of PD modeling. The PD model group （n = 15） was used to establish the PD model. The control group （n = 10） was injected with normal saline containing 0.2 g/L ascorbic acid into two areas of the right medial forebrain bundle. MAIN OUTCOME MEASURES： Survival of dopaminergic neurons in the substantia nigra pars compacta was determined using Nissl staining. Apoptosis of dopaminergic neurons was detected using TUNEL techniques. Expression of anti-apoptotic protein, Bcl-2, and pro-apoptotic protein, Bax, were assayed by immunohistochemistry. RESULTS： Following 6-hydroxydopamine injection, the number of substantia nigra pars compacta neurons was reduced in the stimulation and PD model groups, compared to the control group. At 2 and 4 weeks post-surgery, the grey value of Nissl stained images was significantly less in the PD model and stimulation groups （P 〈 0.05）, and the stimulation group exhibited greater grey values compared to the model group （P 〈 0.05）. At 2 and 4 weeks post-surgery, the number of apoptotic neurons was significantly less in the stimulation group compared to the model group （P 〈 0.05）. In addition, Bcl-2 and Bax expression, as well as the Bcl-2/Bax ratio, was much higher in the stimulation group compared to the model group （P 〈 0.05）. CONCLUSION： HFS-STN has a neuroprotective effect on dopaminergic neurons in the substantia nigra pars compacta of PD rats by promoting Bcl-2 expression, inhibiting Bax expression, and reducing the number of apoptotic dopaminergic neurons.
文摘Degeneration and death of the neurons of the substantia nigra can cause a deficit in brain dopamine, leading to loss of movement control The subthalamic nucleus is a junction of basal ganglia neural circuit and can regulate the efferent information of basal ganglia and control motor activity. High-frequency stimulation of the subthalamic nucleus can alter dopamine levels as well as related factor expression in the corpus striatum and thereby improve the symptoms of Parkinson＇s disease.
文摘Epilepsy is one of the most common serious neurological disorders. Pharmacoresistant epilepsy patients are poorly controlled or their seizures are refractory to drug treatment. Resective surgery is frequently a promising therapy in this population, however, not all the patients meet the eligibility criteria for the surgical treatment. Deep brain stimulation has been investigated in clinical studies and animal studies as an alternative treatment, but the optimal stimulation parameters remain an issue. The present study was designed to investigate the effect of unilateral high-frequency stimulation (HFS) of hippocampus on seizure development by using the hippocampal rapid kindling method (hRK) in rats, and compared the results with those of low-frequency stimulation previously published by our group. We used male Wistar rats implanted with electrodes in the ventral hippocampus. All rats underwent hRK (biphasic square wave pulses, 20 Hz for 10 seconds) during three consecutive days (twelve stimulations per day). The control group (hRK;n = 7) received only RK stimulus, while the treated group (HFS-hRK;n = 9) received also HFS (biphasic square wave pulses, 130 Hz for 30 seconds) immediately before the RK stimulus, during three consecutive days. At the end of behavioral testing 78% (p 0.01) of the animals receiving HFS treatment were still not fully kindled staying in stages 0 -III (p 0.01). HFS group needed a higher number of stimulations to achieve stage III (p 0.05) with respect to control group. However, no significant differences in the cumulative daily afterdischarge duration were observed. HFS did not present significant differences compared with LFS in any of studied parameters. The findings suggest that unilateral HFS applied on hippocampus effectively inhibited the epileptogenic process induced by hippocampal rapid kindling. According to the comparative results about hippocampal rapid kindled animals stimulated with HFS and LFS (5 Hz), we found no conclusive information on which treatment is most efficient.
文摘BACKGROUND： Subthalamic nucleus-high frequency stimulation （STN-HFS） plays an important role in the treatment of Parkinson＇s disease, but the mechanisms underlying STN-HFS remain unclear. Some studies have demonstrated that STN stimulation inhibits the firing activity of substantia nigra pars reticulata neurons. OBJECTIVE： To investigate the effects of different-frequency STN stimulation and microiontophoresis of gamma-aminobutyric acid （GABA） and its antagonist, bicuculline, on spontaneous firing activity in a rat model of Parkinson＇s disease, and to analyze the action pathway of high frequency stimulation in firing activity inhibition of substantia nigra pars reticulata neurons. DESIGN, TIME AND SETTING： This neuroelectrophysiological, animal experiment was performed at the Electrophysiology Laboratory of Liaoning Medical University, China from March to August 2008. MATERIALS： 6-hydroxydopamine （6-OHDA） （Sigma, USA）, A320R isolated stimulus and DAM80 preamplifier （World Precision Instruments, USA）, 6400A microiontophoresis apparatus （Dagan, USA）, and Spike 2 biological signal acquisition system （CED, UK） were used in this study. METHODS： A total of 20 Sprague Dawley rats were used to establish a Parkinson＇s disease model via injection of 6-OHDA into the right striatum. Electrical stimulation （0.06-ms width, 0.4-mA intensity 20-200-Hz frequency, 5-second train duration） was delivered to the subthalamic nucleus. Peripheral channels were separately filled with GABA （pH 3.5, 0.2 mol/L）, bicuculline （pH 4.0, 0.01 mol/L）, and NaCI （pH 7.0, 3 mol/L）. The electrode was positioned with a WK-2 microelectrode propulsion device, and was slowly inserted into the substantia nigra pars reticulata to record spontaneous firing activity of substantia nigra pars reticulata neurons. MAIN OUTCOME MEASURES： The number and firing rate of substantia nigra pars reticulata neurons which were either inhibited or excited were measured. RESULTS： Substantia nigra pars reticulata neurons were inhibited by STN stimulation. The proportion of inhibited substantia nigra pars reticulata neurons increased with increasing stimulation frequency. GABA had a tonic inhibitory effect on substantia nigra pars reticulata neurons. Microiontophoresis of bicuculline suppressed the inhibitory effect of STN-HFS on 67% （4/6） of substantia nigra pars reticulata neurons. CONCLUSION： STN-HFS ameliorated abnormal activity in substantia nigra pars reticulata neurons via the inhibitory effect of GABA treatment in a rat model of Parkinson＇s disease.
文摘Background The advent of brain stimulation techniques to treat movement disorders and psychiatric diseases has shown potential to decode the neural mechanism that underlies the cognitive process by modulating the interrupted circuit.Here,the present investigation aimed at evaluating the influence of deep brain stimulation of the anterior nucleus thalamus （ANT-DBS） on memory.Methods Thirty-two rats were randomized into phosphate buffer saline （PBS） group （n=8,rats received PBS injections without implantation of electrodes into the ANT）,Alzheimer＇s dementia （AD） group （n=8,rats received Aβ1-40 injections without implantation of electrodes into the ANT）,ANT sham stimulation group （n=8,rats received Aβ1-40 injections with implantation of electrodes into the ANT but without stimulation） and ANT stimulation group （n=8,rats received Aβ1-40 injections with implantation of electrodes into the ANT and stimulation）.A Morris maze test was used for determining the effect of electrical stimulation on cognitive function in rats.The data were assessed statistically with one-way analysis of variance （ANOVA） followed by Tukey＇s tests for multiple post hoc comparisons.Results The data showed that in the training test,PBS group and AD group managed to learn the hidden-platform faster and faster while AD group needed a significantly longer time to reach the platform than PBS group （P ＜0.05）.Meanwhile,ANT stimulation group demonstrated a significantly shorter time to reach the platform （P ＜0.05） compared to the AD group,while there was no significant difference between the ANT sham stimulation group and the AD group （P ＞0.05）.On the probe test,the AD group spent less time （（10.15±2.34） seconds） in the target quadrant than the PBS group （（28.20±2.75） seconds） （P ＜0.05）.And the times of platform-traversing of the AD group （3.35±1.12） significantly decreased compared with the PBS group （8.69±2.87） （P ＜0.05）.However,the times of platform-traversing and the time spent in the target quadrant of the ANT stimulation group significantly increased compared to the AD group （P ＜0.05）,while times of platformtraversing or the time spent in the target quadrant was not significantly different between the ANT sham stimulation group and the AD group （P ＞0.05）.Conclusion Bilateral high-frequency stimulation of the ANT may be useful as a potential therapeutic modality for cognitive dysfunction in AD.
基金funded by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation):project ID 431549029-SFB 1451the Marga-und-Walter-Boll-Stiftung(#210-10-15)(to MAR)a stipend from the'Gerok Program'(Faculty of Medicine,University of Cologne,Germany)。
文摘Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of knowledge about the underlying modes of action and optimal treatment modalities,a thorough translational investigation of noninvasive brain stimulation in preclinical animal models is urgently needed.Thus,we reviewed the current literature on the mechanistic underpinnings of noninvasive brain stimulation in models of central nervous system impairment,with a particular emphasis on traumatic brain injury and stroke.Due to the lack of translational models in most noninvasive brain stimulation techniques proposed,we found this review to the most relevant techniques used in humans,i.e.,transcranial magnetic stimulation and transcranial direct current stimulation.We searched the literature in Pub Med,encompassing the MEDLINE and PMC databases,for studies published between January 1,2020 and September 30,2024.Thirty-five studies were eligible.Transcranial magnetic stimulation and transcranial direct current stimulation demonstrated distinct strengths in augmenting rehabilitation post-stroke and traumatic brain injury,with emerging mechanistic evidence.Overall,we identified neuronal,inflammatory,microvascular,and apoptotic pathways highlighted in the literature.This review also highlights a lack of translational surrogate parameters to bridge the gap between preclinical findings and their clinical translation.
基金supported by the Fundamental Research Funds for the Central Universities,Nos.G2021KY05107,G2021KY05101the National Natural Science Foundation of China,Nos.32071316,32211530049+1 种基金the Natural Science Foundation of Shaanxi Province,No.2022-JM482the Education and Teaching Reform Funds for the Central Universities,No.23GZ230102(all to LL and HH).
文摘Although previous studies have demonstrated that transcranial focused ultrasound stimulation protects the ischemic brain,clear criteria for the stimulation time window and intensity are lacking.Electrical impedance tomography enables real-time monitoring of changes in cerebral blood perfusion within the ischemic brain,but investigating the feasibility of using this method to assess post-stroke rehabilitation in vivo remains critical.In this study,ischemic stroke was induced in rats through middle cerebral artery occlusion surgery.Transcranial focused ultrasound stimulation was used to treat the rat model of ischemia,and electrical impedance tomography was used to measure impedance during both the acute stage of ischemia and the rehabilitation stage following the stimulation.Electrical impedance tomography results indicated that cerebral impedance increased after the onset of ischemia and decreased following transcranial focused ultrasound stimulation.Furthermore,the stimulation promoted motor function recovery,reduced cerebral infarction volume in the rat model of ischemic stroke,and induced the expression of brain-derived neurotrophic factor in the ischemic brain.Our results also revealed a significant correlation between the impedance of the ischemic brain post-intervention and improvements in behavioral scores and infarct volume.This study shows that daily administration of transcranial focused ultrasound stimulation for 20 minutes to the ischemic hemisphere 24 hours after cerebral ischemia enhanced motor recovery in a rat model of ischemia.Additionally,our findings indicate that electrical impedance tomography can serve as a valuable tool for quantitatively evaluating rehabilitation after ischemic stroke in vivo.These findings suggest the feasibility of using impedance data collected via electrical impedance tomography to clinically assess the effects of rehabilitatory interventions for patients with ischemic stroke.
基金supported by STI 2030-Major Projects,No.2021ZD0201603(to JL)the Joint Foundation Program of the Chinese Academy of Sciences,No.8091A170201(to JL)+1 种基金the National Natural Science Foundation of China,Nos.T2293730(to XC),T2293731(to XC),T2293734(to XC),62471291(to YW),62121003(to XC),61960206012(to XC),62333020(to XC),and 62171434(to XC)the National Key Research and Development Program of China,Nos.2022YFC2402501(to XC),2022YFB3205602(to XC).
文摘Neuromodulation techniques effectively intervene in cognitive function,holding considerable scientific and practical value in fields such as aerospace,medicine,life sciences,and brain research.These techniques utilize electrical stimulation to directly or indirectly target specific brain regions,modulating neural activity and influencing broader brain networks,thereby regulating cognitive function.Regulating cognitive function involves an understanding of aspects such as perception,learning and memory,attention,spatial cognition,and physical function.To enhance the application of cognitive regulation in the general population,this paper reviews recent publications from the Web of Science to assess the advancements and challenges of invasive and non-invasive stimulation methods in modulating cognitive functions.This review covers various neuromodulation techniques for cognitive intervention,including deep brain stimulation,vagus nerve stimulation,and invasive methods using microelectrode arrays.The non-invasive techniques discussed include transcranial magnetic stimulation,transcranial direct current stimulation,transcranial alternating current stimulation,transcutaneous electrical acupoint stimulation,and time interference stimulation for activating deep targets.Invasive stimulation methods,which are ideal for studying the pathogenesis of neurological diseases,tend to cause greater trauma and have been less researched in the context of cognitive function regulation.Non-invasive methods,particularly newer transcranial stimulation techniques,are gentler and more appropriate for regulating cognitive functions in the general population.These include transcutaneous acupoint electrical stimulation using acupoints and time interference methods for activating deep targets.This paper also discusses current technical challenges and potential future breakthroughs in neuromodulation technology.It is recommended that neuromodulation techniques be combined with neural detection methods to better assess their effects and improve the accuracy of non-invasive neuromodulation.Additionally,researching closed-loop feedback neuromodulation methods is identified as a promising direction for future development.
基金supported by the Defitech Foundation(Morges,CH)to FCHthe Bertarelli Foundation-Catalyst program(Gstaad,CH)to FCH+2 种基金the Wyss Center for Bio and Neuroengineering the Lighthouse Partnership for AI-guided Neuromodulation to FCHthe Fonds de recherche du Quebec-Sante(FRQS#342969)to CEPthe Neuro X Postdoctoral Fellowship Program to CEP。
文摘Brain lesions,such as those caused by stroke or traumatic brain injury(TBI),frequently result in persistent motor and cognitive impairments that significantly affect the individual patient's quality of life.Despite differences in the mechanisms of injury,both conditions share a high prevalence of motor and cognitive impairments.These deficits show only limited natural recovery.
基金supported by the Capital Fund for Health Improvement and Research,No.2022-2-2048(to WZ)the National Natural Science Foundation of China,No.81970992(to WZ)+3 种基金Capital Clinical Characteristic Application Research,No.Z121107001012161(to WZ)the Natural Science Foundation of Beijing,No.7082032(to WZ)the Key Technology R&D Program of Beijing Municipal Education Commission,No.KZ201610025030(to WZ)Project of Scientific and Technological Development of Traditional Chinese Medicine in Beijing,No.JJ2018-48(to WZ)。
文摘Alzheimer's disease is the most common type of cognitive disorder,and there is an urgent need to develop more effective,targeted and safer therapies for patients with this condition.Deep brain stimulation is an invasive surgical treatment that modulates abnormal neural activity by implanting electrodes into specific brain areas followed by electrical stimulation.As an emerging therapeutic approach,deep brain stimulation shows significant promise as a potential new therapy for Alzheimer's disease.Here,we review the potential mechanisms and therapeutic effects of deep brain stimulation in the treatment of Alzheimer's disease based on existing clinical and basic research.In clinical studies,the most commonly targeted sites include the fornix,the nucleus basalis of Meynert,and the ventral capsule/ventral striatum.Basic research has found that the most frequently targeted areas include the fornix,nucleus basalis of Meynert,hippocampus,entorhinal cortex,and rostral intralaminar thalamic nucleus.All of these individual targets exhibit therapeutic potential for patients with Alzheimer's disease and associated mechanisms of action have been investigated.Deep brain stimulation may exert therapeutic effects on Alzheimer's disease through various mechanisms,including reducing the deposition of amyloid-β,activation of the cholinergic system,increasing the levels of neurotrophic factors,enhancing synaptic activity and plasticity,promoting neurogenesis,and improving glucose metabolism.Currently,clinical trials investigating deep brain stimulation for Alzheimer's disease remain insufficient.In the future,it is essential to focus on translating preclinical mechanisms into clinical trials.Furthermore,consecutive follow-up studies are needed to evaluate the long-term safety and efficacy of deep brain stimulation for Alzheimer's disease,including cognitive function,neuropsychiatric symptoms,quality of life and changes in Alzheimer's disease biomarkers.Researchers must also prioritize the initiation of multi-center clinical trials of deep brain stimulation with large sample sizes and target earlier therapeutic windows,such as the prodromal and even the preclinical stages of Alzheimer's disease.Adopting these approaches will permit the efficient exploration of more effective and safer deep brain stimulation therapies for patients with Alzheimer's disease.
基金supported by the National Nature Science Foundation of China,No.81870838Liaoning Province Distinguished Professor Support Program of China,No.XLYC1802096+1 种基金Shenyang Clinical Medicine Research Center of Anesthesiology of China,Nos.19-110-4-24,20-204-4-44the Outstanding Scientific Foundation of Shengjing Hospital of China,No.201708(all to PZ)。
文摘High-frequency spinal cord stimulation(HF-SCS) has been established as an effective therapy for neuropathic pain. However, the analgesic mechanisms involved in HF-SCS remain to be clarified. In our study, adult rat neuropathic pain was induced by spinal nerve ligation. Two days after modeling, the rats were subjected to 4 hours of HF-SCS(motor threshold 50%, frequency 10,000 Hz, and pulse width 0.024 ms) in the dorsal horn of the spinal cord. The results revealed that the tactile allodynia of spinal nerve-injured rats was markedly alleviated by HFSCS, and the effects were sustained for 3 hours after the stimulation had ceased. HF-SCS restored lysosomal function, increased the levels of lysosome-associated membrane protein 2(LAMP2) and the mature form of cathepsin D(matu-CTSD), and alleviated the abnormally elevated levels of microtubule-associated protein 1 A/B-light chain 3(LC3)-II and sequestosome 1(P62) in spinal nerve-injured rats. HF-SCS also mostly restored the immunoreactivity of LAMP2, which was localized in neurons in the superficial layers of the spinal dorsal horn in spinal nerve-injured rats. In addition, intraperitoneal administration of 15 mg/kg chloroquine for 60 minutes reversed the expression of the aforementioned proteins and shortened the timing of the analgesic effects of HF-SCS. These findings suggest that HF-SCS may exhibit longlasting analgesic effects on neuropathic pain in rats through improving lysosomal dysfunction and alleviating autophagic flux. This study was approved by the Laboratory Animal Ethics Committee of China Medical University, Shenyang, China(approval No. 2017 PS196 K) on March 1, 2017.
基金Supported by Key Diagnosis and Treatment Program of Suzhou,No.LCZX201919 and No.LCZX202016The Scientific and Technological Program of Suzhou,No.SS201752 and No.SS202069Introduction Project of Suzhou Clinical Expert Team,No.SZYJTD201715。
文摘BACKGROUND Cognitive impairments are core characteristics of schizophrenia,but are largely resistant to current treatments.Several recent studies have shown that highfrequency repetitive transcranial magnetic stimulation(rTMS)of the left dorsolateral prefrontal cortex(DLPFC)can reduce negative symptoms and improve certain cognitive deficits in schizophrenia patients.However,results are inconsistent across studies.AIM To examine if high-frequency rTMS of the DLPFC can improve visual memory deficits in patients with schizophrenia.METHODS Forty-seven chronic schizophrenia patients with severe negative symptoms on stable treatment regimens were randomly assigned to receive active rTMS to the DLPFC(n=25)or sham stimulation(n=22)on weekdays for four consecutive weeks.Patients performed the pattern recognition memory(PRM)task from the Cambridge Neuropsychological Test Automated Battery at baseline,at the end of rTMS treatment(week 4),and 4 wk after rTMS treatment(week 8).Clinical symptoms were also measured at these same time points using the Scale for the Assessment of Negative Symptoms(SANS)and the Positive and Negative Syndrome Scale(PANSS).RESULTS There were no significant differences in PRM performance metrics,SANS total score,SANS subscores,PANSS total score,and PANSS subscores between active and sham rTMS groups at the end of the 4-wk treatment period,but PRM performance metrics(percent correct and number correct)and changes in these metrics from baseline were significantly greater in the active rTMS group at week 8 compared to the sham group(all P<0.05).Active rTMS treatment also significantly reduced SANS score at week 8 compared to sham treatment.Moreover,the improvement in visual memory was correlated with the reduction in negative symptoms at week 8.In contrast,there were no between-group differences in PANSS total score and subscale scores at either week 4 or week 8(all P>0.05).CONCLUSION High-frequency transcranial magnetic stimulation improves visual memory and reduces negative symptoms in schizophrenia,but these effects are delayed,potentially due to the requirement for extensive neuroplastic changes within DLPFC networks.
基金funded by the National Natural Science Foundation of China,No.81471338 and No.81671284(to XJZ)the Changzhou Science&Technology Program of China,No.CE20145045(to XJZ)the Changzhou High-Level Medical Talents Training Project of China,No.2016CZLJ018(to XJZ)
文摘Repetitive magnetic stimulation is effective for treating posttraumatic neuropathies following spinal or axonal injury.Neurotropin is a potential treatment for nerve injuries like demyelinating diseases.This study sought to observe the effects of high-frequency repetitive magnetic stimulation,neurotropin and their combined use in the treatment of peripheral nerve injury in 32 adult male Sprague-Dawley rats.To create a sciatic nerve injury model,a 10 mm-nerve segment of the left sciatic nerve was cut and rotated through 180°and each end restored continuously with interrupted sutures.The rats were randomly divided into four groups.The control group received only a reversed autograft in the left sciatic nerve with no treatment.In the high-frequency repetitive magnetic stimulation group,peripheral high-frequency repetitive magnetic stimulation treatment(20 Hz,20 min/d)was delivered for 10 consecutive days after auto-grafting.In the neurotropin group,neurotropin therapy(0.96 NU/kg per day)was administrated for 10 consecutive days after surgery.In the combined group,the combination of peripheral high-frequency repetitive magnetic stimulation(20 Hz,20 min/d)and neurotropin(0.96 NU/kg per day)was given for 10 consecutive days after the operation.The Basso-Beattie-Bresnahan locomotor rating scale was used to assess the behavioral recovery of the injured nerve.The sciatic functional index was used to evaluate the recovery of motor functions.Toluidine blue staining was performed to determine the number of myelinated fibers in the distal and proximal grafts.Immunohistochemistry staining was used to detect the length of axons marked by neurofilament 200.Our results reveal that the Basso-Beattie-Bresnahan locomotor rating scale scores,sciatic functional index,the number of myelinated fibers in distal and proximal grafts were higher and axon lengths were longer in the high-frequency repetitive magnetic stimulation,neurotropin and combined groups compared with the control group.These measures were not significantly different among the high-frequency repetitive magnetic stimulation,neurotropin and combined groups.Therefore,our results suggest that peripheral high-frequency repetitive magnetic stimulation or neurotropin can promote the repair of injured sciatic nerves,but their combined use seems to offer no significant advantage.This study was approved by the Animal Ethics Committee of the Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University,China on December 23,2014(approval No.2014keyan002-01).
基金supported by the National Natural Science Foundation of China,Nos.81672261(to XH),81972151(to HZ),82372568(to JL)the Natural Science Foundation of Guangdong Province,Nos.2019A1515011106(to HZ),2023A1515030080(to JL)。
文摘Prolife ration of neural stem cells is crucial for promoting neuronal regeneration and repairing cerebral infarction damage.Transcranial magnetic stimulation(TMS)has recently emerged as a tool for inducing endogenous neural stem cell regeneration,but its underlying mechanisms remain unclea r In this study,we found that repetitive TMS effectively promotes the proliferation of oxygen-glucose deprived neural stem cells.Additionally,repetitive TMS reduced the volume of cerebral infa rction in a rat model of ischemic stro ke caused by middle cerebral artery occlusion,im p roved rat cognitive function,and promoted the proliferation of neural stem cells in the ischemic penumbra.RNA-sequencing found that repetitive TMS activated the Wnt signaling pathway in the ischemic penumbra of rats with cerebral ischemia.Furthermore,PCR analysis revealed that repetitive TMS promoted AKT phosphorylation,leading to an increase in mRNA levels of cell cycle-related proteins such as Cdk2 and Cdk4.This effect was also associated with activation of the glycogen synthase kinase 3β/β-catenin signaling pathway,which ultimately promotes the prolife ration of neural stem cells.Subsequently,we validated the effect of repetitive TMS on AKT phosphorylation.We found that repetitive TMS promoted Ca2+influx into neural stem cells by activating the P2 calcium channel/calmodulin pathway,thereby promoting AKT phosphorylation and activating the glycogen synthase kinase 3β/β-catenin pathway.These findings indicate that repetitive TMS can promote the proliferation of endogenous neural stem cells through a Ca2+influx-dependent phosphorylated AKT/glycogen synthase kinase 3β/β-catenin signaling pathway.This study has produced pioneering res ults on the intrinsic mechanism of repetitive TMS to promote neural function recove ry after ischemic stro ke.These results provide a stro ng scientific foundation for the clinical application of repetitive TMS.Moreover,repetitive TMS treatment may not only be an efficient and potential approach to support neurogenesis for further therapeutic applications,but also provide an effective platform for the expansion of neural stem cells.
文摘Repetitive transcranial magnetic stimulation （rTMS） has been utilized as a therapeutic tool for neurodegenerative disorders including Alzheimer＇s disease. However, the precise mechanisms of its clinical effects remain unknown. β-amyloid （Aβ） exhibits direct neurotoxic effects and is closely related to neuronal degeneration in Alzheimer＇s disease. Therefore, it has been hypothesized that the neuroprotective effects of rTMS are related to the mechanisms of protection against Aβ neurotoxicity. Organotypic hippocampal slices were prepared from 8-day old, Sprague Dawley rats. The tissue slices were exposed to 100 μmol/L Al3142 since day 12 in vitro with and without high-frequency （20 Hz） magnetic stimulation. Magnetic stimulation efficacy was evaluated by measuring neuronal nuclei （NeuN） protein expression and by observing cultures following propidium iodide fluorescence staining and bromodeoxyuridine （BrdU） immunohistochemistry. Lactate dehydrogenase activity was detected in the culture media to evaluate hippocampal neuronal damage. Our results demonstrated that high-frequency magnetic stimulation significantly reversed the reduction of NeuN protein expression because of Aβ1-42 exposure （P 〈 0.05） and significantly reduced the number of damaged cells in the hippocampal slices （P 〈 0.05）. However, lactate dehydrogenase levels and anti-BrdU staining results did not reveal any statistical differences These findings indicate that high-frequency magnetic stimulation might have protective effect on hippocampal neurons from Aβ1-42 neurotoxicity.
基金This work was supported by the National Natural Science Foundation of China,No.81874032(to GZH)the Science and Technology Planning Project of Shenzhen of China,No.JCYJ20160427191726109(to FZ)+1 种基金the Science and Technology Planning Project of Guangdong Province of China,No.2016A020215202(to SHC)Shenzhen Health and Family Planning System Research Project of China,No.SZXJ2017069(to SHC).
文摘Individuals with amnestic mild cognitive impairment(aMCI)have a high risk of developing Alzheimer’s disease.Although repetitive transcranial magnetic stimulation(rTMS)is considered a potentially effective treatment for cognitive impairment in patients with aMCI,the neuroimaging mechanisms are poorly understood.Therefore,we performed a double-blind randomized sham-controlled trial in which rTMS was applied to the left dorsolateral prefrontal cortex of aMCI patients recruited from a community near the Third Hospital Affiliated to Sun Yat-sen University,China.Twenty-four patients with aMCI were randomly assigned to receive true rTMS(treatment group,n=12,6 men and 6 women;age 65.08±4.89 years)or sham stimulation(sham group,n=12,5 men and 7 women;age 64.67±4.77 years).rTMS parameters included a stimulation frequency of 10 Hz,stimulation duration of 2 seconds,stimulation interval of 8 seconds,20 repetitions at 80%of the motor threshold,and 400 pulses per session.rTMS/sham stimulation was performed five times per week over a period of 4 consecutive weeks.Our results showed that compared with baseline,Montreal Cognitive Assessment scores were significantly increased and the value of the amplitude of low-frequency fluctuation(ALFF)was significantly increased at the end of treatment and 1 month after treatment.Compared with the sham group,the ALFF values in the right inferior frontal gyrus,triangular part of the inferior frontal gyrus,right precuneus,left angular gyrus,and right supramarginal gyrus were significantly increased,and the ALFF values in the right superior frontal gyrus were significantly decreased in the treatment group.These findings suggest that high-frequency rTMS can effectively improve cognitive function in aMCI patients and alter spontaneous brain activity in cognitive-related brain areas.This study was approved by the Ethics Committee of Shenzhen Baoan Hospital of Southern Medical University,China(approval No.BYL20190901)on September 3,2019 and registered in the Chinese Clinical Trials Registry(registration No.ChiCTR1900028180)on December 14,2019.
基金This work was supported by grants from the National Natural Science Foundation of China （No. 81070901, No. 81141013）, the Beijing Outstanding Talents Project （No. 2011 D003034000019）, and Beijing Nova Program （No. 2008B043）.
文摘Background Opiate addiction remains intractable in a large percentage of patients, and relapse is the biggest hurdle to recovery. Many studies have identified a central role of the nucleus accumbens （NAc） in addiction. Deep brain stimulation （DBS） has the advantages of being reversible, adjustable, and minimally invasive, and it has become a potential neurobiological intervention for addiction. The purpose of our study was to investigate whether high-frequency DBS in the NAc effectively attenuates the reinstatement of morphine seeking in morphine-primed rats. Methods A morphine-dependent group of rats was given increasing doses of morphine during conditioned place preference training. A control group of rats was given equal volumes of saline. After the establishment of this model, withdrawal syndromes were precipitated in these two groups by administering naloxone, and the differences in withdrawal symptoms between the groups were analyzed. Electrodes for DBS were implanted in the bilateral shell of the NAc in the experimental group. The rats were stimulated daily in the NAc for 5 hours per day over 30 days. Changes in the conditioned place preference test and withdrawal symptoms in the rats were investigated and place navigation studies were performed using the Morris water maze. The data were assessed statistically with one-way analysis of variance （ANOVA） followed by Tukey＇s tests for multiple post hoc comparisons. Results High-frequency stimulation of the bilateral NAc prevented the morphine-induced reinstatement of morphine seeking in the conditioned place preference test. The time spent in the white compartment by rats following 30 days of DBS （（268.25±25.07） seconds） was not significantly different compared with the time spent in the white compartment after relapse was induced by morphine administration （（303.29±34.22） seconds）. High-frequency stimulation of the bilateral NAc accelerated the innate decay of drug craving in morphine-dependent rats without significantly influencing learning and memory. Conclusion Bilateral high-frequency stimulation of the shell of the NAc may be useful as a novel therapeutic modality for the treatment of severe morphine addiction.
基金supported by the Capital Health Research and Development Special Funds of China,No.2016-1-2011
文摘Brief-pulse stimulation at 50 Hz has been shown to terminate afterdischarges observed in epilepsy patients. However, the optimal pulse stimulation parameters for terminating cortical electrical stimulation-induced afterdischarges remain unclear. In the present study, we examined the effects of different brief-pulse stimulation frequencies（5, 50 and 100 Hz） on cortical electrical stimulation-induced afterdischarges in 10 patients with refractory epilepsy. Results demonstrated that brief-pulse stimulation could terminate cortical electrical stimulation-induced afterdischarges in refractory epilepsy patients. In conclusion,（1） a brief-pulse stimulation was more effective when the afterdischarge did not extend to the surrounding brain area.（2） A higher brief-pulse stimulation frequency（especially 100 Hz） was more likely to terminate an afterdischarge.（3） A low current intensity of brief-pulse stimulation was more likely to terminate an afterdischarge.
基金supported by the National Natural Science Foundation of China,No.82001155(to LL)the Natural Science Foundation of Zhejiang Province,No.LY23H090004(to LL)+5 种基金the Natural Science Foundation of Ningbo,No.2023J068(to LL)the Fundamental Research Funds for the Provincial Universities of Zhejiang Province,No.SJLY2023008(to LL)the College Students'Scientific and Technological Innovation Project(Xin Miao Talent Plan)of Zhejiang Province,No.2022R405A045(to CC)the Student ResearchInnovation Program(SRIP)of Ningbo University,Nos.20235RIP1919(to CZ),2023SRIP1938(to YZ)the K.C.Wong Magna Fund in Ningbo University。
文摘A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.
基金Supported by Shanghai 2020“Science and Technology Innovation Action Plan”Medical Innovation Research Special Program:20Y21902800Shanghai Municipal Health Commission Shanghai Three-Year Action Plan to Further Accelerate the Development of Traditional Chinese Medicine Inheritance and Innovation:ZY(2021-2023)−0302)+1 种基金Shanghai Key Specialty(Acupuncture)Construction Project:shslczdzk04701Shanghai 2024"Science and Technology Innovation Action Plan"star cultivation(Sail special):24YF2740600.
文摘Transcutaneous electrical acupoint stimulation(TEAS)is a kind of physical therapy that use electric cur-rent through the electrodes placed on the surface of acupoints to produce clinical effects in the human body,which is characterized by less adverse reaction and convenient operation.It has been widely used in the treatment of various diseases.This review introduces six major clinical applications of TEAS,named analgesia,regulation of gastrointestinal function,improvement of reproductive function,enhancement of cognitive function,promotion of limb function recovery and relief of fatigue.Besides,TEAS has been ap-plied to the treatment of other chronic diseases such as hypertension and diabetes,achieving satisfactory clinical effects.However,two crucial challenges are encountered in the development of TEAS.One is the lack of standardization in the selection of parameters such as waveform,frequency,intensity and stimula-tion duration.The other is the limitation on the flexibility in the acupoint selection.This review analyzes key issues that need to be addressed in the current clinical application of TEAS,such as the selection of parameters and acupoints,and this review provides a certain reference value for optimizing regimens of TEAS and promoting its development and application.
