High-frequency repetitive transcranial magnetic stimulation promotes neural stem cell proliferation after ischemic stroke

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.

Delayed improvements in visual memory task performance among chronic schizophrenia patients after high-frequency repetitive transcranial magnetic stimulation

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.

Neuroimaging mechanisms of high-frequency repetitive transcranial magnetic stimulation for treatment of amnestic mild cognitive impairment:a double-blind randomized sham-controlled trial

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.

Analyzing the Combination Effects of Repetitive Transcranial Magnetic Stimulation and Motor Control Training on Balance Function and Gait in Patients with Stroke-Induced Hemiplegia

Objective:To analyze the effects of repetitive transcranial magnetic stimulation combined with motor control training on the treatment of stroke-induced hemiplegia,specifically focusing on the impact on patients’balance function and gait.Methods:Fifty-two cases of hemiplegic stroke patients were randomly divided into two groups,26 in the control group and 26 in the observation group,using computer-generated random grouping.All participants underwent conventional treatment and rehabilitation training.In addition to these,the control group received repetitive transcranial magnetic pseudo-stimulation therapy+motor control training,while the observation group received repetitive transcranial magnetic stimulation therapy+motor control training.The balance function and gait parameters of both groups were compared before and after the interventions and assessed the satisfaction of the interventions in both groups.Results:Before the invention,there were no significant differences in balance function scores and each gait parameter between the two groups(P>0.05).However,after the intervention,the observation group showed higher balance function scores compared to the control group(P<0.05).The observation group also exhibited higher step speed and step frequency,longer step length,and a higher overall satisfaction level with the intervention compared to the control group(P<0.05).Conclusion:The combination of repetitive transcranial magnetic stimulation and motor control training in the treatment of stroke-induced hemiplegia has demonstrated positive effects.It not only improves the patient’s balance function and gait but also contributes to overall physical rehabilitation.

Contribution of glial cells to the neuroprotective effects triggered by repetitive magnetic stimulation:a systematic review

Repetitive transcranial magnetic stimulation has been increasingly studied in different neurological diseases,and although most studies focus on its effects on neuronal cells,the contribution of nonneuronal cells to the improvement trigge red by repetitive transcranial magnetic stimulation in these diseases has been increasingly suggested.To systematically review the effects of repetitive magnetic stimulation on non-neuronal cells two online databases.Web of Science and PubMed were searched fo r the effects of high-frequency-repetitive transcranial magnetic stimulation,low-frequencyrepetitive transcranial magnetic stimulation,intermittent theta-bu rst stimulation,continuous thetaburst stimulation,or repetitive magnetic stimulation on non-neuronal cells in models of disease and in unlesioned animals or cells.A total of 52 studies were included.The protocol more frequently used was high-frequency-repetitive magnetic stimulation,and in models of disease,most studies report that high-frequency-repetitive magnetic stimulation led to a decrease in astrocyte and mic roglial reactivity,a decrease in the release of pro-inflammatory cyto kines,and an increase of oligodendrocyte proliferation.The trend towards decreased microglial and astrocyte reactivity as well as increased oligodendrocyte proliferation occurred with intermittent theta-burst stimulation and continuous theta-burst stimulation.Few papers analyzed the low-frequency-repetitive transcranial magnetic stimulation protocol,and the parameters evaluated were restricted to the study of astrocyte reactivity and release of pro-inflammatory cytokines,repo rting the absence of effects on these paramete rs.In what concerns the use of magnetic stimulation in unlesioned animals or cells,most articles on all four types of stimulation reported a lack of effects.It is also important to point out that the studies were developed mostly in male rodents,not evaluating possible diffe rential effects of repetitive transcranial magnetic stimulation between sexes.This systematic review supports that thro ugh modulation of glial cells repetitive magnetic stimulation contributes to the neuroprotection or repair in various neurological disease models.Howeve r,it should be noted that there are still few articles focusing on the impact of repetitive magnetic stimulation on non-neuronal cells and most studies did not perform in-depth analyses of the effects,emphasizing the need for more studies in this field.

Repetitive transcranial magnetic stimulation promotes neurological functional recovery in rats with traumatic brain injury by upregulating synaptic plasticity-related proteins

Studies have shown that repetitive transcra nial magnetic stimulation(rTMS)can enhance synaptic plasticity and improve neurological dysfunction.Howeve r,the mechanism through which rTMS can improve moderate traumatic brain injury remains poorly understood.In this study,we established rat models of moderate traumatic brain injury using Feeney's weight-dropping method and treated them using rTMS.To help determine the mechanism of action,we measured levels of seve ral impo rtant brain activity-related proteins and their mRNA.On the injured side of the brain,we found that rTMS increased the protein levels and mRNA expression of brain-derived neurotrophic factor,tropomyosin receptor kinase B,N-methyl-D-aspartic acid receptor 1,and phosphorylated cAMP response element binding protein,which are closely associated with the occurrence of long-term potentiation.rTMS also partially reve rsed the loss of synaptophysin after injury and promoted the remodeling of synaptic ultrastructure.These findings suggest that upregulation of synaptic plasticity-related protein expression is the mechanism through which rTMS promotes neurological function recovery after moderate traumatic brain injury.

Repetitive transcranial magnetic stimulation combined with olanzapine and amisulpride for treatment-refractory schizophrenia

BACKGROUND Treatment-refractory schizophrenia(TRS),accounting for approximately 30%of all schizophrenia cases,has poor treatment response and prognosis despite treatment with antipsychotic drugs.AIM To analyze the therapeutic effectiveness of repetitive transcranial magnetic stimulation(rTMS)combined with olanzapine(OLZ)and amisulpride(AMI)for TRS and its influence on the patient’s cognitive function.METHODS This study enrolled 114 TRS patients who received treatment at the First Affiliated Hospital of Zhengzhou University between July 2019 and July 2022.In addition to the basic OLZ+AMI therapy,54 cases of the control group(Con group)received modified electroconvulsive therapy,while 60 cases of the research group(Res group)received rTMS.Data on therapeutic effectiveness,safety(incidence of drowsiness,headache,nausea,vomiting,or memory impairment),Positive and Negative Symptom Scale,Montreal Cognitive Assessment Scale,and Schizophrenia Quality of Life Scale were collected from both cohorts for comparative analyses.RESULTS The Res group elicited a higher overall response rate and better safety profile when compared with the Con group.Additionally,a significant reduction was observed in the post-treatment Positive and Negative Symptom Scale and Schizophrenia Quality of Life Scale scores of the Res group,presenting lower scores than those of the Con group.Furthermore,a significant increase in the Montreal Cognitive Assessment Scale score was reported in the Res group,with higher scores than those of the Con group.CONCLUSION The treatment of TRS with rTMS and OLZ+AMI is effective and safe.Moreover,it can alleviate the patients’mental symptoms,improve their cognitive function and quality of life,and has a high clinical application value.

Effects of different frequencies of repetitive transcranial magnetic stimulation on the recovery of upper limb motor dysfunction in patients with subacute cerebral infarction

Studies have confirmed that low-frequency repetitive transcranial magnetic stimulation can decrease the activity of cortical neurons, and high-frequency repetitive transcranial magnetic stimulation can increase the excitability of cortical neurons. However, there are few studies concerning the use of different frequencies of repetitive transcranial magnetic stimulation on the recovery of upper-limb motor function after cerebral infarction. We hypothesized that different frequencies of repetitive transcranial magnetic stimulation in patients with cerebral infarction would produce different effects on the recovery of upper-limb motor function. This study enrolled 127 patients with upper-limb dysfunction during the subacute phase of cerebral infarction. These patients were randomly assigned to three groups. The low-frequency group comprised 42 patients who were treated with 1 Hz repetitive transcranial magnetic stimulation on the contralateral hemisphere primary motor cortex(M1). The high-frequency group comprised 43 patients who were treated with 10 Hz repetitive transcranial magnetic stimulation on ipsilateral M1. Finally, the sham group comprised 42 patients who were treated with 10 Hz of false stimulation on ipsilateral M1. A total of 135 seconds of stimulation was applied in the sham group and high-frequency group. At 2 weeks after treatment, cortical latency of motor-evoked potentials and central motor conduction time were significantly lower compared with before treatment. Moreover, motor function scores were significantly improved. The above indices for the low- and high-frequency groups were significantly different compared with the sham group. However, there was no significant difference between the low- and high-frequency groups. The results show that low- and high-frequency repetitive transcranial magnetic stimulation can similarly improve upper-limb motor function in patients with cerebral infarction.

Low frequency repetitive transcranial magnetic stimulation improves motor dysfunction after cerebral infarction

Low frequency(≤ 1 Hz) repetitive transcranial magnetic stimulation(r TMS) can affect the excitability of the cerebral cortex and synaptic plasticity. Although this is a common method for clinical treatment of cerebral infarction, whether it promotes the recovery of motor function remains controversial. Twenty patients with cerebral infarction combined with hemiparalysis were equally and randomly divided into a low frequency r TMS group and a control group. The patients in the low frequency r TMS group were given 1-Hz r TMS to the contralateral primary motor cortex with a stimulus intensity of 90% motor threshold, 30 minutes/day. The patients in the control group were given sham stimulation. After 14 days of treatment, clinical function scores(National Institute of Health Stroke Scale, Barthel Index, and Fugl-Meyer Assessment) improved significantly in the low frequency r TMS group, and the effects were better than that in the control group. We conclude that low frequency(1 Hz) r TMS for 14 days can help improve motor function after cerebral infarction.

Research hotspots and effectiveness of repetitive transcranial magnetic stimulation in stroke rehabilitation

Repetitive transcranial magnetic stimulation, as a relatively new type of rehabilitation treatment, is a painless and non-invasive method for altering brain excitability. Repetitive transcranial magnetic stimulation has been widely used in the neurorehabilitation of stroke patients. Here, we used CiteSpace software to visually analyze 315 studies concerning repetitive transcranial magnetic stimulation for stroke rehabilitation from 1999 to 2019, indexed by Web of Science, to clarify the research hotspots in different periods and characterize the gradual process of discovery in this field. We found that four main points were generally accepted:(1) repetitive transcranial magnetic stimulation has a positive effect on motor function recovery in patients with subcortical stroke;(2) it may be more advantageous for stroke patients to receive low-frequency repetitive transcranial magnetic stimulation in the unaffected hemispheres than to receive high-frequency repetitive transcranial magnetic stimulation in affected hemisphere;(3) low-frequency repetitive transcranial magnetic stimulation has become a potential therapeutic tool for patients with non-fluent aphasia after chronic stroke for neurological rehabilitation and language recovery;and(4) there are some limitations to these classic clinical studies, such as small sample size and low test efficiency. Our assessment indicates that prospective, multi-center, large-sample, randomized controlled clinical trials are still needed to further verify the effectiveness of various repetitive transcranial magnetic stimulation programs for the rehabilitation of stroke patients.

Combined effect of repetitive transcranial magnetic stimulation and physical exercise on cortical plasticity

Physical exercise can minimize dysfunction and optimize functional motor recovery after stroke by modulating cortical plasticity.However,the limitation of physical exercise is that large amounts of time and effort are necessary to significantly improve motor function,and even then,substantial exercise may not be sufficient to normalize the observed improvements.Thus,interventions that could be used to strengthen physical exercise-induced neuroplasticity may be valuable in treating hemiplegia after stroke.Repetitive transcranial magnetic stimulation seems to be a viable strategy for enhancing such plasticity.As a non-invasive cortical stimulation technique,repetitive transcranial magnetic stimulation is able to induce longterm plastic changes in the motor system.Recently,repetitive transcranial magnetic stimulation was found to optimize the plastic changes caused by motor training,thereby enhancing the long-term effects of physical exercise in stroke patients.Therefore,it is believed that the combination of repetitive transcranial magnetic stimulation and physical exercise may represent a superior method for restoring motor function after stroke.

Effects of High Frequency Repetitive Transcranial Magnetic Stimulation on KCC2 Expression in Rats with Spasticity Following Spinal Cord Injury

The effect of high-frequency repetitive transcranial magnetic stimulation(r TMS) on potassium-chloride cotransporter-2(KCC2) protein expression following spinal cord injury(SCI) and the action mechanism were investigated. SCI models were established in SD rats. Five groups were set up randomly: normal control group, SCI 7-day(7 D) model group, SCI 14-day(14 D) model group, SCI-7 DrTMS group and SCI-14 DrTMS group(n=5 each). The rats in SCI rTMS groups were treated with 10 Hz rTMS from 8 th day and 15 th day after SCI respectively, once every day, 5 days every week, a total of 4 weeks. After the model establishment, motor recovery and spasticity alleviation were evaluated with BBB scale once a week till the end of treatment. Finally, different parts of tissues were dissected out for detection of variations of KCC2 protein using Western blotting and polymerase chain reaction(PCR) technique. The results showed that the BBS scores after treatment were significantly higher in SCI-7 DrTMS group than in SCI-14 DrTMS group(P<0.05). As compared with normal control groups, The KCC2 protein in SCI model groups was down-regulated after SCI, and the decrease was much more significant in SCI-14 D model group than in SCI-7 D group(P<0.05). As compared with SCI model groups, KCC2 protein in rTMS groups was up-regulated after the treatment(P<0.05). The up-regulation of KCC2 protein content and expression was more obvious in SCI-7 DrTMS group than in SCI-14 DrTMS group(P<0.05). It was concluded that 10 Hz rTMS can alleviate spasticity in rats with SCI, which might be attributed to the up-regulation of KCC2 protein. It was also suggested that the high-frequency rTMS treatment after SCI at early stage might achieve more satisfactory curative effectiveness.

Increased activation of the caudate nucleus and parahippocampal gyrus in Parkinson's disease patients with dysphagia after repetitive transcranial magnetic stimulation:a case-control study

Repetitive transcranial magnetic stimulation(r TMS)has been shown to effectively improve impaired swallowing in Parkinson's disease(PD)patients with dysphagia.However,little is known about how r TMS affects the corresponding brain regions in this patient group.In this casecontrol study,we examined data from 38 PD patients with dysphagia who received treatment at Beijing Rehabilitation Medicine Academy,Capital Medical University.The patients received high-frequency r TMS of the motor cortex once per day for 10 successive days.Changes in brain activation were compared via functional magnetic resonance imaging in PD patients with dysphagia and healthy controls.The results revealed that before treatment,PD patients with dysphagia showed greater activation in the precentral gyrus,supplementary motor area,and cerebellum compared with healthy controls,and this enhanced activation was weakened after treatment.Furthermore,before treatment,PD patients with dysphagia exhibited decreased activation in the parahippocampal gyrus,caudate nucleus,and left thalamus compared with healthy controls,and this activation increased after treatment.In addition,PD patients with dysphagia reported improved subjective swallowing sensations after r TMS.These findings suggest that swallowing function in PD patients with dysphagia improved after r TMS of the motor cortex.This may have been due to enhanced activation of the caudate nucleus and parahippocampal gyrus.The study protocol was approved by the Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University(approval No.2018 bkky017)on March 6,2018 and was registered with Chinese Clinical Trial Registry(registration No.Chi CTR 1800017207)on July 18,2018.

Clinical application of repetitive transcranial magnetic stimulation in stroke rehabilitation

Proper stimulation to affected cerebral hemisphere would promote the functional recovery of patients with stroke. Effects of repetitive transcranial magnetic stimulation on cortical excitability can be can be altered by the stimulation frequency, intensity and duration. There has been no consistent recognition regarding the best stimulation frequency and intensity. This study reviews the intervention effects of repetitive transcranial stimulation on motor impairment, dysphagia, visuospatial neglect and aphasia, and summarizes the stimulation frequency, intensity and area for repetitive transcranial magnetic stimulation to yield the best therapeutic effects.

Does a combined intervention program of repetitive transcranial magnetic stimulation and intensive occupational therapy affect cognitive function in patients with post-stroke upper limb hemiparesis?

Low-frequency repetitive transcranial magnetic stimulation(LF-r TMS) to the contralesional hemisphere and intensive occupational therapy(i OT) have been shown to contribute to a significant improvement in upper limb hemiparesis in patients with chronic stroke. However, the effect of the combined intervention program of LF-r TMS and i OT on cognitive function is unknown. We retrospectively investigated whether the combined treatment influence patient's Trail-Making Test part B(TMT-B) performance, which is a group of easy and inexpensive neuropsychological tests that evaluate several cognitive functions. Twenty-five patients received 11 sessions of LF-r TMS to the contralesional hemisphere and 2 sessions of i OT per day over 15 successive days. Patients with right- and left-sided hemiparesis demonstrated significant improvements in upper limb motor function following the combined intervention program. Only patients with right-sided hemiparesis exhibited improved TMT-B performance following the combined intervention program, and there was a significant negative correlation between Fugl-Meyer Assessment scale total score change and TMT-B performance. The results indicate the possibility that LF-r TMS to the contralesional hemisphere combined with i OT improves the upper limb motor function and cognitive function of patients with right-sided hemiparesis. However, further studies are necessary to elucidate the mechanism of improved cognitive function.

Motor cortex transcranial magnetic stimulation to reduce intractable postherpetic neuralgia with poor response to other threapies:Report of two cases

BACKGROUND Postherpetic neuralgia(PHN)is a typical neuropathic pain condition that appears in the lesioned skin regions following the healing of shingles.The pain condition tends to persist,which is often accompanied by negative emotions(e.g.,anxiety and depression)and substantially reduces the quality of life.In addition to analgesia(e.g.,pregabalin and gabapentin),nerve radiofrequency technology is an effective treatment for intractable PHN.However,there is still a significant portion of patients who do not benefit from this treatment.As a non-invasive form of brain stimulation,repetitive transcranial magnetic stimulation(rTMS)targeting the motor cortex is able to reduce neuropathic pain with grade A evidence.CASE SUMMARY Here we report two cases in which motor cortex rTMS was used to treat intractable PHN that did not respond to initial drug and radiofrequency therapies.Moreover,we specifically investigated rTMS efficacy at 3 mo following treatment.CONCLUSION Motor cortex rTMS can treat intractable PHN that did not respond to initial drug and radiofrequency therapies.

Short-term effects of repetitive transcranial magnetic stimulation on sleep bruxism-a pilot study

The purpose of this study was to investigate the effects of repetitive transcranial magnetic stimulation(r TMS)on patients with sleep bruxism(SB).Twelve patients with SB were included in an open,single-intervention pilot study.r TMS at 1 Hz and an intensity of80%of the active motor threshold was applied to the‘hot spot’of the masseter muscle representation at the primary motor cortex bilaterally for 20 min per side each day for 5 consecutive days.The jaw-closing muscle electromyographic(EMG)activity during sleep was recorded with a portable EMG recorder at baseline,during r TMS treatment and at follow-up for 5 days.In addition,patients scored their jaw-closing muscle soreness on a 0–10 numerical rating scale(NRS).Data were analysed with analysis of variance.The intensity of the EMG activity was suppressed during and after r TMS compared to the baseline(P 5 0.04;P 5 0.02,respectively).The NRS score of soreness decreased significantly during and after r TMS compared with baseline(P,0.01).These findings indicated a significant inhibition of jaw-closing muscle activity during sleep along with a decrease of muscle soreness.This pilot study raises the possibility of therapeutic benefits from r TMS in patients with bruxism and calls for further and more controlled studies.