Peripheral magnetic stimulation

  • 文章类型: Journal Article
    Search and development of new physiotherapeutic technologies of regenerative medicine for the treatment of patients with different diseases is an urgent task of modern medicine.
    OBJECTIVE: To analyze scientific data on the effectiveness of the peripheral magnetic stimulation (PMS) application in patients with different diseases.
    METHODS: An analysis of publications in databases of electronic resources (PEDro, PubMed, Embase, eLibrary, Cochrane Library) over the past 20 years was carried out, the results of PMS application in patients with different nosologies were presented.
    RESULTS: The majority of the presented articles confirm the clinical effectiveness of PMS application mainly in patients with diseases of the nervous system, spine and genitourinary system.
    CONCLUSIONS: Further research to confirm the effectiveness of the therapeutic impact of magnetic stimulation in patients with other nosologies is needed.
    Поиск и разработка новых физиотерапевтических технологий восстановительной медицины для лечения пациентов с разными заболеваниями является актуальной задачей современной медицины.
    UNASSIGNED: Анализ научных данных об эффективности применения периферической магнитной стимуляции (ПМС) у пациентов с разными заболеваниями.
    UNASSIGNED: Был осуществлен анализ публикаций в базах данных электронных ресурсов (PEDro, PubMed, Embase, eLibrary, Кохрейновская библиотека) за последние 20 лет, в которых представлены результаты применения ПМС у пациентов с разными нозологиями.
    UNASSIGNED: Большинством представленных работ подтверждена клиническая эффективность применения ПМС в основном у пациентов с заболеваниями нервной системы, позвоночника и мочеполовой системы.
    UNASSIGNED: Необходимо продолжение научных исследований с целью подтверждения эффективности лечебного воздействия магнитной стимуляции у пациентов с другими нозологиями.
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  • 文章类型: Journal Article
    背景:吞咽困难已被世界卫生组织确认为医学残疾。改善舌骨肌功能在咽部吞咽困难中起重要作用。这项研究的目的是评估经颅磁刺激(TMS)的治疗,外周磁刺激(PMS),和电刺激(ES)用于吞咽困难。
    方法:将40名健康受试者随机分为四组:TMS+PMS,TMS,PMS,和ES。TMS刺激舌骨肌的皮质代表区,PMS直接刺激舌骨肌,它们都在10Hz的频率下,总共有1800个脉冲。ES的强度基于受试者的耐受水平,通常2-5mA。应用功能性近红外光谱(fNIRS)和舌骨肌的运动诱发电位(MEP)评估刺激对健康受试者干预前后吞咽皮质兴奋性的直接影响。
    结果:fNIRS结果显示,四组健康受试者在干预前和干预后的多个通道均有明显的激活。在这些频道中,激活水平在TMS+PMS组中最明显,其次是TMS,PMS,和ES组,分别。关于MEP结果,干预后观察表明,TMS+PMS组的双侧潜伏期减少,双侧波幅增加.此外,TMS组左侧波幅增加。
    结论:在fNIRS中,所有四种刺激方法都显著激活了健康受试者的吞咽皮层,TMS+PMS的激活最为明显,其次是TMS,PMS,和ES。
    BACKGROUND: Dysphagia has been recognized by the World Health Organization as a medical disability. Improving mylohyoid muscle function plays an important role in pharyngeal dysphagia. The aim of this study was to evaluate the treatment of transcranial magnetic stimulation (TMS), peripheral magnetic stimulation (PMS), and electrical stimulation (ES) for dysphagia.
    METHODS: Forty healthy subjects were randomly divided into four groups: TMS+PMS, TMS, PMS, and ES. TMS stimulated the cortical representative area of the mylohyoid muscle and the PMS was directly stimulating the mylohyoid muscle, both of them at a frequency of 10 Hz for a total of 1,800 pulses. The intensity of ES was based on the subject\'s tolerance level, usually 2-5 mA. Functional near infrared spectroscopy (fNIRS) and motor evoked potential (MEP) of the mylohyoid muscle were used to evaluate the immediate effects of stimulation on swallowing cortex excitability of healthy subjects before and after intervention.
    RESULTS: The fNIRS results revealed notable activation across multiple channels in the four groups of healthy subjects both pre- and post- the intervention. Among these channels, the activation levels were most pronounced in the TMS+PMS group, followed by the TMS, PMS, and ES groups, respectively. Regarding the MEP results, post-intervention observations indicated a reduction in bilateral latency and an increase in bilateral amplitude in the TMS+PMS group. Additionally, the left amplitude exhibited an increase in the TMS group.
    CONCLUSIONS: In fNIRS, all four stimulation methods significantly activated the swallowing cortex of healthy subjects, and the activation of TMS+PMS was the most obvious, followed by TMS, PMS, and ES.
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  • 文章类型: Randomized Controlled Trial
    背景:非侵入性技术,如中枢间歇性θ脉冲刺激(iTBS)和重复外周磁刺激(rPMS),已显示出改善中风患者运动功能的前景。然而,rPMS和中枢iTBS的联合疗效尚未得到广泛研究.这项随机对照试验旨在研究rPMS和中枢iTBS在卒中患者中的协同作用。
    方法:在本研究中,28例中风患者被随机分配接受1200脉冲的真实或假rPMS在患肢的radial神经上,随后在同侧半球出现1200脉冲的中央iTBS。患者在两周内接受了10次干预。主要结果指标是Fugl-Meyer评估上肢(FMA-UE)和动作研究手臂测试(ARAT)。活动和参与的次要结果包括功能独立性措施-自我护理(FIM-Selfcare)和卒中影响量表(SIS)。在干预前后评估结局指标。
    结果:两组干预后FMA-UE和FIM-Selfcare均有明显改善(p<0.05)。只有rPMS+iTBS组在ARAT-Grasp和SIS-强度和日常生活活动能力方面有显著改善(p<0.05)。然而,两组间所有结局指标的变化评分均无差异.
    结论:总体而言,研究结果表明,rPMS可能对中枢iTBS具有协同作用,以改善抓握功能和参与。总之,这些发现凸显了rPMS在卒中康复中作为中枢iTBS辅助治疗的潜力.需要进一步的大规模研究来充分探索rPMS对中枢iTBS的协同作用。
    背景:该试验在ClinicalTrials.govIDNo.NCT04265365,回顾性注册,2020年2月11日。
    BACKGROUND: Non-invasive techniques such as central intermittent theta burst stimulation (iTBS) and repetitive peripheral magnetic stimulation (rPMS) have shown promise in improving motor function for patients with stroke. However, the combined efficacy of rPMS and central iTBS has not been extensively studied. This randomized controlled trial aimed to investigate the synergistic effects of rPMS and central iTBS in patients with stroke.
    METHODS: In this study, 28 stroke patients were randomly allocated to receive either 1200 pulses of real or sham rPMS on the radial nerve of the affected limb, followed by 1200 pulses of central iTBS on the ipsilesional hemisphere. The patients received the intervention for 10 sessions over two weeks. The primary outcome measures were the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and the Action Research Arm Test (ARAT). Secondary outcomes for activities and participation included the Functional Independence Measure-Selfcare (FIM-Selfcare) and the Stroke Impact Scale (SIS). The outcome measures were assessed before and after the intervention.
    RESULTS: Both groups showed significant improvement in FMA-UE and FIM-Selfcare after the intervention (p < 0.05). Only the rPMS + iTBS group had significant improvement in ARAT-Grasp and SIS-Strength and activity of daily living (p < 0.05). However, the change scores in all outcome measures did not differ between two groups.
    CONCLUSIONS: Overall, the study\'s findings suggest that rPMS may have a synergistic effect on central iTBS to improve grasp function and participation. In conclusion, these findings highlight the potential of rPMS as an adjuvant therapy for central iTBS in stroke rehabilitation. Further large-scale studies are needed to fully explore the synergistic effects of rPMS on central iTBS.
    BACKGROUND: This trial was registered under ClinicalTrials.gov ID No.NCT04265365, retrospectively registered, on February 11, 2020.
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  • 文章类型: Journal Article
    目的:慢性腰背痛是一个重要的社会问题,导致医疗费用和生活质量的增加。本研究旨在评估非侵入性脊柱电磁模拟(SEMS)治疗非特异性慢性下腰痛(CLBP)的可行性和有效性。方法:进行单中心前瞻性研究以评估SEMS在减轻疼痛和改善残疾方面的作用。共有17名患者每周接受两次至三次SEMS。使用数字评定量表和改良的Oswestry残疾问卷来评估疼痛和残疾。结果:接受SEMS的参与者在疼痛和残疾方面表现出统计学上的显着降低。结论:目前的结果表明,非侵入性SEMS可以有效地减轻与CLBP相关的疼痛和改善残疾。
    Aim: Chronic low back pain represents a significant societal problem leading to increased healthcare costs and quality of life. This study was designed to evaluate the feasibility and effectiveness of non-invasive spinal electromagnetic simulation (SEMS) to treat nonspecific chronic low back pain (CLBP). Methods: A single-site prospective study was conducted to evaluate SEMS in reducing pain and improving disability. A total of 17 patients received SEMS two to three sessions a week. The Numeric Rating Scale and the Modified Oswestry Disability Questionnaire were used to assess pain and disability. Results: Participants receiving SEMS exhibited statistically significant reductions in pain and disability. Conclusion: Current results suggest that non-invasive SEMS can be an effective treatment in reducing pain and improving disability associated with CLBP.
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  • 文章类型: Controlled Clinical Trial
    目的:对外周磁刺激(PMS)治疗慢性外周神经性疼痛的相关文献进行系统综述。
    方法:对MEDLINE的系统搜索,EMBASE,中部,CINHAL,WebofScience,和ProQuest从开始至2023年7月进行,以确定任何以英语发表的设计的研究,这些研究纳入了接受PMS治疗慢性周围神经性疼痛障碍(疼痛>3个月)的成年患者(≥18岁).
    结果:确定了23项研究,其中包括15项随机对照试验(RCT),五个案例系列,两个病例报告,和一项非随机试验。PMS方案因研究而异,在1天至1年的治疗中,每次5至240分钟。纳入研究的结果参差不齐,一些研究表明有好处,而另一些研究没有显着差异。在九项安慰剂对照随机对照试验中,四个报告了支持PMS使用的统计学显著发现。在荟萃分析中,在使用0-1个月内,与对照组相比,PMS显着降低了疼痛评分(0-10数字评定量表的平均差-1.64,95%置信区间-2.73至-0.56,p=0.003,I2=94%,7项研究[264名参与者],证据质量非常低),但不是在1-3个月和>3个月的PMS使用(非常低和低质量的证据,分别)。使用PMS报告的不良反应最少至无。
    结论:有有限且低质量的证据可以对PMS的使用提出明确的建议,然而,现有的数据令人鼓舞,特别是这种新颖模式的短期应用。需要大量高质量的随机对照试验来确定PMS的确切疗效和安全性。
    OBJECTIVE: To provide a systematic review of the literature on the effects of peripheral magnetic stimulation (PMS) in the treatment of chronic peripheral neuropathic pain.
    METHODS: A systematic search of MEDLINE, EMBASE, CENTRAL, CINHAL, Web of Science, and ProQuest was conducted from inception to July 2023 to identify studies of any design published in English language that enrolled adult patients (≥18 years) that received PMS for treatment of a chronic peripheral neuropathic pain disorder (pain > 3 months).
    RESULTS: Twenty-three studies were identified which included 15 randomized controlled trials (RCTs), five case series, two case reports, and one non-randomized trial. PMS regimens varied across studies and ranged from 5 to 240 min per session over 1 day to 1 year of treatment. Results across included studies were mixed, with some studies suggesting benefits while others showing no significant differences. Of nine placebo-controlled RCTs, four reported statistically significant findings in favor of PMS use. In the meta-analysis, PMS significantly reduced pain scores compared to control within 0-1 month of use (mean difference -1.64 on a 0-10 numeric rating scale, 95% confidence interval -2.73 to -0.56, p = 0.003, I2 = 94%, 7 studies [264 participants], very low quality of evidence), but not at the 1-3 months and >3 months of PMS use (very low and low quality of evidence, respectively). Minimal to no adverse effects were reported with PMS use.
    CONCLUSIONS: There is limited and low-quality evidence to make definitive recommendations on PMS usage, however, the available data is encouraging, especially for short-term applications of this novel modality. Large high-quality randomized controlled trials are required to establish definitive efficacy and safety effects of PMS.
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  • 文章类型: Journal Article
    痉挛,其特征是肌肉张力的速度依赖性增加和过度的反射,是上运动神经元综合征患者的常见并发症,比如中风幸存者。Sensitization,神经系统对感官刺激的反应增强,已经成为痉挛的潜在原因。这篇透视文章探讨了三种针对致敏的新兴治疗方法。最近的研究已经调查了痉挛的新治疗方式,包括体外冲击波疗法(ESWT),重复外周磁刺激(rPMS),和针刺。ESWT在减少上肢和下肢痉挛方面显示出有希望的结果,可能通过一氧化氮产生等机制,流变性质变化,和神经肌肉传递功能障碍。rPMS提供了一种非侵入性的方法,可以通过增加感觉输入来减少痉挛,增强皮层激活,并发挥组织软化作用。针刺也显示了对减少痉挛的积极作用。观察到的高度异质性表明需要更严格的研究来证实这些发现。最近,作者发明的机械针刺和无菌水注射也有望通过消除敏化来减少痉挛。总之,本文讨论的新兴治疗方案为解决痉挛敏化和改善运动功能提供了有希望的途径.然而,需要进一步的研究来验证他们的发现,优化治疗方案,并研究其对痉挛患者运动恢复和整体生活质量的长期影响。
    Spasticity, characterized by a velocity-dependent increase in muscle tone and exaggerated reflexes, is a common complication in individuals with upper motor neuron syndrome, such as stroke survivors. Sensitization, the heightened responsiveness of the nervous system to sensory stimuli, has emerged as a potential cause of spasticity. This perspective article explores three emerging treatments targeting sensitization. Recent studies have investigated novel treatment modalities for spasticity, including Extracorporeal Shockwave Therapy (ESWT), repetitive peripheral magnetic stimulation (rPMS), and needling. ESWT has shown promising results in reducing spasticity in both the upper and lower extremities, potentially through mechanisms such as nitric oxide production, rheological property changes, and neuromuscular transmission dysfunction. rPMS offers a non-invasive approach that may reduce spasticity by increasing sensory input, enhancing cortical activation, and exerting tissue-softening effects. Needling has also demonstrated positive effects on spasticity reduction. The high heterogeneity observed indicates the need for more rigorous research to confirm these findings. Recently, mechanical needling and sterile water injection invented by the author is also promising for reducing spasticity through removing sensitization. In conclusion, the emerging treatment options discussed in this perspective article provide promising avenues for addressing sensitization in spasticity and improving motor function. However, further research is needed to validate their findings, optimize treatment protocols, and investigate their long-term effects on motor recovery and overall quality of life in individuals with spasticity.
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  • 文章类型: Journal Article
    Stroke is a central nervous system disease that causes structural lesions and functional impairments of the brain, resulting in varying types, and degrees of dysfunction. The bimodal balance-recovery model (interhemispheric competition model and vicariation model) has been proposed as the mechanism of functional recovery after a stroke. We analyzed how combinations of motor observation treatment approaches, transcranial electrical (TES) or magnetic (TMS) stimulation and peripheral electrical (PES) or magnetic (PMS) stimulation techniques can be taken as accessorial physical therapy methods on symptom reduction of stroke patients. We suggest that top-down and bottom-up stimulation techniques combined with action observation treatment synergistically might develop into valuable physical therapy strategies in neurorehabilitation after stroke. We explored how TES or TMS intervention over the contralesional hemisphere or the lesioned hemisphere combined with PES or PMS of the paretic limbs during motor observation followed by action execution have super-additive effects to potentiate the effect of conventional treatment in stroke patients. The proposed paradigm could be an innovative and adjunctive approach to potentiate the effect of conventional rehabilitation treatment, especially for those patients with severe motor deficits.
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  • 文章类型: Journal Article
    周围磁刺激是一种潜在的有前途的方式来帮助管理术后疼痛。我们系统综述了外周磁刺激对急性和慢性术后疼痛的影响。MEDLINE,科克伦中部,EMBASE,ProQuest论文,和ClinicalTrials.gov从一开始一直搜索到2021年5月。我们纳入了任何研究设计的研究,这些研究设计包括在围手术期接受外周磁刺激的年龄≥18岁的患者,并评估了术后疼痛。共纳入17项随机对照试验和1项非随机临床试验。18项研究中有13项发现外周磁刺激对术后疼痛评分有积极影响。在我们的荟萃分析中,在术后前7天内,外周磁刺激比假手术或无干预更有效(0-10数字评分的平均差[MD]-1.64,95%置信区间[CI]-2.08至-1.20,I2=77%,6项研究[231例患者])。手术后1个月和2个月也是如此(MD-1.82,95%CI-2.48至-1.17,I2=0%,3项研究[104例患者];MD-1.96,95%CI-3.67至-0.26,I2=84%,3项研究[分别为104例患者])。在手术后6个月和12个月的持续性疼痛没有观察到差异,术后急性阿片类药物消耗,或组间不良事件。结果受到异质性和通常低质量研究的限制,以及证据质量低或非常低。需要高质量和充分的盲化试验来明确确认围手术期外周磁刺激的益处。观点:本综述评估外周磁刺激(PMS)对术后疼痛的疗效和安全性。结果有助于阐明PMS在术后疼痛管理中的作用,并确定需要更多研究的差距。
    Peripheral magnetic stimulation (PMS) is a potentially promising modality to help manage postoperative pain. We systematically reviewed the effect of PMS on acute and chronic postoperative pain. MEDLINE, Cochrane CENTRAL, EMBASE, ProQuest Dissertations, and clinical trials.gov were searched from inception until May 2021. We included studies of any study design that included patients ≥18 years of age undergoing any type of surgery that administered PMS within the perioperative period and evaluated postoperative pain. Seventeen randomized controlled trials and 1 nonrandomized clinical trial were included into the review. Thirteen out of the 18 studies found a positive effect with PMS on postoperative pain scores. In our meta-analysis, peripheral magnetic stimulation was more efficacious than sham or no intervention within the first 7 postoperative days (mean difference [MD] -1.64 on a 0 to 10 numerical rating score, 95% confidence interval [CI] -2.08 to -1.20, I2 = 77%, 6 studies, 231 patients). This was also true at 1 and 2 months after surgery (MD -1.82, 95% CI -2.48 to -1.17, I2 = 0%, 3 studies, 104 patients; and MD -1.96, 95% CI -3.67 to -.26, I2 = 84%, 3 studies, 104 patients, respectively). A difference was not seen with persistent pain at 6 and 12-months after surgery, acute postoperative opioid consumption, or adverse events between groups. Results are limited by heterogeneity and generally low-quality studies, as well as low or very low quality of evidence. High-quality and adequately blinded trials are needed to definitively confirm the benefits of peripheral magnetic stimulation administered in the perioperative period. PERSPECTIVE: This review evaluates the efficacy and safety of PMS on postoperative pain. The results help elucidate PMS\' role in postoperative pain management and identify gaps where more research is required.
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  • 文章类型: Journal Article
    配对的皮质神经元刺激(或电PCMS:ePCMS)是电刺激与神经的重复配对,对主运动皮层(TMS-of-M1)进行经颅磁刺激,以无创地影响脊柱可塑性。我们将ePCMS与新的无痛PCMS协议进行了比较,该协议在预激活的胫骨前肌(TA)中将磁刺激与M1的TMS-of-M1(mPCMS)配对。16名健康成年人参加了两次会议(mPCMS,ePCMS),每个都有180对0.2Hz的[低强度TMS-of-M1+神经刺激]。在pre-PCMS的单脉冲TMS的TA运动诱发电位(MEP),立即和PCMS后30分钟,进行聚类分析,以区分应答者和非应答者。还测试了成对脉冲TMS-of-M1和F波,并探索了BDNF多态性的影响。两种PCMS协议均显着增加了MEP幅度(每个n=9个响应者),但随着时间的推移,mPCMS诱导更大的MEP增加的时程有所不同。在mPCMS中BDNF-蛋氨酸载体的数量倾向于大于Val66Val,而在ePCMS中相反,因此需要进一步调查。预激活的TA的MEP变化可能发生在运动神经元前水平,并且随着时间的推移,更大的mPCMS后遗症可能与招募的传入有关。mPCMS似乎可以在未来的研究中进行测试,作为一种无痛的非侵入性方法,可以在脊髓损伤中诱导持续的运动神经元前可塑性。
    Paired corticomotoneuronal stimulation (or electrical PCMS: ePCMS) is the repetitive pairing of an electrical stimulus to a nerve with a transcranial magnetic stimulation of the primary motor cortex (TMS-of-M1) to noninvasively influence spinal plasticity. We compared ePCMS with the new painless PCMS protocol pairing a magnetic stimulus to the nerve with TMS-of-M1 (mPCMS) in the preactivated tibial anterior muscle (TA). Sixteen healthy adults participated in two sessions (mPCMS, ePCMS), each with 180 pairs of [low-intensity TMS-of-M1 + nerve stimulation] at 0.2 Hz. TA motor-evoked potentials (MEP) to single-pulse TMS at pre-PCMS, immediately and 30 min after PCMS, were cluster-analyzed to discriminate responders and non-responders. Paired-pulse TMS-of-M1 and F-waves were also tested and BDNF polymorphism influence was explored. Both PCMS protocols significantly increased MEP amplitudes (n = 9 responders each), but the time-course differed with mPCMS inducing larger MEP increase over time. The number of BDNF-methionine carriers tended to be larger than Val66Val in mPCMS and the reverse in ePCMS, thus warranting further investigations. The MEP changes of the preactivated TA likely occurred at the pre-motoneuronal level and larger mPCMS after-effects over time may be related to the afferents recruited. mPCMS seems relevant to be tested in future studies as a painless noninvasive approach to induce sustained pre-motoneuronal plasticity in spinal cord injury.
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  • 文章类型: Journal Article
    背景:面瘫(FP)是中风后的常见症状,影响患者的生活质量和预后。最近,外周磁刺激(PMS)对外周和中枢神经系统的损害具有潜在的影响。然而,PMS对卒中后FP的影响尚不清楚。
    方法:在本研究中,我们在9例中风FP患者的面神经上应用了PMS。同时,采用激光散斑对比成像(LSCI)技术,对19例健康受试者和9例中风患者进行PMS干预前后的面部皮肤血流量(SkBF)进行了研究。将整个面部分为14个区域,以比较不同子区域中的SkBF。
    结果:在基线SkBF中,我们发现,在健康受试者中,左脸和右脸之间的SkBF没有显着差异。然而,在第7区,受影响和未受影响的面孔之间的SkBF存在显着差异(Chin地区,p=0.046)。在PMS干预后的五分钟内(Pre_0-5分钟),SkBF在区域5(p=0.014)和区域7(p=0.046)中增加,并且在区域3(p=0.088)和区域6(p=0.069)中增加。在干预后的5到10分钟(后6-10分钟),区域5的SkBF增加(p=0.009),区域6(p=0.021)和区域7(p=0.023),并且在区域3(p=0.080)和左右整个面部(p=0.051)中存在增加趋势。
    结论:这些初步结果表明,PMS干预可以增加FP卒中患者的面部皮肤血流量。可以进行进一步的随机对照试验以探索其可能的临床疗效。
    BACKGROUND: Facial paralysis (FP) is a common symptom after stroke, which influences the quality of life and prognosis of patients. Recently, peripheral magnetic stimulation (PMS) shows potential effects on peripheral and central nervous system damage. However, the effect of PMS on FP after stroke is still unclear.
    METHODS: In this study, we applied PMS on the facial nerve of nine stroke patients with FP. At the same time, laser speckle contrast imaging (LSCI) was used to explore the facial skin blood flow (SkBF) in 19 healthy subjects and nine stroke patients with FP before and after the PMS intervention. The whole face was divided into 14 regions to compare the SkBF in different sub-areas.
    RESULTS: In baseline SkBF, we found that there were no significant differences in the SkBF between the left and right faces in the healthy subjects. However, there was a significant difference in the SkBF between the affected and unaffected faces in Region 7 (Chin area, p = 0.046). In the following five minutes after the PMS intervention (Pre_0-5 min), the SkBF increased in Region 5 (p = 0.014) and Region 7 (p = 0.046) and there was an increasing trend in Region 3 (p = 0.088) and Region 6 (p = 0.069). In the five to ten minutes after the intervention (Post_6-10 min), the SkBF increased in Region 5 (p = 0.009), Region 6 (p = 0.021) and Region 7 (p = 0.023) and there was an increasing trend in Region 3 (p = 0.080) and left and right whole face (p = 0.051).
    CONCLUSIONS: These pilot results indicate that PMS intervention could increase facial skin blood flow in stroke patients with FP. A further randomized controlled trial can be performed to explore its possible clinical efficacy.
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