The Facilitative Effects of Left-side Vagus Nerve Magnetic Modulation on Upper Extremity Motor Function in Stroke Patients

The Facilitative Effects of Left-side Vagus Nerve Magnetic Modulation on Upper Extremity Motor Function in Stroke Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Facilitative Effects of Left-side Vagus Nerve Magnetic Modulation on Upper Extremity Motor Function in Stroke Patients Xia-Hua Liu, Nan-Nan Zhang, Ting Gao, Ke-Ling Cheng, Zhi-Yong Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7229219/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and Objectives: This study aimed to conducted a clinical trial to evaluate the safety and feasibility of Vague Nerve Magnetic Modulation (VNMM) treatment on upper extremity motor function in stroke patients. Methods: A total of 44 stroke patients with upper extremity motor impairment were enrolled and randomly assigned to either a real VNMM group (N = 22) or a sham VNMM group (N = 22). The intervention consisted of 5-Hz VNMM applied to the left vagus nerve, which administered five days per week for a duration of four weeks. All patients underwent evaluations including Fugl-Meyer Assessment Upper Extremity (FMA-UE), the Wolf Motor Function Test (WMFT), the Functional Independence Measure (FIM) and parameters of Motor-evoked potentials (MEPs) at baseline and post-intervention. Results: All participants tolerated the intervention well throughout the study. The findings demonstrated that a four-week course of VNMM was feasible for addressing upper extremity motor impairment in stroke patients. Significant improvements were noted in all outcome measures in both the real and sham VNMM groups. However, the magnitude of improvement was significantly greater in the real VNMM group compared to the sham VNMM group ( P < 0.001). Analysis of covariance further confirmed that the improvements in all outcomes were more pronounced in the real VNMM group following treatment compared to the sham group. Notably, neither disease duration nor baseline disease severity was found to correlate with the efficacy of VNMM. Conclusion: Our study concluded that VNMM represents a safe and feasible treatment option for stroke patients with upper extremity motor dysfunction. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Stroke, a prevalent cerebrovascular disease in clinical settings, ranks as one of the leading causes of mortality and disability on a global scale 1 . Upper extremity motor impairment is one of the commonest symptoms after stroke, manifesting in approximately 80% of individuals who have experienced an acute stroke event. Although a significant proportion of stroke survivors exhibit considerable spontaneous recovery, as many as 50–60% still experience persistent long-term problems six months post-stroke 2 – 4 . This significantly diminishes the quality of life in stroke patients, therefore, enhancing upper extremity motor function constitutes a core component of stroke rehabilitation 5 . The current treatment for upper extremity motor impairment typically encomprises intensive, high-dose, goal directed, and repetitive rehabilitations or occasionally involves methods such as constraint-induced movement therapy and electrical stimulation 6 . However, given the limited efficacy of these existing therapies, there is an urgent need for novel and more effective treatment strategies 7 – 8 . Vagus nerve modulation (VNM) has emerged as a promising brain stimulation-based priming technique, which involves a variety of stimulation modalities applied to the vagus nerve network. In the context of ischemic stroke, VNM has garnered increasing attention 9 . One form of VNM is vagus nerve stimulation (VNS), which utilizes either implanted or transcutaneous electrodes. Accumulating evidence has gradually demonstrated that VNS can efficiently facilitate motor function recovery in stroke patients 10 – 13 . Studies have demonstrated that the application of VNS during motor training in rats with ischemic stroke can significantly enhance forelimb motor recovery. Moreover, this intervention has been shown to induce input-specific reorganization of cortical neurons in rats 14 – 15 . A multicenter, randomized, double-blind trial conducted by Dawson et al. has confirmed the efficacy of implantable vagus nerve stimulation (iVNS) combined with upper extremity motor training in stroke patients 16 . Moreover, several studies have integrated transcutaneous auricular vagus nerve stimulation (taVNS) with conventional rehabilitation training or robot-assisted arm training to enhance upper extremity motor function in hemiplegic patients, and these combinations have been proven to be effective 17 – 19 . Thus, whether it is invasive or non-invasive, VNS appears to be a potential option in terms of safety and efficacy for addressing upper extremity motor impairment following stroke. Additionally, another noninvasive form of VNS is Vagus Nerve Magnetic Modulation (VNMM), which involves repetitive magnetic stimulation of the extracranial vagus nerve. Studies have demonstrated that VNMM can enhance swallowing function in stroke patients, improve consciousness states in patients with disorders of consciousness, and ameliorate cognitive dysfunction in patients with traumatic brain injury 20 – 22 . In addition, animal studies have also highlighted the promising potential of VNMM as a treatment strategy for myocardial ischemia-reperfusion injury in rats. Emerging neuroimaging evidence has demonstrated that non-invasive VNM contributes to the improvement of clinical outcomes, likely by mimicking the direct brain effects of iVNS 23 – 26 . Thus, the application of VNMM in neurorehabilitation can offer similar therapeutic effects to conventional VNS without the need for surgical implantation, thereby circumventing the potential risks associated with surgical complications. However, to the best of our knowledge, there have been no prior reports regarding the application of VNMM for facilitating upper extremity motor recovery in stroke survivors. Given the promising effects of VNS on poststroke motor recovery and the established safety and feasibility of VNMM in treating other neurological disorders, we hypothesize that VNMM may facilitate recovery from upper extremity motor dysfunction in stroke survivors. Based on these premises, this study employed VNMM to treat stroke patients with upper extremity motor impairment. The primary objectives were to observe the safety and feasibility of VNMM in stroke patients and to determine whether it could serve as a potential adjunct to upper extremity rehabilitation protocols. Method Participants Between March 2023 and April 2025, we consecutively recruited 50 stroke patients with upper extremity motor dysfunction at the Department of Rehabilitation Medicine, the First Affiliated Hospital of Fujian Medical University. Following screening based on the inclusion and exclusion criteria, 44 patients were randomized into two groups. A total of six participants were excluded from our study, among whom five did not meet the inclusion criteria, and one declined to participate. The inclusion criteria were as follows: (1) First occurrence of a unilateral supratentorial stroke (aged ≥ 18 and ≤ 80 years), confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) within 6 months of onset; (2) Presence of unilateral upper extremity hemiplegia; and (3) Normal cognitive function, with the ability to follow instructions and complete the study. Patients were excluded based on the following criteria: (1) Previous impairment of the vagus nerve; (2) Current use of any other stimulation device, such as a pacemaker or other neurostimulator; (3) Medical or mental instability; (4) Upper extremity motor dysfunction caused by reasons other than stroke; (5) Severe consciousness disorders or cognitive impairment, rendering the patient unable to cooperate with treatment; (6) Botulinum toxin injections or other non-study active rehabilitation of the upper limb within the past 3 months; (7) Use of neuropsychotropic drugs, such as antidepressants or benzodiazepines. VNMS Intervention Protocol A randomized, double-blind, sham-controlled clinical trial was conducted. A total of 44 eligible participants were assigned to the real VNMM group and the sham VNMM group at a 1:1 ratio using stratified randomization with gender and age as factors. A brief flowchart of the entire study is shown in Fig. 1. A commercially available stimulator (YIRUIDE Mag-TD, YRD Co, Ltd, Wuhan, China) was utilized for stimulation in both groups. A 99-mm figure-of-eight coil was positioned over the left mastoid process to target the vagus nerve proximal to its exit from the skull through the jugular foramen. The stimulus coil was oriented tangentially to the mastoid for the real intervention, whereas it was positioned vertically to the mastoid for the sham intervention (Fig. 2). Prior to stimulation, the participants’ resting motor threshold (RMT) was determined, which is defined as the minimum intensity required to elicit a motor-evoked potential. The stimulation protocol consisted of a frequency of 5Hz, with 10 seconds of stimulation followed by a 10-second interval, totaling 1800 pulses. This regimen was administered once daily for 5 days per week over a 4-week treatment period. The stimulation intensity was individually adjusted to a tolerable level for each patient, ensuring that it did not exceed 120% of the RMT. Outcome measurements The primary outcome measure was the change score of the Fugl-Meyer Assessment-Upper Extremity (FMA-UE). The FMA-UE is a widely used tool for evaluating upper extremity motor impairment and coordination/speed in stroke patients. The FMA-UE comprises 33 items, each scored on a scale ranging from 0 to 2, culminating in a maximum total score of 66 points. The secondary outcome measurements included the Wolf Motor Function Test (WMFT), Functional Independence Measure (FIM), and Motor-Evoked Potentials (MEPs) examination. First, the WMFT is a standardized observational scale extensively used to assess upper extremity function during task-oriented activities. The WMFT comprises 15 items, including six upper limb movements and nine functional tasks. Each item is scored on a 6-point ordinal scale ranging from 0 to 5, with a maximum possible total score of 75. Second, the FIM is a comprehensive method for assessing patients' ability to perform activities of daily living and their capacity for self-care and community living. The FIM comprises six domains, totaling 18 items. Each item is rated on a 7-point scale, ranging from 1 (total assistance required) to 7 (complete independence), with a maximum possible total score of 126 points. Finally, all participants underwent a Transcranial Magnetic Stimulation (TMS)-induced MEP session to assess the corticospinal excitability of the hand motor cortices and the integrity of the corticospinal conduction pathway 27 – 28 . We recorded MEP parameters, including the resting motor threshold (RMT), MEP latency, and central motor conduction time (CMCT) 29 – 30 . MEP latency refers to the interval between the stimulation of the motor cortex and the onset of the motor response, while CMCT denotes the conduction time from the cerebral cortex to the anterior horn alpha motor neurons of the spinal cord. The examination procedure in this study was conducted in accordance with established practice guidelines 31 . The examination was well tolerated by all participants without any adverse events. All primary and secondary outcomes will be assessed at baseline and after 4 weeks of intervention. Both participants and the study staff responsible for outcome assessment were blinded to the intervention arm. All assessments were conducted by trained research assistants who were unaware of whether the patients were receiving the intervention or sham treatments. Safety evaluation We evaluated and recorded patients for adverse effects, including changes in heart rate, nausea, local pain at the stimulation site, neck pain, muscular neck stiffness, headache, psychotic symptoms, seizure, and transient hearing changes, before and after each stimulation session. This was done to assess safety and was documented on a case report form (CRF). In the event of any adverse event, the coaches or project managers would provide the corresponding treatment to the participant. Statistical analysis For all analyses, data normality was assessed using the Shapiro-Wilk Test. For comparisons of demographic data between the real and sham intervention groups, a Chi-square Test was used to evaluate gender distribution and side of hemiplegia, while continuous variables were compared using the Independent Samples T-test for normally distributed data or the Mann-Whitney U Test for non-normally distributed data. To determine the effect of VNMM on upper extremity motor function, we used the paired-sample t-test for normally distributed data or the Wilcoxon Signed-Rank test for non-normally distributed data to compare pre- and post-stimulation data (including FMA-UE, WMFT, FIM, MEP, CMCT, and RMT) within the real and sham VNMM groups separately. An Independent Samples T-test was conducted for normally distributed data, or the Mann-Whitney U Test for non-normally distributed data, to compare the differences in pre- and post-treatment values, as well as the improvement ratios of outcomes (including FMA-UE, WMFT, FIM, MEP, CMCT, and RMT) after treatment between the real and sham VNMM groups. The improvement ratio was defined as the quotient of the difference value before and after intervention divided by the baseline value (before intervention). To ensure the reliability of the results, analysis of covariance (ANCOVA) was employed to adjust the model, with the post-treatment index as the dependent variable, the group as the independent variable, and the pre-treatment index as the covariate. To explore predictors of treatment response, correlation analyses were conducted in the real stimulation group to examine the relationship between disease duration and the VNMM treatment effect (post-treatment change in functional scores), as well as between baseline disease severity (FMA-UE score pre-treatment) and the treatment effect. Pearson’s correlation analysis was used for normally distributed data, while Spearman’s correlation analysis was employed for non-normally distributed data. Statistical analyses were conducted using SPSS 26.0 (IBM Co., Inc., Chicago, IL, USA), with significance set at P < 0.05. All graphs were produced using GraphPad Prism. Results A total of 44 patients participated in this study, with each group (real VNMM group and sham VNMM group) comprising 22 participants. No participant dropped out of the study in either group. No adverse events were reported throughout the entire duration of the study, indicating that both the real and sham VNMM interventions were well-tolerated. The demographic and clinical characteristics of all participants are summarized in Table 1. There were no significant differences between the two treatment groups in terms of age, gender distribution, lesion side, disease duration, FMA-UE, WMFT, FIM, MEP, CMCT, and RMT (P > 0.05). (Tables 1–2) For the primary outcome measure (FMA-UE scores), as shown in Table 2, our results indicated that FMA-UE scores were significantly improved post-stimulation in both the real and sham VNMM groups ( P < 0.001). To further analyze the difference between the real and sham VNMM groups, an Independent Samples T-test was conducted to compare the difference in FMA-UE scores after treatment. This revealed that the increase in FMA-UE scores was significantly greater in the real stimulation group than in the sham stimulation group ( P = 0.018). After adjusting for confounding factors using analysis of covariance (ANCOVA), the FMA-UE score of the real VNMM group post-treatment was significantly higher than that of the sham VNMM group, indicating a significant difference and superior treatment effect in the real VNMM group (F = 68.827, P < 0.001). We also found that the real VNMM group had a significantly greater improvement ratio in FMA-UE than the sham VNMM group (Fig. 3). The effects of VNMM on secondary outcomes mirrored the pattern observed for the FMA-UE scores, as shown in Table 2 and Fig. 4. Statistically significant differences were found in the changes of WMFT, FIM, MEP, CMCT, and RMT between pre- and post-stimulation in both the real and sham VNMM groups ( P < 0.05). A significant improvement was observed in the real VNMM group compared to the sham VNMM group after treatment (WMFT: F = 48.291, P < 0.001; FIM: F = 133.481, P < 0.001; MEP: F = 90.368, P < 0.001; CMCT: F = 58.834, P < 0.001; RMT: F = 8.987, P = 0.005). Correlation analyses did not identify statistically significant associations between disease duration and the effect of VNMM, nor between baseline disease severity and the effect of VNMM in the real VNMM group. (Tables 3.) Disscussion This preliminary clinical research aimed to evaluate the safety and feasibility of VNMM in facilitating the recovery of upper extremity motor function in stroke patients. Recent evidence has highlighted the promising potential of VNMM as a treatment strategy for several clinical neurological disorders, as well as in animal models. In this study, compared to the sham VNMM group, the real VNMM group exhibited significant improvements in FMA-UE, WMFT, FIM scores, and MEP parameters. Therefore, our study demonstrated that VNMM significantly improved upper extremity motor symptoms in stroke patients. Furthermore, the protocol for VNMM in our research appears safe, as no severe adverse events related to VNMM were reported in the patients. Several studies have investigated the impact of the laterality effects of VNM in humans. Based on the asymmetrical innervation of the heart by the left and right vagus nerves, global regulatory approval for VNM is currently limited to implantation on the left vagus nerve only 32 – 34 . Previous studies have also demonstrated that left-sided VNM, when combined with hemiplegic limb training, can improve motor function in stroke patients as well as in rat stroke models 12 – 13 、 35 – 36 . However, there are also differing viewpoints regarding the laterality effects of VNM. Premchand et al. demonstrated that both left- and right-sided VNS were equally effective and safe 37 . In contrast, Peng X et al. revealed that, in a stroke population, ipsilesional taVNS provided the largest direct brain activation 38 . Moreover, a recent retrospective case series identified only four studies reporting right-sided VNS in a total of seven patients, suggesting that right-sided VNS may be safe and effective but potentially less tolerable than left-sided VNS 39 . Additionally, Sims et al. indicated that mastoid stimulation can be a reliable method for vagus nerve assessment due to its anatomic accessibility 40 . Thus, in our study, we chose the left vagus nerve, targeted at the mastoid, as the stimulation site to avoid any unexpected safety risks. No adverse effects were documented in either the real or sham VNMM interventions throughout our study. The rationale for using the VNMM parameters in the present study was based on meta-parameters derived from relevant studies 22 , 41 – 42 . We applied a frequency of 5 Hz for magnetic stimulation of the vagus nerve, which did not cause discomfort due to the contraction of the sternocleidomastoid muscle. The intensity of the intervention was set according to the patient’s maximum tolerable intensity 22 . In our study, we observed improvements in motor capacity as measured by the FMA-UE, WMFT, and FIM in both the real and sham VNMM groups. The improvement in the sham VNMM group may be attributed to the sound generated by the sham stimulus, which closely resembles that of the real stimulus. This similarity in auditory feedback could potentially trigger psychological factors in patients, thereby producing therapeutic effects. However, patients in the real VNMM group demonstrated significantly greater improvements in upper extremity motor function, suggesting that 5 Hz VNMM can enhance upper extremity motor function and functional performance in daily life for hemiplegic patients post-stroke. This finding is consistent with previous research 43 – 45 . For instance, Wang MH et al. demonstrated that patients with subacute stroke receiving taVNS treatment exhibited greater improvements in FMA-UE and activities of daily living scores compared to the sham group 45 . VNMM is a novel form of neuromodulation that delivers magnetic pulses to the cervical bundle of the vagus nerve. The application of VNMM for enhancing upper extremity motor function in stroke patients is theorized to occur through the activation of the ascending neuromodulatory network. This network releases plasticity-promoting neuromodulators, such as acetylcholine and norepinephrine, throughout the cortex 46 . MEP, CMCT and RMT can predict the prognosis of stroke patients and are related to the excitability of the motor cortex, motor recovery, and the improvement of corticospinal tract conduction 28 , 47 – 48 . In this study, we examined the MEPs, CMCT, and RMT of the motor cortex to reflect changes in brain plasticity before and after treatment in patients. It was found that, after treatment, the MEP, CMCT, and RMT of the real VNMM group were significantly improved compared with the sham VNMM group. This suggests a trend toward increased cortical excitability in the primary motor cortex (M1). With respect to the correlation between motor function improvement and changes in MEPs, studies have shown incongruent results. Choi et al. 49 and Kim et al. 50 indicated that changes in MEPs are significantly associated with baseline disease severity. However, in this study, we were unable to reproduce the relationship between changes in MEP and motor functional outcomes, such as FMA-UE scores, which is consistent with the findings of Jo JY et al 30 . Given the limited mechanistic understanding of VNMS in upper extremity motor function in stroke patients and the preliminary nature of our exploration of the intervention's effects, potential biases in the results may arise from confounding factors not yet considered. Therefore, neurophysiological methods such as functional magnetic resonance imaging (fMRI) or functional near-infrared spectroscopy (fNIRS) are warranted for a more in-depth investigation of the underlying mechanisms. Despite the valuable insights gained from this study, we acknowledge that the present study has several limitations. First, tangential coil stimulation may elicit more muscle contraction and a larger noise sensation compared to vertical coil stimulation, thereby potentially producing a stronger placebo effect in the real stimulation group than in the sham stimulation group. Second, the absence of follow-up after the study prevented the measurement of the sustained effects of VNMM in this study. Third, future studies should consider incorporating brain neurotransmitter measurements or neurophysiological methods, which are more specific for exploring the mechanism of VNMM on brain network remodeling in stroke patients. Conclusion In summary, the present study suggests that 5 Hz VNMM administered over the mastoid of the left vagus nerve is effective in improving upper extremity motor function in stroke patients and is well-tolerated. Our study provides evidence that left-side VNMM can be utilized as a therapeutic method for stroke patients. Future studies may further explore the mechanisms underlying the effects of VNMM on brain network remodeling in stroke patients. Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University (Approval Number: MRCTA, ECFAH of FMU [2022]409) and registered in the Chinese Clinical Trial Registry (Registration Number: ChiCTR2400082767). Written informed consent was obtained from all participants or their legal guardians prior to enrollment. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding This work was supported by the Natural Science Fundation of Fujian Province (No.2023J01603, Fujian; X-H-L) and Joint Funds for the Innovation of Science and Technology, Fujian Province (No.2024Y9141, Fujian; X-H-L). This work was also supported by Joint Funds for the Innovation of Science and Technology, Fujian Province (No.2021Y9105, Fujian; Z-Y-W). Author Contribution XHL, ZYW, and KLC formulated and designed the study concept; XHL, ZYW, and KLC analyzed the data and manuscript drafting or manuscript revision for important intellectual content; XHL and KLC enrolled the patients and conducted clinical assessments; NNZ and TG conducted clinical interventions; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors. Acknowledgments The authors would like to thank the kind patients, families, caregivers, and members who participated in this research. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. References GBD 2021 Diabetes Collaborators. 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Epilepsy Res. 1995;20(3):221–7. 10.1016/0920-1211(94)00083-9 . Morris GL 3rd, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05 [published correction appears in Neurology. 2000;54(8):1712]. Neurology. 1999;53(8):1731–1735. 10.1212/wnl.53.8.1731 Hays SA, Khodaparast N, Ruiz A, et al. The timing and amount of vagus nerve stimulation during rehabilitative training affect poststroke recovery of forelimb strength. NeuroReport. 2014;25(9):676–82. 10.1097/WNR.0000000000000154 . Xie YL, Wang S, Wu Q, Chen X. Vagus nerve stimulation for upper limb motor impairment after ischemic stroke: a meta-analysis. Medicine. 2021;100(46):e27871. 10.1097/MD.0000000000027871 . Premchand RK, Sharma K, Mittal S, et al. Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial. J Card Fail. 2014;20(11):808–16. 10.1016/j.cardfail.2014.08.009 . Peng X, Baker-Vogel B, Sarhan M, et al. Left or right ear? A neuroimaging study using combined taVNS/fMRI to understand the interaction between ear stimulation target and lesion location in chronic stroke. Brain Stimul. 2023;16(4):1144–53. 10.1016/j.brs.2023.07.050 . Zanello M, Voges B, Chelvarajah R, et al. Right-sided vagus nerve stimulation: Worldwide collection and perspectives. Ann Clin Transl Neurol. 2025;12(3):565–76. 10.1002/acn3.52312 . Sims HS, Yamashita T, Rhew K, Ludlow CL. Assessing the clinical utility of the magnetic stimulator for measuring response latencies in the laryngeal muscles. Otolaryngol Head Neck Surg. 1996;114(6):761–7. 10.1016/S0194-59989670099-2 . Aziz Q, Rothwell JC, Barlow J, et al. Esophageal myoelectric responses to magnetic stimulation of the human cortex and the extracranial vagus nerve. Am J Physiol. 1994;267(5 Pt 1):G827–35. 10.1152/ajpgi.1994.267.5.G827 . Vespa S, Stumpp L, Bouckaert C, et al. Vagus Nerve Stimulation-Induced Laryngeal Motor Evoked Potentials: A Possible Biomarker of Effective Nerve Activation. Front Neurosci. 2019;13:880. 10.3389/fnins.2019.00880 . Published 2019 Aug 27. Chang JL, Coggins AN, Saul M, et al. Transcutaneous Auricular Vagus Nerve Stimulation (tAVNS) Delivered During Upper Limb Interactive Robotic Training Demonstrates Novel Antagonist Control for Reaching Movements Following Stroke. Front Neurosci. 2021;15:767302. 10.3389/fnins.2021.767302 . Published 2021 Nov 25. Li JN, Xie CC, Li CQ, et al. Efficacy and safety of transcutaneous auricular vagus nerve stimulation combined with conventional rehabilitation training in acute stroke patients: a randomized controlled trial conducted for 1 year involving 60 patients. Neural Regen Res. 2022;17(8):1809–13. 10.4103/1673-5374.332155 . Wang MH, Wang YX, Xie M, et al. Transcutaneous auricular vagus nerve stimulation with task-oriented training improves upper extremity function in patients with subacute stroke: a randomized clinical trial. Front Neurosci. 2024;18:1346634. 10.3389/fnins.2024.1346634 . Published 2024 Mar 8. Attenello F, Amar AP, Liu C, Apuzzo ML. Theoretical Basis of Vagus Nerve Stimulation. Prog Neurol Surg. 2015;29:20–8. 10.1159/000434652 . Cakar E, Akyuz G, Durmus O, et al. The relationships of motor-evoked potentials to hand dexterity, motor function, and spasticity in chronic stroke patients: a transcranial magnetic stimulation study. Acta Neurol Belg. 2016;116(4):481–7. 10.1007/s13760-016-0633-2 . Veldema J, Nowak DA, Gharabaghi A. Resting motor threshold in the course of hand motor recovery after stroke: a systematic review. J Neuroeng Rehabil. 2021;18(1):158. 10.1186/s12984-021-00947-8 . Published 2021 Nov 3. Choi TW, Jang SG, Yang SN, Pyun SB. Factors affecting the motor evoked potential responsiveness and parameters in patients with supratentorial stroke. Ann Rehabil Med. 2014;38(1):19–28. 10.5535/arm.2014.38.1.19 . Kim GW, Won YH, Park SH, Seo JH, Ko MH. Can motor evoked potentials be an objective parameter to assess extremity function at the acute or subacute stroke stage? Ann Rehabil Med. 2015;39(2):253–61. 10.5535/arm.2015.39.2.253 . Tables Table 1. Demographic and clinical characteristics of all patients Real rTMS sham rTMS P Patients, N 22 22 NA Gender (male/female) 15/7 11/11 0.220 a Age，years 61.27±11.49 63.77±14.73 0.358 b Time since stroke，days 21.27±8.64 27.45±15.56 0.353 b Lesion side, N (%)(Right/Left/） 10/12 9/13 0.761 a Continuous data are expressed as the mean ± standard deviation. a Chi-square test b Mann-Whitney U -test Table 2. The comparison of scores before and after stimulation in the real and sham intervention groups Real rTMS Sham rTMS P value a P value b P value c P value d Variables Baseline Post rTMS Baseline Post rTMS FMA-UE 23.68±17.07 39.32±17.31 25.82±15.29 27.32±15.06 0.742 e < 0.001 g < 0.001 g 0.018 f WMFT 23.27±14.78 37.82±19.01 23.41±13.27 24.68±12.93 0.860 e < 0.001 g < 0.001 g 0.032 e FIM 60.77±20.08 82.77±19.63 63.14±21.90 64.82±21.35 0.711 f < 0.001 g 0.013 g 0.006 f MEP 23.77±1.65 20.93±1.14 23.23±1.89 22.98±1.84 0.321 f < 0.001 g < 0.001 g < 0.001 f CMCT 13.69±1.22 11.10±1.09 13.60±1.78 13.07±1.70 0.844 f < 0.001 g < 0.001 g < 0.001 e RMT 52.64±13.08 46.82±11.81 55.68±15.06 54.73±15.02 0.478 e 0.008 g 0.002 g 0.018 e FMA-UE = Fugl-Meyer Assessment Scale for Upper Extremity; WMFT = Wolf Motor Function Test; FIM = Functional Independence Measurement; MEP = Motor Evoked Potentials ; CMCT= Central Motor Conduction Time; RMT = Resting Motor Threshold. Continuous data are expressed as mean ± standard deviation . a Comparison between groups (pre-stimulation). b Pre-stimulation vs. post-stimulation in real rTMS. c Pre-stimulation vs. post-stimulation in sham rTMS. d Comparison of differences between groups (real vs. sham group). e Mann-Whitney U -test. f Independent samples t -test. g Paired-samples t test. Bold values showed significance. Table 3.The investigation of the predictors in the effect of rTMS. disease duration baseline disease severity Variables r p r p ΔFMA-UE 0.283 0.202 0.056 0.805 ΔWMFT -0.282 0.204 0.299 0.177 ΔFIM -0.159 0.481 -0.124 0.583 ΔMEP 0.369 0.091 0.253 0.257 ΔCMCT 0.276 0.214 0.045 0.841 ΔRMT 0.082 0.718 0.328 0.137 Δ means Changes in scores before and after treatment. FMA-UE = Fugl-Meyer Assessment Scale for Upper Extremity; WMFT = Wolf Motor Function Test; FIM = Functional Independence Measurement; MEP = Motor Evoked Potentials ; CMCT= Central Motor Conduction Time; RMT = Resting Motor Threshold. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7229219","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":500278125,"identity":"d772319d-6c0f-4c06-b088-327a6980b47f","order_by":0,"name":"Xia-Hua Liu","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xia-Hua","middleName":"","lastName":"Liu","suffix":""},{"id":500278126,"identity":"703cee11-ff08-46d1-aa80-9d6e92a0809c","order_by":1,"name":"Nan-Nan Zhang","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Nan-Nan","middleName":"","lastName":"Zhang","suffix":""},{"id":500278129,"identity":"06da3648-7292-407a-954c-38139082c265","order_by":2,"name":"Ting Gao","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Gao","suffix":""},{"id":500278132,"identity":"2033f87b-c281-40bd-928f-8d9b5b70d79a","order_by":3,"name":"Ke-Ling Cheng","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ke-Ling","middleName":"","lastName":"Cheng","suffix":""},{"id":500278133,"identity":"ddfd4cab-bbec-4941-a1d5-caced29069a5","order_by":4,"name":"Zhi-Yong Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIie3QMQrCMBSA4VcEXR7q+FyqFxCeFBzbsxRBV8GlY4uQXqK3EJwrAXXIAZQu7QGE3kBr0DkZBfMvL8P7CAmAy/WDDdKyB6hPWda0NgTLL0G5D8iOwIfQRozRingq4IeQEd8bAQShP09NBFQQF0r2uIpFvYVVsCwNJOqIxKTqdyRngjI+mghqwhXy/SQIbcmqu4X45lmT825RqCdPVNx9Mlu8BUke6CHW0fByaZo2CX0jAbqynjO9yab1d6O81nOa2my7XC7XX/YCnVpGZhAxMt8AAAAASUVORK5CYII=","orcid":"","institution":"Fujian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Zhi-Yong","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-07-28 03:08:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7229219/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7229219/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89560321,"identity":"95c6819a-d5a4-4ced-8ac0-1fedc75dabe8","added_by":"auto","created_at":"2025-08-21 10:18:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":33437,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"figure51.png","url":"https://assets-eu.researchsquare.com/files/rs-7229219/v1/cacda9b38b69377cfa7767dd.png"},{"id":89560322,"identity":"c485fc94-2ab5-4cf1-b374-e33926ee1c67","added_by":"auto","created_at":"2025-08-21 10:18:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":399716,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"figure52.png","url":"https://assets-eu.researchsquare.com/files/rs-7229219/v1/cbe3744cbd7bb7820ed83a42.png"},{"id":89564413,"identity":"e3eda16d-9da9-4ac7-ad57-60b0b47b5a91","added_by":"auto","created_at":"2025-08-21 10:34:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":185400,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"figure53.png","url":"https://assets-eu.researchsquare.com/files/rs-7229219/v1/526ca27cf8896ef3968594b9.png"},{"id":89560328,"identity":"c07fc48e-8959-4249-89d9-c932da537da1","added_by":"auto","created_at":"2025-08-21 10:18:53","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":184060,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"figure54.png","url":"https://assets-eu.researchsquare.com/files/rs-7229219/v1/2ece13bf900a9cc3680461aa.png"},{"id":94473807,"identity":"df926e09-a2bc-486c-89a3-a9d647ded685","added_by":"auto","created_at":"2025-10-27 15:45:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1726342,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7229219/v1/8cb487da-7e39-4fda-bb01-3c62d8c8062d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Facilitative Effects of Left-side Vagus Nerve Magnetic Modulation on Upper Extremity Motor Function in Stroke Patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eStroke, a prevalent cerebrovascular disease in clinical settings, ranks as one of the leading causes of mortality and disability on a global scale\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Upper extremity motor impairment is one of the commonest symptoms after stroke, manifesting in approximately 80% of individuals who have experienced an acute stroke event. Although a significant proportion of stroke survivors exhibit considerable spontaneous recovery, as many as 50–60% still experience persistent long-term problems six months post-stroke\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e–\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. This significantly diminishes the quality of life in stroke patients, therefore, enhancing upper extremity motor function constitutes a core component of stroke rehabilitation\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. The current treatment for upper extremity motor impairment typically encomprises intensive, high-dose, goal directed, and repetitive rehabilitations or occasionally involves methods such as constraint-induced movement therapy and electrical stimulation\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, given the limited efficacy of these existing therapies, there is an urgent need for novel and more effective treatment strategies\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eVagus nerve modulation (VNM) has emerged as a promising brain stimulation-based priming technique, which involves a variety of stimulation modalities applied to the vagus nerve network. In the context of ischemic stroke, VNM has garnered increasing attention\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. One form of VNM is vagus nerve stimulation (VNS), which utilizes either implanted or transcutaneous electrodes. Accumulating evidence has gradually demonstrated that VNS can efficiently facilitate motor function recovery in stroke patients\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e–\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Studies have demonstrated that the application of VNS during motor training in rats with ischemic stroke can significantly enhance forelimb motor recovery. Moreover, this intervention has been shown to induce input-specific reorganization of cortical neurons in rats\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e–\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. A multicenter, randomized, double-blind trial conducted by Dawson et al. has confirmed the efficacy of implantable vagus nerve stimulation (iVNS) combined with upper extremity motor training in stroke patients\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Moreover, several studies have integrated transcutaneous auricular vagus nerve stimulation (taVNS) with conventional rehabilitation training or robot-assisted arm training to enhance upper extremity motor function in hemiplegic patients, and these combinations have been proven to be effective\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Thus, whether it is invasive or non-invasive, VNS appears to be a potential option in terms of safety and efficacy for addressing upper extremity motor impairment following stroke. Additionally, another noninvasive form of VNS is Vagus Nerve Magnetic Modulation (VNMM), which involves repetitive magnetic stimulation of the extracranial vagus nerve. Studies have demonstrated that VNMM can enhance swallowing function in stroke patients, improve consciousness states in patients with disorders of consciousness, and ameliorate cognitive dysfunction in patients with traumatic brain injury\u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e–\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In addition, animal studies have also highlighted the promising potential of VNMM as a treatment strategy for myocardial ischemia-reperfusion injury in rats. Emerging neuroimaging evidence has demonstrated that non-invasive VNM contributes to the improvement of clinical outcomes, likely by mimicking the direct brain effects of iVNS\u003csup\u003e\u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e–\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Thus, the application of VNMM in neurorehabilitation can offer similar therapeutic effects to conventional VNS without the need for surgical implantation, thereby circumventing the potential risks associated with surgical complications. However, to the best of our knowledge, there have been no prior reports regarding the application of VNMM for facilitating upper extremity motor recovery in stroke survivors.\u003c/p\u003e\u003cp\u003eGiven the promising effects of VNS on poststroke motor recovery and the established safety and feasibility of VNMM in treating other neurological disorders, we hypothesize that VNMM may facilitate recovery from upper extremity motor dysfunction in stroke survivors. Based on these premises, this study employed VNMM to treat stroke patients with upper extremity motor impairment. The primary objectives were to observe the safety and feasibility of VNMM in stroke patients and to determine whether it could serve as a potential adjunct to upper extremity rehabilitation protocols.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003e\u003cb\u003eParticipants\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBetween March 2023 and April 2025, we consecutively recruited 50 stroke patients with upper extremity motor dysfunction at the Department of Rehabilitation Medicine, the First Affiliated Hospital of Fujian Medical University. Following screening based on the inclusion and exclusion criteria, 44 patients were randomized into two groups. A total of six participants were excluded from our study, among whom five did not meet the inclusion criteria, and one declined to participate. The inclusion criteria were as follows: (1) First occurrence of a unilateral supratentorial stroke (aged ≥ 18 and ≤ 80 years), confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) within 6 months of onset; (2) Presence of unilateral upper extremity hemiplegia; and (3) Normal cognitive function, with the ability to follow instructions and complete the study. Patients were excluded based on the following criteria: (1) Previous impairment of the vagus nerve; (2) Current use of any other stimulation device, such as a pacemaker or other neurostimulator; (3) Medical or mental instability; (4) Upper extremity motor dysfunction caused by reasons other than stroke; (5) Severe consciousness disorders or cognitive impairment, rendering the patient unable to cooperate with treatment; (6) Botulinum toxin injections or other non-study active rehabilitation of the upper limb within the past 3 months; (7) Use of neuropsychotropic drugs, such as antidepressants or benzodiazepines.\u003c/p\u003e\u003cp\u003e\u003cb\u003eVNMS Intervention Protocol\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA randomized, double-blind, sham-controlled clinical trial was conducted. A total of 44 eligible participants were assigned to the real VNMM group and the sham VNMM group at a 1:1 ratio using stratified randomization with gender and age as factors. A brief flowchart of the entire study is shown in Fig.\u0026nbsp;1.\u003c/p\u003e\u003cp\u003eA commercially available stimulator (YIRUIDE Mag-TD, YRD Co, Ltd, Wuhan, China) was utilized for stimulation in both groups. A 99-mm figure-of-eight coil was positioned over the left mastoid process to target the vagus nerve proximal to its exit from the skull through the jugular foramen. The stimulus coil was oriented tangentially to the mastoid for the real intervention, whereas it was positioned vertically to the mastoid for the sham intervention (Fig.\u0026nbsp;2). Prior to stimulation, the participants’ resting motor threshold (RMT) was determined, which is defined as the minimum intensity required to elicit a motor-evoked potential. The stimulation protocol consisted of a frequency of 5Hz, with 10 seconds of stimulation followed by a 10-second interval, totaling 1800 pulses. This regimen was administered once daily for 5 days per week over a 4-week treatment period. The stimulation intensity was individually adjusted to a tolerable level for each patient, ensuring that it did not exceed 120% of the RMT.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcome measurements\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe primary outcome measure was the change score of the Fugl-Meyer Assessment-Upper Extremity (FMA-UE). The FMA-UE is a widely used tool for evaluating upper extremity motor impairment and coordination/speed in stroke patients. The FMA-UE comprises 33 items, each scored on a scale ranging from 0 to 2, culminating in a maximum total score of 66 points.\u003c/p\u003e\u003cp\u003eThe secondary outcome measurements included the Wolf Motor Function Test (WMFT), Functional Independence Measure (FIM), and Motor-Evoked Potentials (MEPs) examination. First, the WMFT is a standardized observational scale extensively used to assess upper extremity function during task-oriented activities. The WMFT comprises 15 items, including six upper limb movements and nine functional tasks. Each item is scored on a 6-point ordinal scale ranging from 0 to 5, with a maximum possible total score of 75. Second, the FIM is a comprehensive method for assessing patients' ability to perform activities of daily living and their capacity for self-care and community living. The FIM comprises six domains, totaling 18 items. Each item is rated on a 7-point scale, ranging from 1 (total assistance required) to 7 (complete independence), with a maximum possible total score of 126 points. Finally, all participants underwent a Transcranial Magnetic Stimulation (TMS)-induced MEP session to assess the corticospinal excitability of the hand motor cortices and the integrity of the corticospinal conduction pathway\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e–\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. We recorded MEP parameters, including the resting motor threshold (RMT), MEP latency, and central motor conduction time (CMCT)\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e–\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. MEP latency refers to the interval between the stimulation of the motor cortex and the onset of the motor response, while CMCT denotes the conduction time from the cerebral cortex to the anterior horn alpha motor neurons of the spinal cord. The examination procedure in this study was conducted in accordance with established practice guidelines\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. The examination was well tolerated by all participants without any adverse events.\u003c/p\u003e\u003cp\u003eAll primary and secondary outcomes will be assessed at baseline and after 4 weeks of intervention. Both participants and the study staff responsible for outcome assessment were blinded to the intervention arm. All assessments were conducted by trained research assistants who were unaware of whether the patients were receiving the intervention or sham treatments.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSafety evaluation\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe evaluated and recorded patients for adverse effects, including changes in heart rate, nausea, local pain at the stimulation site, neck pain, muscular neck stiffness, headache, psychotic symptoms, seizure, and transient hearing changes, before and after each stimulation session. This was done to assess safety and was documented on a case report form (CRF). In the event of any adverse event, the coaches or project managers would provide the corresponding treatment to the participant.\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eFor all analyses, data normality was assessed using the Shapiro-Wilk Test. For comparisons of demographic data between the real and sham intervention groups, a Chi-square Test was used to evaluate gender distribution and side of hemiplegia, while continuous variables were compared using the Independent Samples T-test for normally distributed data or the Mann-Whitney U Test for non-normally distributed data.\u003c/p\u003e\u003cp\u003eTo determine the effect of VNMM on upper extremity motor function, we used the paired-sample t-test for normally distributed data or the Wilcoxon Signed-Rank test for non-normally distributed data to compare pre- and post-stimulation data (including FMA-UE, WMFT, FIM, MEP, CMCT, and RMT) within the real and sham VNMM groups separately. An Independent Samples T-test was conducted for normally distributed data, or the Mann-Whitney U Test for non-normally distributed data, to compare the differences in pre- and post-treatment values, as well as the improvement ratios of outcomes (including FMA-UE, WMFT, FIM, MEP, CMCT, and RMT) after treatment between the real and sham VNMM groups. The improvement ratio was defined as the quotient of the difference value before and after intervention divided by the baseline value (before intervention). To ensure the reliability of the results, analysis of covariance (ANCOVA) was employed to adjust the model, with the post-treatment index as the dependent variable, the group as the independent variable, and the pre-treatment index as the covariate.\u003c/p\u003e\u003cp\u003eTo explore predictors of treatment response, correlation analyses were conducted in the real stimulation group to examine the relationship between disease duration and the VNMM treatment effect (post-treatment change in functional scores), as well as between baseline disease severity (FMA-UE score pre-treatment) and the treatment effect. Pearson’s correlation analysis was used for normally distributed data, while Spearman’s correlation analysis was employed for non-normally distributed data. Statistical analyses were conducted using SPSS 26.0 (IBM Co., Inc., Chicago, IL, USA), with significance set at P \u0026lt; 0.05. All graphs were produced using GraphPad Prism.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 44 patients participated in this study, with each group (real VNMM group and sham VNMM group) comprising 22 participants. No participant dropped out of the study in either group. No adverse events were reported throughout the entire duration of the study, indicating that both the real and sham VNMM interventions were well-tolerated. The demographic and clinical characteristics of all participants are summarized in Table\u0026nbsp;1. There were no significant differences between the two treatment groups in terms of age, gender distribution, lesion side, disease duration, FMA-UE, WMFT, FIM, MEP, CMCT, and RMT (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). (Tables\u0026nbsp;1\u0026ndash;2)\u003c/p\u003e\u003cp\u003eFor the primary outcome measure (FMA-UE scores), as shown in Table\u0026nbsp;2, our results indicated that FMA-UE scores were significantly improved post-stimulation in both the real and sham VNMM groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). To further analyze the difference between the real and sham VNMM groups, an Independent Samples T-test was conducted to compare the difference in FMA-UE scores after treatment. This revealed that the increase in FMA-UE scores was significantly greater in the real stimulation group than in the sham stimulation group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018). After adjusting for confounding factors using analysis of covariance (ANCOVA), the FMA-UE score of the real VNMM group post-treatment was significantly higher than that of the sham VNMM group, indicating a significant difference and superior treatment effect in the real VNMM group (F\u0026thinsp;=\u0026thinsp;68.827, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). We also found that the real VNMM group had a significantly greater improvement ratio in FMA-UE than the sham VNMM group (Fig.\u0026nbsp;3).\u003c/p\u003e\u003cp\u003eThe effects of VNMM on secondary outcomes mirrored the pattern observed for the FMA-UE scores, as shown in Table\u0026nbsp;2 and Fig.\u0026nbsp;4. Statistically significant differences were found in the changes of WMFT, FIM, MEP, CMCT, and RMT between pre- and post-stimulation in both the real and sham VNMM groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). A significant improvement was observed in the real VNMM group compared to the sham VNMM group after treatment (WMFT: F\u0026thinsp;=\u0026thinsp;48.291, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; FIM: F\u0026thinsp;=\u0026thinsp;133.481, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; MEP: F\u0026thinsp;=\u0026thinsp;90.368, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; CMCT: F\u0026thinsp;=\u0026thinsp;58.834, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; RMT: F\u0026thinsp;=\u0026thinsp;8.987, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e\u003cp\u003eCorrelation analyses did not identify statistically significant associations between disease duration and the effect of VNMM, nor between baseline disease severity and the effect of VNMM in the real VNMM group. (Tables\u0026nbsp;3.)\u003c/p\u003e"},{"header":"Disscussion","content":"\u003cp\u003eThis preliminary clinical research aimed to evaluate the safety and feasibility of VNMM in facilitating the recovery of upper extremity motor function in stroke patients. Recent evidence has highlighted the promising potential of VNMM as a treatment strategy for several clinical neurological disorders, as well as in animal models. In this study, compared to the sham VNMM group, the real VNMM group exhibited significant improvements in FMA-UE, WMFT, FIM scores, and MEP parameters. Therefore, our study demonstrated that VNMM significantly improved upper extremity motor symptoms in stroke patients. Furthermore, the protocol for VNMM in our research appears safe, as no severe adverse events related to VNMM were reported in the patients.\u003c/p\u003e\u003cp\u003eSeveral studies have investigated the impact of the laterality effects of VNM in humans. Based on the asymmetrical innervation of the heart by the left and right vagus nerves, global regulatory approval for VNM is currently limited to implantation on the left vagus nerve only\u003csup\u003e\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Previous studies have also demonstrated that left-sided VNM, when combined with hemiplegic limb training, can improve motor function in stroke patients as well as in rat stroke models\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e、\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. However, there are also differing viewpoints regarding the laterality effects of VNM. Premchand et al. demonstrated that both left- and right-sided VNS were equally effective and safe\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. In contrast, Peng X et al. revealed that, in a stroke population, ipsilesional taVNS provided the largest direct brain activation\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Moreover, a recent retrospective case series identified only four studies reporting right-sided VNS in a total of seven patients, suggesting that right-sided VNS may be safe and effective but potentially less tolerable than left-sided VNS\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Additionally, Sims et al. indicated that mastoid stimulation can be a reliable method for vagus nerve assessment due to its anatomic accessibility\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Thus, in our study, we chose the left vagus nerve, targeted at the mastoid, as the stimulation site to avoid any unexpected safety risks. No adverse effects were documented in either the real or sham VNMM interventions throughout our study.\u003c/p\u003e\u003cp\u003eThe rationale for using the VNMM parameters in the present study was based on meta-parameters derived from relevant studies\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. We applied a frequency of 5 Hz for magnetic stimulation of the vagus nerve, which did not cause discomfort due to the contraction of the sternocleidomastoid muscle. The intensity of the intervention was set according to the patient\u0026rsquo;s maximum tolerable intensity\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In our study, we observed improvements in motor capacity as measured by the FMA-UE, WMFT, and FIM in both the real and sham VNMM groups. The improvement in the sham VNMM group may be attributed to the sound generated by the sham stimulus, which closely resembles that of the real stimulus. This similarity in auditory feedback could potentially trigger psychological factors in patients, thereby producing therapeutic effects. However, patients in the real VNMM group demonstrated significantly greater improvements in upper extremity motor function, suggesting that 5 Hz VNMM can enhance upper extremity motor function and functional performance in daily life for hemiplegic patients post-stroke. This finding is consistent with previous research\u003csup\u003e\u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. For instance, Wang MH et al. demonstrated that patients with subacute stroke receiving taVNS treatment exhibited greater improvements in FMA-UE and activities of daily living scores compared to the sham group\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eVNMM is a novel form of neuromodulation that delivers magnetic pulses to the cervical bundle of the vagus nerve. The application of VNMM for enhancing upper extremity motor function in stroke patients is theorized to occur through the activation of the ascending neuromodulatory network. This network releases plasticity-promoting neuromodulators, such as acetylcholine and norepinephrine, throughout the cortex\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. MEP, CMCT and RMT can predict the prognosis of stroke patients and are related to the excitability of the motor cortex, motor recovery, and the improvement of corticospinal tract conduction\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. In this study, we examined the MEPs, CMCT, and RMT of the motor cortex to reflect changes in brain plasticity before and after treatment in patients. It was found that, after treatment, the MEP, CMCT, and RMT of the real VNMM group were significantly improved compared with the sham VNMM group. This suggests a trend toward increased cortical excitability in the primary motor cortex (M1). With respect to the correlation between motor function improvement and changes in MEPs, studies have shown incongruent results. Choi et al.\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e and Kim et al.\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e indicated that changes in MEPs are significantly associated with baseline disease severity. However, in this study, we were unable to reproduce the relationship between changes in MEP and motor functional outcomes, such as FMA-UE scores, which is consistent with the findings of Jo JY et al\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Given the limited mechanistic understanding of VNMS in upper extremity motor function in stroke patients and the preliminary nature of our exploration of the intervention's effects, potential biases in the results may arise from confounding factors not yet considered. Therefore, neurophysiological methods such as functional magnetic resonance imaging (fMRI) or functional near-infrared spectroscopy (fNIRS) are warranted for a more in-depth investigation of the underlying mechanisms.\u003c/p\u003e\u003cp\u003eDespite the valuable insights gained from this study, we acknowledge that the present study has several limitations. First, tangential coil stimulation may elicit more muscle contraction and a larger noise sensation compared to vertical coil stimulation, thereby potentially producing a stronger placebo effect in the real stimulation group than in the sham stimulation group. Second, the absence of follow-up after the study prevented the measurement of the sustained effects of VNMM in this study. Third, future studies should consider incorporating brain neurotransmitter measurements or neurophysiological methods, which are more specific for exploring the mechanism of VNMM on brain network remodeling in stroke patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, the present study suggests that 5 Hz VNMM administered over the mastoid of the left vagus nerve is effective in improving upper extremity motor function in stroke patients and is well-tolerated. Our study provides evidence that left-side VNMM can be utilized as a therapeutic method for stroke patients. Future studies may further explore the mechanisms underlying the effects of VNMM on brain network remodeling in stroke patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\u003cp\u003e This study was approved by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University (Approval Number: MRCTA, ECFAH of FMU [2022]409) and registered in the Chinese Clinical Trial Registry (Registration Number: ChiCTR2400082767). Written informed consent was obtained from all participants or their legal guardians prior to enrollment.\u003c/p\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis work was supported by the Natural Science Fundation of Fujian Province (No.2023J01603, Fujian; X-H-L) and Joint Funds for the Innovation of Science and Technology, Fujian Province (No.2024Y9141, Fujian; X-H-L). This work was also supported by Joint Funds for the Innovation of Science and Technology, Fujian Province (No.2021Y9105, Fujian; Z-Y-W).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eXHL, ZYW, and KLC formulated and designed the study concept; XHL, ZYW, and KLC analyzed the data and manuscript drafting or manuscript revision for important intellectual content; XHL and KLC enrolled the patients and conducted clinical assessments; NNZ and TG conducted clinical interventions; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e\u003cp\u003eThe authors would like to thank the kind patients, families, caregivers, and members who participated in this research.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGBD 2021 Diabetes Collaborators. 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Theoretical Basis of Vagus Nerve Stimulation. Prog Neurol Surg. 2015;29:20\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000434652\u003c/span\u003e\u003cspan address=\"10.1159/000434652\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCakar E, Akyuz G, Durmus O, et al. The relationships of motor-evoked potentials to hand dexterity, motor function, and spasticity in chronic stroke patients: a transcranial magnetic stimulation study. Acta Neurol Belg. 2016;116(4):481\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s13760-016-0633-2\u003c/span\u003e\u003cspan address=\"10.1007/s13760-016-0633-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVeldema J, Nowak DA, Gharabaghi A. Resting motor threshold in the course of hand motor recovery after stroke: a systematic review. J Neuroeng Rehabil. 2021;18(1):158. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12984-021-00947-8\u003c/span\u003e\u003cspan address=\"10.1186/s12984-021-00947-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Published 2021 Nov 3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChoi TW, Jang SG, Yang SN, Pyun SB. Factors affecting the motor evoked potential responsiveness and parameters in patients with supratentorial stroke. Ann Rehabil Med. 2014;38(1):19\u0026ndash;28. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5535/arm.2014.38.1.19\u003c/span\u003e\u003cspan address=\"10.5535/arm.2014.38.1.19\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim GW, Won YH, Park SH, Seo JH, Ko MH. Can motor evoked potentials be an objective parameter to assess extremity function at the acute or subacute stroke stage? Ann Rehabil Med. 2015;39(2):253\u0026ndash;61. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5535/arm.2015.39.2.253\u003c/span\u003e\u003cspan address=\"10.5535/arm.2015.39.2.253\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Demographic and clinical characteristics of all patients\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 294px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 117px;\"\u003e\n \u003cp\u003eReal rTMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 128px;\"\u003e\n \u003cp\u003esham rTMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePatients, N\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGender (male/female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11/11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.220\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAge，years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e61.27\u0026plusmn;11.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e63.77\u0026plusmn;14.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.358\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTime since stroke，days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21.27\u0026plusmn;8.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27.45\u0026plusmn;15.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.353\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLesion side, N (%)(Right/Left/）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10/12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9/13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.761\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eContinuous data are expressed as the mean \u0026plusmn; standard deviation.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Chi-square test\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u0026nbsp;\u003c/sup\u003eMann-Whitney \u003cem\u003eU\u003c/em\u003e-test\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. The comparison of scores before and after stimulation in the real and sham intervention groups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"777\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 210px;\"\u003e\n \u003cp\u003eReal rTMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 210px;\"\u003e\n \u003cp\u003eSham rTMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003ePost rTMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003ePost rTMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003eFMA-UE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e23.68\u0026plusmn;17.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e39.32\u0026plusmn;17.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e25.82\u0026plusmn;15.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e27.32\u0026plusmn;15.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.742\u003csup\u003ee\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.018\u003c/strong\u003e\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003eWMFT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e23.27\u0026plusmn;14.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e37.82\u0026plusmn;19.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e23.41\u0026plusmn;13.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e24.68\u0026plusmn;12.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.860\u003csup\u003ee\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.032\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ee\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003eFIM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e60.77\u0026plusmn;20.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e82.77\u0026plusmn;19.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e63.14\u0026plusmn;21.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e64.82\u0026plusmn;21.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.711\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003csup\u003ef\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003eMEP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e23.77\u0026plusmn;1.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e20.93\u0026plusmn;1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e23.23\u0026plusmn;1.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e22.98\u0026plusmn;1.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.321\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ef\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003eCMCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e13.69\u0026plusmn;1.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e11.10\u0026plusmn;1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e13.60\u0026plusmn;1.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e13.07\u0026plusmn;1.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.844\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ee\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003eRMT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e52.64\u0026plusmn;13.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e46.82\u0026plusmn;11.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e55.68\u0026plusmn;15.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 105px;\"\u003e\n \u003cp\u003e54.73\u0026plusmn;15.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e0.478\u003csup\u003ee\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.018\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ee\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFMA-UE = Fugl-Meyer Assessment Scale for Upper Extremity; WMFT = Wolf Motor Function Test; FIM = Functional Independence Measurement; MEP = Motor Evoked Potentials ; CMCT= Central Motor Conduction Time; RMT = Resting Motor Threshold.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eContinuous data are expressed as mean \u0026plusmn; standard deviation .\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eComparison between groups (pre-stimulation). \u003csup\u003eb\u0026nbsp;\u003c/sup\u003ePre-stimulation vs. post-stimulation in real rTMS. \u003csup\u003ec\u0026nbsp;\u003c/sup\u003ePre-stimulation vs. post-stimulation in sham rTMS. \u003csup\u003ed\u0026nbsp;\u003c/sup\u003eComparison of differences between groups (real vs. sham group). \u003csup\u003ee\u0026nbsp;\u003c/sup\u003eMann-Whitney \u003cem\u003eU\u003c/em\u003e-test.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ef\u0026nbsp;\u003c/sup\u003eIndependent samples \u003cem\u003et\u003c/em\u003e-test. \u0026nbsp;\u003csup\u003eg\u0026nbsp;\u003c/sup\u003ePaired-samples t test. Bold values showed significance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.The investigation of the predictors in the effect of rTMS.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"541\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 203px;\"\u003e\n \u003cp\u003edisease duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 221px;\"\u003e\n \u003cp\u003ebaseline disease severity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003er\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026Delta;FMA-UE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.283\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.202\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.056\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.805\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026Delta;WMFT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.282\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.299\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.177\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026Delta;FIM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.481\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e-0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.583\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026Delta;MEP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.369\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.091\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.257\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026Delta;CMCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.276\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.214\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.841\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026Delta;RMT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.082\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.718\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.328\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.137\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026Delta;\u0026nbsp;means Changes in scores before and after treatment.\u003c/p\u003e\n\u003cp\u003eFMA-UE = Fugl-Meyer Assessment Scale for Upper Extremity; WMFT = Wolf Motor Function Test; FIM = Functional Independence Measurement; MEP = Motor Evoked Potentials ; CMCT= Central Motor Conduction Time; RMT = Resting Motor Threshold.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7229219/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7229219/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground and Objectives:\u003c/h2\u003e\u003cp\u003eThis study aimed to conducted a clinical trial to evaluate the safety and feasibility of Vague Nerve Magnetic Modulation (VNMM) treatment on upper extremity motor function in stroke patients.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eA total of 44 stroke patients with upper extremity motor impairment were enrolled and randomly assigned to either a real VNMM group (N\u0026thinsp;=\u0026thinsp;22) or a sham VNMM group (N\u0026thinsp;=\u0026thinsp;22). The intervention consisted of 5-Hz VNMM applied to the left vagus nerve, which administered five days per week for a duration of four weeks. All patients underwent evaluations including Fugl-Meyer Assessment Upper Extremity (FMA-UE), the Wolf Motor Function Test (WMFT), the Functional Independence Measure (FIM) and parameters of Motor-evoked potentials (MEPs) at baseline and post-intervention.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003eAll participants tolerated the intervention well throughout the study. The findings demonstrated that a four-week course of VNMM was feasible for addressing upper extremity motor impairment in stroke patients. Significant improvements were noted in all outcome measures in both the real and sham VNMM groups. However, the magnitude of improvement was significantly greater in the real VNMM group compared to the sham VNMM group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Analysis of covariance further confirmed that the improvements in all outcomes were more pronounced in the real VNMM group following treatment compared to the sham group. Notably, neither disease duration nor baseline disease severity was found to correlate with the efficacy of VNMM.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e\u003cp\u003eOur study concluded that VNMM represents a safe and feasible treatment option for stroke patients with upper extremity motor dysfunction.\u003c/p\u003e","manuscriptTitle":"The Facilitative Effects of Left-side Vagus Nerve Magnetic Modulation on Upper Extremity Motor Function in Stroke Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-21 10:18:48","doi":"10.21203/rs.3.rs-7229219/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"863cb406-eaab-41fc-9423-6f6157d8647e","owner":[],"postedDate":"August 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T14:31:59+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-21 10:18:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7229219","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7229219","identity":"rs-7229219","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}