Authors: Yuanyuan Liu, Ruizhu Lin, Xinbao Tian, Junyi Wang, Ying Tao, Ning Zhu
Categories: Study Protocol, Motor-evoked potentials (MEPs), Repetitive transcranial magnetic stimulation (rTMS), Serum biomarkers, Stroke, Virtual reality training
Source: Trials
Balance dysfunction affects 70% of stroke patients. Emerging neurophysiological approaches, such as virtual reality therapy (VRT) and repetitive transcranial magnetic stimulation (rTMS), have been proven by clinical studies that the balance function of stroke patients can be improved when applied alone, but there are relatively few studies on the combined treatment of balance dysfunction after stroke. This study aimed to evaluate the impact of a 4-week intensive intervention combining VRT and rTMS on both balance function and brain plasticity among stroke patients.
This single-blind, randomized controlled trial was conducted at the Rehabilitation Medical Center of the Rehabilitation General Hospital of Ningxia Medical University. A cohort of 136 stroke patients, with durations of 2 to 24 weeks post-stroke, were enrolled in the study. Participants were randomly allocated in a 1:1:1 ratio to four the VR group (n = 34), the rTMS group (n = 34), the combined treatment group receiving both VR and rTMS (n = 34), and the control group undergoing traditional balance training (n = 34). All patients underwent a standardized inpatient rehabilitation program over 4 weeks. The VR group received daily 30-min sessions of VR therapy for 20 days. The rTMS group underwent daily sessions of rTMS stimulation for 20 min, targeting the motor imagery region in the affected hemisphere. The combination group received VR therapy after completing their rTMS treatment. The control group received conventional balance training, with each session lasting 30 min. Additionally, all patients received an extra 60 min of standard rehabilitation therapy twice daily. Assessments were conducted at baseline, 2 weeks, and 4 weeks post-treatment, using the Berg Balance Scale (BBS) as the primary measure, and secondary measures including the Timed Up-and-Go Test (TUGT), Fugl-Meyer Assessment-Lower Extremity (FMA-LE), and 6-m walking test (6MWT), as well as assessments for brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VGEF), tyrosine receptor kinase (TrκB), motor-evoked potential latency (PL), central motor conduction time (CMCT), and amplitude.
The widespread application of VR technology and rTMS in clinical settings is well-established. However, the potential synergistic effects of combining these modalities on balance function and neuroplasticity in stroke patients remain uncertain. Our hypothesis suggests that the integration of VR with rTMS may result in more pronounced improvements in both balance function and neuroplasticity among stroke patients, surpassing the outcomes achievable with VR alone, rTMS alone, or traditional therapy. The possible mechanism is that VR-based training combined with rTMS plays a superimposed effect, promoting better repair of damaged neurons and ultimately improving balance function in stroke patients. The positive results anticipated from this trial could provide objective evidence advocating for the concurrent use of VR and rTMS in clinical interventions.
The study protocol underwent review and approval by the Medical Research Ethics Committee of the General Hospital of Ningxia Medical University on January 26, 2024 (No. KYLL-2024–0162). Subsequently, it was registered in the Chinese Clinical Trial Registry on March 11, 2024 (registration ChiCTR2400081775). Currently, the study is still ongoing.
Keywords: Stroke, Repetitive transcranial magnetic stimulation (rTMS), Virtual reality training, Motor-evoked potentials (MEPs), Serum biomarkers
Stroke, defined as an acute cerebral injury resulting from the sudden rupture or occlusion of blood vessels in the brain [1], ranks as the second leading cause of adult mortality and the primary cause of disability in developed countries [2]. Balance dysfunction is a common motor impairment observed in individuals who have suffered from strokes, affecting around 70–80% of patients [3]. This condition significantly impedes the ability to perform daily activities. The process of functional recovery after a stroke relies on the brain’s ability to adapt and reorganize itself, which begins during the early stages of injury. Rehabilitation training plays a vital role in facilitating this adaptability, and its effectiveness depends on factors such as the intensity, frequency, format of training, and the motivation of participants [2].
Traditional balance training often faces challenges due to limited access to medical resources and low patient adherence [4]. In some traditional balance training, patients may lack some advanced and attractive training equipment, or lack of creativity in manual training content, resulting in insufficient training enthusiasm, and unable to adhere to the long-term completion of training, resulting in poor training results. As a result, it may fail to achieve the desired intensity and dosage of training. However, with the advancement of computer technology and the widespread adoption of intelligent medical treatments, novel neurophysiological interventions such as virtual reality (VR) technology and repetitive transcranial magnetic stimulation (rTMS) have emerged. These interventions have shown promise in enhancing balance function in stroke patients [5, 6]. Research has indicated that the utilization of virtual reality (VR) technology and multi-sensory stimulation can enhance the activation of motor brain regions and reconstruct synaptic connections within the nervous system. This, in turn, plays a significant role in the reorganization and recovery of neural structure following a stroke [7]. In a systematic review and meta-analysis of 10 studies (n = 550), the results showed that virtual reality (VR) training demonstrated superior efficacy in enhancing upper limb function and balance in stroke survivors [8]. Liang Ming et al. [9]. demonstrated that VR task-oriented training had the potential to restore the equilibrium of inhibitory signals between the two cerebral hemispheres, augment cortical motor neuron excitability on the affected side, facilitate functional reorganization within the central motor nervous system, and ultimately lead to improvements in both motor function and balance. By emitting a pulsed magnetic field through a coil, repetitive transcranial magnetic stimulation (rTMS) has the ability to modulate excitability within specific areas of the cerebral cortex as well as blood flow in brain tissue. Consequently, it facilitates nerve function reconstruction and repair within infarcted regions [10, 11]. Additionally, rTMS promotes the formation of new neuronal associations, thereby inducing brain plasticity [12]. A study conducted by Li Haining et al. demonstrated that combining low-frequency with high-frequency rTMS significantly enhances patients’ balance abilities while also reducing central motor conduction time and improving daily living activities [13].
Brain-derived neurotrophic factor (BDNF) is a widely distributed neurotrophic factor that can facilitate the plasticity of synapses and promote nerve regeneration in the adult brain [14, 15]. The specific binding receptor for BDNF is the tyrosine kinase receptor B (TrκB). When bound to BDNF, TrκB undergoes phosphorylation, leading to the activation of a series of downstream signaling pathways associated with BDNF/Trκb, which plays a crucial role in normal brain development and synaptic plasticity [16]. Vascular endothelial growth factor (VEGF) is an extremely specific pro-angiogenic factor that shows a positive correlation with recovery of neurological function [17]. Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) and virtual scene interaction systems can enhance cerebral metabolism, stimulate the expression of BDNF and VEGF, promote proliferation and differentiation of neural cells, improve perfusion of cerebral blood flow, alleviate neuronal defects, and facilitate recovery of nerve function [18, 19].
This study will use a randomized controlled trial design to investigate the clinical effects of VR task training combined with TMS on balance dysfunction in stroke patients. We will use the BBS scale as the primary outcome index for assessing balance function and the secondary indexes TUGT, FMA-LE, and 6MWT for assessing lower limb motor function and walking ability. We will also explore the possible molecular and neurophysiological mechanisms of VR task-based training combined with rTMS to promote the recovery of balance function after stroke through the measurement of BDNF, VEGF, TrκB factor levels, and MEP in the serum of the tested patients with the aim of providing new theoretical basis and more effective treatment programs for clinical treatment.
In this clinical trial, we conducted a randomized control study with a single-blind design. A total of 136 stroke patients who met the eligibility criteria were randomly assigned to four VR group, r TMS group, combination group (VR and r TMS), and control group (traditional balance training). Evaluations were conducted at baseline, at 2 weeks post-rehabilitation intervention, and again at 4 weeks post-intervention. The assessment battery included eligibility criteria, balance and motor function scales, neuroelectrophysiological studies, and serologic investigations. To minimize assessment bias, evaluations were independently conducted by an intermediate-level physical therapist and an attending physician. Two evaluators were unaware of patient grouping, intervention methods, and data analysis. Figure 1 illustrates the study flow chart, while Table 1 presents the enrollment, intervention, and evaluation schedule.
Fig. 1 Flow chart of participant selection
We are actively seeking patients who have been diagnosed with stroke and are being treated at the Rehabilitation Medicine Center of the General Hospital of Ningxia Medical University. Once eligible patients are admitted to the hospital, they will be given basic information about the study, and if they are interested, a member of our research team will give them a detailed description of the trial process and its potential benefits. We will begin the study after obtaining informed consent from participating patients. All assessments, tests, and treatments will be performed free of charge at the Rehabilitation Center of General Hospital of Ningxia Medical University. The recruitment materials we used were approved by the ethical committees of the centers. All participants will receive comprehensive information about the assessment and intervention programs as well as serological testing on a voluntary basis, and their trial data will be monitored by supervisors.
The inclusion criteria for this study are (1) age between 18 and 75 years; (2) first occurrence of stroke; (3) meeting the diagnostic criteria for ischemic stroke outlined in the “Diagnostic points for Major Cerebrovascular Diseases in China 2019” issued by the Chinese Society of Neurology, confirmed through head imaging; (4) disease duration ranging from 2 to 24 weeks; (5) Brunnstrom stage ≥ 3 for hemiplegic lower limb; (6) absence of oral medications that may interfere with balance; and (7) satisfactory cognitive function assessed by MMSE score > 23.
Patients are excluded if they meet any of the following (1) severe psychiatric disorders; (2) limb movement disorders caused by bone, joint, or neuromuscular diseases; (3) chronic lung disease; (4) major organ dysfunction (heart, lung, liver, kidney, etc.), cancer, or any changes in their condition at any time; (5) other conditions affecting balance such as vestibular and cerebellar lesions; (6) history of epilepsy, visual impairment, vertigo, and other related diseases; and (7) contraindications to transcranial magnetic stimulation (TMS), such as intracranial metal or implanted cardiac pacemaker.
Indicators of discontinuation include (1) serious adverse events that render continuation of the trial inappropriate, (2) poor compliance with prescribed treatment, and (3) patient withdrawal from the study voluntarily.
According to previous research by Cao Yongsheng et al. [20], using BBS as the primary outcome measure, the effect size of VR technology in improving BBS scores was calculated to be 0.906 using Gpower3.1.9.2 software [21]. Considering a power value of 0.955 and α value set at 0.05, sample size estimation yielded that this study design requires 112 cases or 28 cases per group. Accounting for a potential dropout rate of 20%, the final sample size was determined to be 34 cases per group, resulting in a total sample size of 136 cases.
With the participant’s consent, the computer will generate a number between 1 and 136 to randomly assign the participant to one of four the VR group, the transcranial magnetic stimulation group, the connection group, or the control group. The assigned number will be used for data collection and analysis. A list of each participant’s assigned group will be securely stored in an opaque envelope. Participants will receive the appropriate envelope upon completion of the informed consent process, randomization process, and baseline data collection. The researcher responsible for the analysis of the results had no knowledge of the groups until the data analysis process was completed.
Due to the inherent nature of VR training and technical limitations, it was not feasible to use a double-blind study design. Therefore, only the evaluators and statisticians were blinded. The VR session training and transcranial magnetic stimulation manipulation will be conducted by physical therapists with intermediate-level qualifications, and participants receive independent treatment to prevent any form of communication. The therapists will provide the subject, evaluator, or statistician with the necessary information regarding the assignment. Independent investigators will be responsible for performing analytical tasks during data management and statistical analysis.
Data from the four patient cohorts will be meticulously collected by highly trained physicians and therapists at three designated time baseline assessment (T1), 2 weeks post-intervention (T2), and 4 weeks post-intervention (T3). Serological markers, including BDNF, VEGF, and TrκB, will be obtained between 00 AM and 30 AM the following day after a fasting period of 10 to 12 h. All assessments of balance and motor function—specifically the Berg Balance Scale (BBS), Timed Up and Go Test (TUGT), and Fugl-Meyer Assessment for Lower Extremity (FMA-LE)—will be conducted using standardized scales at 00 AM. The motor-evoked potential (MEP) test will take place at 30 PM on the same day.
Patients in the VR group, rTMS group, combined group, and control group underwent routine clinical pharmacotherapy and conventional rehabilitation treatment (CRT) (2 sessions of 60 min each DAY). Additionally, patients in the VR group underwent VR game training for balance function (1 session of 30 min), while those in the rTMS group received transcranial magnetic stimulation (1 session of 20 min). The combined group received a combination of VR and rTMS stimulation, whereas the control group underwent traditional balance training (1 session of 30 min). All enrolled patients were treated for 4 weeks, with sessions conducted 5 days per week, resulting in a total of 20 sessions. Traditional balance training was designed to match the intensity and complexity level similar to that of VR games. In this study, two experienced physical therapists provided the VR treatment and rTMS treatment, respectively, while two evaluators performed functional assessments and evaluations for all patients without knowledge of their assigned groups.
Each group of patients undergoes pharmacological intervention aimed at maintaining optimal blood pressure and blood lipid levels. Conventional rehabilitation treatment includes a comprehensive conventional rehabilitation program based on the specific motor dysfunction and comprehensive evaluation of each patient. This program encompasses exercise therapy, occupational therapy, physical factor therapy, and positive psychological counseling throughout the treatment process. Exercise therapy primarily involves conventional muscle-strengthening exercises, joint mobility training, nerve stimulation methods, and motor relearning programs. The primary objective is to enhance limb motor function and facilitate the restoration of sensation. Training sessions were conducted twice a day for 60 min.
Occupational therapy mainly focuses on affected upper limb joint movement training, active assistance, and active training for the affected upper limb, along with roller training, wooden nail board training, object extraction training for the affected upper limb, and finger grasping and opening exercises, among others. The main aim was to improve motor ability in the upper limbs as well as fine movements of the hand. Physical factors were treated with neuromuscular facilitation apparatus, with a stimulation frequency of 3–1000 Hz.
The aforementioned treatments were administered by experienced physical therapists and occupational therapists who underwent the same training. Therapists adjust the intensity and duration of exercise based on the patient’s level of fatigue and recovery. Furthermore, patients are provided psychological counseling, comprehensive support, and comfort upon admission and are encouraged to actively participate in their treatment. If a patient experiences speech difficulties, additional speech training can be arranged.
In addition to conventional treatment, the patients undergo daily 30-min VR training using the Virtual Reality Digital Twin Stroke Hemiplegia Rehabilitation Evaluation and Training System (Beijing NuoYiteng Technology Co, LTD), which comprises both hardware and software components. The software includes VR games for balance training, an optical inertial hybrid data tracking and processing system, a doctor-client control system, etc. The hardware components include a head-mounted VR-integrated device, motion capture gloves, and a high-precision binocular camera, among others (Fig. 2). Participants utilize a portable VR headset and hand motion capture device to achieve spatial positioning within the virtual environment and engage in interactive tasks during VR training. Real-time assessment and recording of patient activity and position are facilitated through inertial motion capture and optical localization techniques. Figure 3 provides a visual representation of this setup.
Fig. 2 Hardware components. a Head-mounted VR-integrated device and motion capture gloves b High precision binocular camera and display screen
Fig. 3 Visual representation. a Visual inertial motion capture b Optical positioning
Before VR training, the treatment staff establishes the patient’s account information and selects an appropriate training task. The patient wears a sensor-equipped head-mounted display, gloves, and vest during the procedure to capture and record their active movements and joint angles. The immersive virtual environment provided by the head-mounted display offers comprehensive visual, auditory, and motor feedback, allowing therapists to dynamically adjust the training difficulty based on patient feedback. Following the application of sensor equipment, all patients undergo body posture correction to ensure accurate sensor capture from various orientations by cameras.
Participants are instructed to complete three tasks, as depicted in Fig. 4: fruit catching, tennis playing, and obstacle avoidance. The fruit grasping game primarily aims to enhance patients’ trunk rotation and sitting balance through alternating grasping and lowering of fruits using both upper limbs. In the tennis match, patients are required to hold a virtual racquet and strike a tennis ball thrown by the opposing robot while seated or standing. Patients are expected to respond within a time frame of 2 s. During obstacle avoidance, patients need to skillfully navigate around moving obstacles to improve their dynamic balance ability. Initially, due to the limited functionality of the affected limb and trunk, the participants are made to perform the training while seated. As their balance function improves over time, they can gradually transition into performing the training while standing. The system records difficulty levels and performance metrics for each game task, ultimately generating a comprehensive training report.
Fig. 4 Three tasks. a Game 1 Catch fruiting b Game 2 Tennis playing c Game 3 Obstacles avoiding
The magnetic field stimulator utilized in this study was the YRD CCY-I magnetic field stimulator manufactured by Wuhan Yiruide Medical Equipment New Technology Co., LTD. Prior to treatment, the resting motor threshold (RMT) was measured. Patients were fitted with an international 10–20 system positioning cap and a single coil “8” coil with a diameter of 70 mm was employed. Stimulation targeted the primary motor cortex (M1) on the affected side, while recording the motor-evoked potential (MEP) from the abductor pollex brevis muscle as the target muscle. At least five sets of ten consecutive stimuli were administered, ensuring that more than 50 microvolts could be recorded. The minimum stimulus intensity required for MEP output served as the MEP value. The central position of the “8” shaped coil was in close proximity to the surface of the skull. The target stimulation point was chosen as the representative area of the lower limb motor cortex within the primary motor cortex (M1) region on the affected side. High-frequency magnetic stimulation, with an intensity set at 80% resting motor threshold (RMT), was repetitively applied for 1200 sequences. Each treatment session lasted for 20 min and was administered once daily, 5 days a week, over a 4-week period. Throughout the treatment duration, strict instructions were given to maintain stable head positioning in order to prevent any disruption to the site being stimulated by the coil (as depicted in Fig. 5).
Fig. 5 Stable head positioning. a YRD CCY-I magnetic field stimulator b International 10–20 system positioning cap c Diagram of the coil stimulation site
The Berg Balance Scale (BBS) is a widely used clinical tool abroad for evaluating balance function in patients with cerebrovascular and brain injuries. It assesses the patient’s ability to actively shift their center of gravity through various functional activities, providing a comprehensive evaluation of dynamic and static balance in sitting and standing positions. Comprising fourteen items, each rated on a five-point scale from 0 to 4, the BBS generates a total score out of 56 points by summing individual item scores. Ultimately, this total score reflects the subject’s overall balance ability, with higher scores indicating better balance.
After a fasting period of 10 to 12 h, peripheral venous blood (5 ml) is drawn the next morning between 00 and 30. The blood samples are then centrifuged at a speed of 2000r/min for 20 min after being kept at room temperature for 60 min. Subsequently, the serum samples are separated, and the data are recorded. Once all serum samples are collected, Enzyme-linked immunosorbent assay (ELISA) is performed to determine the concentration of serum BDNF using Servicebio’s GEH0039-48 T kit. VEGF levels are measured using Servicebio’s GEH0022-48 T kit, and TrκB concentrations are determined by the Hangzhou Union Branch. The experimental process strictly adheres to the provided instructions.
The CCY-I magnetic field stimulator (Wuhan Yiruide Medical Equipment New Technology Co, LTD) is employed as the testing equipment, with the standard “8” coil employed for cortical magnetic stimulation. During examination, the participants assume either a supine or seated position while wearing a positioning cap and maintaining full body relaxation. Electrode positions are cleaned with 75% alcohol prior to placement of surface recording electrodes at the muscle belly of the contralateral abductor pollex brevis, reference electrodes at the tendon, and ground electrodes at the wrist. The coil position is adjusted to elicit MEP, with measurement completed when the amplitude evoked by 5 out of 10 consecutive stimuli exceeds 50 μv. Thumb abductor muscle amplitude, latency, and central conduction time are recorded and averaged for final measurement results.
The Fugl-Meyer lower extremity component is utilized for the comprehensive assessment of lower limb motor function, balance function, joint range of motion, pain intensity, sensory function, and other related factors. Additionally, a detailed evaluation is conducted on the coordinated and dissociated movements exhibited by subjects during walking. Each item is scored from 0 to 2 with a total score of 34, where higher scores indicate superior limb motor function.
The participants are seated in chairs equipped with backrests while placing their hands on armrests. They received instructions to rapidly stand up upon receiving a designated password, walk 2.4 m forward without delay, and execute a rapid turn-around maneuver before returning to their initial position on the chair by sitting down once more. Timing begins when each participant’s back separates from the chair’s backrest and ends when they resume sitting. This procedure is repeated twice for each participant to calculate an average outcome.
Try to select a spacious indoor corridor with minimal pedestrian traffic, and designate markers using colored ribbons on the floor at the starting point and return point. Prepare a stopwatch and instruct the patient to ambulate back and forth within the designated distance as efficiently as possible. Ambulation should be performed silently, without running or jumping, while ensuring no hesitation during the return journey. If necessary, brief leaning against the wall is permitted before resuming ambulation until completing 6 min. Calculate the total distance covered by the patient in 6 min and round it to meters. Blood pressure and heart rate measurements will be recorded.
There is no follow-up of patients in this study, because the stroke patients we included had relatively good motor function. After rehabilitation intervention, most of the patients could achieve their rehabilitation goals, so they would not choose to be readmitted for rehabilitation. Data from participants who stopped or deviated from the intervention program will not be included in the statistical analysis.
Potential adverse reactions in this trial include subjects experiencing headaches within the magnetic stimulation area and local scalp, as well as facial muscle convulsions during rTMS evaluation and treatment. These symptoms are typically mild and can be alleviated following the stimulation. The most severe adverse effect is seizures, although recent studies indicate an extremely low incidence rate. Another observed adverse reaction among subjects during VR training is vertigo, with a few patients also reporting headaches and tinnitus. If participants encounter any of these discomforting symptoms during VR or rTMS, the trial can be halted at any time for appropriate treatment.
The hospital’s ethics committee conducts biannual reviews to assess compliance with established protocols and evaluate the trial’s progress. The project management team convenes every 2 weeks to monitor the advancement of the trial. The Steering Committee also meets biweekly to provide guidance to the research team, ensuring smooth execution of the experiment. During the data collection phase, the team will convene monthly to uphold the integrity and reliability of the experimental data.
Any amendment will first be discussed and agreed upon in the Steering Committee and then submitted to the hospital Ethics Committee and scientific research department for approval. After approval, a formal revision plan will be formed and stored together with other experimental documents. Any deviation from the protocol will be recorded and required to be signed by the investigator. Necessary updates to the clinical trial application will be implemented by the trial lead after approval by the Steering Committee, the scientific research department, and the Ethics Committee.
Both the hospital ethics committee and the study steering committee deemed the trial to have a relatively low level of risk, thereby obviating the need for a dedicated data monitoring committee. The subjects’ baseline, assessment, and treatment outcome data will be securely stored in specifically designated folders on a laptop under strict supervision by a data manager. The acquisition, recording, and storage of data will be diligently overseen by trial managers (NZ, YYL) to ensure its integrity and authenticity. All collected data from subjects throughout the study will be retained for a minimum period of 5 years and subjected to statistical analysis upon completion of the trial.
We employ SPSS 22.0 statistical software to construct and process all collected data. Parameters following a normal distribution are compared using ANOVA tests, while parameters with skewed distributions are compared using the Kruskal–Wallis test. Measurement data are presented as mean ± standard deviation (X ± s), and count data are analyzed using the chi-square test. Group comparisons utilize analysis of variance, with pairwise comparisons within groups conducted using the LSD-t (least significant difference) method. For group comparisons at all time points, repeated measures analysis of variance (ANOVA) with Bonferroni correction is applied. A significant level of P < 0.05 is considered statistically significant. Subjects who successfully complete the study according to the intervention plan are included in the analysis while missing or non-protocol-conforming data are excluded.
All subjects are recruited by a single clinician and undergo rigorous screening based on predefined inclusion and exclusion criteria to ensure the enrollment of eligible patients in the study. Two evaluators separately assess the participants’ demographic information, motor function, and neurological status, and the collected data are entered into a dedicated computer system for secure storage. The entire study process is supervised and guided by experts specialized in clinical trials, medical ethics, statistics, and data management, who are responsible for monitoring both participant safety and data integrity. In this study, all researchers are fully committed to safeguarding the personal information and privacy of all participants involved. All personal details, assessment records, and laboratory test results are securely stored in a password-protected computer accessible exclusively to authorized members of the study team and data statisticians.
The Department of Rehabilitation Medicine at Ningxia Medical University General Hospital will function as the trial coordination center. The Steering Committee, chaired by NZ and RZL, is tasked with reviewing the final proposal, guiding the trial process, and monitoring research progress. XBT is responsible for obtaining essential trial documentation, securing approval from the Ethics Committee, and coordinating its audit processes. Both XBT and YT are accountable for recruiting and evaluating trial participants, while YYL oversees the implementation of interventions. Data collection and analysis will be conducted by XBT and JYW. The aforementioned personnel will convene biweekly to discuss test progress. Additionally, since Beijing Nuoyiteng Technology Effective Company provides hardware equipment for VR training, we conduct a monthly video conference to communicate developments in software usage.
Balance impairment is a frequently observed complication that arises after stroke, primarily due to the inability of high central lesions to control low central lesions and an imbalance in the function of balance reflexes. This leads to difficulties in maintaining normal balance ability [22]. Restoring balance is a common goal for stroke patients, and training programs are often employed for this purpose. However, conventional training methods suffer from monotony, lack of appeal, and poor patient adherence, which ultimately limits their effectiveness in terms of intensity and dosage [23]. Virtual reality (VR) and repetitive transcranial magnetic stimulation (rTMS) are two emerging and effective rehabilitation modalities [5, 24]. In comparison to conventional exercise-based rehabilitation, VR provides patients with immersive and engaging training scenarios, thereby promoting a more relaxed and active participation. Numerous studies have confirmed that VR training offers certain advantages in improving the balance function of patients with movement disorders [8]. Marques-Sule et al. utilized the Nintendo Wii-VR balance board for rehabilitating the hemiplegic lower limbs of 29 chronic stroke patients, resulting in significant improvements. The Berg Balance Scale (BBS) values and Barthel Index (BI) values of all patients showed enhancement compared to pre-training levels [25]. However, some studies have suggested that VR training is not superior to traditional methods [26], thus necessitating further confirmation regarding its efficacy. Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive brain stimulation technique, has demonstrated its potential in enhancing the balance function among stroke patients [27]. Chen Danfeng observed the effects of combining rTMS with core stability training on the balance function of stroke patients and found that this combination significantly improved motor function, balance ability, and activities of daily living; therefore suggesting its clinical applicability [28]. Huang Yuan et al.’s study also provided evidence supporting rTMS’s capability to promote brain plasticity and enhance motor function among patients [29].
The utilization of virtual reality training elicits cerebral cortex stimulation through visual, auditory, and proprioceptive inputs, thereby constituting a peripheral intervention. Conversely, repetitive transcranial magnetic stimulation (rTMS) provides direct and precise stimulation to brain injury or functional brain areas with accurate localization, thus representing a central intervention. Previous studies have independently demonstrated the efficacy of both VR and rTMS in enhancing balance function among stroke patients; however, limited literature exists on the combined application of these two methods specifically for improving post-stroke balance function, with an unclear underlying mechanism.
There is currently no agreement within the industry regarding the appropriate methods for assessing the effectiveness of VR technology and rTMS. A meta-analysis of existing literature has indicated that commonly utilized tools for evaluating the impact of VR technology and rTMS on balance function in stroke patients include BBS (Berg Balance Scale), TUGT (Timed Up-and-Go Test), and FMA (Fugl-Meyer Assessment) [30]. In addition to their ability to enhance nerve cell proliferation, differentiation, cerebral blood flow perfusion, and nerve function recovery [18], BDNF (brain-derived neurotrophic factor), and VEGF (vascular endothelial growth dactor) have been recognized as reliable indicators for evaluating brain plasticity. Henceforth, this study aims at assessing balance function through employing BBS, TUGT, FMA, and 6MWT (six-minute walk test); simultaneously measuring MEP (motor-evoked potential) alongside factors like BDNF, VEGF, and TrκB (TrkB receptor tyrosine kinase isoform β) to evaluate neural plasticity among stroke patients.
The total sample size of 136 was determined based on the BBS as the primary efficacy indicator, taking into account a dropout rate of 20%. This accounts for participants who achieved significant functional improvement during the initial phase of treatment and reached their desired outcome before completing the trial. Additionally, it acknowledges that certain patients may discontinue due to discomfort during VR training or rTMS treatment.
The main limitation of this trial is its single-center design, which hinders the involvement of multiple centers due to the current unavailability of VR equipment at other sites within the region. Therefore, it is essential to conduct large-scale multicenter trials in order to determine the benefits of combining VR with repetitive transcranial magnetic therapy. Additionally, existing VR technology cannot fully replicate all aspects of rehabilitation training; hence participants in both traditional balance training group and VR group will receive comparable training movements and intensity. Furthermore, this study only monitored functional changes during a 4-week period of inpatient rehabilitation and lacked long-term follow-up data. Future studies should be designed to observe prolonged rehabilitation effects.
Recruitment for the study is ongoing, with an expected completion timeline of 8 to 10 months, encompassing all subsequent assessments. The recruitment phase started on April 1, 2024, and is estimated to be completed by December 31, 2024. Protocol version 1.0 (December 2023).
The present study was financially supported by the Key Project of the Research and Development Program of Ningxia Hui Autonomous Region (2022BEG02047).
After obtaining participants’ approval, we plan to share all data and findings, with the exception of Biological specimens information, by publishing an article in well-regarded scholarly journals once the trial concludes.
The meticulous planning of the collection, laboratory evaluation, and conservation of biospecimens for genetic or molecular analyses in this trial and potential future ancillary studies aligns with the stringent criteria established by Nature journal.
The project design was carried out by YYL and NZ, while the protocol modification was executed by NZ and RZL. Feasibility analysis was conducted by YYL and YT, with recruitment and evaluation of trial participants jointly managed by XBT and YT. The intervention measures will be supervised and completed by YYL. Statistical analysis will be performed by XBT and JYW, while trial execution monitoring will be the responsibility of NZ and RZL. YYL wrote the manuscript, which was revised by NZ and RZL. All authors collaborated to refine the research plan, and the final manuscript was approved unanimously.
The study protocol was approved by the Medical Research Ethics Committee of the General Hospital of Ningxia Medical University on January 26, 2024 (approval KYLL-2024–0162) and was registered in the Chinese Clinical Trial Registry on March 11, 2024 (registration ChiCTR2400081775). Prior to study participation, all patients should provide detailed written informed consent, and their authorization is obtained for utilizing their blood samples for scientific purposes.
Upon receiving consent from the participants, we plan to publish all data and findings as research articles in academic journals following the conclusion of the trial.
The authors declare that they have no competing interests.