Study design
This randomized controlled trial aims to investigate the effectiveness of virtual reality (VR) technology in the rehabilitation of postoperative patients with CSM. A total of 78 eligible patients will be recruited and randomly assigned to either the routine rehabilitation group or the VR training combined with routine rehabilitation group (1:1). The primary outcome measure will be the Japanese Orthopaedic Association (JOA)(Table 1) cervical myelopathy evaluation scale, and secondary measures will include the visual analog scale (VAS), neck disability index (NDI), and functional magnetic resonance imaging (fMRI) scans.[18, 19] The intervention will follow a standardized protocol, and independent researchers will execute and supervise the random allocation of the trial. The study protocol adheres to the SPIRIT recommendation. For the SPIRIT checklist,see additional file 1,and the study design is presented in Figs. 1 and 2.
Participants
The aim of this study is to recruit 78 postoperative CSM patients with JOA scores between 5 and 15 and aged between 20 and 75 years. All eligible participants will be recruited from the orthopedic and rehabilitation medicine departments of our hospital and other Chinese hospitals. Prior to the experiment, we will provide a comprehensive explanation of the study's purpose, the type of intervention, and the potential risks and benefits of using VR technology to the participants who consent to take part. We will respect their decision to withdraw from the study at any time for any reason.
Table 1: Japanese Orthopaedic Association (JOA) score for patients with cervical myelopathic
Motor function
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Upper extremity
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The thumb and fingers
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0 [Complete disturbance] The patient cannot use chopsticks or a spoon/fork, and cannot fasten a button on his or her own.
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1 [Severe disturbance] The patient cannot use chopsticks or write, and can barely use a spoon/fork.
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2 [Moderate disturbance] The patient can pick up a large object with chopsticks but can hardly write. He/she can fasten a large button.
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3 [Slight disturbance] The patient makes awkward use of chopsticks, writes in a clumsy manner, but can fasten buttons on his/her shirt.
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4 [Normal] Normal
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Lower extremity
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0 [complete disturbance] The patient cannot stand or walk alone.
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(0.5 The patient can stand up.)
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1 [Severe disturbance] The patient needs support to walk on a flat surface.
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(1.5 The patient can walk on a flat surface without any support but the walking is not stable.)
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2 [Moderate disturbance] The patient can walk on a flat surface without any support, but needs a handrail to walk up and down stairs.
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(2.5 The patient can walk on a flat surface without any support, but needs a handrail only to walk down stairs.)
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3 [Slight disturbance] The patient can walk fast, although awkwardly.
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4 [Normal] Normal
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Sensory function
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Upper extremity
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0 [Severe disturbance] Complete sensory loss (touch sensation, pain sensation)
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(0.5 Partial sensory loss ≤ 5/10 (touch sensation, pain sensation); intolerable pain or numbness)
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1 [Moderate disturbance] Partial sensory loss ≥ 6/10 (touch sensation, pain sensation); numbness and hypersensitivity.
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(1.5 [Slight disturbance] Slight numbness (normal sensation))
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2 [Normal] Normal
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Trunk
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0 [Severe disturbance] Complete sensory loss (touch sensation, pain sensation)
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(0.5 Partial sensory loss ≤ 5/10 (touch sensation, pain sensation); intolerable pain and numbness)
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1 [Moderate disturbance] Partial sensory loss ≥ 6/10 (touch sensation, pain sensation); numbness and hypersensitivity.
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(1.5 [Slight disturbance] Slight numbness (normal sensation))
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2 [Normal] Normal
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Lower extremity
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0 [Severe disturbance] Complete sensory loss (touch sensation, pain sensation)
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(0.5 Partial sensory loss ≤ 5/10 (touch sensation, pain sensation); intolerable pain and numbness)
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1 [Moderate disturbance] Partial sensory loss ≥ 6/10 (touch sensation, pain sensation); numbness and hypersensitivity.
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(1.5 [Slight disturbance] Slight numbness (norm sensation))
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2 [Normal] Normal
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Urinary bladder function
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0 [Severe disturbance] Urinary retention, incontinence
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1 [Moderate disturbance] Feeling of residual urine, straining of oneself, dull urination, elongation of urination (retarded urination), urinary incontinence
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2 [Slight disturbance] Retarded urination, pollakisuria
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3 [Normal] normal
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Total 17
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Enrollment
Inclusion criteria
All participants must meet the following criteria: (1) Be diagnosed with CSM and have undergone surgery between 24 hours and three months prior to enrollment; (2) Aged between 20 and 75 years old, of either gender; (3) Japanese Orthopedic Association (JOA) score of 5 to 15; (4) Educational experience not less than primary school; (5) No cognitive dysfunction;(6) Be able to comprehend and agree to participate in this study by signing the informed consent form. (Their personal information will be protected confidentiality).
Exclusion criteria
Participants will be excluded if they meet any of the following conditions: (1) Contraindications for magnetic resonance imaging (such as the cardiac pacemaker, cardiac stent, artificial heart valve, bone fracture fixation plate, or claustrophobia); (2) Concurrent limb fractures, degenerative diseases of the lumbar or thoracic vertebrae, cerebrovascular disease, other neurological disorders, intraspinal space-occupying lesions, history of cervical trauma, previous cervical spine surgery, hip or knee joint diseases, or other serious systemic diseases; (3) Severe cardiopulmonary dysfunction; (4) Pregnancy or lactation.
Withdrawal or dropout criteria
In this study, the intervention measures for both the trial group and the control group may be stopped if the subject meets any of the following criteria: (1) The subject requests to withdraw from the clinical study; (2) The subject is unable to complete the relevant test as required, which affects the data collection; (3) The subject receives other treatments during the treatment period without authorization; (4) The subject experiences adverse events or serious adverse events during the trial that is not suitable for continuing to participate in this study; (5) The subject's disease worsens significantly or develops some complications, or special physiological changes that are not suitable for continuing to participate in this study; (6) The researcher considers it unsuitable for the subject to continue participating in this study.
Intervention
Interventions using VR technology were conducted on the GRAIL system (Netherlands Motek Medical Company SY02097646), with all participants undergoing diagnostic assessment by a professional spine specialist or rehabilitation medicine physician prior to participation to ensure suitability. The training time was scheduled in accordance with GRAIL guidelines to ensure that the VR intervention was appropriate and safe, as it has been shown to be the most effective intensity of training for patients with CSM. All intervention measures were carried out by qualified therapists, and the participants' reactions were recorded after each intervention. Safety measures were taken to prevent harm to all participants.
Conventional rehabilitation group
Patients in the rehabilitation group underwent a program that primarily focused on strength training to improve their activities and coordination.[20] This program involved an assessment of the postoperative limb muscle strength, sensation, and motor function of the patients to develop functional training program correspondingly based on existing problems. The program included the following exercises: (1) Finger extension and forceful bending and gripping movements repeated 5–10 times, and the training sessions were appropriately increased. (2) Patients were guided to perform active knee and hip joint movements 24 hours after surgery, 3 times a week for 15 minutes each time. (3) Straight leg lift exercises were performed 2 times a week for 15 minutes each time. (4) Isometric contraction exercises, such as the quadriceps femoris, were performed 3 times a week for 10 minutes each time. (5) Ankle joint dorsiflexion and plantar flexion exercises were performed 3 times a week for 15–20 minutes each time. (6) Walking training was performed 3 times a week for 10–20 minutes each time.
Conventional rehabilitation and virtual reality training group
The same specific plan as previously described was used for conventional rehabilitation treatment. Additionally, virtual reality technology was used in the form of GRAIL treatment. The treatment plan involved instructing patients to perform corresponding activities on a treadmill, while suspended by a harness and surrounded by suitable virtual scenes. The frequency of treatment was three times a week, with each session lasting 15–20 minutes. This treatment lasted for four weeks, with a doctor present to guide and monitor the patient throughout the sessions.
Inclusion procedure
Prior to the intervention, individuals who express interest in participating in the study will be invited to schedule an appointment for additional information.
If they choose to participate, they will sign an informed consent form under the guidance of independent researchers and be screened to determine if they meet the inclusion and exclusion criteria. Participants who meet all inclusion criteria and have no exclusion criteria will be included in the study. Descriptive data will be carefully collected before randomization, including general information such as age, gender, race, occupation, height, weight, body mass index (BMI), blood pressure, education level, medical history, medication use, smoking, drug use, or alcohol consumption. In addition, all participants will be assessed using three scales: the JOA score, the VAS score, and the NDI score.
Measurements
Figure 2 lists the schedule of all study assessments and timeframe in details. The assessments are described briefly below:
Primary outcome measurement
The primary outcome measure was the change in the JOA score for the cervical spine. The JOA score consists of a total of 17 points, with 4 points each for upper and lower limb motor function, 2 points each for upper and lower limb and trunk sensation, and 3 points each for bladder function. Patients were assessed using the JOA score before intervention, after intervention, and during follow-up, in accordance with the JOA evaluation criteria for cervical spine disease treatment established by the Japanese Orthopaedic Association.The results were categorized into five groups: >75% as excellent, 50%-74% as good, 20%-49% as fair, 0–19% as no change, and < 0 as deterioration.
Secondary outcome measures
The secondary outcome measures primarily consisted of VAS score, NDI score and neuroimaging data.Data will be collected at the baseline assessment and the end of intervention (4 weeks after randomization).
Visual analogue scale (VAS)
The VAS is a widely used tool to assess pain levels in clinical practice, including in China. The VAS uses a movable ruler that is 10 cm long and marked with 10 graduated points. The two ends of the ruler are labeled as "no pain" and "worst possible pain" respectively, with the score ranging from 0 to 10. The following grading system is commonly used: 0–2 for no pain, 3–4 for mild discomfort, 5–6 for moderate discomfort, 7–8 for severe discomfort, and 9–10 for extreme discomfort.
Neck Disability Index (NDI) score
The NDI score measures disability related to neck pain and includes 10 items related to neck pain intensity, personal care, lifting, reading, headache, concentration, working, sleeping, driving, and recreation. Each item is scored from 0 to 5, with higher scores indicating more severe disability. The results are interpreted as: 0–20% indicates mild disability, 21–40% indicates moderate disability, 41–60% indicates severe disability, 61%-80% indicates very severe disability, and 81%-100% indicates complete disability or the need for further examination to rule out symptom exaggeration.
Neuroimaging scans
The data for this study were collected at the Radiology Department of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, which is affiliated with Shanghai University of Traditional Chinese Medicine. Participants were positioned in a supine position with their heads secured using a specially designed head mask. All magnetic resonance imaging (MRI) scans were performed using a Siemens Magnetom Verio 3.T MRI scanner. Resting-state functional MRI (fMRI) data were obtained using a single-shot echo-planar imaging (EPI) sequence with interleaved scanning of 43 slices, flip angle of 90°, matrix of 64×64, TR of 300ms, slice thickness of 3.0mm, FOV of 230×230mm2, and gap of (voxel size 3.6×3.6×3.0mm3). T1-weighted structural scans were obtained using a weighted fast spoiled gradient-echo (FSPGR) sequence with TR/TI/TE of 190/900/2.93ms, flip angle of 9°, FOV of 256×256 mm2, slice thickness of 1.0mm, matrix of 256×256, and average of 1.0 All assessment scales and MRI scans were conducted prior to the intervention and then repeated after 4 weeks of intervention.
Safety assessment
Any adverse events such as discomfort caused by MRI procedures, headaches, or VR training that cannot be tolerated will be recorded throughout the intervention period and reported to the ethics committee to ensure safety. The Grail operators should be familiar with the trial protocol and procedures related to safety, and ethics must strictly follow the Grail operation guidelines. In case of an adverse event during the intervention, the participant will receive appropriate medical care, and all details should be recorded and reported to the principal investigator and ethics committee to determine if the trial should continue for the participant. All collected adverse events will be truthfully reported in future publications, and the incidence rate of adverse events will also be considered in the analysis.
Protocol amendment
This trial will be conducted in accordance with Protocol Version 1.0.Any modifications to the protocol will be formally amended and submitted to the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, affiliated with Shanghai University of Traditional Chinese Medicine. The study will be conducted in compliance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. Any deviations from the protocol will be documented and reported to the Ethics Committee.
Sample size calculation
The goal of our study is to investigate the effectiveness of VR technology in the rehabilitation of patients with CSM after surgery. Due to a lack of research on the effect of VR technology on the rehabilitation of CSM patients after surgery, we conducted a small-sample pilot study. The sample size was estimated based on the improvement in JOA scores for cervical spondylosis of the Japanese Orthopaedic Association. One month after surgery, the average JOA scores and standard deviations for the VR rehabilitation intervention group (n = 10) and the conventional rehabilitation group (n = 10) were 15.30 (SD = 0.90) and 14.7 (SD = 0.78), respectively, with an effect size (Cohen's D) of 0.71. Using Gpower 3.1 software, we calculated the required sample size, which, with a Type I error of α = 0.05 and a Type II error of β = 0.2, estimated a sample size of n = 64. Accounting for a dropout rate of 20%, each group required 39 participants, for a total of 78 participants. Finally, we randomly allocated the 78 participants into the VR training combined with rehabilitation intervention group and the conventional rehabilitation group, each consisting of 39 participants.
Randomization and allocation concealment
After the baseline evaluation, each eligible participant will be randomly assigned to either the intervention group or the control group in a 1:1 ratio. The random allocation cards will be generated using the random permutation principle with a random number table generated by SPSS21. These cards will be placed in opaque envelopes, with the envelope numbers corresponding to the card numbers. The envelopes will be opened in the order of the participants' visits, and the participants will be randomly assigned to either the conventional rehabilitation group or the conventional rehabilitation combined with virtual reality training group based on the grouping specified on the card inside the envelope. This method of random allocation will ensure that the assignment is unbiased and that each participant has an equal chance of being assigned to either group.
Blinding
This trial is a randomized controlled study that involves treatments that cannot be blinded, so blinding procedures are not possible.
Data Collection and Management
Initially, the screening personnel will review the inclusion and exclusion criteria and collect basic characteristic data prior to random allocation. Trained assessors, who are blinded to allocation and not involved in intervention, will play a crucial role in measuring the primary and secondary outcomes. The data for all participants will be recorded in a designed case report form (CRF). Additionally, each CRF will be checked twice to ensure the accuracy and completeness of data collection throughout the study. All relevant documents will be coded with specific identification numbers and kept in a secure, locked box to safeguard the privacy and data safety of the subjects.The magnetic resonance scans obtained during the study will be saved on a computer with restricted access and a password known only to the principal investigator. The materials will be securely stored for 5 years after the trial in compliance with medical record retention regulations and good clinical practice principles. The study will also be monitored for safety by a physical therapist and two clinical doctors who are not involved in the research. They will ensure that standard operating procedures (SOPs) are followed, monitor the study's progress, review all adverse events, and halt the trial if any measures cause significant adverse effects such as headaches, nausea, or vomiting. The assessors will report any adverse events to the data safety monitoring board (DSMB) and the ethics committee of Yueyang Integrated Chinese and Western Medicine Hospital affiliated with Shanghai University of Traditional Chinese Medicine.
Statistical analysis
All non-imaging data analyses will be performed using SPSS version 21 by an independent statistician who is blinded to the treatment and control groups to ensure objectivity and reduce bias. The statistical significance level for testing will be set at 0.05 with a two-tailed test. Continuous variables will be presented as mean, standard deviation, and maximum or minimum values based on their statistical distributions. Independent sample t-tests or non-parametric tests (Mann-Whitney U test) will be used to compare the results presented as continuous variables and mean values to validate the effectiveness of the intervention. Furthermore, intra- and inter-group comparisons were made at four weeks to observe the differences between the two intervention methods. If necessary, logistic regression, general linear correlation, or regression will be used to compare different types of results based on the variable type and distribution. Basic data comparison between the treatment and control groups will be performed using t-tests, chi-square tests, or non-parametric tests. Participants who drop out during the intervention period will not be excluded according to the intention-to-treat principle, and missing data will be replaced using the last observation carried forward method to maintain statistical power and avoid bias.
The amplitude of low frequency fluctuation (ALFF) is an indicator of the amplitude energy of the low-frequency spectrum and reflects the spontaneous activity of neurons in the resting state of the brain. ALFF is a useful tool for analyzing functional MRI data to study longitudinal neural changes and explore the relationship between brain plasticity and the recovery of sensory and motor function induced by stimulation.[21] In this study, REST 1.9 software from Beijing Normal University (http://www.restfmri.net/) will be used to perform linear drift and calculate the amplitude of signal oscillation in each voxel in the low-frequency range (0.01–0.1 Hz) to obtain ALFF images. Finally, the ALFF values of each participant will be Z-transformed for further statistical analysis.
Longitudinal measurements in a resting state task and further correlation analysis of imaging and scale score data obtained from baseline and post-intervention measurements to explore the relationship between brain remodeling and postoperative sensory and motor function recovery in CSM patients.