A Single-blind Randomized Controlled Trial of Multisensory Stimulation Virtual Reality to Improve Motor and Cognitive Function in Stroke Patients
Phase: NA
Conditions: Stroke
Sponsor: First Affiliated Hospital of Chongqing Medical University

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Safety and Efficacy of Multisensory Stimulation Virtual Reality for
Stroke Patients
Study Protocol
NCT06275516
Sponsor: Department of Rehabilitation Medicine, The First Affiliated
Hospital of Chongqing Medical University
2024.3.10

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Contents
1.
Background.....................................................................................................................................1
2.
Objectives and Expected Outcomes................................................................................................. 2
3.
Trial Design and Statistical Methods............................................................................................... 3
4.
Procedures and Clinical Pathway.................................................................................................... 4
5.
Safety Considerations and Benefits..................................................................................................9
6.
Participant Selection and Ethics.................................................................................................... 10
7.
Informed Consent Procedures....................................................................................................... 11
8.
Financing and Compensation.........................................................................................................12
9.
Data Management and Quality Assurance.....................................................................................12
10.
Privacy and Confidentiality........................................................................................................... 13
11.
Dissemination and Publication.......................................................................................................14
Reference...................................................................................................................................................... 14

1
Study protocol
Background
Stroke is one of the leading diseases threatening public health in China, characterized by high
incidence, disability, mortality, and recurrence rates. Approximately 75% of stroke survivors are
left with varying degrees of motor dysfunction, imposing a heavy psychological and economic
burden on families and society [1,2]. In 2021, the GBD 2019 Stroke Collaborators reported in
Lancet Neurology that stroke has become the third leading cause of disability worldwide [3].
Although acute treatments have improved with the widespread implementation of stroke units,
thrombolysis, and mechanical thrombectomy, a significant number of patients (>75%) still
experience severe impairments in multiple domains—including motor function, speech, and
cognition，which drastically affect their quality of life, independence, and social participation [1].
Therefore, there is an urgent need to advance neurorehabilitation strategies. Currently,
rehabilitation for post-stroke motor dysfunction predominantly relies on conventional exercise and
physical therapies. While effective, these methods face challenges such as high costs, lengthy
treatment cycles, variable therapist expertise, and poor patient adherence. Furthermore, optimal
central nervous system recovery requires patients to develop functional motor patterns through
coupled sensory, motor, and cognitive feedback. Thus, exploring precise and high-quality
rehabilitation strategies is of great clinical significance.
In
recent
years,
emerging
technologies
like
telerehabilitation,
exoskeleton
robots,
and
brain-computer interfaces have been increasingly applied to stroke rehabilitation. Among them,
virtual reality
(VR) offers unique advantages.
By breaking the scenario-constraints of
conventional therapy, VR provides multi-sensory stimulation and dynamic environments
characterized by interaction, immersion, and imagination (the "3I" features) [4,5]. Recognized by
Nature for its distinct potential in rehabilitation [5,6], VR has been widely used and proven
effective in promoting limb motor recovery. However, its widespread clinical application is often
hindered by unclear mechanisms, unstandardized protocols, and sometimes the "misuse" or
superficial application of the technology. Some studies report that while both VR and conventional
therapies improve upper limb motor function, there is no significant difference between them [7,8].
A multicenter, single-blind, randomized controlled trial also showed that VR, as an add-on to

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conventional therapy, yielded no significant additional benefits for subacute stroke patients [9].
Furthermore, a meta-analysis of 72 studies indicated that current VR trials generally have small
sample sizes, and using VR is not necessarily more beneficial than conventional methods, though
it may serve as a useful adjunct to increase overall therapy time [10]. Consequently, the true
efficacy and necessity of VR in stroke rehabilitation remain controversial.
Beyond motor deficits, cognitive impairment is a common post-stroke sequela linked to neural
damage in functional areas such as the cortical limbic system and frontal white matter [11,12]. VR
uniquely addresses this by providing interactive, multi-modal sensory stimuli (visual, auditory,
and haptic) that foster real-world-like brain and behavioral responses [13]. In a fully immersive
VR system, physical movements are dynamically coupled with the virtual environment, enhancing
the patient's sense of presence and providing the cognitive-motor integration essential for
neurological recovery.
In summary, while the clinical efficacy of VR in treating post-stroke motor dysfunction remains
debated, exploring the neural remodeling mechanisms of multi-sensory VR stimulation is an
urgent challenge. As there is a lack of rigorously designed randomized controlled trials in this area,
this study aims to provide high-quality evidence for the effectiveness of multi-sensory VR in
improving post-stroke motor function and to further elucidate its underlying neural mechanisms.
Objectives and Hypotheses
Primary Research Objective
The primary objective of this study is to compare the effects of multi-sensory virtual reality
(VR)-enhanced treadmill training versus treadmill training alone on the improvement of lower
limb motor function, balance, and gait in stroke patients, and to explore the underlying
neuroplasticity mechanisms using functional near-infrared spectroscopy (fNIRS).
Scientific Hypotheses and Expected Outcomes
It is hypothesized that multi-sensory VR intervention will be superior to conventional treadmill
training
in
improving
lower
limb
motor
function
in
stroke
patients.
By
integrating
multi-dimensional quantitative assessments, including clinical scales, three-dimensional gait
analysis, and fNIRS, which aims to further elucidate the internal mechanisms by which VR

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promotes neural remodeling. Ultimately, the findings will provide high-quality, evidence-based
support for the clinical implementation of VR technology in post-stroke motor rehabilitation.
Trial Design and Statistical Methods
Overall Framework and Timepoints
This study is a single center randomized single blind controlled trial. A total of 40 stroke patients
will be enrolled and randomly assigned to either the multi-sensory virtual reality enhanced
treadmill training group or the treadmill training group in a 1 to 1 ratio. The entire trial includes a
baseline period and a 4-week intervention period and a 3 month follow up period. Based on
conventional rehabilitation both groups will receive their respective treadmill interventions with a
frequency of 7 sessions per week for 4 consecutive weeks. Assessments will be conducted at four
key time points including baseline on Day 0 and mid intervention at Week 2 and post intervention
at Week 4 and long term follow up at Week 12. The evaluation system focuses on lower limb
motor function and neural remodeling mechanisms. The primary outcome measure is the
Fugl-Meyer Assessment Lower Limb scale. Secondary outcomes include three-dimensional gait
analysis and the Berg Balance Scale and the Activities of Daily Living scale and the Mini Mental
State Examination and the Montreal Cognitive Assessment and functional near infrared
spectroscopy. Adverse events such as falls and dizziness will be recorded throughout the study to
evaluate clinical safety.
Study Type
This study is a single center randomized single blind controlled trial.
Sample Size and Statistical Framework
Sample Size Calculation
The sample size for this study was estimated using PASS 15.0 software before the start of the trial.
Based on parameters from previous research we set the significance level at 0.1 and the power at
0.8 and the allowable error at 6.5 and the standard deviation at 8.0 for the calculation. The results

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indicated that 20 patients are required for each group and the total sample size is 40.
Statistical Methods
All data analysis will be performed using SPSS 27.0 statistical software. The Kolmogorov
Smirnov test will be used to evaluate the normal distribution of data before description.
Continuous variables with a normal distribution will be expressed as mean and standard deviation
while non normal data will be presented as median and interquartile range. Categorical variables
will be described using frequencies and percentages. In the analysis of efficacy and safety before
and after treatment we will use independent or paired t tests for normally distributed data and
Mann Whitney U tests for non-normal data. Comparisons of categorical variables such as adverse
events will be conducted using the Chi square test or Fisher’s exact test. Correlation analysis will
use Pearson or Spearman tests depending on the data distribution. For key observation indicators
during the follow up period a linear mixed model will be used for repeated measures analysis to
test group differences as well as time and interaction effects. To control for potential heterogeneity
caused by age the study will also perform stratified analysis by age group. A P value of less than
0.05 will be considered statistically significant for all tests.
Procedures and Clinical Pathway
Study Design
This study is a prospective single center randomized parallel controlled clinical trial. The entire
research period is divided into a baseline screening and assessment phase as well as a 4 week
clinical intervention period and a 3 month long term follow up period. Following enrollment both
groups will receive their established rehabilitation interventions 7 times per week for 4
consecutive weeks. To scientifically quantify the intervention efficacy and the disease recovery
process the study avoids high frequency and fragmented visit schedules and instead establishes
four precise clinical assessment time points including baseline on Day 0 and mid intervention at
Week 2 and post intervention at Week 4 and long term follow up at Week 12.
Clinical Visits and Assessment Sequence
Screening Period at V0
Initial screening of subjects will be completed before the trial officially begins. Researchers must
verify whether stroke patients diagnosed via neuroimaging meet all inclusion and exclusion
criteria and collect detailed medical histories and complete basic physical examinations and obtain
written informed consent signed by the patients.
Randomization and Baseline Assessment at V1

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Patients meeting the screening criteria will be randomly assigned to either the intervention group
or the control group and comprehensive collection of baseline core data will be performed on Day
0. The assessment focuses strictly on the core endpoint of this study which primarily involves the
lower limb Fugl-Meyer Assessment score. Secondary evaluations performed simultaneously
include three-dimensional gait detection and the Berg Balance Scale and the Activities of Daily
Living scale and the Mini Mental State Examination and the Montreal Cognitive Assessment.
Furthermore, brain function detection using fNIRS based on real world walking paradigms will
also be completed.
Intervention Period and Process Assessment at V2 to V21
Patients will officially enter a 4-week treadmill intervention phase with 7 sessions per week.
During the intervention the research team will continuously monitor and record the frequency and
severity of safety related adverse events such as falls and dizziness. At two key time points
including mid intervention at Week 2 and post intervention at Week 4 professional rehabilitation
therapists who are blinded to the group assignments will perform repeated assessments of all
motor and cognitive and fNIRS brain function indicators identical to those at baseline.
Follow up Period at V22
A long-term observation phase will begin after the 4-week intervention is completed. The final
follow up assessment will be conducted at Week 12 which is 3 months after the intervention.
Evaluators will again collect all established indicators including FMA LE and BBS and
three-dimensional gait analysis and ADL and MMSE and MoCA as well as fNIRS detection to
scientifically evaluate the long-term functional improvement and brain remodeling effects brought
by the intervention.
Study Flowchart
Randomization and Blinding Design
Randomization and Grouping
A total of 40 stroke patients will be included in this study and assigned into groups using a clear odd
and even number randomization method. Each successfully enrolled patient will be randomly assigned
an independent identification number between 1 and 40. This study follows a 1 to 1 allocation ratio and

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the specific rule is that patients assigned an odd number will be directly allocated to the control group
for treadmill training alone and patients assigned an even number will be allocated to the experimental
group for multi-sensory VR enhanced treadmill training. The allocation concealment process will be
strictly managed by a designated staff member to ensure the objectivity and fairness of the enrollment
process.
Implementation of Blinding and Unblinding
Since the intervention methods used in the experimental and control groups make it impossible to
blind the subjects and the practitioners this study adopts a single blind setting. To effectively
reduce potential bias caused by subjective assessment a strict single blind evaluation design is
implemented. Throughout the entire trial period all researchers responsible for collecting clinical
data and assessing rehabilitation outcomes will remain completely unaware of the group
assignments and the specific intervention protocols for the patients.
Assessment of Blinding Effectiveness
At the end of the final follow up visit evaluators will be required to make a forced choice
regarding which group they believe the patient was assigned to. This procedure is used to assess
the effectiveness of blinding for the evaluators. The guessing options for the evaluators include the
experimental group or the control group or do not know. Based on the final results the single blind
trial is considered successfully implemented if the proportion of do not know responses is high or
if the proportions of experimental group and control group guesses are similar.
Intervention Protocols and Parameters
Experimental Group
Patients randomly assigned to the experimental group will receive multi-sensory stimulation
virtual reality combined with treadmill training in addition to conventional rehabilitation therapy
which includes physical therapy and motor function training. The intervention frequency is 7
sessions per week for 4 consecutive weeks. This immersive VR system utilizes a circular
projection screen to provide 12 types of virtual visual scenes and is equipped with stereo speakers
and real time odor playback devices to achieve synchronized visual and auditory and olfactory
stimulation. During training the VR environment undergoes real time dynamic adjustments based
on the movement of the treadmill. When terrain fluctuations appear in the virtual scene the

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treadmill generates corresponding inclinations to provide balance related sensory feedback for the
patient. Patients can also interact with the virtual environment through buttons on both sides of the
treadmill or camera-based motion capture gestures based on their individual abilities. Professional
rehabilitation therapists will individually adjust core parameters such as virtual scenes and
ambient music as well as treadmill speed and assistance levels and resistance and inclination
according to the actual rehabilitation needs of each patient.
Control Group
Patients randomly assigned to the control group will also receive conventional rehabilitation
therapy but will only undergo treadmill training alone without any virtual reality environmental
stimulation. The intervention frequency remains strictly consistent with the experimental group at
7 sessions per week for 4 consecutive weeks. To ensure effective matching and comparability of
training intensity between the two groups rehabilitation therapists will customize a treadmill
training plan based on the current physical condition of each patient. During each training session
therapists will timely adjust key parameters such as treadmill speed and assistance levels and
resistance and inclination to ensure the entire rehabilitation program fully meets the specific
treatment needs and physiological tolerance of the patient.
Baseline Data Acquisition
During the study baseline period on Day 0 researchers will systematically collect and record
various basic information and core assessment data of the subjects. The collection will first
include demographic characteristics such as age and sex as well as disease related data such as the
date of stroke diagnosis and previous medical history and comorbidities. Regarding efficacy
evaluation indicators the research will strictly focus on the multi-dimensional system established
in this protocol. Baseline data for motor and balance functions will be quantitatively collected
through the Fugl-Meyer Assessment Lower Limb scale and the Berg Balance Scale as well as an
objective three-dimensional gait analysis system. Cognitive status and activities of daily living
will be assessed using the Mini Mental State Examination and the Montreal Cognitive Assessment
and the Activities of Daily Living scale. Furthermore, functional near infrared spectroscopy
detection based on real world walking paradigms will be completed during the baseline phase to
obtain initial cortical blood oxygen changes and functional connectivity benchmark data. All
information will be accurately entered into the Case Report Forms to serve as the core control
standard for evaluating subsequent intervention efficacy.
Treatment Compliance Monitoring
To evaluate compliance with the research treatment any reasons for non-compliance should also

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be recorded in detail.
Concomitant Medication and Therapy
All medications and other treatments including dosages and dates used for other comorbidities
during the trial period must be recorded in the Case Report Forms. The relevant information must
be documented on the concomitant treatment page of the Case Report Forms.
Clinical Outcome Measures
The clinical outcome evaluation system of this study has been strictly streamlined to ensure
precise quantification of rehabilitation efficacy and neural mechanisms. The primary outcome
measure is clearly defined as the Fugl-Meyer Assessment Lower Limb scale and it is used for the
core assessment of lower limb motor function recovery. Secondary outcome measures focus on
comprehensive
functional
performance
and
cranial
nerve
remodeling
including
motor
biomechanics and balance control evaluated via three-dimensional gait analysis and the Berg
Balance Scale. Additional measures include independence in daily living measured by the
Activities of Daily Living scale and cognitive status reflected by the Mini Mental State
Examination combined with the Montreal Cognitive Assessment as well as cortical blood oxygen
changes and functional connectivity during specific walking tasks measured by functional near
infrared spectroscopy. Furthermore, safety evaluation indicators primarily monitor the frequency
and severity of adverse events such as falls and dizziness during the intervention to ensure the
overall clinical safety of the subjects.
Evaluation Methods
All clinical scales and three-dimensional gait analysis as well as functional near infrared
spectroscopy brain function tests in this study will be completed at the Department of
Rehabilitation Medicine of the First Affiliated Hospital of Chongqing Medical University. To
minimize subjective assessment bias all scale measurements and objective tests will be strictly
performed by rehabilitation therapists who have received standardized professional training and
the evaluators remain completely blinded to the specific intervention protocols and group
assignments
of
the
patients.
Regarding
the
assessment
schedule
the
collection
of
all
aforementioned indicators is strictly standardized to be completed at four key time points
including baseline on Day 0 and mid intervention at Week 2 and post intervention at Week 4 and

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three months after the intervention at Week 12.
Safety Evaluation and Adverse Events
The safety evaluation of this study primarily focuses on the occurrence of adverse events during
the intervention and the core indicators include the frequency of events such as falls and dizziness
during the intervention process. If a subject experiences a serious adverse event such as a severe
fall leading to functional impairment or intense dizziness or severe vomiting the research team
will immediately terminate the participation of that patient to ensure medical safety. All adverse
events must be recorded in detail and the overall incidence rate of adverse events will be
objectively calculated by dividing the total number of adverse events by the total number of
subjects. Furthermore, the sponsor will be responsible for the medical follow up costs of the
subjects if any serious adverse events directly related to this clinical trial occur.
Safety Considerations and Benefits
Potential Risks and Mitigation
This clinical trial is relatively safe overall however there is still a potential risk of adverse events
such as falls and dizziness during the virtual reality combined with treadmill intervention. During
the screening phase before enrollment the research team has strictly excluded patients at high risk
of such adverse events. If mild discomfort occurs during the intervention the principal investigator
and the team will make timely clinical assessments and provide appropriate treatment based on the
actual condition of the subject. It must be emphasized that if a serious adverse event occurs such
as a severe fall leading to impaired motor function or heavy vertigo or even projectile vomiting the
researchers will immediately terminate the participation of that patient to ensure medical safety.
Discomfort and Technical Safety
During conventional rehabilitation interventions subjects may experience a certain degree of
physical fatigue or mild dizziness. Very few patients withdraw from studies due to these common
discomforts. If a subject experiences discomfort during training professional rehabilitation
therapists will individually adjust parameters such as treadmill speed and assistance levels and
resistance and inclination based on the current physical state of the patient to effectively alleviate
symptoms and ensure safety. Additionally, the imaging assessment method used in this study such

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as functional near infrared spectroscopy is a completely non-invasive detection method and will
not cause any harm to the human body under routine operation.
Direct and Indirect Benefits
Subjects participating in this trial will receive all comprehensive clinical assessments and
objective tests prescribed in the protocol free of charge under the full follow up and professional
management of the research team. Through standardized multi-sensory intervention, the lower
limb motor function and gait performance of the subjects are expected to achieve positive
improvements. Furthermore, if any serious adverse event directly related to the research occurs
during the trial the sponsor will provide full coverage and bear the subsequent medical follow up
costs. The participation of subjects will also provide solid data support for elucidating the
neuroplasticity mechanisms of virtual reality technology in promoting stroke recovery and further
promote more precise and efficient clinical rehabilitation practices in the future.
Participant Selection and Ethics
Identification of Study Population
This trial will recruit 40 patients with confirmed stroke at the Department of Rehabilitation
Medicine of the First Affiliated Hospital of Chongqing Medical University. The diagnosis of the
research subjects must be clearly confirmed as a first episode stroke through clinical evaluation
and neuroimaging.
Inclusion and Exclusion Criteria
Inclusion Criteria
1）Diagnosis of first stroke confirmed by neuroimaging such as CT or MRI.
2）Age between 18 and 85 years.
3）Lower limb Fugl-Meyer Assessment (FMA-LE) score of less than 34.
4）Ability to complete walking with minimal assistance.
5）Mini Mental State Examination (MMSE) score between 20 and 30 and the ability to
understand and follow instructions during the trial.
6）Patients who voluntarily sign the informed consent form.
Exclusion Criteria

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1）Presence of severe visual or hearing impairment.
2）Women who are pregnant or breastfeeding.
3）Presence of unrepaired cranial defects or metal implants in the body following brain surgery.
4）Presence of other diseases affecting lower limb motor function such as osteoarthritis or recent
lower limb fractures.
5）Previous
history
of
severe
mental
illness
or
other
neurological
diseases
or
acute
cardiopulmonary insufficiency or multi organ failure or brain tumors or epilepsy.
Safety Monitoring and Protection
During the clinical intervention the research team will closely monitor and properly record
potential adverse events such as falls and dizziness. If a patient experiences a serious adverse
event such as a severe fall leading to impaired motor function or heavy vertigo or even projectile
vomiting the researchers will immediately terminate the participation of that patient to effectively
ensure the life and health and medical safety of the subjects.
Study Completion and Termination
The research is considered officially completed when the last subject in the trial finishes the
established follow up assessment. Throughout the trial the principal investigator has the right to
terminate the study at any time based on clinical safety considerations especially when
assessments find that continuing the intervention may harm the legal rights and physical or mental
health of the subjects.
Informed Consent Procedures
The informed consent process of this study will be implemented by the research team from the
Department of Rehabilitation Medicine at the First Affiliated Hospital of Chongqing Medical
University. Researchers will provide patients and their families with a detailed and easy to
understand explanation of the research protocol and procedures regarding multi-sensory virtual
reality for improving motor function after stroke. The information provided clearly includes that
the study intends to recruit 40 patients with confirmed stroke. After signing the informed consent
form patients will undergo a strict check of inclusion and exclusion criteria and those who meet
the criteria will be randomly assigned to groups. These participants will receive core assessments
of motor function and balance and gait and cognitive function as well as fNIRS brain function at

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the intervention and follow up nodes. The research team will give patients and their families
sufficient time for consideration and once voluntary participation is confirmed the subject or their
legal representative will sign and date the informed consent form. This trial does not include
subjects who lack the capacity for civil conduct. If a subject or their legal representative is
illiterate the informed consent process must be completed with the participation of an independent
witness who will also sign and confirm the document. The informed consent form will be prepared
in duplicate and after being signed by the investigator one copy will be kept by the subject or their
legal representative and the other will be archived by the research team. The entire process of
obtaining informed consent will be standardized and recorded in the medical records of the patient.
If there are important protocol updates involving the trial in the future, they must be approved by
the Ethics Committee before being fully explained to the patients again to obtain their renewed
consent.
Financing and Compensation
The intervention period of this study is clear and relatively safe and adverse events occur very
rarely. During the participation in this study the project team will provide all clinical scale
assessments and objective instrument tests as well as corresponding rehabilitation interventions
related to the trial free of charge. If a subject experiences a serious adverse event directly related
to participating in this clinical trial the sponsor will be responsible for bearing the full cost of
medical follow up and treatment to effectively protect the rights and economic interests of the
subject.
Data Management and Quality Assurance
Data Acquisition and Entry Standards
Under the premise of obtaining full informed consent from the subjects the original data will be
directly collected by professional researchers who have received unified training through paper
forms or assessment instruments. To effectively avoid human bias that may occur during the
digitalization of clinical data all original information will be entered into an electronic database in
parallel by two independent researchers using a double entry method. If inconsistencies are found
when comparing the information entered by the two people the research team will carefully check
the original paper or instrument records to thoroughly investigate and correct errors to ensure the

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accuracy of the final clinical data.
Quality Control and Traceability
Researchers responsible for data management will conduct a comprehensive and centralized check
on the authenticity and completeness and accuracy of all collected data strictly according to the
requirements of the study protocol. The core content of the quality control audit covers whether
the actual enrolled cases strictly meet the inclusion and exclusion criteria stipulated in the protocol
and whether the baseline and subsequent follow up assessments were completed on time within
the strict time windows as well as whether adjustments to intervention parameters and all adverse
events occurring during the study were recorded truthfully and in detail. Furthermore, all
modifications involving data must strictly comply with traceability standards. If there is a need to
correct the paper version of the Case Report Form it is strictly forbidden to smear or cover the
original data. The original error must be crossed out with a single line and the correct data must be
clearly marked beside it along with the signature of the person making the change and the date and
the reason for the modification. The corresponding electronic database system will also fully
enable the operation traceability function to completely record the status before and after every
data change and the information of the operator to comprehensively guarantee the credibility and
scientific rigor of the trial data.
Privacy and Confidentiality
After signing the informed consent form the research team will immediately assign a unique and
independent code to each subject which will serve as their sole identification code throughout the
entire study period and in the clinical research database. All collected original medical data will be
strictly stored under this code and only authorized researchers can link the research data to the
subject themselves through a confidential identification code list. Throughout the entire process of
collection and transmission and processing and storage of patient data this study will strictly
comply with relevant data protection laws and regulations to maximize the protection of personal
privacy of the patients. In any final report or publicly published academic article related to this
trial the research team will absolutely not use or disclose any sensitive information that could
identify the personal identity of the subjects.

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Dissemination and Publication
The final results of this study are planned to be shared through public reports at professional
scientific and academic conferences or published in peer reviewed academic journals for extensive
scientific exchange and sharing. When conducting any form of research result presentation or oral
statement or article publication the research team will strictly implement confidentiality principles
and will never involve or disclose any personal identity information or privacy protection content
of the subjects. Meanwhile after the entire trial is completed, we will also provide timely feedback
on the overall progress of the research and the final beneficial results to all subjects who
participated in this trial.
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