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Abstract
Introduction Deep brain stimulation (DBS) and vagus nerve stimulation (VNS) can improve motor function in patients with poststroke hemiplegia. No comparison study exists.
Methods and analysis This is a randomised, double-blind, controlled clinical trial involving 64 patients who had their first stroke at least 6 months ago and are experiencing poststroke limb dysfunction. These patients must receive necessary support at home and consent to participate. The aim is to evaluate the effectiveness and safety of DBS and VNS therapies. Patients are excluded if they have implantable devices that are sensitive to electrical currents, severe abnormalities in their lower limbs or are unable to comply with the trial procedures. The study has two parallel, distinct treatment arms: the Stimulation Group and the Sham Group. Initially, the Stimulation Group will undergo immediate electrical stimulation postsurgery, while the Sham Group will receive non-stimulation 1 month later. After 3 months, these groups will swap treatments, with the Stimulation Group discontinuing stimulation and the Sham Group initiating stimulation. Six months later, both groups will resume active stimulation. Our primary outcomes will meticulously assess motor function improvements, using the Fugl-Meyer Assessment, and safety, monitored by tracking adverse reaction rates. Furthermore, we will gain a comprehensive view of patient outcomes by evaluating secondary measures, including clinical improvement (National Institutes of Health Stroke Scale), surgical complications/side effects, quality of life (36-item Short Form Questionnaire) and mental health status (Hamilton Anxiety Rating Scale/Hamilton Depression Rating Scale). To ensure a thorough understanding of the long-term effects, we will conduct follow-ups at 9 and 12 months postsurgery, with additional long-term assessments at 15 and 18 months. These follow-ups will assess the sustained performance and durability of the treatment effects. The statistical analysis will uncover the optimal treatment strategy for poststroke hemiplegia, providing valuable insights for clinicians and patients alike.
Ethics and dissemination This study was reviewed and approved by the Ethical Committee of Chinese PLA General Hospital (S2022-789-01). The findings will be submitted for publication in peer-reviewed journals with online accessibility, ensuring adherence to the conventional scientific publishing process while clarifying how the research outcomes will be disseminated and accessed.
Trial registration number NCT06121947.
- stroke
- neurosurgery
- physical therapy modalities
- research design
- stroke medicine
- electric stimulation therapy
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- stroke
- neurosurgery
- physical therapy modalities
- research design
- stroke medicine
- electric stimulation therapy
STRENGTHS AND LIMITATIONS OF THIS STUDY
The study is the first randomised controlled study comparing the efficacy and safety of deep brain stimulation and vagus nerve stimulation for poststroke hemiplegia.
The outcomes are evaluated blindly through randomly shuffled and standardised videos to minimise potential biases.
One possible limitation is that operators and doctors will not be blinded because of the nature of the surgical intervention.
Introduction
Background and rationale
Strokes, defined as ‘a sudden onset of focal (or global) neurological deficit of presumed vascular origin, lasting at least 24 hours or resulting in death, and not attributable to non-vascular causes’,1–4 are surpassed only by cancer and cardiovascular disease as leading causes of death. In 2019, strokes accounted for 11.6% of all deaths worldwide, with a 70% increase in incidence and a 43% rise in fatality rate since 1990.5 Projections indicate that the number of stroke deaths will escalate from 6.6 million in 2020 to 9.7 million by 2050, and the total cost of expenses associated with stroke could more than double, from US$891 billion in 2020 to as much as US$2.3 trillion in 2050, encompassing both direct medical costs and indirect burdens.6 Previous studies show that 1%–4% of stroke survivors develop long-term motor problems in their limbs, including uncontrolled movements, stiffness, shaking or vascular parkinsonism. There are two main types: too much movement (hyperkinesia) and insufficient movement (hypokinesia).7–9 Right now, there are not great treatments for these lasting motor issues. Traditional rehabilitation is often not very helpful, expensive and takes a long time, making it hard for patients to stick to their plans. New methods are being tried, like deep brain stimulation (DBS)10 11 and vagus nerve stimulation (VNS) therapy.12–17 These use electricity to stimulate the brain or nerves, helping motor function. They have been proven safe and effective for other neurological problems and have shown promise in patients who had stroke based on animal and human studies.18 19
DBS has demonstrated remarkable therapeutic outcomes in treating previously challenging conditions like Parkinson’s disease, Major syndrome. Inspired by these successes, researchers have explored its use in restoring motor function after stroke. Animal studies and clinical trials have shown DBS to be effective in this context.20–23 Elias et al reviewed nine studies involving 32 patients with dyskinesia who had stroke, finding significant symptom improvement in at least 13 patients after DBS. Another study with 20 patients who had stroke reported motor function improvements in 11 out of 14 patients who received DBS electrodes in the internal capsule’s posterior limb.24 Franzini et al also reported motor function gains in three patients who had stroke treated with DBS targeting the contralateral internal capsule hindlimb. In 2023, a study on 12 patients who had stroke with moderate to severe upper limb motor deficits found that DBS of the cerebellar dentate nucleus increased their Fugl-Meyer motor function score by 7 points and with no severe complications. DBS can regulate neuroplasticity25 26 and neural pathways,27–29 promote nerve repair and regeneration,30–32 reduce inflammatory responses and brain function damage,33 34 repair brain connections and networks35 36 and other mechanisms to exert therapeutic effects. DBS, being an ideal, safe and reversible treatment for poststroke hemiplegia, holds immense potential for future advancements in stroke recovery therapies.37
The mesencephalic locomotor region (MLR), situated at the pontomesencephalic junction between the substantia nigra and locus coeruleus, comprises diverse neuronal populations. Key cell types are GABA, glutamatergic and cholinergic neurons, structuring four subregions: pedunculopontine nucleus, rostrocaudal areas of pre-cuneiform and cuneiform nuclei (CnF), along with the adjacent mesencephalic reticular formation.38 Stimulating MLR triggers concurrent changes in muscle tension and movement. Glutamatergic neuron activation initiates movement, while cholinergic neurons regulate ongoing motion. Information from the cortex reaches MLR, undergoes encoding and feeds back through its structures, generating movement instructions that loop back to the motor cortex. MLR is crucial in regulating motor pathways, relaying cortical excitation to the motor nerve circuit. Bilateral MLR stimulation elicits symmetrical excitation in pons and medulla oblongata reticular formations, activating the spinal motor network. Recent research has revealed that the selective activation of glutamatergic neurons within the CnF significantly enhances motor function in mice with chronic spinal cord injury, hinting at the promising potential of optogenetics in treating a wide array of movement disorders, including Parkinson’s disease, spinal cord injuries, poststroke dyskinesia and beyond.39–42 Recently, the MLR has garnered attention as a potential target for DBS to address motor dysfunction poststroke, and it has garnered significant attention as a primary therapeutic target.43 44 Research conducted in these studies has revealed that MLR-DBS enhances walking speed and limb coordination in rodent models of acute stroke, underscoring its potential therapeutic benefits. It is a promising therapeutic approach for glutamatergic neurons within the cuneate nucleus fasciculus. This stimulation triggers robust afferent and efferent fibre responses, facilitating rapid movement initiation via spinal reticular fibres and ultimately enhancing motor function. This mechanism holds significant potential for improving movement disorders that arise poststroke. Fluri et al found that high-frequency stimulation of the MLR in rats with poststroke hemiplegia improved walking speed and gait, enabling them to cross beams more steadily with fewer errors. It suggests MLR-HFS (High-frequency stimulation）could help alleviate motor dysfunction poststroke. Rats regained their independent beam-crossing ability after MLR-HFS by protecting brainstem and spinal cord motor centres from poststroke abnormal cortical signals, fostering compensatory neural circuits. More recently, Schuhmann et al delved into the neuroinflammatory implications of MLR-HFS in a mouse model that mimics photothrombotic stroke. Although MLR-HFS did not impact the infarct size, it effectively diminished the concentration of proinflammatory cells, thereby reinforcing its potential as a therapeutic strategy.45 46 In 2022, multiple studies expanded our understanding of MLR-DBS and its effects on motor function. Chang et al employed Electromyography(EMG) recordings, joint kinematics and treadmill tests in Yucatan micro pigs, implanting Medtronic 3389 electrodes into the MLR. They found that stimulation centred on the cuneate nucleus enhanced movement, with stimulation frequency regulating movement speed and step frequency.47 Van der Zouwen et al highlighted the importance of Vglut2-positive neurons in the cuneate nucleus for promoting locomotion while preserving braking and turning abilities, ensuring smooth navigation. These findings point to clinical potential, as cuneate nucleus stimulation enhances motor function in conditions like Parkinson’s disease, spinal cord injury and stroke. Krämer et al conducted a positron emission tomography (PET) study on poststroke hemiplegic rats, implanting electrodes in the right MLR. They observed a significant increase in 2-[18F]Fluoro-2-deoxyglucose ([18F]FDG) uptake on the right side postintervention, with absent uptake in the left cortico-striatal thalamic loop. Notably, MLR-HFS elevated glucose metabolism in the right associated cortex compared with the ipsilateral sensorimotor cortex, indicating that MLR-HFS may reverse long-range network effects causing chronic motor symptoms poststroke.48
The Food and Drug Administration (FDA) has approved VNS for treating refractory partial epilepsy and severe recurrent depression. Emerging research indicates its potential in poststroke motor dysfunction.49 Combining VNS with rehabilitation therapy significantly enhances motor recovery after stroke, supported by extensive preclinical and clinical evidence.50 Dawson et al randomly divided 21 patients who had chronic ischaemic stroke into two groups: one received VNS-paired rehabilitation, while the other underwent rehabilitation alone. After the intervention, there was a notable difference in Fugl-Meyer Assessment for Upper Extremity (FMA-UE) scores between the two groups.51 Similarly, Kimberley et al found statistically significant improvements in FMA-UE and Wolf Motor Function Test(WMFT) scores after 90 days of VNS implantation in poststroke patients.52 Dawson conducted a follow-up study and the results showed that VNS-paired rehabilitation therapy significantly improved motor function in patients with chronic ischaemic stroke motor dysfunction. VNS improves movement function by reducing inflammation and cell death, promoting blood vessel growth and neuroprotection, maintaining blood-brain barrier integrity and minimising harmful chemical events. Its therapeutic benefits make it a promising treatment option for poststroke motor dysfunction.53–56 Although DBS and VNS both exhibit promising potential as treatments for poststroke motor dysfunction, there is currently no direct comparison between the two methods specifically for this condition.57 58
Objective
We have developed a multi-centre randomised controlled trial protocol. Our primary goal is to rigorously evaluate the effectiveness and safety of both DBS and VNS in improving motor function recovery after a stroke. The secondary purpose of this study is to explore the underlying mechanisms of neurological treatment of poststroke motor dysfunction and its impact on a patient’s quality of life, psychosocial status, as measured by National Institutes of Health Stroke Scale (NIHSS) scores, 36-item Short Form Questionnaire (SF-36), Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD).
Methods and analysis
Study design
The multicenterre, randomised, double-blind, controlled trial start date is 10 November 2023, with an estimated end date of 30 October 2030. The study will recruit 64 participants who have experienced a sudden onset of focal (or global) neurological deficit of presumed vascular origin, lasting for at least 24 hours or resulting in death, and which is not attributable to non-vascular causes. They will be assigned to either the DBS or VNS group. Each group will split into two subgroups: a stimulation group and a sham stimulation group. The stimulation subgroups will commence electrical stimulation, while the control subgroups will receive sham stimulation 1 month after surgery. After a 3-month follow-up, the machines will be stopped stimulation, and a 2-week washout period will follow. During this time, the control subgroups will receive stimulation. All patients will be under stimulation by the end of the 6-month follow-up. Independent researchers will continue to monitor patients at 9, 12, 15 and 18 months postoperatively. The primary outcomes focus on motor function improvement measured by the FMA Scale and safety assessed by the incidence of adverse reactions. The secondary outcomes of the study encompass a diverse range of functional assessments, including the evaluation of clinical symptom improvement through the NIHSS, monitoring surgical complications and side effects, assessing quality of life with the SF-36 survey for a multidimensional view and quantifying mental well-being with the HAMA and HAMD scales to gain insights into patients’ emotional health and psychological states. Statistical analysis will elucidate the optimal treatment strategy for poststroke hemiplegia (figure 1).
Brief flowchart of the entire study with draw. DBS, deep brain stimulation; VNS, vagus nerve stimulation.
Participants
First, we will post recruitment notices on the official websites. We then will register patient information and conduct initial screening via phone and video calls. Patients who clear this screening proceed to the outpatient clinic, where they undergo further screening by third-party evaluators. After a thorough evaluation, patients deemed suitable for surgery will be admitted to the hospital. During the perioperative period, patients undergo a reassessment based on the inclusion and exclusion criteria outlined in table 1 to ascertain surgical indications and contraindications. Those who successfully pass this screening will be enrolled in the clinical trial by third-party evaluators, who will gather baseline data and perform necessary evaluations.
Patients were included into the exclusion criteria
Sample size
Statistical experts recommended a 1:1 ratio for the experimental and control groups. Based on the literature review, we observed that VNS for poststroke motor dysfunction yields a higher FMA-UE score compared with the control group (VNS: 5.8±6.0, Control: 2.8±5.2; p=0.008, difference: 2.96, 95% CI: 0.83 to 5.08). For DBS in poststroke motor dysfunction, FMA-UE scores showed no significant decrease from baseline on surgical implantation. However, combining DBS stimulation with rehabilitation training further boosted scores by 7 points (p=0.0005). As DBS effects waned, scores stabilised, indicating long-term benefits.
In summary, the average Fugl-Meyer score improvement ranged from 2.96 to 7.00 for VNS and DBS, with a midpoint of 4.98 used for sample size estimation. This study aims to detect differences in mean scores between the experimental (u1) and control (u2) groups using a two-sided hypothesis test (H0: u1−u2=0, H1: u1−u2≠0). With a significance level of 5%, power of 90%, and an anticipated dropout rate of 20%, PASS V.15 software calculated a total sample size of 48 (24 per group).59–64 Furthermore, to account for potential electrode implantation bias and the need for four groups, enrolling 64 patients—32 in each group—would ensure a balanced group size by the previous conclusion. Drawing from DBS-MLR, we are confident that this sample size will yield clinically meaningful results, fulfilling the objectives.65 66
Randomisation and blinding
The OpenClinica platform will generate random numbers for central randomisation. On enrollment, each centre will request a random number for a patient after entering their basic information, accessible only to one coordinator per centre. An independent statistician will assign patients 1:1 to either the DBS or VNS treatment group post-baseline assessment. The third-party evaluators will assess outpatient recovery, guiding rehabilitation training and electrical stimulation. Allocation concealment will ensure study quality, with allocation details secured in a sealed envelope by a non-study participant. Rehabilitation therapists, patients, evaluators and data analysts will remain blinded until data collection and analysis are complete. Operators and doctors will not be blinded for patient safety and rights protection.67
Intervention
All patients will undergo neuromodulation surgery 1 week after baseline assessment, perioperative preparation, and exclusion of surgical contraindications. Although DBS and VNS are not yet standard surgical treatments in China, they are increasingly being applied to patients with poststroke motor dysfunction. The specific surgical procedure is as follows:
DBS implantation
Before surgery, a high-resolution MRI scan fusion will determine stereotaxic coordinates using preset paths. We will get CnF coordinates from MRI brainstem markers, adjust them and confirm with tract mapping. Then, we will place DBS electrodes (L301C; Beijing Pins Medical) along these paths to map CnFs, create a tunnel under and thread the electrode wire. The intracranial electrode will attach to the wire’s top, secure to the bone with a titanium connector and connect to the PINS G101 generator. The wire’s bottom will connect, lock and go into the right subclavian area. We will test the system to ensure it works well, keeping impedance low, and the left side will follow the same steps. Since this is the first study on DBS-CnF for poststroke hemiplegia, we do not know the best stimulation settings. Past studies suggest low-frequency (≤50 Hz) and moderate pulse widths (200–1000 μs). Given MLR’s similarity across animals, we will start with 20 Hz, 400 μs and 2.0–4.5 V, adjusting based on patient response during surgery68–71 (figure 2).
Schematic representation of the surgical locations in the DBS and VNS.
VNS implantation
The surgeon will make incisions under the left neck and collarbone region, and create a 3 cm transverse incision beneath the collarbone. Subsequently, on the left side of the neck, dissection of skin and platysma muscle, exposing the anterior border of the left sternocleidomastoid muscle. The surgeon then will locate the carotid artery and proceed with further dissection to reveal the carotid sheath, which encases the artery and associated structures. The opening carotid sheath is adjacent to the internal carotid artery and vein. The surgeon will separate and expose a 4 cm segment of the vagus nerve. An electrode will be inserted and positioned around the vagus nerve, ensuring its secure fixation. The opposite end of the electrode will be connected to the pulse generator, which will be implanted within the chest region. Finally, the surgical team conducts tests to verify the proper functioning of the electrode-transmitter connection and impedance levels. Once confirmed, the incisions will be closed individually.
Outcome measurement
The third-party evaluators will evaluate all outcome measures at baseline, 1 month before surgery (perioperative period) and during follow-up evaluations at 1, 3, 6, 9, 12, 15 and 18 months postsurgery (refer to tables 2 and 3). If unforeseen circumstances hinder outpatient clinic attendance, video or telephone follow-ups will temporarily substitute until outpatient treatment resumes. During subsequent clinic visits, patients and their families will receive counselling on prior non-clinic follow-up outcomes and undergo a comprehensive reassessment. The personnel involved in the follow-up evaluations will remain blinded to the randomised controlled trial. The subject’s stroke location and timing will be recorded at T1, and all measurement results will be securely stored and uploaded to a third-party’s online data management system in the future.
Outcome measurement
Outcome assessment schedule
Primary outcome
Effect of motor function intervention
The effect of motor function intervention on patients who had stroke will be assessed using the FMA Scale, a widely adopted clinical tool rooted in Brunnstrom staging. FMA employs a 3-point scoring system (0–2 points) across 50 items, encompassing movement (100 points), balance (14 points), sensation (24 points), range of motion (44 points) and pain (not 44 points, as mentioned earlier; corrected to reflect the total), totaling 226 points. A higher FMA Score indicates superior motor function. The primary outcome focuses on the change in FMA Score after 4 weeks of intervention compared with baseline, primarily contrasting the DBS and VNS with a secondary comparison between the stimulation and sham stimulation groups.72
Safety
It will be quantified by the incidence of adverse events (AEs) postsurgery, calculated as the ratio of affected patients (T2) to the total patient population (T1). A higher incidence translates to reduced safety. Across various clinical scales and follow-up durations, this will be considered safe if the AE incidence rate remains below the threshold of 5%.
Secondary outcome
Overall improvement in clinical symptoms
The evaluation will use the NIHSS, a prevalent and highly regarded stroke assessment tool in neurology. It is widely adopted for its time efficiency, convenience, reliability, effectiveness and comprehensive content. It is a valuable predictor of patient prognosis, with scores ranging from 0 to 42 points. A higher score on the NIHSS indicates a poorer prognosis.73
The incidence of surgical complications and side effects
The evaluation will encompass monitoring AEs (pain, falls), surgical complications and side effects throughout the intervention and follow-up. Vital signs, physical exams, sleep duration and other objective measures will be compared presurgery and postsurgery. Subjective symptom improvements will also be recorded and assessed. Data will be gathered through monitoring, self-reporting on case report forms (CRFs) and intervention relevance assessment.74–76
Quality of life
The SF-36 will be used to evaluate quality of life. This user-friendly, patient-accepted tool adheres to rigorous reliability and validity standards, enjoying widespread use across diverse fields. As a self-administered questionnaire, SF-36 encompasses 36 items assessing health status across eight multi-item dimensions. It calculates physical and mental health scores (PCS & MCS), with higher scores indicating better health status.77
Mental improvement
Psychosocial status will encompass a broad spectrum of factors related to the patient’s emotional, social and psychological well-being, potentially influenced by their stroke and the recovery process. The mental and psychological well-being will be evaluated using the HAMA and the HAMD. The HAMA, renowned for its clinical assessment of anxiety, encompasses 14 items, each graded on a five-point scale (ranging from 0 to 4), totaling 56 points. A higher score on the HAMA indicates more severe anxiety symptoms. Similarly, HAMD, particularly the HAMD-24 version, is widely employed in clinical depression assessment. A heightened score on the HAMD signifies the exacerbation of depressive symptoms.78 79
Assessment of brain network connectivity and mechanisms
Neuroimaging assessment
Participants will receive brain [18F]FDG-PET at baseline at the end of the intervention. PET can effectively reflect the cerebral glucose metabolism in patients who had stroke, compared with the metabolism of the cortex around the lesion is significantly increased (average change in standardised uptake value ratio), exploring the impact of MLR-DBS on long-range network effects in patients with poststroke hemiplegia and analysing the potential mechanism of action.80
Electrophysiological assessment
Electrophysiological assessments post-SCI predict functional outcomes, giving insight into spinal pathology, stability and potential recovery. Due to CnF’s proximity to the brainstem,Local Field Potentials (LFPs) are monitored during surgery and after, with lead temporarily outside. LFPs will be recorded around the target area and neuronal activity changes with MLR-DBS. Perioperative and final EEG recordings helped understand neuronal dynamics.81
Data management and analysis
Data collection
Postsurgery, patients will undergo evaluations at various intervals up to 18 months, conducted by third-party evaluators unaffiliated with the clinical trial. These evaluations will strictly adhere to predefined standards, test plans and standardised documentation (table 3), as assessed by a qualified, blinded third-party physician using an internationally recognised scale during each follow-up. To uphold patient rights and ethical clinical trial principles, necessary oral medications will be prescribed during follow-ups, excluding those that could significantly impact the study. Before each evaluation, all medications will be suspended for 24 hours. The follow-up method will primarily involve outpatient visits, with alternatives such as telephone and WeChat video follow-ups available in unforeseen situations. When conditions allow, outpatient follow-ups will be promptly resumed to validate and reassess the data collected through non-outpatient means.
Data analysis
To ensure meticulousness, scoring adheres to the prescribed scale, promptly quantifying visit result changes from the baseline. Tailored multifactor analysis models and statistical methodologies will be employed to adjust for confounding factors or covariates influencing pre-to-post-treatment value shifts. For inter-group assessments, the choice of hypothesis testing methods is data-driven, with group t-tests or Wilcoxon rank-sum tests favoured for measurement data, paired t-tests or paired signed-rank tests for intra-group comparisons, and paired signed-rank tests specifically used for analysing change dynamics. χ2 or exact probability tests will be applied to count data, while Wilcoxon rank-sum tests for ordinal grade data. Effectiveness will be evaluated by contrasting pretreatment and post-treatment improvement rates on the scoring scale, derived using the formula: [(Postoperative Score−Preoperative Score)/Preoperative Score]*100%. An improvement rate exceeding 25% signifies a noteworthy therapeutic effect. Safety will be quantified by the incidence of AEs postsurgery, calculated as the ratio of affected patients (T2) to the total patient population (T1). A higher incidence translates to reduced safety. Across various clinical scales and follow-up durations, this will be considered safe if the AE incidence rate remains below the threshold of 5%.
During future follow-up studies, encountering missing values will necessitate an initial attempt at data supplementation. If this approach proves unfeasible, a thorough analysis of the missing data will follow, examining its causes, type, proportion within the dataset and distributional traits. Following this analysis, an evaluation will be made to determine if the intended analytical model can inherently accommodate missing values, thereby guiding the decision on whether and how to tackle these absences. In instances where missing values occur randomly, using known variables for estimation can be an effective strategy moving forward. However, when missingness is non-random, the straightforward deletion of such values risks introducing bias into the model, necessitating the adoption of meticulous data imputation techniques in the future to mitigate this risk. For scenarios where missing data are entirely random and limited in quantity, listwise deletion (also referred to as case-wise deletion) will serve as an efficient means of managing the gaps. Conversely, in cases of non-random missing data, pairwise deletion (also known as complete observation analysis) will be advised to reduce bias and maximise the retention of information within the dataset.
Handling missing values
During future follow-up studies, when encountering missing values, an initial attempt at data supplementation will be made. If this approach proves unfeasible, a thorough analysis of the missing data will follow, examining its causes, type, proportion within the dataset and distributional traits. Following this analysis, an evaluation will be conducted to determine if the intended analytical model can inherently accommodate missing values, thereby guiding the decision on whether and how to address these absences. In instances where missing values occur randomly in the future, using known variables for estimation can be an effective strategy. However, when missingness is non-random, the straightforward deletion of such values risks introducing bias into the model, necessitating the adoption of meticulous data imputation techniques in the future to mitigate this risk. For scenarios where missing data are entirely random and limited in quantity, listwise deletion (also referred to as case-wise deletion) will serve as an efficient means of managing the gaps in the future. Conversely, in cases of non-random missing data, pairwise deletion (also known as complete observation analysis) will be advised to reduce bias and maximise the retention of information within the dataset.
Intentionality analysis
During the upcoming study, challenges are often anticipated to emerge, potentially hindering the assessment of outcomes due to subject attrition and non-compliance with the research protocol. These non-compliance issues may include unauthorised use of interventions, missed treatments, poor adherence to the study plan or failure to meet the predefined inclusion criteria. To address these concerns, the study will adopt a rigorous analytical approach that encompasses all subjects who will be randomised, strictly adhering to the outcomes of the randomisation process. This methodology will ensure that the contributions of all randomised participants are taken into account in the analysis, thereby preserving the statistical power and enhancing the validity of the study’s future findings.
Data monitoring
Before the initiation of the clinical trial, all researchers will embark on a comprehensive, week-long training programme to ensure a thorough comprehension of trial requirements among participants, thereby fostering seamless cooperation. Where practical, subjects will be granted access to essential rehabilitation equipment and examinations at no cost, adhering to the project’s budgetary constraints. Dedicated professionals will supervise the research process, conducting routine inspections and verifying raw data against CRFs to maintain consistency. In terms of data management and monitoring, a robust system will be implemented, involving dual data entry by two blinded research assistants into a secure online platform. To guarantee accuracy, rigorous checks by specialised personnel will precede any descriptive or statistical analysis. Access to the dataset will be strictly regulated and confined solely to trial management and the data safety and monitoring board. Data storage and handling will adhere meticulously to the regulations stipulated by the investigator’s institution and study site. To uphold blinding, standardised follow-up visit videos will be captured with patients wearing surgical caps, concealing the data collection timeline from evaluators. These videos will then be uploaded to a centralised unit for unbiased scoring by two seasoned neurologists, who will remain unaware of the video’s context. During the analysis phase, the data administrator will assign anonymous group labels (A and B) to the datasets, ensuring confidentiality before their submission to data analysts.
Adverse events
During the rehabilitation journey, a few selected patients may encounter AEs, including accidental injuries, skin complications, bleeding, muscle aches, joint discomfort and rashes. Each AE will be diligently documented in a dedicated CRF, comprehensively outlining its timing, severity, duration, connection to the intervention, and anticipated outcome. Should a serious AE arise in the future, the researcher will swiftly and openly communicate with the ethics committee, abiding by their directives without fail. Prompt action will be taken to address all AEs, with the utmost importance placed on the safety and well-being of participants. Follow-up care will be guaranteed, ensuring that subjects' physical health returns to its pre-intervention state.
Discussion
This study rigorously formulated a research protocol grounded in current clinical evidence, recommendations, theories and practice standards. Before the comprehensive study, the Medical Research Council devised and evaluated a complex intervention framework, undergoing thorough scrutiny of proposed interventions and assessing the feasibility, acceptability and safety of methodological procedures.82–87 The trial is underway at multiple centres, including People’s Liberation Army General Hospital, Air Force Medical Centre, Beijing Tongren Hospital, and Shanghai Deji Hospital, pioneering the investigation into the safety and efficacy of DBS and VNS in enhancing motor function among stroke survivors, encompassing ischaemic, haemorrhagic, and other stroke types. We enrolled patients with different causes of the stroke, not only ensures uniform patient enrolment by preventing misclassification of non-stroke events but also enhances the applicability of our findings by making them more easily comparable and integrable with other studies adhering to globally recognised standards. Furthermore, this clarity provides insight into stroke subtypes, enabling future analyses to delve into treatment responses across diverse stroke types, such as ischaemic vsversus haemorrhagic strokes, despite our primary focus on evaluating the efficacy of specific treatments or interventions.
Thus far, we have enrolled three patients: two undergoing VNS and one receiving MLR-DBS. Notably, none have reported significant discomfort or adverse effects. Ongoing data collection and follow-up are underway. Drawing from literature and surgeon expertise, we tailored stimulation parameters for each patient, introducing initial MLR-DBS parameters at 20 Hz, 400 μs, and 2.0–4.5 V, gradually adjusting frequency and pulse width based on individual intraoperative responses. Our ultimate aspiration is to optimise long-term motor function recovery among patients with severe poststroke motor dysfunction. The study’s findings will serve as vital evidence guiding treatment choices for patients with poststroke hemiplegia.
There are several limitations in our trial’s protocol design. First, the lack of intracranial electrode implantation in the VNS group, despite identical rehabilitation and interventions, may compromise patient blindness, as they may be aware of not receiving intracranial stimulation. Second, while neurosurgeons are aware of patient safety, their primary role is electrode implantation, excluding them from subsequent assessments and DBS programming, thus minimising potential bias through precise electrode positioning. Lastly, our study employs open-loop DBS, acknowledging that closed-loop neuromodulation exhibits superior efficacy. As such, future studies should explore closed-loop DBS for further optimisation.
Patients and public involvement
Patients and the public are not involved in the design and implementation of this trial.
Ethics and dissemination
All study procedures adhere rigorously to the latest Declaration of Helsinki (www.wma.net) and pertinent ethical principles. Ethical approval is currently under review (S2022-789-01), and the protocol has been registered on ClinicalTrials.gov with the identifier NCT06121947. Participants will be comprehensively informed about the study’s objectives, eligibility requirements, procedures, potential risks, and expected benefits. Their informed consent is imperative for participation, and they retain the unfettered right to withdraw from the study in time. On completion, the results will be disclosed openly, subjected to rigorous peer review, and disseminated to participants, stakeholders, and policymakers, notably the Beijing Municipal Economic and Information Technology Commission and the Beijing Municipal Health and Family Planning Commission.
Ethics statements
Patient consent for publication
References
Footnotes
JX and BL contributed equally.
Contributors ZM is the guarantor. Participation of patients and the public. The initial research idea was conceived by the research team. Patients who had stroke, physical therapists and neurologists participated in the preparation of the proposal, conducting face-to-face interviews. JX contributed to conceptualisation, investigation and writing–original draft. BL and GS contributed to writing–review and editing. SL contributed to data curation, investigation, writing–review and editing. ZF contributed to visualisation, writing–review and editing. YZ contributed to resources, writing–review and editing. HY contributed to supervision, writing–review and editing. DL contributed to software, writing–review and editing. QC contributed to formal analysis, writing–review and editing. CY contributed to data curation, writing–review and editing. ZM contributed to writing–review and editing. XY contributed to funding acquisition, resources, writing–review and editing.
Funding This study was supported by grants from the China Brain Project (2021ZD0200407).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.