A Randomized, Double-blind Controlled Trial Investigating the Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) in Improving Upper Extremity Motor Function in Stroke Patients
Phase: NA
Conditions: Upper Extremity Dysfunction, Stroke
Sponsor: Qiuyou Xie

Version number: 1.0; Version date: 2023.04.18
Research unit: Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University;
A single-center randomized, double-blind controlled trial of
Transcutaneous Vagus Nerve stimulation (ta-VNS) for improvement
of upper extremity motor function in stroke patients
Title
A single-center randomized, double-blind controlled trial of
Transcutaneous Vagus Nerve stimulation (taVNS) for improvement of
upper extremity motor function in stroke patients
Application
Department of Rehabilitation, Zhujiang Hospital, Southern Medical
University
Purpose
Primary objectives: To investigate the facilitative effect of
transcutaneous auricular vagus nerve stimulation with upper limb motor
rehabilitation training on the improvement of upper limb motor function
in stroke.
Secondary objective: To examine the necessity of pairing with motor
function training for transcutaneous auricular vagus nerve stimulation to
improve upper limb dysfunction in stroke.
Research
hypothesis
1) The test group will show significantly greater improvement in upper
limb motor function in stroke patients compared to the control group.
2) Upper limb motor rehabilitation training paired with transcutaneous
auricular vagus nerve stimulation will be significantly more effective in
improving upper limb motor function in stroke patients compared with
the unpaired test group.
Design
Exploratory single-center, double-blind, randomized controlled trial
Sample size
Sample size was determined: n = 2*[(Zα+Zβ)σ/d]2 (sample size
estimated using the statistical effect force analysis software
G*Power3.1). The sample size for this study was estimated as 40 study
patients per group based on the effect size (effefect size, Cohend's d =
0.632) and α = 0.05, β = 0.80 from the trial by Dawson et al. (2021).
The sample size was adjusted to 50 patients per group based on the
clinical sample dropout rate (20%). The final study population was 150
patients with ischemic stroke. Of these, 50 received upper extremity
motor rehabilitation paired with transcutaneous auricular vagal
stimulation, 50 received upper extremity motor rehabilitation with
unpaired transcutaneous auricular vagal stimulation, and 50 received
upper extremity motor rehabilitation paired with sham-stimulation
(control group).

Version number: 1.0; Version date: 2023.04.18
Research unit: Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University;
Eligibility
Inclusion Criteria:
- Patients diagnosed with stroke according to a clinically qualified
physician with reference to the Chinese Stroke Prevention and Control
Guideline (2021)
- Patients in the acute/recovery phase (after 2 weeks of onset) with
stable signs
- No previous neuropsychiatric-related diseases
- No significant impairment of cognitive function and able to
cooperate in completing the corresponding rehabilitation training
- With unilateral upper limb dysfunction
- Male or female, 18-80 years of age
- Patients who have not received various neuromodulation
rehabilitation treatments
- No contraindications to taVNS
- Subjects voluntarily cooperate with the study and agree to sign an
informed consent
Exclusion Criteria:
- Patients have other mental health disorders (dementia, Parkinson's
disease, depression, schizophrenia, bipolar disorder, etc.)
- Patients have uncontrolled epilepsy, i.e., having had a seizure within
4 weeks prior to enrollment
- Patients have cardiac arrhythmias or other abnormalities
- Patients have a history of respiratory disease or disorder, including
pneumonia, dyspnea and asthma
- The presence of gastrointestinal disorders such as diarrhea and
vomiting that make it difficult for the patient to cooperate
- Patients have a history of vasovagal syncope
- Patients are under treatment with other neurostimulation/modulation
- The presence of severe spasticity, other serious injuries to the upper
extremities, or other medical conditions
- Patients have difficulty in understanding and communication, so
they can’t complete the test
- Women who are pregnant or breastfeeding
Major
interventions
1) Paired taVNS:
-Intervention: Upper extremity motor rehabilitation training will be
conducted with paired taVNS. The stimulator will be placed on the left
ear of the patient. While the patient performs the action training, the
EMG signal feature caused by the action will trigger an electrical
stimulation of the transcutaneous auricular vagus nerve. The amplitude
of the electrical stimulation will be adjusted under patients’ pain
threshold. The intervention will be performed once a day for 40-60
minutes for 14 days.

Version number: 1.0; Version date: 2023.04.18
Research unit: Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University;
2) Unpaired taVNS:
-Intervention: Upper extremity motor rehabilitation training will be
conducted with unpaired taVNS. The stimulator will be placed on the
patient's left ear. Patients will receive 30 minutes of stimulation, with
pulses of 500 ms occurring every 5-7 seconds. A total of 300
stimulations will be completed with pulses of 500 ms. After that motor
training will be performed. The motor training will be identical to that
of the paired group. The amplitude of the electrical stimulation will be
adjusted under patients’ pain threshold. The intervention will be
conducted once a day, with 30 minutes of stimulation followed by 30
minutes of motor training each time for 14 days.
3) Sham taVNS: Upper limb motor rehabilitation training will be
conducted with paired taVNS sham-stimulation. The stimulator will be
placed on the patient's left ear. The amplitude of the electrical
stimulation will be adjusted at 0 mA. The intervention will be
conducted once a day for 40-60 minutes for 14 days.
Evaluating
indicator
Primary outcome: The score of Fugl-Meyer Assessment of Upper
Extremity (FMA-UE) will be tracked before and after the intervention
in the paired taVNS, unpaired taVNS, and sham taVNS groups.
Secondary outcome: Changes in ADL (Modified Barthel Index), the
Hong Kong version of the Functional Test for the Hemiplegic Upper
Extremity (FTHUE-HK), Wolf Motor Function Test (WMFT), EEG,
and EMG features will be tracked after the intervention among
participants.
Statistical
method
1. Primary endpoints: ANOVA, paired-sample t-test, and
independent-sample t-test will be used.
(1) For the main efficacy index FMA-UE scores, paired sample t-test
will be performed before and after the intervention to compare whether
there will be a significant change before and after the intervention.
Since this statistical operation is based on multiple comparisons, there
may be a bias of alpha inflation. Therefore, the statistical results will be
corrected based on Bonferroni's principle.
(2) The FMA-UE scores before and after the intervention will be
summed and subtracted to obtain the FMA-UE change scores of the
indicators before and after the intervention (i.e., the main intervention
effect), and a one-way three-level (paired vs. unpaired vs.
pseudo-stimulated) analysis of variance (ANOVA) will be performed on
the main intervention effect of the three groups to obtain the variability
of the main intervention effect of the three groups.
(3) Independent samples t-tests will be conducted for the main
intervention effects among groups. The main intervention effects of the
two experimental groups will be obtained. And the main intervention
effects of the paired experimental group and the unpaired experimental
group will be compared by independent sample t-test.

Version number: 1.0; Version date: 2023.04.18
Research unit: Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University;
2. Secondary endpoints: ANOVA, paired samples t-test, independent
samples t-test
(1) Paired-samples t-tests will be performed before and after the
intervention for WMFT, Brunnstrom scale, Modified Barthel Index,
FTHUE-HK, and EMG characteristics to compare whether there will be
significant changes before and after the intervention. Since this
statistical manipulation is based on multiple comparisons and there
would be a bias for alpha inflation, and the statistical results will be
corrected based on Bonferroni's principle.
(2) The WMFT, Brunnstrom scale, Modified Barthel Index,
FTHUE-HK, and EMG characteristics before and after the intervention
were summed and subtracted. To obtain the WMFT, Brunnstrom
assessment, ADL, FTHUE-HK, and changes in EMG characteristics of
the indicators before and after the intervention (i.e., secondary
intervention effects), and the secondary intervention effects of the three
groups were subjected to a one-way three-level (paired vs. unpaired vs.
pseudo-stimulation) multiple test analysis of variance (Multivariate
ANOVA) to obtain the variability of the secondary intervention effects
in the three groups.
3) The WMFT, Brunnstrom scale, Modified Barthel Index, FTHUE-HK,
and change in EMG characteristics of the paired and unpaired test
groups will be tested by independent samples t-tests to obtain the
difference of secondary intervention effects between paired and
unpaired groups. To compensate the alpha inflation bias, the statistical
results will be corrected based on Bonferroni's principle.
#Table 1 Schematic timeline of the study
TIMEPOINT
Enrollment
Allocation
Post-Allocation
Close-out
ts
t0
t1
t2
t3
t4
t5
Enrolment
×
Eligibility screen
×
Informed consent
×
Demographic
×
information
Medical history
×
Vital signs
×
×
×
×
×
×
Randomization
×
Allocation
×
Interventions
Paired ta-VNS
×

Version number: 1.0; Version date: 2023.04.18
Research unit: Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University;
ta-VNS
×
Sham ta-VNS
×
Assessments
FMA-UE
×
×
×
×
WMFT
×
×
×
×
Brunnstrom
×
×
×
×
Modified Barthel
Index
×
×
×
×
FTHUE-HK
×
×
×
×
Adverse events
×
×
×
×
×
×
×
1) Demographic information includes the patients date of birth, sex and race;
2) Medical history includes stroke and other clinically significant past and present
medical history and pre-existing/combined medications;
3) Vital signs include blood pressure, pulse rate, respiration and body temperature;
Reference:
1)
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Kimberley, T. J. (2021). Vagus nerve stimulation paired with rehabilitation for upper limb
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device trial. The Lancet, 397(10284), 1545-1553.
2)
Liu, Y., Zhang, L., Zhang, X., Ma, J., & Jia, G. (2022). Effect of combined vagus nerve
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3)
De Smet, S., Ottaviani, C., Verkuil, B., Kappen, M., Baeken, C., & Vanderhasselt, M. A.
(2023). Effects of non‐invasive vagus nerve stimulation on cognitive and autonomic
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Chang, J. L., Coggins, A. N., Saul, M., Paget-Blanc, A., Straka, M., Wright, J., ... &
Volpe, B. T. (2021). Transcutaneous auricular vagus nerve stimulation (tAVNS) delivered
during upper limb interactive robotic training demonstrates novel antagonist control for
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Monge-Pereira, E., Molina-Rueda, F., Rivas-Montero, F. M., Ibáñez, J., Serrano, J. I.,
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