taVNS Paired With Motor Training for Upper-extremity Rehabilitation in Stroke Patients

Stroke Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05943431
• Other study ID #: L20230613
• Status: Recruiting
• Phase: N/A
• Start date: August 1, 2023
• Est. completion date: December 1, 2025

Study information

• Verified date: January 2024
• Source: Zhujiang Hospital
• Contact: Xue-Zhen XIAO, PhD
• Phone: +8613425122570
• Email: xuezhenxiao[@]brainclos.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background: Recently, there has been increasing attention on the application of transcutaneous auricular vagus nerve stimulation (taVNS) in ischemic stroke. This innovative technique involves non-invasive electrical stimulation of the vagus nerve. A controlled study by Dawson et al. (2021), conducted using a randomized, double-blind approach, has demonstrated that vagus nerve stimulation (VNS) when paired with motor function training, can effectively promote the improvement of motor dysfunction in stroke patients. In the same year, the Food and Drug Administration approved the use of VNS, alongside motor rehabilitation training, for upper extremity dysfunction caused by stroke. However, it is worth noting that VNS requires surgical procedures with contraindications. Consequently, researchers are exploring taVNS as a potential alternative intervention. Compared to VNS, taVNS offers a low-risk and user-friendly intervention that eliminates the need for surgery and the associated postoperative complications. A recent meta-analysis has shown that the efficacy of taVNS in upper extremity rehabilitation for stroke patients can be comparable to that of VNS. Therefore, pairing taVNS with motor training holds promise as a valuable clinical tool for post-stroke rehabilitation. Methods and Design: This study presents a protocol for a single-center randomized, double-blind controlled trial. A total of 150 participants will be enrolled and randomly assigned to one of three groups (Group 1, Group 2, or Group 3) in a 1:1:1 ratio. Each patient will undergo a total of 14 treatment sessions. In Group 1, patients will receive motor training paired with taVNS. In Group 2, patients will receive motor training and taVNS interventions, seperately. In Group 3, patients will receive motor training paired with sham taVNS. Primary and secondary outcome measures will be assessed at baseline and after taVNS treatment. The primary outcome will be determined by evaluating the behavioral response to treatment, using the Fugl-Meyer Assessment of Upper Extremity (FMA-UE). Discussion: This study aims to elucidate the role of paired taVNS in the rehabilitation of upper extremity dysfunction in stroke patients. The researchers propose a novel approach by pairing taVNS with individualized training actions, utilizing electromyography (EMG) during motor training to precisely trigger taVNS.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: December 1, 2025
• Est. primary completion date: July 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Patients diagnosed with ischemic 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;
• Patients who have not received various neuromodulation rehabilitation treatments;
• No contraindications to taVNS;
• Patients voluntarily cooperated with the study and signed an informed consent form.

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 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 communication and understanding and inability to cooperate in completing the test;
• Women who are pregnant or breastfeeding.

Related Conditions & MeSH terms

• Stroke
• Upper Extremity Dysfunction

Intervention

Device:
• 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 evoked by the action will trigger an electrical stimulation of the transcutaneous auricular vagus nerve. The amplitude of the electrical stimulation will be adjusted under the patient's pain threshold. The intervention will be performed daily for 14 days.
• Unpaired taVNS
The stimulator will be placed on the patient's left ear. Patients will receive taVNS with pulses every 5-7 seconds. Following the stimulation, 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 the patient's pain threshold. The intervention will be performed daily for 14 days.
• Sham taVNS
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 performed daily for 14 days.

Locations

Country	Name	City	State
China	Zhujiang Hospital of Southern Medical University	Guangzhou	Guangdong

Sponsors (3)

Lead Sponsor	Collaborator
Qiuyou Xie	BrainClos Co., LTD., Zhuhai Fudan Innovation Institute

Country where clinical trial is conducted

China, 

References & Publications (7)

Badran BW, Peng X, Baker-Vogel B, Hutchison S, Finetto P, Rishe K, Fortune A, Kitchens E, O'Leary GH, Short A, Finetto C, Woodbury ML, Kautz S. Motor Activated Auricular Vagus Nerve Stimulation as a Potential Neuromodulation Approach for Post-Stroke Motor Rehabilitation: A Pilot Study. Neurorehabil Neural Repair. 2023 Jun;37(6):374-383. doi: 10.1177/15459683231173357. Epub 2023 May 20. — View Citation

Chang JL, Coggins AN, Saul M, Paget-Blanc A, Straka M, Wright J, Datta-Chaudhuri T, Zanos S, Volpe BT. Transcutaneous Auricular Vagus Nerve Stimulation (tAVNS) Delivered During Upper Limb Interactive Robotic Training Demonstrates Novel Antagonist Control for Reaching Movements Following Stroke. Front Neurosci. 2021 Nov 25;15:767302. doi: 10.3389/fnins.2021.767302. eCollection 2021. — View Citation

Cook DN, Thompson S, Stomberg-Firestein S, Bikson M, George MS, Jenkins DD, Badran BW. Design and validation of a closed-loop, motor-activated auricular vagus nerve stimulation (MAAVNS) system for neurorehabilitation. Brain Stimul. 2020 May-Jun;13(3):800-803. doi: 10.1016/j.brs.2020.02.028. Epub 2020 Feb 27. — View Citation

Dawson J, Liu CY, Francisco GE, Cramer SC, Wolf SL, Dixit A, Alexander J, Ali R, Brown BL, Feng W, DeMark L, Hochberg LR, Kautz SA, Majid A, O'Dell MW, Pierce D, Prudente CN, Redgrave J, Turner DL, Engineer ND, Kimberley TJ. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet. 2021 Apr 24;397(10284):1545-1553. doi: 10.1016/S0140-6736(21)00475-X. — View Citation

De Smet S, Ottaviani C, Verkuil B, Kappen M, Baeken C, Vanderhasselt MA. Effects of non-invasive vagus nerve stimulation on cognitive and autonomic correlates of perseverative cognition. Psychophysiology. 2023 Jun;60(6):e14250. doi: 10.1111/psyp.14250. Epub 2023 Jan 22. — View Citation

Liu Y, Zhang L, Zhang X, Ma J, Jia G. Effect of Combined Vagus Nerve Stimulation on Recovery of Upper Extremity Function in Patients with Stroke: A Systematic Review and Meta-Analysis. J Stroke Cerebrovasc Dis. 2022 Jun;31(6):106390. doi: 10.1016/j.jstrokecerebrovasdis.2022.106390. Epub 2022 Mar 22. — View Citation

Monge-Pereira E, Molina-Rueda F, Rivas-Montero FM, Ibanez J, Serrano JI, Alguacil-Diego IM, Miangolarra-Page JC. Electroencephalography as a post-stroke assessment method: An updated review. Neurologia. 2017 Jan-Feb;32(1):40-49. doi: 10.1016/j.nrl.2014.07.002. Epub 2014 Oct 5. English, Spanish. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes from Baseline Fugl-Meyer Assessment of Upper Extremity (FMA-UE) Scores	The Fugl-Meyer Assessment - Upper Extremity (FMA-UE) is a stroke-specific assessment that measures performance at the body function/impairment domain. It uses an ordinal scale for scoring 33 items for the upper limb function with a total possible score of 66. The FMA-UE is one of the most widely used quantitative measures of motor impairment after stroke. Studies have shown excellent inter-rater, and intra-rater reliability, and construct validity of FMA-UE. In addition, empirical evidence suggests that the FMA-UE is responsive to the change in rehabilitation. Higher scores are indicative of better outcomes.; The primary outcome measures are as follows: Difference in the changes from baseline FMA-UE scores between paired taVNS and shame taVNS groups.; Difference in the changes from baseline FMA-UE scores between unpaired taVNS and shame taVNS groups.; Difference in the changes from baseline FMA-UE scores between paired taVNS and unpaired taVNS groups.	Immediately after 14 days' sessions
Secondary	Changes from Baseline Wolf motor function test (WMFT)	The Wolf motor function test (WMFT) is a widely used measure for upper extremity motor abilities. It uses a 6-point ordinal scale for scoring 17 items with a total core of 85. Higher scores are indicative of better outcomes.; We will compare the differences in the changes from baseline WMFT scores between paired taVNS and shame taVNS groups, between unpaired taVNS and shame taVNS groups, and between paired taVNS and unpaired taVNS groups.	Immediately after 14 days' sessions
Secondary	Changes from Baseline Brunnstrom recovery stages (BRS)	The Brunnstrom recovery stages (BRS) is a measure for assessing motor function. The BRS contains 3 items rated on a 6-level Likert-type scale. Higher scores are indicative of better outcomes.; We will compare the differences in the changes from baseline BRS scores between paired taVNS and shame taVNS groups, between unpaired taVNS and shame taVNS groups, and between paired taVNS and unpaired taVNS groups.	Immediately after 14 days' sessions
Secondary	Changes from Baseline Barthel Index (BI)	The Barthel Index (BI) is a measure of independence in the activities of daily living (ADLs). The BI includes the 10 ADLs with a total score of 100. Higher scores are indicative of better outcomes.; We will compare the differences in the changes from baseline BI scores between paired taVNS and shame taVNS groups, between unpaired taVNS and shame taVNS groups, and between paired taVNS and unpaired taVNS groups.	Immediately after 14 days' sessions
Secondary	Changes from Baseline Hong Kong version of the Functional Test for the Hemiplegic Upper Extremity (FTHUE-HK)	The Hong Kong version of the Functional Test for the Hemiplegic Upper Extremity (FTHUE-HK) is another measure for ADL. It uses a 7-point ordinal scale for scoring 12 items with a total score of 84. Higher scores are indicative of better outcomes.; We will compare the differences in the changes from baseline FTHUE-HK scores between paired taVNS and shame taVNS groups, between unpaired taVNS and shame taVNS groups, and between paired taVNS and unpaired taVNS groups.	Immediately after 14 days' sessions
Secondary	Changes from Baseline EMG features	EMG will be acquired from 2 channels on the upper limb. When participants perform motor training, the peak amplitudes and the zero crossing rate of EMG signals at the time domain and the relative spectral power (RSP) of EMG signals at 20 to 200 Hz will be calculated on-line.; Difference in the changes from baseline EMG features between paired taVNS and shame taVNS groups.; Difference in the changes from baseline EMG features scores between unpaired taVNS and shame taVNS groups.; Difference in the changes from baseline EMG features scores between paired taVNS and unpaired taVNS groups.	Immediately after 14 days' sessions
Secondary	Changes from Baseline EEG features	EEG will be acquired from 66 channels following the international 10-20 System for 10 mins. The relative spectral power (RSP) of participants will be calculated by the selected artifact-free EEG epochs at five frequency bands: d (1-4 Hz), ? (4-8 Hz), a (8-13 Hz), ß (13-30 Hz), and ? (30-45 Hz). The investigators will perform off-line analysis to calculate RSP.; Difference in the changes from baseline EEG features between paired taVNS and shame taVNS groups.; Difference in the changes from baseline EEG features scores between unpaired taVNS and shame taVNS groups.; Difference in the changes from baseline EEG features scores between paired taVNS and unpaired taVNS groups.	Immediately after 14 days' sessions