Clinical trial NCT05943431: taVNS Paired With Motor Training for Upper-extremity Rehabilitation in Stroke Patients
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Upper Extremity Dysfunction
Stroke
Keywords: Upper Extremity Dysfunction
Ischemic Stroke
Transcutaneous auricular vagus nerve stimulation
Electromyography
Lead sponsor: Zhujiang Hospital
Sponsor class: OTHER
Collaborators: name: Zhuhai Fudan Innovation Institute
name: BrainClos Co., LTD.
First posted: 2023-07-13
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Changes from Baseline Fugl-Meyer Assessment of Upper Extremity (FMA-UE) Scores
timeFrame: Immediately after 14 days' sessions
Secondary outcomes:
measure: Changes from Baseline Wolf motor function test (WMFT)
timeFrame: Immediately after 14 days' sessions
measure: Changes from Baseline Brunnstrom recovery stages (BRS)
timeFrame: Immediately after 14 days' sessions
measure: Changes from Baseline Barthel Index (BI)
timeFrame: Immediately after 14 days' sessions
measure: Changes from Baseline Hong Kong version of the Functional Test for the Hemiplegic Upper Extremity (FTHUE-HK)
timeFrame: Immediately after 14 days' sessions
measure: Changes from Baseline EMG features
timeFrame: Immediately after 14 days' sessions
measure: Changes from Baseline EEG features
timeFrame: Immediately after 14 days' sessions
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Zhujiang Hospital of Southern Medical University
state: Guangdong
Study officials:
affiliation: Southern Medical University, China
name: Qiuyou Xie, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
citation: 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.