Transcutaneous Vagus Nerve Stimulation (tVNS) and Robotic Training to Improve Arm Function After Stroke

Study Overview
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Brief Summary
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The purpose of this study is to evaluate if multiple therapy sessions of Transcutaneous Vagus Nerve Stimulation (tVNS) combined with robotic arm therapy lead to a greater functional recovery in upper limb mobility after stroke than that provided by robotic arm therapy in a sham stimulation condition.

Detailed Description
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Promising new animal research suggests that vagus nerve stimulation paired with motor intervention induces movement-specific plasticity in the motor cortex and improves limb function after stroke. These results were recently extended to the first clinical trial, in which patients with stroke demonstrated significant improvements in upper limb function following rehabilitation paired with implanted VNS. Currently, vagus nerve stimulation is being used clinically to treat a number of human diseases including migraine headaches, epilepsy, and depression, and these investigations are expanding to deliver stimulation via a transcutaneous route to potentially improve intervention efficacy and decrease side effects. This pilot study will combine non-invasive transcutaneous stimulation of the vagus nerve with upper limb robotic therapy to investigate the potential of tVNS to augment improvements gained with robotic therapy in patients with chronic hemiparesis after stroke.

Official Title
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Evaluating the Use of Transcutaneous Vagus Nerve Stimulation (tVNS) and Robotic Training to Improve Upper Limb Motor Recovery After Stroke

Conditions
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Stroke, Cerebrovascular Accident (CVA), Hemiparesis

Intervention / Treatment
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* Device: Transcutaneous Vagus Nerve Stimulation (tVNS)
* Device: Sham Transcutaneous Vagus Nerve Stimulation (tVNS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals between 18 and 85 years of age First single focal unilateral supratentorial ischemic stroke with diagnosis verified by brain imaging (MRI or CT scans) that occurred at least 6 months prior Cognitive function sufficient to understand the experiments and follow instructions (per interview with Speech Pathologist or PI) Fugl-Meyer assessment 12 to 44 out of 66 (neither hemiplegic nor fully recovered motor function in the muscles of the shoulder, elbow, and wrist). Exclusion Criteria: Botox treatment within 3 months of enrollment Fixed contraction deformity in the affected limb Complete and total flaccid paralysis of all shoulder and elbow motor performance Prior injury to the vagus nerve Severe dysphagia Introduction of any new rehabilitation interventions during study Individuals with scar tissue, broken skin, or irremovable metal piercings that may interfere with the stimulation or the stimulation device Highly conductive metal in any part of the body, including metal injury to the eye; this will be reviewed on a case by case basis for PI to make a determination Pregnant or plan on becoming pregnant or breastfeeding during the study period Significant arrhythmias, including but not limited to, atrial fibrillation, atrial flutter, sick sinus syndrome, and A-V blocks (enrollment to be determined by PI review) Presence of an electrically, magnetically or mechanically activated implant (including cardiac pacemaker), an intracerebral vascular clip, or any other electrically sensitive support system; Loop recorders will be reviewed on a case by case basis by PI and the treating Cardiologist to make a determination

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a double-blind, sham controlled treatment study in which patients will have a 50/50 chance of receiving robotic arm therapy with either active transcutaneous vagus nerve stimulation (tVNS) or sham tVNS (placebo).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: active tVNS + robotic arm therapy<br>Transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting  60 minutes, 3x per week for 3 weeks. | Device: Transcutaneous Vagus Nerve Stimulation (tVNS)<br>* tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear.<br>* Other names: Transauricular Vagus Nerve Stimulation;|
| Sham Comparator: sham tVNS + robotic arm therapy<br>Sham (placebo) transcutaneous Vagus Nerve Stimulation (tVNS) will be delivered non-invasively via the ear (targeting the auricular branch of the vagus nerve) during robotic arm therapy sessions lasting  60 minutes, 3x per week for 3 weeks. | Device: Sham Transcutaneous Vagus Nerve Stimulation (tVNS)<br>* tVNS is a non-invasive form of vagus nerve stimulation, activating the auricular branch of the vagus nerve transcutaneously through the cymba concha at the pinna of the ear. Sham tVNS means the patient is wearing the device, but it is turned off and not delivering current during the treatment. This is a placebo condition, which is used as a study control.<br>* Other names: Sham Transauricular Vagus Nerve Stimulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Absolute Change From Baseline in Electromyographic (EMG) Peak Amplitude of the Bicep/Tricep | The median absolute change in surface electromyographic (sEMG) peak amplitude of the bicep/tricep during gravity-eliminated, unassisted extensor movements was calculated from baseline to discharge at 3 weeks (immediately following the intervention) and again at 16 weeks (3 months follow-up from the intervention) in each training condition (sham tVNS + robotic arm training vs. active tVNS + robotic arm training). Bicep and tricep peak sEMG amplitude scores were calculated as a percentage of the maximal volitional contraction (MVC), with larger values indicating a greater absolute change (negative or positive) in bicep/tricep peak muscle activity during extensor movements. | baseline, discharge at 3 weeks (immediately following the intervention), and follow-up at 16 weeks (3 months after the intervention) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Change From Baseline in Upper Extremity Fugl Meyer Assessment Score | The median change in Upper Extremity Fugl-Meyer Score will be calculated from baseline to discharge at 3 weeks (immediately following the intervention) and again at 16 weeks (3 months follow-up from the intervention) in each training condition (sham tVNS + robotic arm training vs. active tVNS + robotic arm training). The median change in Upper Extremity Fugl Meyer score is reported, with a range 0-66 points, and with higher values indicating better functional status. | baseline, discharge at 3 weeks (immediately following the intervention), and follow-up at 16 weeks (3 months after the intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VNS, Transcutaneous vagus nerve stimulation (tVNS), robotic therapy, occupational therapy, motor rehabilitation