Combining Non-Invasive Vagus Nerve Stimulation and Robotic Training in Upper Limb-Impaired Chronic Stroke Patients

Study Overview
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Brief Summary
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Previous studies suggested that both robot-assisted rehabilitation and non-invasive vagus nerve stimulation can improve upper limb function in chronic stroke patients. Aim of present study is to explore whether the combination of these two approaches might enhance their positive effects on motor recovery. Safety and efficacy of this combination will be assessed within a proof-of-principle, double-blinded, randomized, sham-controlled trial. Transcutaneous vagus nerve stimulation (tVNS) will be delivered at left ear, in order to improve the response to the following robot-assisted therapy. Patients with both ischemic and hemorrhagic chronic stroke will be randomized to robot-assisted therapy associated with real or sham tVNS, delivered for 10 working days. Change in Fugl-Meyer has been chosen as primary outcome, while changes in several quantitative indicators of motor performance extracted by the robot as secondary outcomes.

Official Title
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Combining Non-Invasive Vagus Nerve Stimulation and Robotic Training in Upper Limb-Impaired Chronic Stroke Patients

Conditions
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Stroke

Intervention / Treatment
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* Device: Transcutaneous vagal nerve stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: first-ever ischemic or hemorrhagic stroke at least 1 year earlier hand function impairment ability to give informed consent and comprehend instructions Exclusion Criteria: previous surgical intervention on vagus nerve low hearth rate (< 60 bpm) cognitive impairment or any substantial decrease in alertness, language reception, or attention that might interfere with understanding instructions for motor testing apraxia excessive pain in any joint of the paretic extremity advanced liver, kidney, cardiac or pulmonary disease history of significant alcohol or drug abuse depression or use of neuropsychotropic drugs such as antidepressants or benzodiazepines pregnant women

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Robotic therapy and real tVNS<br>This group receives REAL vagus nerve stimulation during robotic rehabilitation. | Device: Transcutaneous vagal nerve stimulation<br>* The stimulation of the auricular branch of the vagus nerve will be performed through an electric stimulator and two Ag-AgCl electrodes placed in the left external acoustic meatus at the inner side of the tragus. For sham stimulation, electrodes will be attached to the left ear lobe. tVNS will be delivered as trains lasting 30 s and composed by 600 pulses (intra-train pulse frequency = 20 Hz; pulse duration = 0.3 ms) repeated every 5 min for 60 min. The intensity of stimulation will individually adjusted to a level ranging above the detection threshold and below the pain threshold. In this range, when possible, the investigators will chose an intensity of 8 mA. Each day, for 10 consecutive working days, each patient will receive a session of robotic therapy during the real or sham tVNS stimulation<br>|
| Active Comparator: Robotic therapy and sham tVNS<br>This group receives SHAM VNS during robotic rehabilitation. Sham VNS is not effective. Both groups receive the same amount of robotic rehabilitation. | Device: Transcutaneous vagal nerve stimulation<br>* The stimulation of the auricular branch of the vagus nerve will be performed through an electric stimulator and two Ag-AgCl electrodes placed in the left external acoustic meatus at the inner side of the tragus. For sham stimulation, electrodes will be attached to the left ear lobe. tVNS will be delivered as trains lasting 30 s and composed by 600 pulses (intra-train pulse frequency = 20 Hz; pulse duration = 0.3 ms) repeated every 5 min for 60 min. The intensity of stimulation will individually adjusted to a level ranging above the detection threshold and below the pain threshold. In this range, when possible, the investigators will chose an intensity of 8 mA. Each day, for 10 consecutive working days, each patient will receive a session of robotic therapy during the real or sham tVNS stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fugl-Meyer Score |  | immediately, one months and three months after the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in kinematic data (Motion Accuracy) measured by the robot |  | immediately, one months and three months after the intervention | 
| Change in kinematic data (Motion Direction) measured by the robot |  | immediately, one months and three months after the intervention | 
| Change in kinematic data (Smoothness) measured by the robot |  | immediately, one months and three months after the intervention | 
| Change in kinematic data (Speed) measured by the robot |  | immediately, one months and three months after the intervention | 
| Change in kinematic data (Movement Duration) measured by the robot |  | immediately, one months and three months after the intervention | 
| Change in kinematic data (Efficiency) measured by the robot |  | immediately, one months and three months after the intervention | 
| Incidence of adverse events that are related to treatment |  | intervention period of 10 consecutive working days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ischemic stroke, hemorrhagic chronic, non-invasive vagus nerve stimulation, robot-assisted rehabilitation