Noninvasive Vagus Nerve Stimulation (VNS) for Neuromotor Adaptations

Study Overview
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Brief Summary
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The study will examine how electrical stimulation of vagus nerve (i.e. nerve around the outer ear) from the skin surface during motor training influences a brain hormone (called norepinephrine), brain activity, and motor performance.

Detailed Description
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Motor function is compromised with advanced age, and motor impairment is involved in various neuromotor injuries and disorders including stroke, spinal cord injury, amputation, and aging. Development of effective interventions for facilitating neuromotor adaptation is essential for accelerating or augmenting rehabilitation outcomes in the control of impaired limbs. The ultimate goal of the study is to find non-pharmacological and non-invasive neuromodulating interventions for enhancing the rehabilitation outcomes that may be applied to individuals with impaired motor function. In rats, implanted afferent vagus nerve stimulation paired with motor training enhanced neuromotor adaptation and motor recovery most likely through increased release of central neuromodulators that originate from the brainstem. The investigators propose to translate the findings in rats into humans by applying vagus nerve stimulation noninvasively. Transcutaneous VNS (tVNS) can noninvasively activate the brainstem including locus coeruleus, where norepinephrine (i.e. neuromodulator) is synthesized. However, it is unknown whether tVNS leads to increasing neuromodulators and facilitating neuromotor adaptations when combined with motor training in humans. With potential applicability of this novel intervention for facilitating neuromotor adaptation to various clinical human populations in future scope, it is essential to start with the basic understanding about the effect of tVNS on the neuromotor system and training-induced adaptation in neuromotor behavior in non-disabled humans. The overarching hypothesis is that an application of tVNS increases central norepinephrine and facilitates training-induced neuromotor adaptations in humans. The specific aim is to examine the effect of tVNS on central norepinephrine and training-induced neuromotor adaptations in humans. The effect of applying tVNS concurrently to visuomotor training will be investigated by comparing the changes in central norepinephrine and changes in the visuomotor skill and corticospinal excitability due to training with and without tVNS (sham) in non-disabled humans. The visuomotor skill will be assessed with the root-mean-square error of the produced force against the target force, which will be normalized to the maximal voluntary contraction force (MVC) . The investigators expect that subjects with concurrent tVNS during training show greater increases in the visuomotor skill and corticospinal excitability after training. The investigators also expect that tVNS increases central norepinephrine, and the amount of neuromotor adaptations due to training is associated with that of tVNS-induced increase in central norepinephrine. These expected findings will be the first evidence on the efficacy of concurrent tVNS with motor training for upregulating central norepinephrine and facilitating training-induced neuromotor adaptations in humans. They will open new scientific and clinical fields of study that will lead to the creation of motor rehabilitation paired with tVNS that can enhance rehabilitation outcomes in individuals with motor impairment. Demonstration of associated changes between central norepinephrine and neuromotor adaptations due to tVNS in non-disabled humans is a necessary step for applying tVNS to rehabilitation with the understanding of the underlying mechanism and for potentially using central norepinephrine as a predictor of tVNS efficacy in rehabilitation.

Official Title
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Noninvasive Vagus Nerve Stimulation (VNS) for Neuromotor Adaptations

Conditions
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Healthy Young Adults

Intervention / Treatment
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* Other: tVNS
* Other: Motor training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women in the age range of 18-39 years will be recruited. All subjects will be healthy and right-handed. Subjects will match the ethnic distribution in the local community. Exclusion Criteria: To ensure the safety associated with TMS and transcutaneous afferent vagus nerve stimulation, following adults will be excluded as in our previous studies (Buharin et al. 2013, 2014) and following the standard recommendations (Keel et al. 2001): Younger than 18 years old or older than 39 years old Left-handed Skilled use of hands (e.g. professional musician) High blood pressure (>140/90 mmHg) Had cardiovascular problems Obese (Body Mass Index: > 30 kg/m2) Had sensory deficits in your limb Had alcoholism Had psychiatric disorders Had an adverse reaction to TMS (a technique for non-invasive neural stimulation from the brain) Had a seizure (an abnormal phenomenon of the brain marked by temporary abnormal neuronal activity. Symptoms include involuntary changes in body movement or function, sensation, awareness, or behavior.) Someone in your family has epilepsy (recurrent seizures marking excessive synchronous neuronal activity in the brain) Had an EEG (measurement of the electrical activity of the brain through the use of surface electrodes placed on the scalp) for clinical diagnosis Had a stroke (the loss of brain function due to an interruption in the blood supply to the brain) Had a head injury (include neurosurgery) that required a visit to a hospital Suffer from frequent or severe headaches (e.g., migraine headaches within the last six months) Have any metal permanently in your head (outside the mouth) such as shrapnel, surgical clips, or fragments from welding or metal work. Piercings and other metals on your head are OK if they will be removed before the study. Have any implanted devices such as cardiac pacemakers (a medical device that uses electrical signals to regulate heart beat), medical pumps, or intra-cardiac lines Had any other brain-related condition Had any illness that caused brain injury (i.e. meningitis, aneurysm, brain tumor) Had severe disease such as cardiologic, pulmonary, renal, endocrinal (hyperthyroidism or hypothyroidism), gastrointestinal or others. Taking any medications other than over-the-counter medicine Suspect you might be pregnant (if woman) Have hearing problems, such as impaired hearing, tinnitus, etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham-tVNS to ear lobe<br>Sham-tVNS will be applied to the ear lobe. | Other: tVNS<br>* Intervention<br>Other: Motor training<br>* Same finger training for both arms<br>|
| Active Comparator: tVNS to tragus<br>tVNS will be applied to the tragus. | Other: tVNS<br>* Intervention<br>Other: Motor training<br>* Same finger training for both arms<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visuomotor Skill | Visuomotor skill was assessed with the amount of force error against the target trajectory. In the visuomotor task, subjects produced finger force against a force transducer to match a target trajectory as close as possible. The target was made of three low-frequency sinusoids with each sinusoid at different frequencies and amplitudes. This pattern spanned 20 s. The data in the middle 16 s were used for data analysis. For determining the visuomotor skill, the deviation of produced force from the target trajectory was calculated as the root-mean-square error. In this calculation, the difference between the target and produced force at each sampling point was squared, the squared values were summed across sampling points, and the squared root value of the summed value was determined and normalized to the maximal voluntary contraction (MVC) force. The data were expressed as the ratio of the baseline value (no unit). A lower value is considered a better outcome. | Day 1 (Baseline), Day 2 - 4, and Day 5 (Post) | 
| Brain Excitability (MEP Amplitude) | Brain excitability was assessed with motor evoked potential (MEP) amplitude of the resting first dorsal interosseus muscles as resting corticospinal excitability. Surface EMG electrodes were attached over the muscle in a belly-tendon configuration. Subjects received single-pulse TMS to evoke MEP in the muscle. MEP was obtained from the surface EMG using a high-gain EMG preamplifier. Peak-to-peak- amplitude of MEP in response to TMS were averaged across the intensities of 115-160% relative to the resting motor threshold. Additionally, maximal M-wave amplitude was obtained by stimulating the ulnar nerve that innervates the muscle. MEP amplitude was normalized to the maximal M-wave amplitude of the muscle, so it was expressed in % of maximal M-wave. A higher value is considered higher brain excitability and a better outcome. | Day 1 (Baseline) and Day 5 (Post) | 
| Salivary Amylase Activity | Central noradrenaline was assessed indirectly with salivary amylase activity. Saliva was sampled via salivette strips in the resting state before and after the training. Subjects were seated and rested for 5 minutes before sampling the samples. Collected saliva samples were immediately analyzed by using a dry-chemistry system automatically. Three saliva samples were analyzed and averaged across samples. Salivary amylase activity was measured and expressed in kU/I (kilo units per liter). | Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tVNS, training, neuromotor adaptation