Noninvasive Vagus Nerve Stimulation (VNS) for Neuromotor Adaptations

September 19, 2022 updated by: Georgia Institute of Technology
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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
24

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Georgia
      • Atlanta, Georgia, United States, 30332
        • Human Neuromuscular Physiology Lab

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 39 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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):

    1. Younger than 18 years old or older than 39 years old
    2. Left-handed
    3. Skilled use of hands (e.g. professional musician)
    4. High blood pressure (>140/90 mmHg)
    5. Had cardiovascular problems
    6. Obese (Body Mass Index: > 30 kg/m2)
    7. Had sensory deficits in your limb
    8. Had alcoholism
    9. Had psychiatric disorders
    10. Had an adverse reaction to TMS (a technique for non-invasive neural stimulation from the brain)
    11. 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.)
    12. Someone in your family has epilepsy (recurrent seizures marking excessive synchronous neuronal activity in the brain)
    13. Had an EEG (measurement of the electrical activity of the brain through the use of surface electrodes placed on the scalp) for clinical diagnosis
    14. Had a stroke (the loss of brain function due to an interruption in the blood supply to the brain)
    15. Had a head injury (include neurosurgery) that required a visit to a hospital
    16. Suffer from frequent or severe headaches (e.g., migraine headaches within the last six months)
    17. 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.
    18. 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
    19. Had any other brain-related condition
    20. Had any illness that caused brain injury (i.e. meningitis, aneurysm, brain tumor)
    21. Had severe disease such as cardiologic, pulmonary, renal, endocrinal (hyperthyroidism or hypothyroidism), gastrointestinal or others.
    22. Taking any medications other than over-the-counter medicine
    23. Suspect you might be pregnant (if woman)
    24. Have hearing problems, such as impaired hearing, tinnitus, etc.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
SHAM_COMPARATOR: Sham-tVNS to ear lobe
Sham-tVNS will be applied to the ear lobe.
Other: tVNS
Intervention
Other: Motor training
Same finger training for both arms
ACTIVE_COMPARATOR: tVNS to tragus
tVNS will be applied to the tragus.
Other: tVNS
Intervention
Other: Motor training
Same finger training for both arms

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Visuomotor Skill
Time Frame: Day 1 (Baseline), Day 2 - 4, and Day 5 (Post)
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)
Time Frame: Day 1 (Baseline) and Day 5 (Post)
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
Time Frame: Day 3
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Georgia Institute of Technology

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Minoru Shinohara, PhD, Georgia Institute of Technology

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 20, 2019

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 28, 2021

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 28, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 8, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 10, 2018

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 14, 2018

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 29, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 19, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2022

More Information

Terms related to this study

Keywords

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • H18151
  • 1R03NS106088-01A1 (NIH)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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