Healthy VolunteersESautonomousNCT05289817
Effects of Transcutaneous Electrical Stimulation on the Autonomous Nerve System in Healthy Young People
A study testing Transcutaneous Vagus Nerve Stimulation (t-VNS) and Transcutaneous Sympathetic Ganglion Electrical Stimulation (t-SES) in people with Healthy Volunteers and Cardiovascular System, run by Universidade da Coruña at 1 site in Spain.
Trial summary
Cardiovascular disease is one of the most important causes of death and disability in the world. An autonomic imbalance is associated to cardiovascular risks and disorders. Electrical stimulation (ES) applied by surface electrodes is a non-invasive therapeutic approach with low side-effects. Read more about this study
- Who is it for?
- Ages 18 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy Volunteers, Cardiovascular System, Autonomic Nervous System
- What is being tested?
- Transcutaneous Vagus Nerve Stimulation (t-VNS) and Transcutaneous Sympathetic Ganglion Electrical Stimulation (t-SES)
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteSpain
- Study dates
- 22 Mar 2022to 29 Jun 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- University students and academic or administrative staff, non smokers, self-perceived as healthy
Who cannot join
- No history of neurological, neurosurgical, psychiatric, cardiological disease, pulmonary disease, syncope, seizure, head trauma, cranial or neck surgery, aneurisms, or any condition or treatment which could affect the functioning of the autonomous nerve system or the cardiovascular system (by self-report).
- BMI of 30 or over
- High blood pressure (systolic blood pressure of 140 mmHg or over, or diastolic blood pressure of 90 mmHg or over)
- Spontaneous respiratory rate under 10 breaths per minute
- Professional athletes
- Inability to reach the minimum amplitude required during electrical stimulation
- Any arm or hand pain (dominant side)
- Any contraindication for electrical stimulation (pregnancy or risk or being pregnant, any implanted electronical device, irritation or pain at the skin location for the electrodes, intolerance to electrical stimulation) or any condition which could affect the placement of the electrodes or the perception of the electrical stimulus.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effectiveness of Transcutaneous Electrical Stimulation on the Autonomous and Cardiovascular System on Healthy Young People; a Prospective, Randomized, Single-blind, Controlled Pilot Study
Cardiovascular disease is one of the most important causes of death and disability in the world. An autonomic imbalance is associated to cardiovascular risks and disorders. Electrical stimulation (ES) applied by surface electrodes is a non-invasive therapeutic approach with low side-effects. In the last years, some studies had investigated the effects of ES on the autonomic nervous system and cardiovascular system. However, different intensities, frequencies and electrode locations had been used, which makes difficult to clarify the optimal parameters.
The aim of this study is to analyze the effects of ES on autonomic nervous modulation in healthy subjects comparing three different locations of application for ES.
Read more
Participants will be aleatory assigned to one of three groups for a single-session of 20-minute transcutaneous ES: a) an auricular intermittent ES in an area that is believed to be connected to the vagal nerve (cymba conchae); b) an auricular sham intermittent ES, meaning a real ES but applied on an ear location not connected to the vagal nerve (scapha); and c) an upper back continuous ES (C7-T4), a placement that is thought to be connected to the stellate (sympathetic) ganglion. All the protocols will be stated at a non-painful intensity. After that, the hand grip exercise will be executed.
The heart rate variability (HRV) and heart frequency (HR) will be measured in four main times: the baseline, in the final minutes of the ES, after the ES and after finishing the hand grip exercise. Blood pressure will be measured also at all the time points except during the ES due to the possibility of interferences. Adverse effects will be assessed after ES and 48 h later. The study will provide initial knowledge about how different electrical stimulation locations contribute to reduce sympathetic excitation and improve the sympathovagal balance.
Read the detailed description
Electrical stimulation (ES) of the nervous system, also denominated as neuromodulation, has been investigated for diverse conditions as cardiovascular diseases, chronic pain and psychiatric conditions. It is unknown which locations and parameters can be more effective and better tolerated. The transcutaneous ES is a non-invasive technique which has fewer side-effects than subcutaneous vagus nerve stimulation.
The aim of this study is to analyze the acute effects of transcutaneous ES on autonomic nervous modulation by heart rate variability (HRV), heart frequency (HF) and blood pressure (BP) in healthy subjects comparing three different locations for the ES, before and after a hand-grip exercise. In addition, the tolerance to the current, the side-effects and the perceived exertion will be compared.
Once the participants have given their informed consent and had been checked for exclusion criteria, are invited to an experimental session. Subjects will be advised to refrain from caffeine or alcohol for 12 h and vigorous exercise for at least 24h prior to the intervention.
The participants will remain sitting during the entire session and will be instructed to stay awake and avoid movement. Grip strength will be evaluated by a hydraulic dynamometer (Saehan model SH5001). Participants will remain seated on a chair with their feet and trunk supported, shoulders adducted, elbows flexed at 90º, forearms in neutral position, and wrists with 0º-30º extension. Subjects will be instructed to perform a maximum isometric contraction for three to five seconds, and the peak force will be recorded. Three evaluations will be made with an interval of one minute between them. If the examiner would recognize some compensatory movement by the participant, a new measurement would be taken and registered.
The volunteers will be randomized by sex to one of three groups: cymba conchae at the right ear (active group); C7-T4 placement (active group), scapha at the right ear (sham-group). These three arms will be denominated as Transcutaneous Vagus Electrical Nerve Stimulation (t-VNS); Transcutaneous Sympathetic Ganglion Electrical Nerve Stimulation (t-SNS); and Sham Transcutaneous Vagus Electrical Nerve Stimulation (sham t-VNS), and. Allocation concealment, stratified by sex, will be ensured by the use of sealed envelopes containing the treatment allocation. The sequence will be generated using a computer program by a researcher not implicated in the experimental sessions. The envelopes will be opened just before determining the amplitude for stimulation. The stimulation location will be wiped down with alcohol and the minimum intensity, at which the stimulus is perceived, will be evaluated for the auricular locations, whereas minimum amplitude for muscle contraction between the electrodes will be assessed in cervico-thoracic location.
After 15 minutes of resting, the first assessment (baseline) will be taken (HRV, HR and blood pressure) for 5 minutes. The respiratory frequency will be checked every 5 minutes.
Then the randomized ES will be applied for 20 minutes using the same TENSMED S82 (Enraf Nonius, The Netherlands) symmetrical and rectangular biphasic pulses, at 350 microseconds of phase duration. It will be applied at 10 Hz (t-VNS and sham t-VNS) or 5 Hz (t-SNS). Both the two protocols applied to the auricular region (t-VNS and sham t-VNS) will be delivered by trains, whereas a continuous ES will be selected for the (t-SNS). The minimum amplitude for auricular stimulations (t-VNS and sham t-VNS) will be twice the perception threshold, at a comfortable intensity under the discomfort threshold (pain onset). It will be increased during the stimulation only if the sensation is clearly decreased to a maximum of 9 mA. The perception threshold will be set increasing amplitude by 0.5 mA each 3 seconds from 0 mA. Amplitude in t-SNS will be set at a muscle contraction at a comfortable intensity (under discomfort threshold or pain onset). The motor threshold will be determined by increasing amplitude 0.5 mA each 3 seconds from the perception threshold until a motor contraction is observed. The initial amplitude will be 2 mA over this threshold. It will be increased during the stimulation only if the stimulus falls down (to a maximum of 25 mA).
Another 5-minute period after ES will be recorded and then the 3-minute hand grip exercise (SH5001, Saehan, Korea) at 30% of maximum strength will be required.
The final assessment of cardiovascular and autonomous variables will be obtained during the last 15 minutes. The rating of perceived exertion will be asked (Borg-CR10) whereas a VAS (0 denoting no sensation at all; 10 = indicating discomfort or pain onset) will be used to rate the tolerance to ES. The possible side-effects will be also checked.
The participants will be asked upon completion of the session their presumed group assignment.
Adverse effects will be checked again 48 h after finishing the experimental session.
The ES and the acquisition of the data will be done by physical therapists, but analysis of the main variables will be done by a cardiologist with the assistance of one of the physical therapists with specific knowledge in the area. The data will be introduced by a third researcher, and accuracy of the data will be checked selecting 50% of the data from each arm, by random software. If some mistakes will emerge, then the complete check will be done. The traditional statistical analysis will be reinforced by Bayesian inferences.
This is a pilot study. The objective is to check if there are statistically significant effects from the stimulation on the variables: cardiac variability, heart rate and blood pressure, before or after an isometric exercise of pressure.
For the comparison of the results obtained in the three groups of subjects, the analysis of variance or rank test procedures will be used, based on the normality or non-normality of the data obtained.
The effect of time will be assessed through a longitudinal data analysis that takes into account the dependence. For this purpose, the repeated measures Anova or Friedman's test will be used, in the parametric or non-parametric assumption, as a global comparison procedure. Possible interactions and dependence relationships between measured variables and time will be studied by means of linear regression analysis, generalised linear and/or generalised kernel-type non-parametric modelling.
Comparisons between groups (Anova or its non-parametric equivalent) will be complemented by means of their equivalents in Bayesian analysis, in order to reinforce the information provided by the p-values obtained in each procedure. For this purpose, the corresponding Bayes factors (Kass and Raftery, 1995) and the posteriori distributions of the estimated parameters will be calculated, thus increasing the precision of the confidence intervals.
- Being tested
- Transcutaneous Vagus Nerve Stimulation (t-VNS), Transcutaneous Sympathetic Ganglion Electrical Stimulation (t-SES), Sham Transcutaneous vagus nerve stimulation (Sham t-VNS)
- Keywords
- Electric Stimulation Therapy, Transcutaneous Electric Nerve Stimulation, Parasympathetic Nervous System, Stellate Ganglion, Hearth Rate, Blood Pressure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Transcutaneous Vagus Nerve Stimulation (t-VNS)Device
Type of device and current: portable machine, low frequency current, constant current Type of wave: square biphasic pulses Pulse duration: 350 microseconds Frequency: 10 Hz Number of channels: one Location and electrodes: cymba conchae at right ear (vagus branch nerve area); a clip electrode will be applied with its cathode on anterior cymba conchae, the anode placed behind.
Amplitude: from 2 times the perception threshold (individualized) at a comfortable, non-painful amplitude, and to a maximum of 9 mA. It will be increased, if necessary, each 5 minutes in order to maintain the same level of tingling sensation On-Off times: trains of 30 s on, 5 s rump up, 1 s rump down, 24 s off Duration: 20 minutes
Transcutaneous Sympathetic Ganglion Electrical Stimulation (t-SES)Device
Type of device and current: portable machine, low frequency current, constant current Type of wave: square biphasic pulses Pulse duration: 350 microseconds Frequency: 5 Hz Number of channels: two Location and electrodes: cervicothoracic area (stellate ganglion region); first channel: new 5 cm x 5 cm self-adhesive electrodes will be applied at 1-1.5 cm both sides of the vertebral spinous processes, approximately from C7 to T4, upper cathode on the left side of C7 and lower cathode on the right side.
Amplitude: 2 mA above the muscle contraction threshold (individualized) at a comfortable, non-painful amplitude and to a maximum of 25 mA. It will be increased, if necessary, each 5 minutes in order to maintain the same level of muscle contraction On-Off times: no trains, continuously delivered Duration: 20 minutes
Sham Transcutaneous vagus nerve stimulation (Sham t-VNS)Device
Type of device and current: portable machine, low frequency current, constant current Type of wave: square biphasic pulses Pulse duration: 350 microseconds Frequency: 10 Hz Number of channels: one Location and electrodes: scapha at right ear (non vagus innervated region); a clip electrode will be applied with its cathode on anterior scapha, the anode placed behind.
Amplitude: from 2 times above the perception threshold (individualized) at a comfortable, non-painful amplitude, and to a maximum of 9 mA. It will be increased, if necessary, each 5 minutes in order to maintain the same level of tingling sensation On-Off times: trains of 30 s on, 5 s rump up, 1 s rump down, 24 s off Duration: 20 minutes
| Study group | Role | What they receive |
|---|---|---|
| Transcutaneous Vagus Electrical Nerve Stimulation (t-VNS) | Experimental | Transcutaneous electrical stimulation will be delivered by trains for twenty minutes to the right cymba conchae at the ear. Receives: Device: Transcutaneous Vagus Nerve Stimulation (t-VNS) |
| Transcutaneous Sympathetic Ganglion Electrical Nerve Stimulation (t-SNS) | Active comparator | Transcutaneous electrical stimulation will be delivered continuously for twenty minutes to the cervicothoracic region. Receives: Device: Transcutaneous Sympathetic Ganglion Electrical Stimulation (t-SES) |
| Sham Transcutaneous Vagus Electrical Nerve stimulation (sham t-VNS) | Sham comparator | Transcutaneous electrical stimulation will be delivered by trains for twenty minutes to the right scapha at the ear. Receives: Device: Sham Transcutaneous vagus nerve stimulation (Sham t-VNS) |
What is being measured
The primary outcome is the main question the study is designed to answer.
RR
The time of RR intervals (ms) will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland). The mean values of RR intervals (ms) and the standard deviation of all RR intervals (ms) will be obtained.
Measured: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
RMSSD
Root mean square of successive RR interval differences (ms). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Measured: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
pNN50
Relative number of successive RR interval pairs that differ more than 50 ms (percentage). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Measured: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
HF
High frequency refers to HRV frequency band (0.15-0.4 Hz). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Measured: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
LF
Low frequency refers to HRV frequency band (0.04-0.15 Hz). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Measured: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
LF/HF
The ratio of LF to HF power will be calculated along with normalised LF/HF where baseline values will set to 1. It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Measured: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
SD1
The poincaré plot short term variability (ms). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Measured: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
SD2
The poincaré plot long term variability (ms). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Measured: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
SD2/SD1
Poincaré plot long and short term variability ratio. It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Measured: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Mean heart rate
The mean frequency will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Measured: 5 minutes before Electrical Stimulation, during 20 minutes of Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Systolic blood pressure
Blood pressure will be continuously acquired by SOMNOtouch NIBP (Somnomedics, GmbH, Randersacker, Germany) that is an ambulatory cuffless device for continuous (beat-to-beat), noninvasive BP monitoring. The system consists of a finger photoplethysmograph and three ECG leads, connected to a watch-like control unit placed at the wrist level and equipped with a screen where beat-to-beat pulse waveform, ECG, and PTT changes are displayed. All these measurements are unified to obtain systolic blood pressure in mmHg.
Measured: 5 minutes before Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Diastolic blood pressure
Blood pressure will be continuously acquired by SOMNOtouch NIBP (Somnomedics, GmbH, Randersacker, Germany) that is an ambulatory cuffless device for continuous (beat-to-beat), noninvasive BP monitoring. The system consists of a finger photoplethysmograph and three ECG leads, connected to a watch-like control unit placed at the wrist level and equipped with a screen where beat-to-beat pulse waveform, ECG, and PTT changes are displayed. All these measurements are unified to obtain the diastolic blood pressure in mmHg.
Measured: 5 minutes before Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Mean arterial pressure
Blood pressure will be continuously acquired by SOMNOtouch NIBP (Somnomedics, GmbH, Randersacker, Germany) that is an ambulatory cuffless device for continuous (beat-to-beat), noninvasive BP monitoring. The system consists of a finger photoplethysmograph and three ECG leads, connected to a watch-like control unit placed at the wrist level and equipped with a screen where beat-to-beat pulse waveform, ECG, and PTT changes are displayed. All these measurements are unified to obtain the mean arterial pressure in mmHg.
Measured: 5 minutes before Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Secondary outcomes (3)
Electrical simulation tolerance
The participants will be asked to rate their feelings during electrical stimulation by placing a solid vertical line on a 100-mm scale anchored by opposing descriptors (0=no sensation at all; 100 = pain onset or discomfort). Visual Analogue Scale (VAS) will be "scored" by measuring the rating with a ruler (millimeters)
Measured: 20 minutes after initiating electrical stimulation
Rating of perceived effort
Subjective feelings of effort and fatigue of the arm using de Borg CR-10, from 0 (nothing at all) to 10 (almost maximal)
Measured: Immediately after the hand grip exercise
Adverse effects
All posible adverse effects due to the electrical stimulation and the electrodes will be checked by a questionnaire
Measured: At 20 minutes after initiating electrical stimulation and at 48 hours after the electrical stimulation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Mar 2022
- Study start22 Mar 2022
- Primary completion27 Jun 2022
- Study completion29 Jun 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Healthy VolunteersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The study is a prospective, randomized, three-armed, sham-controlled, single-blind, exploratory clinical trial in healthy subjects
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universidade da Coruña
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Alicia Martínez Rodríguez, Universidade da Coruña
- Investigators
- Alicia Martínez-Rodríguez, PhD, Principal investigator, Universidade da Coruña (UDC)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05289817
- Sponsor's protocol ID
- 2020/011
- Acronym
- ESautonomous
- Status last verified
- Oct 2022
- First submitted
- 10 Feb 2022
- Last updated
- 1 Nov 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effectiveness of Transcutaneous Electrical Stimulation on the Autonomous and Cardiovascular System on Healthy Young People; a Prospective, Randomized, Single-blind, Controlled Pilot Study
- ClinicalTrials.gov ID
- NCT05289817
- Acronym / sponsor ID
- ESautonomous / 2020/011
- Keywords
- Electric Stimulation Therapy, Transcutaneous Electric Nerve Stimulation, Parasympathetic Nervous System, Stellate Ganglion, Hearth Rate, Blood Pressure
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Universidade da CoruñaUniversity, hospital or other
- Study start
- 22 Mar 2022 (actual)
- Primary completion
- 27 Jun 2022 (actual)
- Study completion
- 29 Jun 2022 (actual)
- First posted
- 21 Mar 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Cardiovascular disease is one of the most important causes of death and disability in the world. An autonomic imbalance is associated to cardiovascular risks and disorders. Electrical stimulation (ES) applied by surface electrodes is a non-invasive therapeutic approach with low side-effects. In the last years, some studies had investigated the effects of ES on the autonomic nervous system and cardiovascular system. However, different intensities, frequencies and electrode locations had been used, which makes difficult to clarify the optimal parameters.
The aim of this study is to analyze the effects of ES on autonomic nervous modulation in healthy subjects comparing three different locations of application for ES.
Participants will be aleatory assigned to one of three groups for a single-session of 20-minute transcutaneous ES: a) an auricular intermittent ES in an area that is believed to be connected to the vagal nerve (cymba conchae); b) an auricular sham intermittent ES, meaning a real ES but applied on an ear location not connected to the vagal nerve (scapha); and c) an upper back continuous ES (C7-T4), a placement that is thought to be connected to the stellate (sympathetic) ganglion. All the protocols will be stated at a non-painful intensity. After that, the hand grip exercise will be executed.
The heart rate variability (HRV) and heart frequency (HR) will be measured in four main times: the baseline, in the final minutes of the ES, after the ES and after finishing the hand grip exercise. Blood pressure will be measured also at all the time points except during the ES due to the possibility of interferences. Adverse effects will be assessed after ES and 48 h later. The study will provide initial knowledge about how different electrical stimulation locations contribute to reduce sympathetic excitation and improve the sympathovagal balance.
Detailed description
Electrical stimulation (ES) of the nervous system, also denominated as neuromodulation, has been investigated for diverse conditions as cardiovascular diseases, chronic pain and psychiatric conditions. It is unknown which locations and parameters can be more effective and better tolerated. The transcutaneous ES is a non-invasive technique which has fewer side-effects than subcutaneous vagus nerve stimulation.
The aim of this study is to analyze the acute effects of transcutaneous ES on autonomic nervous modulation by heart rate variability (HRV), heart frequency (HF) and blood pressure (BP) in healthy subjects comparing three different locations for the ES, before and after a hand-grip exercise. In addition, the tolerance to the current, the side-effects and the perceived exertion will be compared.
Once the participants have given their informed consent and had been checked for exclusion criteria, are invited to an experimental session. Subjects will be advised to refrain from caffeine or alcohol for 12 h and vigorous exercise for at least 24h prior to the intervention.
The participants will remain sitting during the entire session and will be instructed to stay awake and avoid movement. Grip strength will be evaluated by a hydraulic dynamometer (Saehan model SH5001). Participants will remain seated on a chair with their feet and trunk supported, shoulders adducted, elbows flexed at 90º, forearms in neutral position, and wrists with 0º-30º extension. Subjects will be instructed to perform a maximum isometric contraction for three to five seconds, and the peak force will be recorded. Three evaluations will be made with an interval of one minute between them. If the examiner would recognize some compensatory movement by the participant, a new measurement would be taken and registered.
The volunteers will be randomized by sex to one of three groups: cymba conchae at the right ear (active group); C7-T4 placement (active group), scapha at the right ear (sham-group). These three arms will be denominated as Transcutaneous Vagus Electrical Nerve Stimulation (t-VNS); Transcutaneous Sympathetic Ganglion Electrical Nerve Stimulation (t-SNS); and Sham Transcutaneous Vagus Electrical Nerve Stimulation (sham t-VNS), and. Allocation concealment, stratified by sex, will be ensured by the use of sealed envelopes containing the treatment allocation. The sequence will be generated using a computer program by a researcher not implicated in the experimental sessions. The envelopes will be opened just before determining the amplitude for stimulation. The stimulation location will be wiped down with alcohol and the minimum intensity, at which the stimulus is perceived, will be evaluated for the auricular locations, whereas minimum amplitude for muscle contraction between the electrodes will be assessed in cervico-thoracic location.
After 15 minutes of resting, the first assessment (baseline) will be taken (HRV, HR and blood pressure) for 5 minutes. The respiratory frequency will be checked every 5 minutes.
Then the randomized ES will be applied for 20 minutes using the same TENSMED S82 (Enraf Nonius, The Netherlands) symmetrical and rectangular biphasic pulses, at 350 microseconds of phase duration. It will be applied at 10 Hz (t-VNS and sham t-VNS) or 5 Hz (t-SNS). Both the two protocols applied to the auricular region (t-VNS and sham t-VNS) will be delivered by trains, whereas a continuous ES will be selected for the (t-SNS). The minimum amplitude for auricular stimulations (t-VNS and sham t-VNS) will be twice the perception threshold, at a comfortable intensity under the discomfort threshold (pain onset). It will be increased during the stimulation only if the sensation is clearly decreased to a maximum of 9 mA. The perception threshold will be set increasing amplitude by 0.5 mA each 3 seconds from 0 mA. Amplitude in t-SNS will be set at a muscle contraction at a comfortable intensity (under discomfort threshold or pain onset). The motor threshold will be determined by increasing amplitude 0.5 mA each 3 seconds from the perception threshold until a motor contraction is observed. The initial amplitude will be 2 mA over this threshold. It will be increased during the stimulation only if the stimulus falls down (to a maximum of 25 mA).
Another 5-minute period after ES will be recorded and then the 3-minute hand grip exercise (SH5001, Saehan, Korea) at 30% of maximum strength will be required.
The final assessment of cardiovascular and autonomous variables will be obtained during the last 15 minutes. The rating of perceived exertion will be asked (Borg-CR10) whereas a VAS (0 denoting no sensation at all; 10 = indicating discomfort or pain onset) will be used to rate the tolerance to ES. The possible side-effects will be also checked.
The participants will be asked upon completion of the session their presumed group assignment.
Adverse effects will be checked again 48 h after finishing the experimental session.
The ES and the acquisition of the data will be done by physical therapists, but analysis of the main variables will be done by a cardiologist with the assistance of one of the physical therapists with specific knowledge in the area. The data will be introduced by a third researcher, and accuracy of the data will be checked selecting 50% of the data from each arm, by random software. If some mistakes will emerge, then the complete check will be done. The traditional statistical analysis will be reinforced by Bayesian inferences.
This is a pilot study. The objective is to check if there are statistically significant effects from the stimulation on the variables: cardiac variability, heart rate and blood pressure, before or after an isometric exercise of pressure.
For the comparison of the results obtained in the three groups of subjects, the analysis of variance or rank test procedures will be used, based on the normality or non-normality of the data obtained.
The effect of time will be assessed through a longitudinal data analysis that takes into account the dependence. For this purpose, the repeated measures Anova or Friedman's test will be used, in the parametric or non-parametric assumption, as a global comparison procedure. Possible interactions and dependence relationships between measured variables and time will be studied by means of linear regression analysis, generalised linear and/or generalised kernel-type non-parametric modelling.
Comparisons between groups (Anova or its non-parametric equivalent) will be complemented by means of their equivalents in Bayesian analysis, in order to reinforce the information provided by the p-values obtained in each procedure. For this purpose, the corresponding Bayes factors (Kass and Raftery, 1995) and the posteriori distributions of the estimated parameters will be calculated, thus increasing the precision of the confidence intervals.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 3
- Model description
- The study is a prospective, randomized, three-armed, sham-controlled, single-blind, exploratory clinical trial in healthy subjects
| Arm | Type | Receives |
|---|---|---|
| Transcutaneous Vagus Electrical Nerve Stimulation (t-VNS) | Experimental | Device: Transcutaneous Vagus Nerve Stimulation (t-VNS)Transcutaneous electrical stimulation will be delivered by trains for twenty minutes to the right cymba conchae at the ear. |
| Transcutaneous Sympathetic Ganglion Electrical Nerve Stimulation (t-SNS) | Active comparator | Device: Transcutaneous Sympathetic Ganglion Electrical Stimulation (t-SES)Transcutaneous electrical stimulation will be delivered continuously for twenty minutes to the cervicothoracic region. |
| Sham Transcutaneous Vagus Electrical Nerve stimulation (sham t-VNS) | Sham comparator | Device: Sham Transcutaneous vagus nerve stimulation (Sham t-VNS)Transcutaneous electrical stimulation will be delivered by trains for twenty minutes to the right scapha at the ear. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- University students and academic or administrative staff, non smokers, self-perceived as healthy
Key exclusion criteria (8 listed)
- No history of neurological, neurosurgical, psychiatric, cardiological disease, pulmonary disease, syncope, seizure, head trauma, cranial or neck surgery, aneurisms, or any condition or treatment which could affect the functioning of the autonomous nerve system or the cardiovascular system (by self-report).
- BMI of 30 or over
- High blood pressure (systolic blood pressure of 140 mmHg or over, or diastolic blood pressure of 90 mmHg or over)
- Spontaneous respiratory rate under 10 breaths per minute
- Professional athletes
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Transcutaneous Vagus Nerve Stimulation (t-VNS)Type of device and current: portable machine, low frequency current, constant current Type of wave: square biphasic pulses Pulse duration: 350 microseconds Frequency: 10 Hz Number of channels: one Location and electrodes: cymba conchae at right ear (vagus branch nerve area); a clip electrode will be applied with its cathode on anterior cymba conchae, the anode placed behind. Amplitude: from 2 times the perception threshold (individualized) at a comfortable, non-painful amplitude, and to a maximum of 9 mA. It will be increased, if necessary, each 5 minutes in order to maintain the same level of tingling sensation On-Off times: trains of 30 s on, 5 s rump up, 1 s rump down, 24 s off Duration: 20 minutes | Device | Transcutaneous Vagus Electrical Nerve Stimulation (t-VNS) |
| Transcutaneous Sympathetic Ganglion Electrical Stimulation (t-SES)Type of device and current: portable machine, low frequency current, constant current Type of wave: square biphasic pulses Pulse duration: 350 microseconds Frequency: 5 Hz Number of channels: two Location and electrodes: cervicothoracic area (stellate ganglion region); first channel: new 5 cm x 5 cm self-adhesive electrodes will be applied at 1-1.5 cm both sides of the vertebral spinous processes, approximately from C7 to T4, upper cathode on the left side of C7 and lower cathode on the right side. Amplitude: 2 mA above the muscle contraction threshold (individualized) at a comfortable, non-painful amplitude and to a maximum of 25 mA. It will be increased, if necessary, each 5 minutes in order to maintain the same level of muscle contraction On-Off times: no trains, continuously delivered Duration: 20 minutes | Device | Transcutaneous Sympathetic Ganglion Electrical Nerve Stimulation (t-SNS) |
| Sham Transcutaneous vagus nerve stimulation (Sham t-VNS)Type of device and current: portable machine, low frequency current, constant current Type of wave: square biphasic pulses Pulse duration: 350 microseconds Frequency: 10 Hz Number of channels: one Location and electrodes: scapha at right ear (non vagus innervated region); a clip electrode will be applied with its cathode on anterior scapha, the anode placed behind. Amplitude: from 2 times above the perception threshold (individualized) at a comfortable, non-painful amplitude, and to a maximum of 9 mA. It will be increased, if necessary, each 5 minutes in order to maintain the same level of tingling sensation On-Off times: trains of 30 s on, 5 s rump up, 1 s rump down, 24 s off Duration: 20 minutes | Device | Sham Transcutaneous Vagus Electrical Nerve stimulation (sham t-VNS) |
Primary outcome
RR
Time frame: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
The time of RR intervals (ms) will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland). The mean values of RR intervals (ms) and the standard deviation of all RR intervals (ms) will be obtained.
RMSSD
Time frame: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Root mean square of successive RR interval differences (ms). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
pNN50
Time frame: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Relative number of successive RR interval pairs that differ more than 50 ms (percentage). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
HF
Time frame: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
High frequency refers to HRV frequency band (0.15-0.4 Hz). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
LF
Time frame: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Low frequency refers to HRV frequency band (0.04-0.15 Hz). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
LF/HF
Time frame: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
The ratio of LF to HF power will be calculated along with normalised LF/HF where baseline values will set to 1. It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
SD1
Time frame: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
The poincaré plot short term variability (ms). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
SD2
Time frame: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
The poincaré plot long term variability (ms). It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
SD2/SD1
Time frame: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Poincaré plot long and short term variability ratio. It will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Mean heart rate
Time frame: 5 minutes before Electrical Stimulation, during 20 minutes of Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
The mean frequency will be obtained from Polar S800 with Polar T31 transmitter (Polar Electro, Kempele, Finland), and it will be extracted with Kubios software (University of Eastern Finland, Kuopio, Finland).
Systolic blood pressure
Time frame: 5 minutes before Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Blood pressure will be continuously acquired by SOMNOtouch NIBP (Somnomedics, GmbH, Randersacker, Germany) that is an ambulatory cuffless device for continuous (beat-to-beat), noninvasive BP monitoring. The system consists of a finger photoplethysmograph and three ECG leads, connected to a watch-like control unit placed at the wrist level and equipped with a screen where beat-to-beat pulse waveform, ECG, and PTT changes are displayed. All these measurements are unified to obtain systolic blood pressure in mmHg.
Diastolic blood pressure
Time frame: 5 minutes before Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Blood pressure will be continuously acquired by SOMNOtouch NIBP (Somnomedics, GmbH, Randersacker, Germany) that is an ambulatory cuffless device for continuous (beat-to-beat), noninvasive BP monitoring. The system consists of a finger photoplethysmograph and three ECG leads, connected to a watch-like control unit placed at the wrist level and equipped with a screen where beat-to-beat pulse waveform, ECG, and PTT changes are displayed. All these measurements are unified to obtain the diastolic blood pressure in mmHg.
Mean arterial pressure
Time frame: 5 minutes before Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise
Blood pressure will be continuously acquired by SOMNOtouch NIBP (Somnomedics, GmbH, Randersacker, Germany) that is an ambulatory cuffless device for continuous (beat-to-beat), noninvasive BP monitoring. The system consists of a finger photoplethysmograph and three ECG leads, connected to a watch-like control unit placed at the wrist level and equipped with a screen where beat-to-beat pulse waveform, ECG, and PTT changes are displayed. All these measurements are unified to obtain the mean arterial pressure in mmHg.
3 secondary outcomes
Electrical simulation tolerance
Time frame: 20 minutes after initiating electrical stimulation
Rating of perceived effort
Time frame: Immediately after the hand grip exercise
Adverse effects
Time frame: At 20 minutes after initiating electrical stimulation and at 48 hours after the electrical stimulation
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Nov 2022.
- Individual participant dataSharing planned: No
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Screening Protocol
Pain
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alicia Martínez-Rodríguez, PhD principal investigator
Universidade da Coruña (UDC)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Transcutaneous Vagus Nerve Stimulation (t-VNS) and Transcutaneous Sympathetic Ganglion Electrical Stimulation (t-SES) in people with Healthy Volunteers and Cardiovascular System, run by Universidade da Coruña at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
RR (time frame: 5 minutes before Electrical Stimulation, During 20 minutes Electrical Stimulation, 5 minutes after Electrical Stimulation, During 3 minutes hand-grip exercise, 15 minutes after hand grip exercise). The study lists 13 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Nov 2022.