Vagus Nerve StimulationsNCT07501611
Acute Cardiovascular Effects of Transcutaneous Auricular Vagus Nerve Stimulation
A study testing Active taVNS condition in people with Vagus Nerve Stimulations, run by Northumbria University at 1 site in United Kingdom.
Trial summary
Introduction Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with arterial hypertension representing the most significant modifiable risk factor (Lim et al., 2012; Mills et al., 2020). Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Vagus Nerve Stimulations
- What is being tested?
- Active taVNS condition
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 1 Mar 2026to 1 Dec 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
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 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Participants will be eligible if they meet the following criteria:
- Age: 18-45 years
- Healthy status: No diagnosed cardiovascular, metabolic, neurological, or psychiatric conditions
- BP: Normotensive (office SBP <140 mmHg and DBP <90 mmHg)
- Body Mass Index (BMI): 18.5-30 kg/m²Non-smoker or light smoker (≤5 cigarettes per day, willing to abstain before testing)
- Ability to understand and provide written informed consent
- Willingness to comply with study procedures, including:
- No regular use of medications affecting cardiovascular or autonomic function (including beta-blockers, calcium channel blockers, antihypertensives, or psychotropic medications)
Who cannot join
- Current participation in another interventional trial
- Clinically significant resting bradycardia (HR <50 bpm)
- Known damage or surgical removal of the vagus nerve
- Established cardiovascular disease (e.g., myocardial infarction, heart failure, arrhythmias, stroke, peripheral vascular disease)
- Diagnosed with hypertension or currently taking antihypertensive medication
- Known diagnosis of trigeminal neuralgia or other chronic pain conditions
Show all 11Show fewer
- Active ear infection or skin conditions affecting the tragus/auricle
- Implanted electronic devices (pacemaker, defibrillator, vagal nerve stimulator)
- Pregnancy or breastfeeding
- Current diagnosis of anxiety, depression, or other psychiatric conditions requiring medication
- History of syncope or severe vasovagal response
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United Kingdom1 site
Northumbria University
Newcastle upon Tyne
Gabriel Cucato, PhD, +44 0191 232 6002, gabriel.cucato@northumbria.ac.uk
About this study
Introduction
Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with arterial hypertension representing the most significant modifiable risk factor (Lim et al., 2012; Mills et al., 2020). While clinical manifestations of arterial hypertension typically emerge in later life, the underlying pathophysiological mechanisms, particularly autonomic dysfunction, begin decades earlier.
Read more
Autonomic imbalance, characterised by sympathetic overactivity and diminished parasympathetic tone, not only precedes sustained arterial hypertension but also independently predicts future cardiovascular risk, even in normotensive individuals (He et al., 2023; Thayer et al., 2010). Reduced heart rate variability (HRV), a non-invasive marker of parasympathetic activity, has been consistently associated with increased cardiovascular morbidity across diverse populations (Task Force, 1996).
Critically, young apparently healthy adults with suboptimal lifestyle factors, including physical inactivity, poor dietary habits, and chronic stress, frequently exhibit reduced HRV and altered sympathovagal balance (Liao et al., 1998). These subclinical autonomic changes represent an early, potentially reversible stage in the cardiovascular disease continuum, suggesting that interventions targeting autonomic balance may prevent or delay progression to overt disease (Goldstein et al., 2011).
The vagus nerve, the main parasympathetic pathway, exerts multiple cardioprotective effects, including heart rate deceleration, baroreflex enhancement, reduced vascular tone, and anti-inflammatory activity (Thayer \& Sternberg, 2006). Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a non-invasive method to enhance vagal activity by delivering electrical stimulation to the auricular branch of the vagus nerve via surface electrodes placed on the tragus or cymba conchae (Badran et al., 2018). Neuroimaging studies confirm that taVNS activates central vagal projections, including the nucleus tractus solitarius, the primary relay station for cardiovascular autonomic control (Frangos et al., 2015).
Preliminary research demonstrates that acute taVNS sessions increase HRV, enhance baroreflex sensitivity, and reduce sympathetic vascular tone in healthy adults (Clancy et al., 2014; De Couck et al., 2017), while emerging evidence suggests clinically meaningful reductions in blood pressure (BP) in hypertensive patients (Mbikyo et al., 2024).
Despite these promising findings, significant knowledge gaps remain. Most studies have examined clinical populations with pre-existing autonomic abnormalities, making it difficult to isolate primary taVNS mechanisms from disease-related compensatory responses. Additionally, chronic intervention protocols preclude detailed characterisation of immediate autonomic and hemodynamic changes. Conducting mechanistic studies in healthy populations offers critical advantages: absence of confounding medications and disease adaptations enables clearer identification of taVNS-induced autonomic and hemodynamic changes, while establishing baseline response patterns provides an essential reference framework for interpreting clinical population responses and informing preventive interventions. Investigation of acute responses permits precise temporal mapping of physiological changes, distinguishing primary mechanisms from downstream consequences, enables efficient optimisation of stimulation parameters, and provides biological plausibility for chronic effects while identifying potential responders to therapy.
Therefore, this study proposes a randomised, sham-controlled crossover study to systematically characterise acute cardiovascular and autonomic responses to a single 60-minute taVNS session in healthy young adults. Using continuous non-invasive BP monitoring and detailed HRV analysis, this study will establish whether taVNS produces acute, measurable changes in BP, heart rate, and autonomic balance in individuals with normal baseline function. We will elucidate the temporal dynamics of taVNS-induced effects, characterise the mechanistic pathways distinguishing cardiac, hemodynamic, and autonomic contributions, and evaluate the specificity of active stimulation versus sham conditions. By establishing baseline physiological response patterns and elucidating acute mechanisms in a well-controlled population, our findings will lay the groundwork for subsequent investigations in at-risk and hypertensive individuals, ultimately contributing to evidence-based, personalised autonomic modulation therapy for cardiovascular disease prevention and management.
Read the detailed description
Before study commencement, the complete randomisation sequence for all 20 participants will be generated using the online random sequence generator available at www.randomizer.org. An independent researcher who is not involved in participant recruitment, screening, data collection, or outcome assessment will use the "Randomise Lists" function to generate 20 distinct randomised orders of the three experimental conditions (active taVNS, sham-sound, and sub-threshold sham). Each participant will be assigned a sequential identification number from 1 to 20, with a corresponding randomised sequence determining which condition they will receive at Visits 2, 3, and 4.
The independent researcher will maintain the master randomisation list in a secure, password-protected electronic file or in a locked physical document, accessible only to them. This ensures allocation concealment throughout the recruitment and enrollment process. On the morning of each experimental session (Visits 2, 3, and 4), the independent researcher will communicate the allocated condition for that specific participant and visit to the research coordinator who is responsible for setting up and operating the taVNS device. This communication will occur via secure email, telephone, or in person, specifying only the condition to be delivered that day (e.g., "Participant 15, Visit 2: Active taVNS").
The research coordinator who receives this information and prepares the device will not be involved in outcome assessments. Importantly, two key individuals will remain blinded throughout the study: the participant, who will not be informed which type of stimulation they are receiving on any given day, and the outcome assessor, who performs all cardiovascular measurements. The randomisation list will be retained in secure study files and will only be fully revealed to the research team after all data collection and preliminary analyses are complete.
Blinding Procedures
This study employs triple-blinding to minimise bias. Participants will be blinded to condition allocation throughout the study. They will be informed that the study is comparing different intensities or modes of vagal stimulation without being told which sessions involve active versus sham stimulation.
The design of the sham conditions, particularly the sham-sound electrode, which produces tactile and auditory cues mimicking active stimulation, facilitates effective participant blinding. The sub-threshold sham condition explicitly communicates that stimulation is below the sensory threshold, maintaining the procedure's credibility without compromising blinding. Outcome assessors will also be blinded. Specifically, the investigator who performs all cardiovascular measurements throughout the study will remain blinded to which condition the participant is receiving during each session. Data analysts will be blinded during statistical analysis, with condition allocation coded numerically. The allocation code will be held securely by the principal investigator and will only be revealed to the statistical analyst after all analyses are complete.
Individuals expressing interest in participating will be invited to attend the Cardiovascular Physiology Laboratory at Northumbria University for an initial screening visit. Upon arrival, the research team will review the Participant Information Sheet with the potential participant, explain all study procedures in detail, and answer any questions. Adequate time will be provided for the individual to consider participation, after which written informed consent will be obtained before any study procedures.
Following consent, participants will undergo a structured interview to collect demographic information, including age, sex, and ethnicity, as well as detailed health history covering cardiovascular, neurological, and psychiatric conditions. Current medication use, including prescription, over-the-counter, and dietary supplements, will be documented. Lifestyle factors will be assessed, including habitual physical activity levels, dietary patterns, smoking status, alcohol consumption, sleep quality, and perceived stress.
Anthropometric measurements will be performed according to standardised procedures. Height will be measured to the nearest 0.1 cm using a wall-mounted stadiometer with the participant standing barefoot. Body mass will be measured to the nearest 0.1 kg using calibrated digital scales with the participant wearing light clothing and no shoes. Body Mass Index will be calculated as mass (in kilograms) divided by height (in meters) squared. Waist circumference will be measured at the narrowest point between the lower rib margin and the iliac crest. Hip circumference will be measured at the widest point of the buttocks. Neck circumference will be measured at the midpoint of the neck below the laryngeal prominence. All circumference measurements will be taken to the nearest 0.1 cm using a non-stretchable measuring tape.
Office BP will be assessed using auscultatory methods with a calibrated mercury sphygmomanometer and stethoscope, according to current guidelines.
The participant will be seated in a quiet room with back supported, feet flat on the floor, and arms supported at heart level. After five minutes of quiet rest, three BP readings will be taken from each arm at one-minute intervals. Korotkoff phase I will be used to identify systolic BP and phase V will be used to identify diastolic BP. The mean of all six readings will be calculated to determine eligibility. Participants with a mean systolic BP of less than 140 mmHg and a diastolic BP of less than 90 mmHg will meet the BP inclusion criterion.
Familiarisation with the taVNS Procedure
Following completion of screening assessments, participants who meet all inclusion criteria and have no exclusion criteria will undergo a familiarisation session to introduce them to the taVNS device and procedure. The research team will explain the mechanism of transcutaneous auricular vagus nerve stimulation and demonstrate the Parasym device and electrode placement. The participant will then have the opportunity to experience the stimulation firsthand. The electrode will be placed on the left tragus, and the participant will be guided to gradually increase the stimulation intensity from zero until they perceive a constant tingling sensation. They will be instructed that during actual experimental sessions, the intensity will be set to one milliampere below their discomfort threshold.
This familiarisation serves multiple purposes: it ensures participants understand what to expect during experimental sessions, allows them to experience the sensation and confirm that they are comfortable proceeding, provides an opportunity to identify individuals who may not tolerate the stimulation, and reduces anxiety and novelty effects during the experimental sessions.
Participants will be encouraged to ask questions and voice any concerns. Only participants who are comfortable with the stimulation and willing to proceed will be enrolled in the study and scheduled for the three experimental sessions.
Experimental Sessions (Visits 2, 3, and 4)
Pre-Session Requirements and Standardisation
To control for factors known to influence cardiovascular and autonomic function, participants will receive detailed standardised instructions before each experimental session. They will be asked to consume only a light meal at least two hours before their scheduled session time and to avoid all caffeine-containing products, including coffee, tea, caffeinated soft drinks, energy drinks, and chocolate, for at least 12 hours before the session. Alcohol consumption will be prohibited for 24 hours before each session.
Participants will be instructed to refrain from vigorous physical activity or structured exercise for 48 hours before each session, though light activities such as walking are permitted. Smokers will be asked not to smoke for at least three hours before their session. They will be encouraged to obtain at least seven hours of sleep the night before each session and to maintain normal hydration levels while avoiding excessive fluid intake immediately before arrival at the laboratory.
All experimental sessions will be scheduled at the same time of day for each participant, commencing between 9:00 and 10:00 AM, to control for circadian variations in cardiovascular parameters and autonomic nervous system activity. Sessions will be separated by a minimum of 48 hours to prevent carryover effects and allow full physiological recovery between interventions. Participants will be asked to record their adherence to pre-session instructions, sleep duration, and any relevant events or symptoms in a brief diary provided for this purpose.
Experimental Session Protocol
Upon arrival at the Cardiovascular Physiology Laboratory, participants will be reminded of the session procedures and allowed to ask questions. They will be asked to void their bladder and change into comfortable, loose-fitting clothing if needed. The laboratory environment will be maintained at a comfortable temperature between 20 and 22 degrees Celsius with dimmed lighting to promote relaxation. Participants will then assume a supine position on a comfortable examination table with the head elevated approximately 30 degrees using pillows to ensure comfort during the extended monitoring period. Please see the experimental session design.
Baseline Assessment Phase (25 minutes)
The first phase of each experimental session consists of a 25-minute baseline assessment period during which participants rest quietly in the supine position. They will be instructed to relax, breathe normally at their natural respiratory rate, remain as still as possible, and avoid talking unless necessary. Immediately at the start of this 25-minute period, the Finapres NOVA non-invasive finger arterial pressure system will be fitted to the non-dominant arm, including the finger cuff (index or middle finger) and brachial calibration cuff, with the arm supported at heart level. The Finapres will record continuously for the entire 25 minutes; however, only the final 10 minutes will be used as the pre-intervention continuous cardiovascular baseline for analysis. A Polar Unite optical heart rate sensor will be placed on the dominant wrist at the same time and will record continuously throughout the 25-minute period, with the final 10 minutes used for baseline heart rate and heart rate variability data. In addition to the continuous recordings, auscultatory BP and heart rate will be obtained at four time points during the baseline period: at 0, 5, 10, and 15 minutes.
Each measurement will be taken from the dominant arm using a calibrated mercury sphygmomanometer and stethoscope. Phases I and V of the Korotkoff sounds will be used to determine systolic and diastolic BP, respectively. All auscultatory measurements will be performed by the same experienced investigator, who will be blinded to the intervention condition. The mean of the final three auscultatory measurements (taken at 5, 10, and 15 minutes) will serve as the discrete baseline BP value for analysis.
Intervention Phase (60 minutes).
Following the baseline assessment, participants will be assigned to one of three intervention conditions according to the randomised allocation sequence. The intervention period is 60 minutes for all three conditions. During this time, participants will be seated. The research team will continuously monitor participants from an adjacent room with a clear view through a window, and two-way communication will be available via an intercom. Brief comfort and safety checks will be conducted at 15, 30, and 45 minutes, asking participants how they are feeling and whether they wish to continue. During the intervention phase, participants may read or use their phones quietly, as these low-intensity activities do not interfere with the safety or function of vagus nerve stimulation devices. They will be asked to avoid excessive movement, talking, or highly stimulating phone content to minimise autonomic fluctuations during monitoring, but passive activities such as reading, browsing, or listening to music are permitted and commonly used in vagus nerve stimulation research protocols.
- Conditions
- Vagus Nerve Stimulations
- Being tested
- Active taVNS condition, Sham-sound condition, Sham Mode
- Keywords
- blood pressure, heart rate variability
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Active taVNS conditionDevice
For the active taVNS condition, the Parasym taVNS system (Parasym Health, London, United Kingdom) will be used. This device delivers transcutaneous electrical stimulation to the auricular branch of the vagus nerve via a surface electrode placed on the left tragus. The stimulation consists of a proprietary waveform comprising micro-pulses with a pulse width of 200 microseconds delivered at a frequency of 20 Hertz. Before commencing the intervention, each participant will personalise the stimulation intensity based on their individual sensitivity threshold, following the same procedure experienced during the familiarisation session. The participant will gradually increase the current intensity from zero until they perceive a constant, clear tingling sensation at the electrode site. The intensity will then be reduced by one milliampere below their reported discomfort threshold. We anticipated a mean stimulation intensity across participants from 13 to 20 milliampers.
Sham-sound conditionDevice
For the sham-sound condition, participants will be asked to adjust the device settings to mimic the intensity range used during the active protocol (Levels 13 to 20), ensuring that the setup procedure and user actions feel identical across sessions. However, in this mode, the device does not deliver any therapeutic electrical stimulation. Instead, a sham electrode, identical in appearance to the active electrode, produces only a mechanical sound that mimics the subtle acoustic feedback associated with active stimulation, without generating electrical current or eliciting any physiological effect. This condition replicates the sensory and procedural aspects of the active session while ensuring no meaningful vagal stimulation is provided, thereby controlling for placebo effects, participant expectations, and non-specific attention effects associated with the intervention procedure.
Sham ModeDevice
For the sub-threshold sham condition, the Parasym device will be switched into its sham mode and set to Level 5, which delivers stimulation intentionally kept below the sensory threshold. Participants will be informed at the beginning of this session: "In this session, the stimulation will be delivered below the sensory threshold, meaning the intensity is very low and you should not feel any sensation. Please confirm that you do not feel anything." Once the device is activated, it will deliver minimal stimulation for a brief period, then automatically ramp down and switch off within approximately 15 seconds. For the remainder of the 60-minute session, no electrical stimulation is delivered, although the device display will appear active to maintain blinding. This condition controls for expectation effects while explicitly informing participants that they should not perceive sensation, thereby maintaining credibility without requiring deception about the absence of sensation
| Study group | Role | What they receive |
|---|---|---|
| Active stimulation session | Experimental | For the active taVNS condition, the Parasym taVNS system (Parasym Health, London, United Kingdom) will be used. This device delivers transcutaneous electrical stimulation to the auricular branch of the vagus nerve via a surface electrode placed on the left tragus. The stimulation consists of a proprietary waveform comprising micro-pulses with a pulse width of 200 microseconds delivered at a frequency of 20 Hertz. Before commencing the intervention, each participant will personalise the stimulation intensity based on their individual sensitivity threshold, following the same procedure experienced during the familiarisation session. The participant will gradually increase the current intensity from zero until they perceive a constant, clear tingling sensation at the electrode site. The intensity will then be reduced by one milliampere below their reported discomfort threshold. We anticipated a mean stimulation intensity across participants from 13 to 20 milliampers. Receives: Device: Active taVNS condition |
| Sham sound condition | Sham comparator | For the sham-sound condition, participants will be asked to adjust the device settings to mimic the intensity range used during the active protocol (Levels 13 to 20), ensuring that the setup procedure and user actions feel identical across sessions. However, in this mode, the device does not deliver any therapeutic electrical stimulation. Instead, a sham electrode, identical in appearance to the active electrode, produces only a mechanical sound that mimics the subtle acoustic feedback associated with active stimulation, without generating electrical current or eliciting any physiological effect. This condition replicates the sensory and procedural aspects of the active session while ensuring no meaningful vagal stimulation is provided, thereby controlling for placebo effects, participant expectations, and non-specific attention effects associated with the intervention procedure. Receives: Device: Sham-sound condition |
| Sham mode condition | Placebo comparator | For the sub-threshold sham condition, the Parasym device will be switched into its sham mode and set to Level 5, which delivers stimulation intentionally kept below the sensory threshold. Participants will be informed at the beginning of this session: "In this session, the stimulation will be delivered below the sensory threshold, meaning the intensity is very low and you should not feel any sensation. Please confirm that you do not feel anything." Once the device is activated, it will deliver minimal stimulation for a brief period, then automatically ramp down and switch off within approximately 15 seconds. For the remainder of the 60-minute session, no electrical stimulation is delivered, although the device display will appear active to maintain blinding. This condition controls for expectation effects while explicitly informing participants that they should not perceive sensation, thereby maintaining credibility without requiring deception about the absence of sensation. Receives: Device: Sham Mode |
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood Pressure (office)
Auscultatory BP measurements will be obtained using a calibrated mercury sphygmomanometer and stethoscope applied to the participant's dominant arm. Systolic BP will be identified at the appearance of the first clear tapping sound (Korotkoff phase I), and diastolic BP will be identified at the disappearance of sounds (Korotkoff phase V). The same experienced evaluator, who remains blinded to condition allocation, will perform all auscultatory measurements throughout the study to minimise inter-observer variability.
Measured: pre intervention and 15, 30, 45 and 60 min post-intervention
Secondary outcomes (6)
Continuous beat-to-beat Blood Pressure
Continuous beat-to-beat BP will be measured using the Finapres NOVA non-invasive finger arterial pressure monitor. All measurements will be obtained with the participant in the supine position, with the measurement arm supported at heart level to ensure hydrostatic equivalence between the finger and the heart. A finger cuff will be placed on either the index or middle finger of the non-dominant arm, selected based on optimal signal quality, and a brachial calibration cuff will be positioned on the upper arm of the same limb. Data will be exported at a sampling frequency of 200 Hz, providing systolic, diastolic, and mean arterial pressures, pulse pressure, and heart rate for each cardiac cycle
Measured: pre-intervention and post-intervention (during all 60 min post-intervention)
Heart Rate and Heart Rate Variability
Heart rate will be monitored continuously using the Polar Unite optical sensor, which uses photoplethysmography to derive heart rate and inter-beat intervals from changes in wrist blood volume. The device will be worn on the dominant wrist and record second-by-second heart rate and high-resolution interval data. HRV analysis will use two stable resting segments: the final 10 minutes of baseline and minutes 50-60 of recovery. Inter-beat intervals will be exported to Kubios HRV Premium for processing. Data will be visually inspected, with artefacts detected at a 0.3-second threshold and corrected via cubic spline interpolation; segments with >5% corrections or <5 minutes of valid data will be excluded. HRV parameters will follow Task Force standards.
Measured: Pre-intervention and minutes 50-60 of post-intervention.
Cardiac Output
Cardiac output will be estimated using the Modelflow algorithm integrated into the Finapres NOVA system.
Measured: Pre-intervention and post-intervention (during all 60 min post-intervention)
Stroke Volume
Stroke volume will be calculated as cardiac output divided by heart rate, then multiplied by 1000 to express it in millilitres
Measured: Pre-intervention and post-intervention (during all 60 min post-intervention)
Total peripheral resistance
Total peripheral resistance will be calculated as mean arterial pressure divided by cardiac output, expressed in millilitres of mercury per minute per litre.
Measured: pre-intervention and post-intervention (during all 60 min post-intervention)
Baroreflex Sensitivity
Baroreflex sensitivity will be assessed during the same time periods used for heart rate variability analysis: the final 10 minutes of pre-intervention baseline and minutes 50 through 60 of post-intervention recovery. The baroreflex sensitivity will be assessed non-invasively using the sequence method applied to synchronised beat-to-beat BP and inter-beat interval data. This technique identifies spontaneous sequences of consecutive cardiac cycles in which progressive increases or decreases in systolic BP are coupled with corresponding changes in inter-beat interval duration, reflecting the baroreflex-mediated heart rate response to BP fluctuations. Data for this analysis will be obtained by synchronising the continuous systolic BP values from the Finapres system with the inter-beat interval data from the Polar Unite sensor.
Measured: Pre-intervention and minutes 50-60 of post-intervention.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Mar 2026
- Study start1 Mar 2026 (estimated)
- Primary completion1 Dec 2027 (estimated)
- Study completion1 Dec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Vagus Nerve StimulationsStudies 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
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Northumbria University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Gabriel Cucato, PhD, Principal investigator, Northumbria University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07501611
- Sponsor's protocol ID
- 12026
- Status last verified
- Mar 2026
- First submitted
- 17 Mar 2026
- Last updated
- 30 Mar 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: There is a plan to make IPD and related data dictionaries available.
Study at a glance
From the registry record, last updated by the sponsor on 30 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Acute Cardiovascular Effects of Transcutaneous Auricular Vagus Nerve Stimulation
- ClinicalTrials.gov ID
- NCT07501611
- Acronym / sponsor ID
- 12026
- Conditions
- Vagus Nerve Stimulations
- Keywords
- blood pressure, heart rate variability
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- Northumbria UniversityUniversity, hospital or other
- Study start
- 1 Mar 2026 (estimated)
- Primary completion
- 1 Dec 2027 (estimated)
- Study completion
- 1 Dec 2027 (estimated)
- First posted
- 30 Mar 2026 (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.
Introduction
Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with arterial hypertension representing the most significant modifiable risk factor (Lim et al., 2012; Mills et al., 2020). While clinical manifestations of arterial hypertension typically emerge in later life, the underlying pathophysiological mechanisms, particularly autonomic dysfunction, begin decades earlier.
Autonomic imbalance, characterised by sympathetic overactivity and diminished parasympathetic tone, not only precedes sustained arterial hypertension but also independently predicts future cardiovascular risk, even in normotensive individuals (He et al., 2023; Thayer et al., 2010). Reduced heart rate variability (HRV), a non-invasive marker of parasympathetic activity, has been consistently associated with increased cardiovascular morbidity across diverse populations (Task Force, 1996).
Critically, young apparently healthy adults with suboptimal lifestyle factors, including physical inactivity, poor dietary habits, and chronic stress, frequently exhibit reduced HRV and altered sympathovagal balance (Liao et al., 1998). These subclinical autonomic changes represent an early, potentially reversible stage in the cardiovascular disease continuum, suggesting that interventions targeting autonomic balance may prevent or delay progression to overt disease (Goldstein et al., 2011).
The vagus nerve, the main parasympathetic pathway, exerts multiple cardioprotective effects, including heart rate deceleration, baroreflex enhancement, reduced vascular tone, and anti-inflammatory activity (Thayer \& Sternberg, 2006). Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a non-invasive method to enhance vagal activity by delivering electrical stimulation to the auricular branch of the vagus nerve via surface electrodes placed on the tragus or cymba conchae (Badran et al., 2018). Neuroimaging studies confirm that taVNS activates central vagal projections, including the nucleus tractus solitarius, the primary relay station for cardiovascular autonomic control (Frangos et al., 2015).
Preliminary research demonstrates that acute taVNS sessions increase HRV, enhance baroreflex sensitivity, and reduce sympathetic vascular tone in healthy adults (Clancy et al., 2014; De Couck et al., 2017), while emerging evidence suggests clinically meaningful reductions in blood pressure (BP) in hypertensive patients (Mbikyo et al., 2024).
Despite these promising findings, significant knowledge gaps remain. Most studies have examined clinical populations with pre-existing autonomic abnormalities, making it difficult to isolate primary taVNS mechanisms from disease-related compensatory responses. Additionally, chronic intervention protocols preclude detailed characterisation of immediate autonomic and hemodynamic changes. Conducting mechanistic studies in healthy populations offers critical advantages: absence of confounding medications and disease adaptations enables clearer identification of taVNS-induced autonomic and hemodynamic changes, while establishing baseline response patterns provides an essential reference framework for interpreting clinical population responses and informing preventive interventions. Investigation of acute responses permits precise temporal mapping of physiological changes, distinguishing primary mechanisms from downstream consequences, enables efficient optimisation of stimulation parameters, and provides biological plausibility for chronic effects while identifying potential responders to therapy.
Therefore, this study proposes a randomised, sham-controlled crossover study to systematically characterise acute cardiovascular and autonomic responses to a single 60-minute taVNS session in healthy young adults. Using continuous non-invasive BP monitoring and detailed HRV analysis, this study will establish whether taVNS produces acute, measurable changes in BP, heart rate, and autonomic balance in individuals with normal baseline function. We will elucidate the temporal dynamics of taVNS-induced effects, characterise the mechanistic pathways distinguishing cardiac, hemodynamic, and autonomic contributions, and evaluate the specificity of active stimulation versus sham conditions. By establishing baseline physiological response patterns and elucidating acute mechanisms in a well-controlled population, our findings will lay the groundwork for subsequent investigations in at-risk and hypertensive individuals, ultimately contributing to evidence-based, personalised autonomic modulation therapy for cardiovascular disease prevention and management.
Detailed description
Before study commencement, the complete randomisation sequence for all 20 participants will be generated using the online random sequence generator available at www.randomizer.org. An independent researcher who is not involved in participant recruitment, screening, data collection, or outcome assessment will use the "Randomise Lists" function to generate 20 distinct randomised orders of the three experimental conditions (active taVNS, sham-sound, and sub-threshold sham). Each participant will be assigned a sequential identification number from 1 to 20, with a corresponding randomised sequence determining which condition they will receive at Visits 2, 3, and 4.
The independent researcher will maintain the master randomisation list in a secure, password-protected electronic file or in a locked physical document, accessible only to them. This ensures allocation concealment throughout the recruitment and enrollment process. On the morning of each experimental session (Visits 2, 3, and 4), the independent researcher will communicate the allocated condition for that specific participant and visit to the research coordinator who is responsible for setting up and operating the taVNS device. This communication will occur via secure email, telephone, or in person, specifying only the condition to be delivered that day (e.g., "Participant 15, Visit 2: Active taVNS").
The research coordinator who receives this information and prepares the device will not be involved in outcome assessments. Importantly, two key individuals will remain blinded throughout the study: the participant, who will not be informed which type of stimulation they are receiving on any given day, and the outcome assessor, who performs all cardiovascular measurements. The randomisation list will be retained in secure study files and will only be fully revealed to the research team after all data collection and preliminary analyses are complete.
Blinding Procedures
This study employs triple-blinding to minimise bias. Participants will be blinded to condition allocation throughout the study. They will be informed that the study is comparing different intensities or modes of vagal stimulation without being told which sessions involve active versus sham stimulation.
The design of the sham conditions, particularly the sham-sound electrode, which produces tactile and auditory cues mimicking active stimulation, facilitates effective participant blinding. The sub-threshold sham condition explicitly communicates that stimulation is below the sensory threshold, maintaining the procedure's credibility without compromising blinding. Outcome assessors will also be blinded. Specifically, the investigator who performs all cardiovascular measurements throughout the study will remain blinded to which condition the participant is receiving during each session. Data analysts will be blinded during statistical analysis, with condition allocation coded numerically. The allocation code will be held securely by the principal investigator and will only be revealed to the statistical analyst after all analyses are complete.
Individuals expressing interest in participating will be invited to attend the Cardiovascular Physiology Laboratory at Northumbria University for an initial screening visit. Upon arrival, the research team will review the Participant Information Sheet with the potential participant, explain all study procedures in detail, and answer any questions. Adequate time will be provided for the individual to consider participation, after which written informed consent will be obtained before any study procedures.
Following consent, participants will undergo a structured interview to collect demographic information, including age, sex, and ethnicity, as well as detailed health history covering cardiovascular, neurological, and psychiatric conditions. Current medication use, including prescription, over-the-counter, and dietary supplements, will be documented. Lifestyle factors will be assessed, including habitual physical activity levels, dietary patterns, smoking status, alcohol consumption, sleep quality, and perceived stress.
Anthropometric measurements will be performed according to standardised procedures. Height will be measured to the nearest 0.1 cm using a wall-mounted stadiometer with the participant standing barefoot. Body mass will be measured to the nearest 0.1 kg using calibrated digital scales with the participant wearing light clothing and no shoes. Body Mass Index will be calculated as mass (in kilograms) divided by height (in meters) squared. Waist circumference will be measured at the narrowest point between the lower rib margin and the iliac crest. Hip circumference will be measured at the widest point of the buttocks. Neck circumference will be measured at the midpoint of the neck below the laryngeal prominence. All circumference measurements will be taken to the nearest 0.1 cm using a non-stretchable measuring tape.
Office BP will be assessed using auscultatory methods with a calibrated mercury sphygmomanometer and stethoscope, according to current guidelines.
The participant will be seated in a quiet room with back supported, feet flat on the floor, and arms supported at heart level. After five minutes of quiet rest, three BP readings will be taken from each arm at one-minute intervals. Korotkoff phase I will be used to identify systolic BP and phase V will be used to identify diastolic BP. The mean of all six readings will be calculated to determine eligibility. Participants with a mean systolic BP of less than 140 mmHg and a diastolic BP of less than 90 mmHg will meet the BP inclusion criterion.
Familiarisation with the taVNS Procedure
Following completion of screening assessments, participants who meet all inclusion criteria and have no exclusion criteria will undergo a familiarisation session to introduce them to the taVNS device and procedure. The research team will explain the mechanism of transcutaneous auricular vagus nerve stimulation and demonstrate the Parasym device and electrode placement. The participant will then have the opportunity to experience the stimulation firsthand. The electrode will be placed on the left tragus, and the participant will be guided to gradually increase the stimulation intensity from zero until they perceive a constant tingling sensation. They will be instructed that during actual experimental sessions, the intensity will be set to one milliampere below their discomfort threshold.
This familiarisation serves multiple purposes: it ensures participants understand what to expect during experimental sessions, allows them to experience the sensation and confirm that they are comfortable proceeding, provides an opportunity to identify individuals who may not tolerate the stimulation, and reduces anxiety and novelty effects during the experimental sessions.
Participants will be encouraged to ask questions and voice any concerns. Only participants who are comfortable with the stimulation and willing to proceed will be enrolled in the study and scheduled for the three experimental sessions.
Experimental Sessions (Visits 2, 3, and 4)
Pre-Session Requirements and Standardisation
To control for factors known to influence cardiovascular and autonomic function, participants will receive detailed standardised instructions before each experimental session. They will be asked to consume only a light meal at least two hours before their scheduled session time and to avoid all caffeine-containing products, including coffee, tea, caffeinated soft drinks, energy drinks, and chocolate, for at least 12 hours before the session. Alcohol consumption will be prohibited for 24 hours before each session.
Participants will be instructed to refrain from vigorous physical activity or structured exercise for 48 hours before each session, though light activities such as walking are permitted. Smokers will be asked not to smoke for at least three hours before their session. They will be encouraged to obtain at least seven hours of sleep the night before each session and to maintain normal hydration levels while avoiding excessive fluid intake immediately before arrival at the laboratory.
All experimental sessions will be scheduled at the same time of day for each participant, commencing between 9:00 and 10:00 AM, to control for circadian variations in cardiovascular parameters and autonomic nervous system activity. Sessions will be separated by a minimum of 48 hours to prevent carryover effects and allow full physiological recovery between interventions. Participants will be asked to record their adherence to pre-session instructions, sleep duration, and any relevant events or symptoms in a brief diary provided for this purpose.
Experimental Session Protocol
Upon arrival at the Cardiovascular Physiology Laboratory, participants will be reminded of the session procedures and allowed to ask questions. They will be asked to void their bladder and change into comfortable, loose-fitting clothing if needed. The laboratory environment will be maintained at a comfortable temperature between 20 and 22 degrees Celsius with dimmed lighting to promote relaxation. Participants will then assume a supine position on a comfortable examination table with the head elevated approximately 30 degrees using pillows to ensure comfort during the extended monitoring period. Please see the experimental session design.
Baseline Assessment Phase (25 minutes)
The first phase of each experimental session consists of a 25-minute baseline assessment period during which participants rest quietly in the supine position. They will be instructed to relax, breathe normally at their natural respiratory rate, remain as still as possible, and avoid talking unless necessary. Immediately at the start of this 25-minute period, the Finapres NOVA non-invasive finger arterial pressure system will be fitted to the non-dominant arm, including the finger cuff (index or middle finger) and brachial calibration cuff, with the arm supported at heart level. The Finapres will record continuously for the entire 25 minutes; however, only the final 10 minutes will be used as the pre-intervention continuous cardiovascular baseline for analysis. A Polar Unite optical heart rate sensor will be placed on the dominant wrist at the same time and will record continuously throughout the 25-minute period, with the final 10 minutes used for baseline heart rate and heart rate variability data. In addition to the continuous recordings, auscultatory BP and heart rate will be obtained at four time points during the baseline period: at 0, 5, 10, and 15 minutes.
Each measurement will be taken from the dominant arm using a calibrated mercury sphygmomanometer and stethoscope. Phases I and V of the Korotkoff sounds will be used to determine systolic and diastolic BP, respectively. All auscultatory measurements will be performed by the same experienced investigator, who will be blinded to the intervention condition. The mean of the final three auscultatory measurements (taken at 5, 10, and 15 minutes) will serve as the discrete baseline BP value for analysis.
Intervention Phase (60 minutes).
Following the baseline assessment, participants will be assigned to one of three intervention conditions according to the randomised allocation sequence. The intervention period is 60 minutes for all three conditions. During this time, participants will be seated. The research team will continuously monitor participants from an adjacent room with a clear view through a window, and two-way communication will be available via an intercom. Brief comfort and safety checks will be conducted at 15, 30, and 45 minutes, asking participants how they are feeling and whether they wish to continue. During the intervention phase, participants may read or use their phones quietly, as these low-intensity activities do not interfere with the safety or function of vagus nerve stimulation devices. They will be asked to avoid excessive movement, talking, or highly stimulating phone content to minimise autonomic fluctuations during monitoring, but passive activities such as reading, browsing, or listening to music are permitted and commonly used in vagus nerve stimulation research protocols.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Active stimulation session | Experimental | Device: Active taVNS conditionFor the active taVNS condition, the Parasym taVNS system (Parasym Health, London, United Kingdom) will be used. This device delivers transcutaneous electrical stimulation to the auricular branch of the vagus nerve via a surface electrode placed on the left tragus. The stimulation consists of a proprietary waveform comprising micro-pulses with a pulse width of 200 microseconds delivered at a frequency of 20 Hertz. Before commencing the intervention, each participant will personalise the stimulation intensity based on their individual sensitivity threshold, following the same procedure experienced during the familiarisation session. The participant will gradually increase the current intensity from zero until they perceive a constant, clear tingling sensation at the electrode site. The intensity will then be reduced by one milliampere below their reported discomfort threshold. We anticipated a mean stimulation intensity across participants from 13 to 20 milliampers. |
| Sham sound condition | Sham comparator | Device: Sham-sound conditionFor the sham-sound condition, participants will be asked to adjust the device settings to mimic the intensity range used during the active protocol (Levels 13 to 20), ensuring that the setup procedure and user actions feel identical across sessions. However, in this mode, the device does not deliver any therapeutic electrical stimulation. Instead, a sham electrode, identical in appearance to the active electrode, produces only a mechanical sound that mimics the subtle acoustic feedback associated with active stimulation, without generating electrical current or eliciting any physiological effect. This condition replicates the sensory and procedural aspects of the active session while ensuring no meaningful vagal stimulation is provided, thereby controlling for placebo effects, participant expectations, and non-specific attention effects associated with the intervention procedure. |
| Sham mode condition | Placebo comparator | Device: Sham ModeFor the sub-threshold sham condition, the Parasym device will be switched into its sham mode and set to Level 5, which delivers stimulation intentionally kept below the sensory threshold. Participants will be informed at the beginning of this session: "In this session, the stimulation will be delivered below the sensory threshold, meaning the intensity is very low and you should not feel any sensation. Please confirm that you do not feel anything." Once the device is activated, it will deliver minimal stimulation for a brief period, then automatically ramp down and switch off within approximately 15 seconds. For the remainder of the 60-minute session, no electrical stimulation is delivered, although the device display will appear active to maintain blinding. This condition controls for expectation effects while explicitly informing participants that they should not perceive sensation, thereby maintaining credibility without requiring deception about the absence of sensation. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- Age: 18-45 years
- Healthy status: No diagnosed cardiovascular, metabolic, neurological, or psychiatric conditions
- BP: Normotensive (office SBP <140 mmHg and DBP <90 mmHg)
- Body Mass Index (BMI): 18.5-30 kg/m²Non-smoker or light smoker (≤5 cigarettes per day, willing to abstain before testing)
- Ability to understand and provide written informed consent
Key exclusion criteria (11 listed)
- Current participation in another interventional trial
- Clinically significant resting bradycardia (HR <50 bpm)
- Known damage or surgical removal of the vagus nerve
- Established cardiovascular disease (e.g., myocardial infarction, heart failure, arrhythmias, stroke, peripheral vascular disease)
- Diagnosed with hypertension or currently taking antihypertensive medication
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 |
|---|---|---|
| Active taVNS conditionFor the active taVNS condition, the Parasym taVNS system (Parasym Health, London, United Kingdom) will be used. This device delivers transcutaneous electrical stimulation to the auricular branch of the vagus nerve via a surface electrode placed on the left tragus. The stimulation consists of a proprietary waveform comprising micro-pulses with a pulse width of 200 microseconds delivered at a frequency of 20 Hertz. Before commencing the intervention, each participant will personalise the stimulation intensity based on their individual sensitivity threshold, following the same procedure experienced during the familiarisation session. The participant will gradually increase the current intensity from zero until they perceive a constant, clear tingling sensation at the electrode site. The intensity will then be reduced by one milliampere below their reported discomfort threshold. We anticipated a mean stimulation intensity across participants from 13 to 20 milliampers. | Device | Active stimulation session |
| Sham-sound conditionFor the sham-sound condition, participants will be asked to adjust the device settings to mimic the intensity range used during the active protocol (Levels 13 to 20), ensuring that the setup procedure and user actions feel identical across sessions. However, in this mode, the device does not deliver any therapeutic electrical stimulation. Instead, a sham electrode, identical in appearance to the active electrode, produces only a mechanical sound that mimics the subtle acoustic feedback associated with active stimulation, without generating electrical current or eliciting any physiological effect. This condition replicates the sensory and procedural aspects of the active session while ensuring no meaningful vagal stimulation is provided, thereby controlling for placebo effects, participant expectations, and non-specific attention effects associated with the intervention procedure. | Device | Sham sound condition |
| Sham ModeFor the sub-threshold sham condition, the Parasym device will be switched into its sham mode and set to Level 5, which delivers stimulation intentionally kept below the sensory threshold. Participants will be informed at the beginning of this session: "In this session, the stimulation will be delivered below the sensory threshold, meaning the intensity is very low and you should not feel any sensation. Please confirm that you do not feel anything." Once the device is activated, it will deliver minimal stimulation for a brief period, then automatically ramp down and switch off within approximately 15 seconds. For the remainder of the 60-minute session, no electrical stimulation is delivered, although the device display will appear active to maintain blinding. This condition controls for expectation effects while explicitly informing participants that they should not perceive sensation, thereby maintaining credibility without requiring deception about the absence of sensation | Device | Sham mode condition |
Primary outcome
Blood Pressure (office)
Time frame: pre intervention and 15, 30, 45 and 60 min post-intervention
Auscultatory BP measurements will be obtained using a calibrated mercury sphygmomanometer and stethoscope applied to the participant's dominant arm. Systolic BP will be identified at the appearance of the first clear tapping sound (Korotkoff phase I), and diastolic BP will be identified at the disappearance of sounds (Korotkoff phase V). The same experienced evaluator, who remains blinded to condition allocation, will perform all auscultatory measurements throughout the study to minimise inter-observer variability.
6 secondary outcomes
Continuous beat-to-beat Blood Pressure
Time frame: pre-intervention and post-intervention (during all 60 min post-intervention)
Heart Rate and Heart Rate Variability
Time frame: Pre-intervention and minutes 50-60 of post-intervention.
Cardiac Output
Time frame: Pre-intervention and post-intervention (during all 60 min post-intervention)
Stroke Volume
Time frame: Pre-intervention and post-intervention (during all 60 min post-intervention)
Total peripheral resistance
Time frame: pre-intervention and post-intervention (during all 60 min post-intervention)
Baroreflex Sensitivity
Time frame: Pre-intervention and minutes 50-60 of post-intervention.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Mar 2026.
- Individual participant dataSharing planned: Yes. There is a plan to make IPD and related data dictionaries available.
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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.
Northumbria University
Newcastle upon Tyne, United Kingdom
Gabriel Cucato, PhD principal investigator
Northumbria University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Active taVNS condition in people with Vagus Nerve Stimulations, run by Northumbria University at 1 site in United Kingdom.
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 8 inclusion and 11 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: opening soon, as of the sponsor's last update on 30 Mar 2026. 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 United Kingdom. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Blood Pressure (office) (time frame: pre intervention and 15, 30, 45 and 60 min post-intervention). 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 30 Mar 2026; AzTrials last refreshed its copy on 7 Nov 2026.