Acute Cardiovascular Effects of Transcutaneous Auricular Vagus Nerve Stimulation

NCT07501611 | Not Yet Recruiting

• 1 other identifier: 12026
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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). 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.

Conditions

Vagus Nerve Stimulations

Keywords

blood pressure; heart rate variability

Outcome Measures

Primary Outcomes (1)

• 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.

  pre intervention and 15, 30, 45 and 60 min post-intervention

Secondary Outcomes (6)

• Continuous beat-to-beat Blood Pressure

  pre-intervention and post-intervention (during all 60 min post-intervention)

• Heart Rate and Heart Rate Variability

  Pre-intervention and minutes 50-60 of post-intervention.

• Cardiac Output

  Pre-intervention and post-intervention (during all 60 min post-intervention)

• Stroke Volume

  Pre-intervention and post-intervention (during all 60 min post-intervention)

• Total peripheral resistance

  pre-intervention and post-intervention (during all 60 min post-intervention)

Other Outcomes (1)

• Safety and Tolerability

  After the intervention

Study Arms (3)

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.

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.

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.

Device: Sham Mode

Interventions

Active taVNS condition DEVICE

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.

Active stimulation session

Sham-sound condition DEVICE

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 sound condition

Sham Mode DEVICE

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

Sham mode condition

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Northumbria University: lead

Study Sites (1)

Northumbria University

Newcastle upon Tyne, United Kingdom

Location

Study Officials

• Gabriel Cucato, PhD

  Northumbria University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 17, 2026
• First Posted: March 30, 2026
• Study Start: March 1, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

GB (1)