Exploring the Effect of taVNS on the Acute Stress Responses

Exploring the effect of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) on the Acute Stress Responses: a Double-blind Randomized Controlled Trial

This single-center randomized controlled trial aims to investigate the effects of transcutaneous auricular vagus nerve stimulation on the acute stress responses.

The primary aim of this study is to assess the efficacy of taVNS in mitigating the acute stress response induced by the Maastricht Acute Stress Task (MAST) among healthy subjects, measured by cortisol levels in saliva samples.

Secondary objectives include:

• Evaluating taVNS's potential to counteract stress-induced sympathetic activation and thereby alleviate stress-related effects, including negative affect, as measuring using the I-PANAS-SF questionnaire, and feelings of stress, pain, and unpleasantness, as measured with 0-100 Visual Analog Scales (VAS)
• Assessing its impact on autonomic outflow parameters, using a blood pressure monitor for blood pressure, and a FitBit smartwatch for heart rate variability, and Shimmer3 GSR sensor for heart rate variability and skin conductance.
• Evaluating the relationship between stress responses and affective symptoms and personality traits, utilizing the Generalized Anxiety Disorder 7-Item Scale (GAD-7), Patient Health Questionnaire (PHQ-9), and the Big Five Inventory (BFI).

Participants will be randomly assigned to either the taVNS or sham stimulation group, administered 30 minutes before the MAST.

Study Overview

• Status: Completed
• Conditions: Healthy Adult Participants
• Intervention / Treatment: Device: Vagal Nerve Stimulation; Device: Sham stimulation

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229ER
      • Maastricht University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy participants (defined as those without a pre-existing medical comorbidity)
• Aged between 18-65 years
• Ability to understand and speak the Dutch language.

Exclusion Criteria:

• Medical history or condition affecting the cardiovascular, respiratory, urogenital, gastrointestinal/hepatic, haematologic/immunologic, HEENT (head, ears, eyes, nose, throat), dermatological/connective tissue, musculoskeletal, metabolic/nutritional, endocrine, neurological/psychiatric systems, as well as prior major surgeries or ongoing laboratory abnormalities that could potentially limit participation or completion of the study protocol;
• Any use of medication, especially those that may influence the autonomic nervous system or the hypothalamus-pituitary-adrenal axis (e.g., beta-agonists or corticosteroids), with the exception of contraceptives and paracetamol;
• Current or lifetime psychopathology (including PHQ-9 and GHD-7 scores > 10);
• Substance abuse (including excessive alcohol consumption);
• Smoking;
• Pregnancy, lactation, or intention to become pregnant during the study period;
• Use of devices (e.g., cochlear implants) or other reasons (e.g. wounds, permanent ear-piercing) which complicate the use of the tVNS device;
• Participation in another clinical study in which the MAST was used;
• Administration of investigational drugs or participation in any scientific intervention study that might interfere with this study (to be determined by the principal investigator) within 180 days preceding the commencement of the study;
• Students and employees of Maastricht University are not precluded from participation, unless they have a direct personal, professional or hierarchical position with regards to any of the study team members or their department.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Transcutaneous Auricular Vagal Nerve Stimulation; Transcutaneous auricular vagal nerve stimulation, for 30 minutes	Device: Vagal Nerve Stimulation; Transcutaneous Auricular Vagal Nerve Stimulation
Placebo Comparator: Sham stimulation; Sham stimulation with a non-conducting electrode, for 30 minutes	Device: Sham stimulation; Sham stimulation with a non-conducting electrode

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuroendocrine stress response	A significant reduction in the neuroendocrine stress response triggered by the MAST following taVNS or sham treatment, assessed through saliva cortisol samples, with a defined threshold of a 35% decrease.	Assessed during one single test day, from pre-intervention baseline to post-MAST assessment (approximately 2-3 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective stress response	Subjective stress responses to the MAST following taVNS or sham treatment, assessed using the negative affect subscale of the International Positive and Negative Affect Schedule Short Form (I-PANAS-SF; total score range: 5-25, with higher scores indicating greater negative affect) and 0-100 Visual Analog Scales (VAS) for stress, pain, and unpleasantness (0=not at all, 100=extremely; higher scores indicate greater perceived stress, pain, or unpleasantness).	Assessed during one single test day, from pre-intervention baseline to post-MAST assessment (approximately 2-3 hours)
Cardiovascular stress response - blood pressure	Changes in systolic and diastolic blood pressure responses to the Maastricht Acute Stress Test (MAST) following transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation, assessed in mmHg. Blood pressure was measured four times.	Assessed during one single test day, from pre-intervention baseline to post-MAST assessment (approximately 2-3 hours)
Autonomic stress response: heart rate variability	Changes in heart rate variability responses to the Maastricht Acute Stress Test (MAST) following transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation, assessed using Fitbit and Shimmer3 GSR. Heart rate variability was measured continuously during the test day.	Assessed during a single test day, from pre-intervention baseline to post-MAST assessment (approximately 2-3 hours)
Electrodermal stress response: skin conductance	Changes in skin conductance responses to the Maastricht Acute Stress Test (MAST) following transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation, assessed in microsiemens (µS).	Assessed during a single test day, from pre-intervention baseline to post-MAST assessment (approximately 2-3 hours)
Anxiety symptoms	Anxiety symptoms assessed using the Generalized Anxiety Disorder-7 questionnaire (GAD-7; total score range: 0-21, with higher scores indicating greater anxiety symptom severity).	Assessed once during the screening visit, prior to the experimental test day
Depressive symptoms	Depressive symptoms assessed using the Patient Health Questionnaire-9 (PHQ-9; total score range: 0-27, with higher scores indicating greater depressive symptom severity).	Assessed once during the screening visit, prior to the experimental test day
Personality traits	Personality traits assessed using the Big Five Inventory-44 (BFI-44). The BFI-44 measures five personality domains (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience). Each domain score is computed as a sum or mean of item responses on a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree), with higher scores indicating greater expression of the respective personality trait.	Assessed once during the screening visit, prior to the experimental test day
Adverse events	Number and severity of adverse events	Assessed during one single test day, from pre-intervention baseline to post-MAST assessment (approximately 2-3 hours)

Collaborators and Investigators

• Sponsor: Daniel Keszthelyi
• Investigators: Principal Investigator: Daniel Keszthelyi, MD, PhD, Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2025
• Primary Completion (Actual): March 12, 2026
• Study Completion (Actual): March 12, 2026

Study Registration Dates

• First Submitted: May 22, 2026
• First Submitted That Met QC Criteria: June 1, 2026
• First Posted (Actual): June 5, 2026

Study Record Updates

• Last Update Posted (Actual): June 5, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Vagal Nerve Stimulation
• Additional Relevant MeSH Terms: Therapeutics; Electric Stimulation Therapy; Vagus Nerve Stimulation
• Other Study ID Numbers: NL87188.068.24

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No