Non-invasive Ultrasonic Auricular Vagus Nerve Stimulation

NCT07283913 | Recruiting FDA Device

• 1 other identifier: FMHS 88-0225
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

The Vagus nerve, one of 12 cranial nerves that connect the brain to the human body, controls specific involuntary functions such as breathing, heart rate, the digestive system and the immune system, and it is crucial to unlocking the relaxation response (parasympathetic nervous system). Vagus nerve stimulation (VNS) can be invasive or non-invasive, and both methods have been trialled in research studies. Some non-invasive VNS involves the use of a device which is placed on the skin, to send electrical impulses to the Vagus nerve. The device sends electrical impulses to some areas of the brain which changes brain activity and helps in treating certain disorders. Invasive methods utilise a surgically implanted Vagus nerve stimulator on the left Vagus nerve in the neck area. VNS is used in treatment of epilepsy and studies has shown to have a therapeutic effect on treatment resistant depression. Currently, research indicates that invasive VNS to treat anxiety yield mixed results, whilst other studies suggest that VNS with exposure-based therapies might enhance outcomes for anxiety patients. Stimulating the Vagus nerve comes with serious technical challenges. Most importantly, electric currents follow the path of least resistance. When running through biological tissues, such as skin, cartilage or bone, it is difficult to aim for the part of the body that needs to be stimulated. This means it isn't always easy to tell whether the Vagus nerve is indeed being stimulated and how much of the current is reaching the Vagus nerve. This problem can be overcome by ultrasound stimulation. Ultrasound stimulation employs high frequency sound waves to stimulate tissue. These soundwaves travel through the human body much more predictably than electric currents. As such, ultrasound stimulation of the Vagus nerve may be more effective than electrical stimulation. The ZenBud device is designed to apply ultrasound stimulation to part of the auricular branch of the Vagus nerve. Ultrasound stimulation allows for more targeted stimulation, increasing the chance of the stimulation reaching the Vagus nerve. The ZenBud device is safe for use in healthy adults and received CE marking. Before testing the therapeutic effect of the Zenbud on patients with symptoms it is important to identify physiological, cognition or emotional changes in health volunteers. Identifying these changes could lead to identifying possible future therapeutic uses for ultrasound-VNS (U-VNS).

Conditions

Healthy Participants

Keywords

ultrasound vagus nerve stimulation; U-VNS; glucose sensor; health volunteers

Outcome Measures

Primary Outcomes (13)

• Continuous Glucose Monitoring (CGM)-derived glycaemic variability

  Baseline to 20-25 days. Measurements taken every 5 minutes continuously through a GCM device. Measurements taken in mg/dL

• Glucose Level measured in mg/dL extracted derived from Continuous Glucose Monitoring (CGM)

  Baseline to 20-25 days with Baseline to 20-25 days. Measurements taken every 5 minutes continuously through a GCM device. Measurements taken in mg/dLin between

• EEG Power in Alpha Band (8-12Hz)

  Baseline to 20-25 days, measured before, during, and after stimulation

• EEG Power in Theta Band (4-7Hz)

  Baseline to 20-25 days, measured before, during, and after stimulation

• EEG Power in Beta Band (13-30Hz)

  Baseline to 20-25 days, measured before, during, and after stimulation

• EEG Power in Gamma Band (31-45Hz)

  Baseline to 20-25 days, measured before, during, and after stimulation

• EEG-derived Event-Related Potential (ERP) amplitude

  Baseline to 20-25 days, measured before, during, and after stimulation

• EEG-derived Time-locked spectral power changes

  Baseline to 20-25 days, measured before, during, and after stimulation

• ECG-derived Heart Rate (HR)

  Baseline to 20-25 days, measured before, during, and after stimulation

• ECG-derived QT interval

  Baseline to 20-25 days, measured before, during, and after stimulation

• ECG-RR Interval (inter-beat Interval)

  Baseline to 20-25 days, measured before, during, and after stimulation

• ECG-derived Heart Rate Variability (HRV)

  Baseline to 20-25 days, measured before, during, and after stimulation

• ECG-derived PR Interval

  Baseline to 20-25 days, measured before, during, and after stimulation

Secondary Outcomes (31)

• Fitbit smartwatch-derived Heart Rate (HR) during sleep

  Baseline to 20-25 days. Measurements taken continuously through a Fitbit device with PPG

• Fitbit smartwatch-derived Daily Heart Rate Variability (HRV)

  Baseline to 20-25 days. Measurements taken continuously through a Fitbit device with PPG

• Fitbit smartwatch-derived resting Heart Rate (HR)

  Baseline to 20-25 days. Measurements taken continuously through a Fitbit device with PPG

• Fitbit smartwatch-derived daily step count

  Baseline to 20-25 days. Measurements taken continuously through a Fitbit device

• Fitbit smartwatch-derived daily ratio of Sedentary (no activity) vs active time

  Baseline to 20-25 days. Measurements taken continuously through a Fitbit device

Study Arms (2)

Active U-VNS

ACTIVE COMPARATOR

Participants receive ultrasound vagus nerve stimulation (U-VNS) applied transcutaneously to the cervical vagus nerve using focused ultrasound.

Device: Ultrasound Vagus Nerve Stimulation (U-VNS)

Sham U-VNS

SHAM COMPARATOR

Participants undergo the same procedure with identical setup and audible sound cues, but no ultrasound energy is delivered.

Device: Ultrasound Vagus Nerve Stimulation (U-VNS)

Interventions

Ultrasound Vagus Nerve Stimulation (U-VNS) DEVICE

30 minutes of U-VNS delivered to the left auricular branch of the vagus nerve via NeurGear ZenBud vagus nerve stimulator applied to the left ear.

Active U-VNS; Sham U-VNS

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant is willing and able to give informed consent for participation in the study
• Not currently taking any medications (except the contraceptive pill)
• Aged 18 or over
• Good general health
• Able and willing to remove any piercings in the left ear
• Able to abstain from exercise and fast from food for 12 hours before the second and third visit

You may not qualify if:

• Current or past diagnosis of a major neurological, neurosurgical, or psychiatric disorder (including self-reported depression)
• Inability to complete informed consent process
• Personal history of cardiac arrhythmia
• Diabetes
• High blood pressure (\>140 mmHg systolic and/or \>90 mmHg diastolic)
• Use of medication or recreational drugs that affect the nervous system in the past 3 months
• Medication intake (such as beta-blockers, glucocorticoids, antidepressants, anti-inflammatory drugs) in the last 7 days - contraceptive medication in women is allowed
• Currently pregnant or breastfeeding
• Allergy to aquasonic gel or any of its components (propylene glycol, glycerin, isothiazolinones)
• Participation in a research study in the last 3 months involving invasive procedures or an inconvenience allowance (required for all UoN FMHS UREC-approved studies)
• BMI \< 18 kg/m² or \> 30 kg/m²
• Excessive consumption of alcohol (\>2 alcoholic beverages/day) or tobacco (\>5 cigarettes/day)
• Previous experience with stress tests
• Known infection in the last 8 weeks

Sponsors & Collaborators

• University of Nottingham: lead
• University of Cambridge: collaborator

Study Sites (2)

Neuromodulation Lab, Medical School, Queen's Medical Centre

Nottingham, Nottinghamshire, NG7 2UH, United Kingdom

RECRUITING

University of Nottingham

Nottingham, United Kingdom

NOT YET RECRUITING

Related Publications (10)

• Colzato L, Beste C. A literature review on the neurophysiological underpinnings and cognitive effects of transcutaneous vagus nerve stimulation: challenges and future directions. J Neurophysiol. 2020 May 1;123(5):1739-1755. doi: 10.1152/jn.00057.2020. Epub 2020 Mar 25.

  PMID: 32208895 BACKGROUND

• Bartolomei F, Bonini F, Vidal E, Trebuchon A, Lagarde S, Lambert I, McGonigal A, Scavarda D, Carron R, Benar CG. How does vagal nerve stimulation (VNS) change EEG brain functional connectivity? Epilepsy Res. 2016 Oct;126:141-6. doi: 10.1016/j.eplepsyres.2016.06.008. Epub 2016 Jul 29.

  PMID: 27497814 BACKGROUND

• Johnson RL, Wilson CG. A review of vagus nerve stimulation as a therapeutic intervention. J Inflamm Res. 2018 May 16;11:203-213. doi: 10.2147/JIR.S163248. eCollection 2018.

  PMID: 29844694 BACKGROUND

• Liu RP, Fang JL, Rong PJ, Zhao Y, Meng H, Ben H, Li L, Huang ZX, Li X, Ma YG, Zhu B. Effects of electroacupuncture at auricular concha region on the depressive status of unpredictable chronic mild stress rat models. Evid Based Complement Alternat Med. 2013;2013:789674. doi: 10.1155/2013/789674. Epub 2013 Jan 29.

  PMID: 23431349 BACKGROUND

• Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology. 2002 Sep 24;59(6 Suppl 4):S3-14. doi: 10.1212/wnl.59.6_suppl_4.s3.

  PMID: 12270962 BACKGROUND

• Butt MF, Albusoda A, Farmer AD, Aziz Q. The anatomical basis for transcutaneous auricular vagus nerve stimulation. J Anat. 2020 Apr;236(4):588-611. doi: 10.1111/joa.13122. Epub 2019 Nov 19.

  PMID: 31742681 BACKGROUND

• Toffa DH, Touma L, El Meskine T, Bouthillier A, Nguyen DK. Learnings from 30 years of reported efficacy and safety of vagus nerve stimulation (VNS) for epilepsy treatment: A critical review. Seizure. 2020 Dec;83:104-123. doi: 10.1016/j.seizure.2020.09.027. Epub 2020 Oct 10.

  PMID: 33120323 BACKGROUND

• Breit S, Kupferberg A, Rogler G, Hasler G. Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders. Front Psychiatry. 2018 Mar 13;9:44. doi: 10.3389/fpsyt.2018.00044. eCollection 2018.

  PMID: 29593576 BACKGROUND

• Yuan H, Silberstein SD. Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part I. Headache. 2016 Jan;56(1):71-8. doi: 10.1111/head.12647. Epub 2015 Sep 14.

  PMID: 26364692 BACKGROUND

• Kohler I, Hacker J, Martin E. Reduction of Anxiety-Related Symptoms Using Low-Intensity Ultrasound Neuromodulation on the Auricular Branch of the Vagus Nerve: Preliminary Study. JMIR Neurotechnol. 2025 May 1;4:e69770. doi: 10.2196/69770. eCollection 2025.

  PMID: 41341418 BACKGROUND

Study Officials

• Marcus Kaiser, Professor

  University of Nottingham

  PRINCIPAL INVESTIGATOR

• Amparo G Gonzalez, PhD

  University of Cambridge

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Alicia Falcon-Caro, PhD

CONTACT

+44 7502043643; Alicia.falconcaro@nottingham.ac.uk

Stefanos A Kontogouris, MSc

CONTACT

+44 7826221912; stefanos.kontogouris@nottingham.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 6, 2025
• First Posted: December 16, 2025
• Study Start: October 1, 2025
• Primary Completion: May 1, 2026
• Study Completion: May 1, 2026
• Last Updated: December 16, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

GB (2)