Frequency-Dependent Effects of Auricular Vagus Nerve Stimulation on Autonomic and Cardiovascular Parameters

Official title

Acute Effects of Different Frequencies of Auricular Vagus Nerve Stimulation on HRV, Blood Pressure, and Respiratory Rate: A Sham-Controlled, Randomized, Crossover Dose-Response Study

Overview

This randomized, sham-controlled, crossover study investigates the acute autonomic effects of transcutaneous cervical vagus nerve stimulation (tcVNS) applied at five different frequencies (0 Hz/sham, 10 Hz, 25 Hz, 50 Hz, 100 Hz) in healthy adults. The primary objective is to determine how stimulation frequency modulates heart rate variability (HRV), blood pressure, and respiratory rate. The study aims to establish a frequency-specific dose-response model using validated physiological measurements.

Detailed description

Transcutaneous cervical vagus nerve stimulation (tcVNS) is a non-invasive neuromodulation technique capable of activating afferent vagal pathways projecting to autonomic brainstem nuclei. Although previous studies demonstrate tcVNS-related modulation of autonomic functions, the frequency-response relationship remains insufficiently explored.

This crossover trial randomizes participants to receive five stimulation conditions (sham, 10 Hz, 25 Hz, 50 Hz, 100 Hz) in counterbalanced order. HRV (Polar H10), blood pressure (Omron), and respiratory rate (Kinovea-based thoracoabdominal video tracking) are collected pre- and post-stimulation. Washout between sessions is ≥48 hours.

The study provides one of the first systematic evaluations of frequency-dependent tcVNS effects in healthy adults.

Interventions

• Device Pulsetto FIT™ - Sham tcVNS
  The Pulsetto FIT™ device is placed bilaterally on the cervical region (posterior margin of the sternocleidomastoid muscle). In the sham condition, the device displays normal operational lights but delivers no electrical stimulation (0 Hz; inactive mode). This condition is used for blinding and as the control comparator. Dose: 10 minutes
• Device Pulsetto FIT™ - tcVNS 10 Hz
  Bilateral transcutaneous cervical vagus nerve stimulation delivered via the Pulsetto FIT™ device at 10 Hz, 250 µs pulse width. Current intensity adjusted to a mild, non-painful tingling sensation, individualized for each participant. Dose: 10 minutes
• Device Pulsetto FIT™ - tcVNS 25 Hz
  Bilateral tcVNS using the Pulsetto FIT™ device at 25 Hz, 250 µs pulse width. Stimulation intensity set at a comfortable sensory level. Dose: 10 minutes
• Device Pulsetto FIT™ - tcVNS 50 Hz
  Bilateral cervical vagus nerve stimulation via Pulsetto FIT™ at 50 Hz, 250 µs pulse width. Intensity adjusted to a tolerable sensory level without discomfort. Dose: 10 minutes
• Device Pulsetto FIT™ - tcVNS 100 Hz
  Bilateral tcVNS delivered with the Pulsetto FIT™ device at 100 Hz, 250 µs pulse width. Highest stimulation frequency used in this protocol; current intensity individualized per participant comfort. Dose: 10 minutes

Primary outcome measures

• Heart Rate Variability (HRV) Changes (ΔRMSSD, ΔHF, ΔLF/HF) [Time frame: Pre- vs Post-stimulation (5-min segments)(5-minute baseline, 5-minute stimulation, 5-minute post period)]

Secondary outcome measures (3)

• Blood Pressure (SBP, DBP, MAP) [Time frame: Pre- vs Post-stimulation (5-minute baseline, 5-minute stimulation, 5-minute post period)]
• Respiratory Rate (breaths per minute) [Time frame: Pre- vs Post-stimulation (5-minute video segments) (5-minute baseline, 5-minute stimulation, 5-minute post period)]
• Discomfort Level (Visual Analog Scale, 0-10) [Time frame: Pre- vs Post-stimulation (5-minute baseline, 5-minute stimulation, 5-minute post period)]

Eligibility criteria

Inclusion criteria

• 18-30 years
• Healthy (self-reported)
• No cardiovascular, neurological, metabolic or psychiatric disorders
• No regular medication affecting autonomic function
• Non-smoker
• BMI 18-29.9

Exclusion criteria

• Pregnancy
• Cardiac arrhythmia
• Hypertension or hypotension
• Chronic respiratory disorders
• Active infection
• Metal implants in cervical area
• Epilepsy
• Syncope history
• Prior vagus stimulation experience

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Single blind

Primary purpose

Basic science

Study locations

Turkey (Türkiye) · 1 center

• Sinop University, Türkeli Vocational School (Türkeli MYO) — Türkeli

Publications

• Kranz S, Lukacs J, Bishop J, Block ME. Intergeneration transfer of diet patterns? Parental self-report of diet and their report of their young adult children with ASD. PLoS One. 2022 Feb 8;17(2):e0263445. doi: 10.1371/journal.pone.0263445. eCollection 2022. PMID 35134082
• Alsoufi B. Curb Your Enthusiasm for the Ozaki Procedure in Small Children. Ann Thorac Surg. 2022 Jan;113(1):378-379. doi: 10.1016/j.athoracsur.2021.03.085. Epub 2021 Apr 8. No abstract available. PMID 33839137
• Nordahl HM, Wells A. Metacognitive Therapy of Early Traumatized Patients With Borderline Personality Disorder: A Phase-II Baseline Controlled Trial. Front Psychol. 2019 Jul 30;10:1694. doi: 10.3389/fpsyg.2019.01694. eCollection 2019. PMID 31417453
• Peuker ET, Filler TJ. The nerve supply of the human auricle. Clin Anat. 2002 Jan;15(1):35-7. doi: 10.1002/ca.1089. PMID 11835542
• Grossman P, Taylor EW. Toward understanding respiratory sinus arrhythmia: relations to cardiac vagal tone, evolution and biobehavioral functions. Biol Psychol. 2007 Feb;74(2):263-85. doi: 10.1016/j.biopsycho.2005.11.014. Epub 2006 Nov 1. PMID 17081672
• Zhang Y, Xiao S, Feng H, Zhang L, Zhou Z, Hu W. Self-interference cancellation using dual-drive Mach-Zehnder modulator for in-band full-duplex radio-over-fiber system. Opt Express. 2015 Dec 28;23(26):33205-13. doi: 10.1364/OE.23.033205. PMID 26831988
• Fernandes TL, Viezzer Fernandes B, Jitumori C, Franco GCN. A Case Report of Oral Bisphosphonate Treatment for Osteoporosis Leading to Atypical Femoral Fracture and Pathologic Mandibular Fracture. Am J Case Rep. 2023 Oct 23;24:e941144. doi: 10.12659/AJCR.941144. PMID 37867315

Identifiers

NCT: NCT07274332 · tcVNS1 · IRB Number (Pending)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗