Transcutaneous auricular Vagus Nerve Stimulation and Median Nerve Stimulation reduce acute stress in young healthy adults: a single-blind sham-controlled crossover study

Abstract

Stress is a major determinant of health and wellbeing. Conventional stress management approaches do not account for the daily-living acute changes in stress that affect quality of life. The combination of physiological monitoring and non-invasive Peripheral Nerve Stimulation (PNS) represents a promising technological approach to quantify stress-induced physiological manifestations and reduce stress during everyday life. This study aimed to evaluate the effectiveness of three well-established transcutaneous PNS modalities in reducing physiological manifestations of stress compared to a sham: auricular and cervical Vagus Nerve Stimulation (taVNS and tcVNS), and Median Nerve Stimulation (tMNS). Using a single-blind sham-controlled crossover study with four visits, we compared the stress mitigation effectiveness of taVNS, tcVNS, and tMNS, quantified through physiological markers derived from five physiological signals peripherally measured on 19 young healthy volunteers. Participants underwent three acute mental and physiological stressors while receiving stimulation. Blinding effectiveness was assessed via subjective survey. taVNS and tMNS relative to sham resulted in significant changes that suggest a reduction in sympathetic outflow following the acute stressors: Left Ventricular Ejection Time Index (LVETI) shortening (tMNS: p = 0.007, taVNS: p = 0.015) and Pre-Ejection Period (PEP)-to-LVET ratio (PEP/LVET) increase (tMNS: p = 0.044, taVNS: p = 0.029). tMNS relative to sham also reduced Pulse Pressure (PP; p = 0.032) and tonic EDA activity (tonicMean; p = 0.025). The nonsignificant blinding survey results suggest these effects were not influenced by placebo. taVNS and tMNS effectively reduced stress-induced sympathetic arousal in wearable-compatible physiological signals, motivating their future use in novel personalized stress therapies to improve quality of life.

Keywords: Median Nerve Stimulation; Vagus Nerve Stimulation; multimodal sensing; non-invasive; physiological signals; stress.

Figure 1

Overview of the single-blind sham-controlled crossover study. (A) Each participant was randomly allocated to one sequence of four different stimulation types, thereby defining the stimulation for each visit. A washout period of 1 week was used between visits. During each visit, the participants received stimulation while undergoing the following three acute stressors listed in the order they occurred in the protocol: mental arithmetic (MA), n-back (NB), and the cold pressor (CP) test. (B) These stressors were preceded by a rest period to capture each participant's baseline state and a period of stimulation calibration followed by a dose finding activity. Next, the stressors started in the aforementioned order, each having three distinct tasks. First, the participants underwent 2 min of the acute stressor (i.e., MA, NB, or CP) while simultaneously receiving stimulation at PT. Next, the stimulation remained active at the same intensity for another 3 min^*. Finally, the participants went through a 5-min break period prior to starting the next stressor. The three Peripheral Nerve Stimulation (PNS) modalities evaluated in this work were (C) transcutaneous auricular Vagus Nerve Stimulation (taVNS), wherein a custom earclip was used to stimulate the tragus, (D) transcutaneous cervical Vagus Nerve Stimulation (tcVNS) that was delivered to the left side of the neck using an electrode bar placed over the carotid sheath, and (E) transcutaneous Median Nerve Stimulation (tMNS), which was delivered to the anterior left wrist using an electrode bar. (F) Sham stimulation was delivered to the left sternocleidomastoid muscle using an electrode bar. (G) Illustration of all PNS and physiological sensing modalities employed in this work. Five physiological signals were measured peripherally: three-electrode Electrocardiogram (ECG) in Lead II configuration, Seismocardiogram (SCG) captured at the mid-sternum with a custom accelerometer module, finger-clip based Photoplethysmogram (PPG), continuous Blood Pressure (CBP) measured with a finger cuff embedded with a blood volume pulse sensor, and electrodermal activity (EDA) measured at the hand palm with two electrodes. ^*The stimulation-only period was not followed for tcVNS, thereby resulting in stressors' durations ranging between 7 and 10 min.

Figure 2

Peripheral nerve stimulation waveform with annotated parameters.

Figure 3

Selected cardiac stress physiomarkers time series for all stimulations: (A) ΔPEP/LVET and (B) ΔLVETI. Data points are expressed as μ±SE. Segments with significant main stimulation effects are identified with stars (^*p < 0.05 and ^**p < 0.01).

Figure 4

Blood pressure stress physiomarkers time series for all stimulations: (A) ΔSBP and (B) ΔDBP, (C) ΔMAP, (D) ΔPP. Data points are expressed as μ±SE. Segments with significant main stimulation effects are identified with stars (^*p < 0.05 and ^**p < 0.01).

Figure 5

ΔtonicMean stress physiomarker time series for all stimulations. Data points are expressed as μ±SE. Segments with significant main stimulation effects are identified with stars (^*p < 0.05 and ^**p < 0.01).