The reflex action of auricular vagus nerve stimulation on the rhythm of the heart in mice

Abstract

Vagus nerve stimulation is an emerging technology and possesses the potential to treat a diverse pool of indications (e.g., pain, epilepsy, depression, migraine). Notably, recent advancement in auricular vagus nerve stimulation creates the possibility of a none or minimal-invasive way of treatment. However, little is understood about the impact of vagus nerve stimulation on the cardiac cycle. Previous studies on heart rate changes due to vagal stimulation have been mostly done with direct stimulation onto the efferent cervical vagus nerve. This work, the focus will be on the effects of vagal stimulation over the auricular pathway on the cardiac cycle.For that purpose, an animal study on anesthetized mice (40 measurements in total) has been conducted in cooperation with the Complutense University of Madrid (Prof. Fivos Panetsos). The mice were sedated with isoflurane by inhalation, and electrocardiograms were recorded via needle electrodes. Stimulation needles were placed inside the cymba concha of the auricle to stimulate the auricular branch of the vagus nerve. Three different protocols were performed, each with a different emphasis. In the first protocol, the focus was on single short stimulus pulses (3 s) with medium to high voltage and their immediate effect on the cardiac cycle. In the second protocol, the mice were eleven times stimulated with constant current for 30 seconds with 5 minutes pause in between. In protocol three, the mice had three times of constant voltage stimulation for 20 minutes with 5 minutes pause in between. The voltage amplitude increased by one volt in each stimulation window.Qualitative and quantitative data analysis was performed. Immediate changes to the cardiac cycle could not be triggered by auricular vagus nerve stimulation with this experimental setup. Furthermore, a decline in heart rate was observed over time in most mice (a median drop of about 80 bpm for protocol one and a decrease of over 200 bpm for protocol two and three), but it is unclear how much of this effect is explicitly due to vagus nerve stimulation. Heart rate variability analysis was done, but interpretation of those are difficult. During the current stimulation, a mean heart rate drop -5.7 bpm was observed. It has been shown in preceding studies that direct stimulation of the efferent cervical vagus nerve will lead to instantaneous changes in the cardiac cycle. However, for auricular vagus nerve stimulation, this effect is not so clear due to the indirection of the information over the brain. Further investigations need to be done to create a better understanding of the impact of auricular vagus nerve stimulation on the cardiac cycle.