Mechanisms underpinning sympathetic nervous activity and its modulation using transcutaneous vagus nerve stimulation

Abstract

What is the topic of this review? This review briefly considers what modulates sympathetic nerve activity and how it may change as we age or in pathological conditions. It then focuses on transcutaneous vagus nerve stimulation, a method of neuromodulation in autonomic cardiovascular control. What advances does it highlight? The review considers the pathways involved in eliciting the changes in autonomic balance seen with transcutaneous vagus nerve stimulation in relationship to other neuromodulatory techniques. The autonomic nervous system, consisting of the sympathetic and parasympathetic branches, is a major contributor to the maintenance of cardiovascular variables within homeostatic limits. As we age or in certain pathological conditions, the balance between the two branches changes such that sympathetic activity is more dominant, and this change in dominance is negatively correlated with prognosis in conditions such as heart failure. We have shown that non-invasive stimulation of the tragus of the ear increases parasympathetic activity and reduces sympathetic activity and that the extent of this effect is correlated with the baseline cardiovascular parameters of different subjects. The effects could be attributable to activation of the afferent branch of the vagus and, potentially, other sensory nerves in that region. This indicates that tragus stimulation may be a viable treatment in disorders where autonomic activity to the heart is compromised.

Keywords: gap junction; neuromodulation; spinal cord; sympathetic nervous system; vagus nerve stimulation.

Figure 1. Sympathetic and heart rate responses to chemoreceptor or noxious stimulation are blunted in the connexin 36 knockout (KO) mouse

Each panel shows the raw data, obtained using the working heart–brainstem preparation, with sympathetic nerve discharge (SND), integrated sympathetic nerve activity (∫SND) and perfusion pressure (pp) and the mean data for integrated sympathetic nerve discharge. Sympathoexcitation upon chemoreceptor stimulation or noxious pinch (arrow denotes point of stimulation) is significantly reduced in Cx36 KO mice compared with wild‐type. Adapted from Lall et al. (2017), with permission.

Figure 2. Relationship between low‐frequency to high‐frequency (LF/HF) ratio and effects of transcutaneous vagus nerve stimulation

A, plotting the baseline LF/HF ratio against age shows a significant relationship between these parameters (R ² = 0.19; P = 0.013). B, there is a relationship between baseline LF/HF ratio and change in LF/HF ratio during transcutaneous vagus nerve stimulation, indicating that higher LF/HF ratios predict a greater decrease in LF/HF during transcutaneous vagus nerve stimulation (R ² = 0.58; P < 0.0005). Adapted with permission from Clancy et al. (2014).

Figure 3. Potential pathways involved in cardiovascular responses elicited by stimulation of the tragus

The pathways in green represent the potential afferent inputs to the CNS, with the dotted lines being those under investigation. Red pathways are interneurones involved in the autonomic modulation, while vagal efferent pathways are in orange and the sympathetic components of the pathways are in blue. Abbreviations: Pa5, paratrigeminal nucleus; DVN, dorsal vagal motor nucleus; NA, nucleus ambiguus; RVLM, rostral ventrolateral medulla; CVLM, caudal ventrolateral medulla; DH, dorsal horn; IML, intermediolateral cell column; SA Node, sinoatrial node.