Frequency-dependent depression of the NTS synapse affects the temporal response of the antihypertensive effect of auricular vagus nerve stimulation (aVNS)

Abstract

Objective. Auricular vagus nerve stimulation (aVNS) has recently emerged as a promising neuromodulation modality for blood pressure (BP) reduction due to its ease of use although its efficacy is still limited compared to direct baroreflex stimulation. Previous studies have also indicated that synaptic depression of nucleus tractus solitarius (NTS) in the baroreflex pathway depends on stimulus frequency. However, the nature of this frequency dependence phenomenon on antihypertensive effect has been unknown for aVNS. We aimed to investigate the antihypertensive effect of aVNS considering frequency-dependent depression characteristic in the NTS synapse. We explored NTS activation and BP reduction induced by aVNS and by direct secondary neuron stimulation (DS). Approach. Both protocols were performed with recording of NTS activation and BP response with stimulation for each frequency parameter (2, 4, 20, 50, and 80 Hz). Main results. The BP recovery time constant was significantly dependent on the frequency of DS and aVNS (DS-2 Hz: 8.17 +/- 4.98; 4 Hz: 9.73 +/- 6.3; 20 Hz: 6.61 +/- 3.28; 50 Hz: 4.93 +/- 1.65; 80 Hz: 4.00 +/- 1.43, p < 0.001, Kruskal-Wallis (KW) H-test/aVNS-2 Hz: 4.02 +/- 2.55; 4 Hz: 8.13 +/- 4.05; 20 Hz: 6.40 +/- 3.16; 50 Hz: 5.18 +/- 2.37; 80 Hz: 3.13 +/- 1.29, p < 0.05, KW H-test) despite no significant BP reduction at 2 Hz compared to sham groups (p > 0.05, Mann-Whitney U-test). Significance. Our observations suggest that the antihypertensive effect of aVNS is influenced by the characteristics of frequency-dependent synaptic depression in the NTS neuron in terms of the BP recovery time. These findings suggest that the antihypertensive effect of aVNS can be improved with further understanding of the neurological properties of the baroreflex associated with aVNS, which is critical to push this new modality for clinical interpretation.