Transcranial electrical stimulation (TES) is a widely accepted neuromodulation modality for treating brain disorders. However, its clinical efficacy is fundamentally limited due to the current shunting effect of the scalp and safety issues. A newer electrical stimulation technique called subcutaneous electrical stimulation (SES) promises to overcome the limitations of TES by applying currents directly at the site of the disorder through the skull. While SES seems promising, the electrophysiological effect of SES compared to TES is still unknown, thus limiting its broader application. Here we comprehensively analyze the SES and TES to demonstrate the effectiveness and advantages of SES. Beagles were bilaterally implanted with subdural strips for intracranial electroencephalography and electric field recording. For the intracerebral electric field prediction, we designed a 3D electromagnetic simulation framework and simulated TES and SES. In the beagle model, SES induces three to four-fold larger cerebral electric fields compared to TES, and significant changes in power ratio of brainwaves were observed only in SES. Our prediction framework suggests that the field penetration of SES would be several-fold larger than TES in human brains. These results demonstrate that the SES would significantly enhance the neuromodulatory effects compared to conventional TES and overcome the TES limitations.

Objectives: 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 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, Kruskal–Wallis 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.