In recent years, electroceuticals have been spotlighted as an emerging treatment for various severe chronic brain diseases, owing to their intrinsic advantage of electrical interaction with the brain, which is the most electrically active organ. However, the majority of research has verified only the short-term efficacy through acute studies in laboratory tests owing to the lack of a reliable miniaturized platform for long-term animal studies. The construction of a sufficient integrated system for such a platform is extremely difficult because it requires multi-disciplinary work using state-of-the-art technologies in a wide range of fields. In this study, we propose a complete system of an implantable platform for long-term preclinical brain studies. Our proposed system, the Extra-Cranial Brain Activator (ECBA), consists of a titanium-packaged implantable module and a helmet-type base station that powers the module wirelessly. The ECBA can also be controlled by a remote handheld device. Using the ECBA, we performed a long-term non-anesthetic study with multiple canine subjects, and the resulting PET-CT scans demonstrated remarkable enhancement in brain activity relating to memory and sensory skills. Furthermore, the histological analysis and high-temperature aging test confirmed the reliability of the system for up to 31 months. Hence, the proposed ECBA system is expected to lead a new paradigm of human neuromodulation studies in the near future.

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.

No abstract