Bioelectronic Medicine and Neuromodulation

Abstract

Bioelectronic medicine -- the therapeutic modulation of neural circuits controlling organ function through targeted electrical stimulation of peripheral nerves -- offers a paradigm-shifting alternative to pharmacological treatment for chronic inflammatory and metabolic diseases. This study developed and evaluated three vagus nerve stimulation (VNS) protocols -- conventional open-loop VNS, closed-loop adaptive VNS triggered by real-time heart rate variability (HRV) biomarkers, and kilohertz frequency alternating current (KHFAC) nerve block -- for anti-inflammatory neuromodulation in a rat model of LPS-induced systemic inflammation (n = 12/group). Closed-loop adaptive VNS reduced serum TNF-alpha by 78.4 +- 6.2% (vs 54.8 +- 8.4% for open-loop VNS; p < 0.001) while delivering 62% fewer total stimulation pulses, demonstrating superior efficacy with reduced off-target stimulation. KHFAC nerve block at 20 kHz selectively inhibited C-fibre afferent signalling (conduction block threshold 2.4 +- 0.4 mA) while preserving A-fibre efferent motor function, enabling selective afferent neuromodulation inaccessible to conventional VNS. The closed-loop system achieved real-time HRV-triggered stimulation with latency of 124 +- 18 ms using an embedded microcontroller (ARM Cortex-M4) with on-device machine learning classification of inflammatory state. Histological assessment confirmed no nerve damage at 4 weeks for all three protocols. These findings establish closed-loop adaptive VNS as a more efficacious and energy-efficient anti-inflammatory neuromodulation strategy and demonstrate KHFAC as a novel fibre-selective modulation tool for bioelectronic medicine.