Neural bridging achieves transcutaneous regulation of vagus nerve function and treatment of depressive disorders.

Abstract

Vagus nerve stimulation (VNS) represents a neuromodulation technique that has shown potential in the treatment of various diseases. However, conventional VNS therapy is constrained by the requirement for implanted electrodes, primarily due to the scarcity of appropriate vagal cutaneous branches. Here, a neural bridging method was employed to connect the sensory nerve with the vagus nerve, thereby facilitating transcutaneous modulation of autonomic nerve function and addressing depressive disorders. Results showed that end-to-side neurorrhaphy induced robust axonal regeneration while preserving vagus nerve integrity. Neural tracing confirmed cervical nerve-to-nucleus tractus solitarius projections. Postoperative auricular stimulation significantly evoked 3.46-fold higher c-Fos+ neurons in the nucleus tractus solitarius versus sham controls. In depressed mice, this approach normalized behavioral deficits. Further investigations revealed concomitant improvements in non-rapid eye movement sleep architecture and suppression of hippocampal neuroinflammatory pathways (e.g., TNF, RNA-seq p ​< ​0.001). Together, this study developed a neural-bridging approach in mice that surgically connected a cutaneous sensory nerve to the cervical vagus nerve. Subsequent gentle auricular stimulation robustly activated the brainstem vagal nucleus and improved depression-like behaviors and sleep, alongside reduced hippocampal inflammatory signaling. As a preclinical proof-of-concept study, translational feasibility and long-term safety in humans require rigorous evaluation.