Wearable vagus nerve stimulation for depression: mechanisms, devices, and the road toward personalized neuromodulation

Abstract

Major depressive disorder remains a leading cause of global disability, with a substantial fraction of patients exhibiting inadequate response to conventional pharmacological and psychotherapeutic treatments. Vagus nerve stimulation has emerged as an effective neuromodulation strategy for treatment-resistant depression, yet implantable systems are limited by surgical risk, cost, and restricted scalability. Recent advances in non-invasive, wearable vagus nerve stimulation technologies, particularly transcutaneous auricular and cervical approaches, offer a promising pathway toward accessible, home-based neuromodulation. This Review synthesizes the anatomical and physiological rationale underlying wearable non-invasive VNS and critically evaluates mechanistic evidence spanning monoaminergic modulation, neuroplasticity, neuroimmune regulation, autonomic control, and large-scale brain network reorganization. We further summarize clinical findings from implantable and non-invasive trials and discuss key engineering considerations, including electrode–skin interfaces, stimulation parameters, wearability, and safety. Finally, we highlight major challenges and future opportunities, emphasizing the integration of flexible bioelectronics, multimodal sensing, and Artificial Intelligence-driven closed-loop control to enable personalized, scalable neuromodulation for depression. Reviews vagus nerve stimulation mechanisms in depression, including autonomic, inflammatory, and neural pathways. Compares major vagus nerve stimulation modalities, with emphasis on transcutaneous auricular and cervical approaches. Analyzes device design, including electrode configuration, stimulation parameters, and ergonomic considerations. Summarizes clinical evidence on the efficacy, safety, and limitations of noninvasive vagunerve stimulation. Identifies challenges in standardization and personalization and proposes AI-assisted, closed-loop approaches. Reviews vagus nerve stimulation mechanisms in depression, including autonomic, inflammatory, and neural pathways. Compares major vagus nerve stimulation modalities, with emphasis on transcutaneous auricular and cervical approaches. Analyzes device design, including electrode configuration, stimulation parameters, and ergonomic considerations. Summarizes clinical evidence on the efficacy, safety, and limitations of noninvasive vagunerve stimulation. Identifies challenges in standardization and personalization and proposes AI-assisted, closed-loop approaches.