Wireless Vagus Nerve Stimulation Patch with 3D Liquid Metal Electrodes—A Non-Surgical Solution for Treatment-Resistant Depression

Depression is one of the most serious mental diseases, affecting approximately 280 million people in the modern population. Alleviating depression is crucial as it often leads to other severe conditions through complex biological connections. Various treatments for depression have been researched and are currently utilized in clinical practice. However, some patients suffer from treatment-resistant depression, which does not respond to conventional antidepressants. To address these challenges, several electrical stimulation treatments such as electroconvulsive therapy have been developed. However, electroconvulsive therapy necessitates anesthesia for the electrical stimulation of the brain and is associated with temporary memory loss. Consequently, vagus nerve stimulation (VNS) has emerged as a promising alternative treatment capable of overcoming these limitations. VNS involves electrical stimulation of the vagus nerve, which modulates brain regions such as the hippocampus and prefrontal cortex. However, traditional VNS systems require surgical implantation of cuff electrodes around the vagus nerve under anesthesia. Transcutaneous auricular VNS has been proposed as a non-invasive alternative, but it has limited efficacy with only 27-50% of patients responding to the treatment. Here, we introduce a skin-attachable, surgery-free, wireless VNS patch with 3D liquid metal electrodes. This VNS patch is applied to the skin on the left cervical region, targeting the vagus nerve. It can operate wirelessly to provide treatment without spatial constraints and enable on-demand activation. Specifically, we determined the optimal stimulation parameters through in-vivo animal experiments, establishing 1 mA, 30 Hz, and 30 minutes as an ideal setting. The alleviation of depression was proven in all 10 mice tested with our VNS system. Additionally, our skin-attachable VNS patch demonstrated rapid tissue recovery in mice with complete healing within seven days and no signs of prolonged immune response, highlighting its potential for safe and minimally invasive therapeutic applications. Electrophysiological analysis, such as phase-amplitude coupling and phase-locking measurements, demonstrated that VNS significantly modulated neural activity and functional connectivity in the hippocampus and prefrontal cortex. These changes led to the normalization of neural circuits involved in mood regulation and facilitated the recovery of cognitive function in depression models. Key biomarkers of neuroplasticity and inflammation, such as brain-derived neurotrophic factor and interleukin-6, were investigated in the hippocampus and the prefrontal cortex. Our research also indicated that VNS treatment can normalize immune function as demonstrated by the assessment of lymph node volume. This VNS system offers a novel therapeutic option for treatment-resistant depression, providing three major advantages: 1) no requirement for surgery, 2) wireless functionality, and 3) proven efficacy.