Publications

Vagal sensory neurons in the nodose ganglia selectively encode specific cytokines, enabling real-time body-brain communication of immune signals. Using in vivo calcium imaging, vagal sensory neurons within the nodose ganglia exhibit distinct real-time neuronal responses to inflammatory cytokines. Groups of individual nodose ganglia neurons are cytokine-selective, while other neurons respond to multiple cytokines while maintaining distinct cytokine-specific patterns for each, indicating that immune signals have distinct neural representations. Vagal sensory neurons express receptors for cytokines and other immune mediators and transmit cytokine-specific neural action potentials to the brain. In mice with dextran sulfate sodium (DSS)-induced colitis, nodose ganglia neuronal activity and cytokine-specific neuronal responses were both altered, indicating that inflammation changes neural excitability.

Musculoskeletal pain and fatigue are common features in systemic lupus erythematosus (SLE). The cholinergic anti-inflammatory pathway is a physiological mechanism diminishing inflammation, engaged by stimulating the vagus nerve. We evaluated the effects of non-invasive vagus nerve stimulation in patients with SLE and with musculoskeletal pain. 18 patients with SLE and with musculoskeletal pain were randomised (2:1) in this double-blind study to receive transcutaneous auricular vagus nerve stimulation (taVNS) or sham stimulation (SS) for 4 consecutive days. Evaluations at baseline, day 5 and day 12 included patient assessments of pain, disease activity (PtGA) and fatigue. Tender and swollen joint counts and the Physician Global Assessment (PGA) were completed by a physician blinded to the patient's therapy. Potential biomarkers were evaluated. taVNS and SS were well tolerated. Subjects receiving taVNS had a significant decrease in pain and fatigue compared with SS and were more likely (OR=25, p=0.02) to experience a clinically significant reduction in pain. PtGA, joint counts and PGA also improved. Pain reduction and improvement of fatigue correlated with the cumulative current received. In general, responses were maintained through day 12. Plasma levels of substance P were significantly reduced at day 5 compared with baseline following taVNS but other neuropeptides, serum and whole blood-stimulated inflammatory mediators, and kynurenine metabolites showed no significant change at days 5 or 12 compared with baseline. taVNS resulted in significantly reduced pain, fatigue and joint scores in SLE. Additional studies evaluating this intervention and its mechanisms are warranted.

The bodies have built-in neural reflexes that continuously monitor organ function and maintain physiological homeostasis. While the field of bioelectronic medicine has mainly focused on the stimulation of neural circuits to treat various conditions, recent studies have started to investigate the possibility of leveraging the sensory arm of these reflexes to diagnose disease states. Neural signals emanating from the body's built-in biosensors and propagating through peripheral nerves must be recorded and decoded to identify the presence or levels of relevant biomarkers of disease. This review outlines studies decoding vagus nerve activity as it related to inflammatory, metabolic, and cardiopulmonary biomarkers to enable the development of real-time diagnostic devices and help advance truly closed-loop neuromodulation technologies.

Recent advances reveal that neural reflexes modulate the immune system, but it was previously unknown whether cytokine mediators of immunity mediate specific neural signals. Methods were developed to isolate and decode specific neural signals recorded from the vagus nerve to discriminate between the cytokines IL-1β and TNF. A bipolar cuff electrode recording activity from the surface of the cervical vagus nerve of mice was used. The methodological waveform successfully detects and discriminates between specific cytokine exposures using neural signals, demonstrating that the nervous system maintains physiological homeostasis through reflex pathways that modulate organ function.