Breakthrough bioelectronic medicine discovery made by decoding immune system's neural signals

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Northwell Health's Feinstein Institute for Medical Research Assistant Professor Theodoros P. Zanos, PhD, and his collaborators are the first to decode specific signals the nervous system uses to communicate immune status and inflammation to the brain. Identifying these neural signals and what they're communicating about the body's health is a major step forward for bioelectronic medicine as it provides insight into diagnostic and therapeutic targets, and device development. These findings were published today in Proceedings of the National Academy of Sciences (PNAS).

It was already known that the vagus nerve, a nerve in the neck, controls the release of molecules called cytokines, which promote inflammation in many disease conditions. However, up until now, it was unknown if each type of cytokine was sending its own specific information about inflammation and immunity to the brain. In Dr. Zanos' study, he successfully decoded the neural signaling of two cytokines - IL-1β and TNF - in the vagus nerve of mice and found that each cytokine triggered their own specific response signal.

"These results show that it is possible to detect specific cytokine signaling from the body's receptors to the brain, through electrical signals in the vagus nerve," said Dr. Zanos, lead author of the PNAS paper. "We will now use the neural decoding methods from this study to identify the neural signaling of a variety of medical conditions in future bioelectronic medicine studies. This is a key step to provide insights to engineer cutting-edge diagnostic and therapeutic devices."

The article, https://medicalxpress.com/news/2018-05-breakthrough-bioelectronic-medicine-discovery-decoding.amp

Significance
Evolution conferred animals with molecular sensors that monitor cellular and organ function to detect changes in the environment. These activate sensory neural responses that drive the action of reflexes that maintain cellular and physiological homeostasis. Recent advances reveal that neural reflexes modulate the immune system, but it was previously unknown whether cytokine mediators of immunity mediate specific neural signals. Here we develop methods to isolate and decode specific neural signals recorded from the vagus nerve to discriminate between the cytokines IL-1β and TNF. This methodological waveform successfully detects and discriminates between specific cytokine exposures using neural signals.

Abstract
The nervous system maintains physiological homeostasis through reflex pathways that modulate organ function. This process begins when changes in the internal milieu (e.g., blood pressure, temperature, or pH) activate visceral sensory neurons that transmit action potentials along the vagus nerve to the brainstem. IL-1β and TNF, inflammatory cytokines produced by immune cells during infection and injury, and other inflammatory mediators have been implicated in activating sensory action potentials in the vagus nerve. However, it remains unclear whether neural responses encode cytokine-specific information. Here we develop methods to isolate and decode specific neural signals to discriminate between two different cytokines. Nerve impulses recorded from the vagus nerve of mice exposed to IL-1β and TNF were sorted into groups based on their shape and amplitude, and their respective firing rates were computed. This revealed sensory neural groups responding specifically to TNF and IL-1β in a dose-dependent manner. These cytokine-mediated responses were subsequently decoded using a Naive Bayes algorithm that discriminated between no exposure and exposures to IL-1β and TNF (mean successful identification rate 82.9 ± 17.8%, chance level 33%). Recordings obtained in IL-1 receptor-KO mice were devoid of IL-1β–related signals but retained their responses to TNF. Genetic ablation of TRPV1 neurons attenuated the vagus neural signals mediated by IL-1β, and distal lidocaine nerve block attenuated all vagus neural signals recorded. The results obtained in this study using the methodological framework suggest that cytokine-specific information is present in sensory neural signals within the vagus nerve.

The paper, http://www.pnas.org/content/early/2018/05/02/1719083115