"The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible 'hard-wired' neural systems."

"By combining optogenetics, anatomical and functional mapping, and measurement of TNF production, our data show the DMN is an important brainstem locus controlling anti-inflammatory signals in the inflammatory reflex."

"Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications."

"In mice, electroacupuncture has been shown to reduce inflammation, but only when certain points on the body are stimulated. Why this is has puzzled scientists, but now, researchers have identified the specific neurons that are involved. They hope that this knowledge could be used in future to help treat certain inflammatory-related diseases."

"The positive mechanistic results reported here extend the preclinical data to the clinic and reveal that vagus nerve stimulation inhibits TNF and attenuates disease severity in RA patients."

"Experimental strategies that selectively target HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity and significantly attenuate damage in diverse models of sterile and infection-induced threat."

"Action potentials originating in the vagus nerve regulate T cells, which in turn produce the neurotransmitter, acetylcholine, required to control innate immune responses."

"The idea of using a nerve-stimulating medical device to treat inflammatory diseases is revolutionary. Its potential emerged from a breakthrough in neurophysiology revealing that electrical signals transmitted in the vagus nerve suppress inflammation. The potential therapeutic implications of this concept are far-reaching, because inflammation is a participant in many disease syndromes, including Alzheimer’s and other neurodegenerative brain diseases, as well as inflammatory bowel disease, congestive heart failure, atherosclerosis, and diabetes."

"...the VN is a major component of the bidirectional communication between the brain and the gut through the brain–gut axis."

"Here, we examine how stressor diversity is imbedded in the neuroimmune axis. Stressors differ in the brain patterns they induce, diversifying the neuronal and endocrine mediators dispatched to the periphery and generating a wide range of potential immune effects. Uncovering this complexity and diversity of the immune response to different stressors will allow us to understand the involvement of stress in pathological conditions, identify ways to modulate it, and even harness the therapeutic potential embedded in an adaptive response to stress."

"Here, we review these regulatory mechanisms and describe the neural circuitry modulating immunity. Understanding these mechanisms reveals possibilities to use targeted neuromodulation as a therapeutic approach for inflammatory and autoimmune disorders."

"A growing knowledge of mechanisms of neural regulation in disease pathogenesis will be instrumental for developing new bioelectronic technologies. Bioelectronic Medicine will be the platform for innovative research and conceptual developments reflecting the progress in the field."

"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. "

"Here we review the anatomical and molecular basis of the neural interface with immunity, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus."

"Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock."

"High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal."

"Here we summarize the role of HMGB1 in inflammation, with a focus on recent findings on its mission as a damage-associated molecular pattern molecule and as a therapeutic target in inflammatory diseases."

"We then describe how stimulation of the vagus nerve and activation of the inflammatory reflex rapidly and specifically curtail traumatic hemorrhage through a novel mechanism termed the neural tourniquet."

"...the interaction of the VN with the sympathetic nervous system is of interest and targeting the anti-inflammatory effect of the VN, i.e. an anti-TNFα pathway, both through its afferent and efferent fibers would be of interest in IBD."

"The data, presented in a poster session at the Digestive Disease Week meeting in Washington, D.C., showed that over 60% of patients achieved significant reductions in their disease activity as assessed by the Crohn’s Disease Activity Index (CDAI)."

"Thus, sympathetic fibers control colonic inflammation by regulating immune cell extravasation from circulation, a mechanism likely relevant in multiple organs."

"Herein is a review of some of the experimental studies that define the inflammatory reflex and its anatomic and physiologic components."

"Here, we show that the brain’s insular cortex (InsCtx) stores immune-related information. Using activity-dependent cell labeling in mice, we captured neuronal ensembles in the InsCtx that were active under two different inflammatory conditions (dextran sulfate sodium [DSS]-induced colitis and zymosan-induced peritonitis). Chemogenetic reactivation of these neuronal ensembles was sufficient to broadly retrieve the inflammatory state under which these neurons were captured. Thus, we show that the brain can store and retrieve specific immune responses, extending the classical concept of immunological memory to neuronal representations of inflammatory information.

"Heart rate variability (HRV) is a validated method to establish autonomic nervous system (ANS) activity. Rheumatoid arthritis (RA) is accompanied by ANS imbalance. We hypothesized that ANS dysfunction may precede the development of RA, which would suggest that it plays a role in its etiopathogenesis."

 "In addition to its intracellular functions, HMGB1 can be extracellularly released, where it mediates activation of innate immune responses, including chemotaxis and cytokine release."

"Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway."

"These results indicate that cachectin (TNF) is a mediator of fatal bacteraemic shock, and suggest that antibodies against cachectin (TNF) offer a potential therapy of life-threatening infection."

"Treating diseases nonpharmacologically, using targeted neurostimulation instead of systemic drugs, is a hallmark of the burgeoning field of bioelectronic medicine. In this review, we provide a brief overview of the discovery and function of the prototypical neuroimmune reflex, the “inflammatory reflex.”

"We have shown that there is an inverse relationship between vagal tone and plasma TNFα level in patients with CD, and have reported, for the first time, that chronic vagus nerve stimulation has anti-inflammatory properties in a rat model of colitis and in a pilot study performed in seven patients with moderate CD. Two of these patients failed to improve after 3 months of vagus nerve stimulation but five were in deep remission (clinical, biological and endoscopic) at 6 months of follow-up and vagal tone was restored. No major side effects were observed."

"Neuroimmunology is one of the fastest-growing fields in the life sciences, and for good reason; it fills the gap between two principal systems of the organism, the nervous system and the immune system. Although both systems affect each other through bidirectional interactions, we focus here on one direction — the effects of the nervous system on immunity."

"The benefits of this paradigm shift toward bioelectronic therapies, compared to drugs is clear, both in terms of reduced side-effects and long-term, cost reduction. However, there are still major challenges that the bioelectronics community needs to address in order to fully realize the potentials of these technologies."