Vagus Nerve

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Background

The vagus nerve is actually two nerves that have two related but distinct regulatory jobs. It is known as the "wandering nerve" because it meanders across the chest to reach its targets. (In Latin, the term "vagus" means wandering.) One branch starts in the lateralized dorsal motor nucleus and is responsible for controlling the heart and lower organs like the stomach, intestines, kidney, and liver. The other major branch, nucleus ambiguus, is involved in speech, eye contact, facial expressions, and the ability to tune in to other people’s voices.

One of the vagus nerve’s jobs is to carry incoming information from nerve receptors in the body to the brain through afferent nerves, providing information about what the body is doing. Some 80% of its fibers are sensory in nature to provide a wide variety of feedback to the brain.

The vagus nerve also transmits outgoing information from the brain via efferent nerves to govern a range of reflex responses. It can signal the organs to be calm so you can “rest-and-digest” during times of safety, or to prepare your body for “fight-or-flight” in dangerous times. It also helps to control muscle movement, keep a person breathing, and to transmit a variety of chemicals through the body.

After eating, healthy vagus nerve communication between the gut and the brain helps to slow you down by using neurotransmitters such as acetylcholine and GABA. These neurotransmitters lower heart rate, blood pressure, and help the heart and organs slow down so that you can rest-and-digest. It is also responsible for keeping the digestive tract in working order, contracting the muscles of the stomach and intestines to help process food, and sending back information about what is being digested and what the body is getting out of it.

In times of stress, the vagus assists the adrenal glands during ‘fight-or-flight’ situations by stimulating the release of epinephrine (adrenaline) in the brain.

Not all vagus nerves are the same. Some people have stronger vagus activity, which means their bodies can relax faster after a stress. The variation is thought to be caused by genetics in approximately 65% of cases, but factors such as obesity and sedentary lifestyles have been found to be associated with low vagal tone. Vagal tone peaks early in life, during childhood, possibly explaining why children are so much more emotionally connected, and why traumatic childhoods are thought to adversely affect its efficacy later in life. There is a steady decline in its performance through adolescence and then it stabilizes in adulthood.

The term “vagal tone” refers to the continuous and automatic activity of the vagus nerve. The vagus nerve is a central component in the parasympathetic nervous system (PNS). The PNS is responsible for the 'resting state' actions of the autonomic nervous system (ANS), that is, the branch of the nervous system which controls bodily functions which are beneath conscious control such as heart rate, digestion, salivation, pupillary diameter, etc.

In healthy people high levels of PNS activity (i.e. high vagal tone) are desirable; this indicates a state of calmness, rest or relaxation, which is a sign that the body is repairing itself. Under resting conditions the vagus nerve acts as a kind of “brake,” firing a rapid and continuous signal to the sino-atrial node of the heart to slow the beat; without such influence the heart would race along at over 100 beats per minute.

When the vagus nerve is firing or stimulated, the response is normally a drop in heart rate or breathing. But, in some cases, excessive stimulation can cause someone to have what is known as a vaso-vagal response, causing fainting or coma because one’s heart rate and blood pressure drop so much. The most common example is when a person faints at a blood draw at the sight of the needle, blood, or experiencing pain.

Why the renewed interest in the vagus nerve? In the late 1990s, Kevin Tracey, a neurosurgeon, was experimenting with a rat’s brain.

We’d injected an anti-inflammatory drug into the brain because we were studying the beneficial effect of blocking inflammation during a stroke,” he recalls. “We were surprised to find that when the drug was present in the brain, it also blocked inflammation in the spleen and in other organs in the rest of the body. Yet the amount of drug we’d injected was far too small to have got into the bloodstream and travelled to the rest of the body.” 

In 2000, Tracey and his colleagues published their conclusions: the brain was using the vagus nerve to tell the spleen to turn off inflammation and return the immune system back to a place of homeostasis. Imagine the possibilities of using the nervous system to help regulate the immune system. How many diseases might we treat?


For you visual types, here's a link to the big picture: http://thelivingproofinstitute.com/wp-content/uploads/2014/07/vagus-nerve-schema-812x1024.jpg


References:

http://www.md-health.com/Vagus-Nerve.html

https://www.psychologytoday.com/blog/the-athletes-way/201405/how-does-the-vagus-nerve-convey-gut-instincts-the-brain

http://www.wisegeek.org/what-is-the-vagus-nerve.htm

http://www.innovateus.net/innopedia/what-function-vagus-nerve

http://www.psych.usyd.edu.au/staff/jamesh/intro_to_vagal_tone.pdf

http://128.196.99.80/JJBAReprints/Movius_Allen_BioPsychology_2005.pdf

http://www.cathlabdigest.com/articles/Hypotension-Cath-Lab-Think-Vagal-Reaction-Early

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122270/

http://www.unknowncountry.com/news/vagus-nerve-our-route-happier-healthier-life

http://www.huffingtonpost.com/2015/05/29/hacking-the-nervous-syste_n_7469526.html

For more detailed anatomy, see: http://emedicine.medscape.com/article/1875813-overview#a1


Measuring/Predicting Vagus Nerve Function

It turns out, one cannot measure vagal tone directly. Vagus nerve function is inferred from its influence on target organs, specifically the heart. In general, an increase vagal tone both slows the heart and makes the heart rate more variable, causing more beat-to-beat change between heart beats. This is due to respiratory sinus arrhythmia (RSA). RSA happens when you breathe in, which temporarily suppresses vagal activity, immediately increasing heart rate, and when you breathe out, it immediately decreases heart rate as vagal activity resumes.

So, changes in heart rate stand in as a measure of vagal tone. More specifically, they look at heart rate variability (HRV). First they look at resting RSA, and then how RSA changes in response to a stressor or task demand and take the difference between resting RSA and task RSA. The larger the difference, the higher your vagal tone, which is related to better health.

References: http://www.psych.usyd.edu.au/staff/jamesh/intro_to_vagal_tone.pdf

http://128.196.99.80/JJBAReprints/Movius_Allen_BioPsychology_2005.pdf


There may also be genetic influences to how well the vagus nerve functions.


Sex-specific association between nerve growth factor polymorphism and cardiac vagal modulation. (2014)
Substantial research has shown that anxiety disorders are associated with decreased cardiac vagal tone, which is a known risk factor for cardiac vulnerability. A functional nerve growth factor (NGF) polymorphism (rs6330, c.104C > T, p.Ala35Val) has been associated with anxiety such that in males but not females, T-allele carriers exhibit higher levels of trait anxiety.

The findings support the view that male T-allele carriers are at increased susceptibility for anxiety by association with low vagal activity and suggest a potential sex-specific genetic link between the highly comorbid anxiety disorders and cardiovascular diseases.
http://www.ncbi.nlm.nih.gov/pubmed/25162994


One also can look at genetic effects on heart rate (HR) and heart rate variability. I haven’t had time to track down many snps, but here are some preliminary results.


Genetic contributions to acute autonomic stress responsiveness in children. (2012)
For HR, we found differences associated with COMT, i.e. children carrying at least one met allele showed lower mean HR increase and slower HR recovery in response to the stressor compared to those with two val alleles (p<.001) as well as a significant decrease in heart rate variability (p<.05). Our findings indicate that these two polymorphisms do indeed influence the ANS response to stress. This study provides further evidence for the crucial role of genetic factors in the modulation of differences in the acute stress response during childhood.
http://www.ncbi.nlm.nih.gov/pubmed/22133998

Genetic contributions of the serotonin transporter to social learning of fear and economic decision making. (2009)
Serotonin (5-HT) modulates emotional and cognitive functions such as fear conditioning (FC) and decision making. This study investigated the effects of a functional polymorphism in the regulatory region (5-HTTLPR) of the human 5-HT transporter (5-HTT) gene on observational FC, risk taking, and susceptibility to framing in decision making under uncertainty, as well as multidimensional anxiety and autonomic control of the heart in healthy volunteers. The present results indicate that in comparison to the homozygotes for the long (l) version of 5-HTTLPR, the carriers of the short (s) version display enhanced observational FC, reduced financial risk taking, and increased susceptibility to framing in economic decision making. We also found that s-carriers have increased trait anxiety due to threat in social evaluation and ambiguous threat perception. In addition, s-carriers also show reduced autonomic control over the heart, and a pattern of reduced vagal tone and increased sympathetic activity in comparison to l-homozygotes. This is the first genetic study that identifies the association of a functional polymorphism in a key neurotransmitter-related gene with complex social-emotional and cognitive processes. The present set of results suggests an endophenotype of anxiety disorders, characterized by enhanced social learning of fear, impaired decision making, and dysfunctional autonomic activity.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799947/

Gene-environment contributions to the development of infant vagal reactivity: the interaction of dopamine and maternal sensitivity. (2008)
This study investigated dopamine receptor genes (DRD2 and DRD4) and maternal sensitivity as predictors of infant respiratory sinus arrhythmia (RSA) and RSA reactivity, purported indices of vagal tone and vagal regulation, in a challenge task at 3, 6, and 12 months in 173 infant-mother dyads. Hierarchical linear modeling (HLM) revealed that at 3 and 6 months, RSA withdrawal in response to maternal separation was greater (suggesting expected physiological regulation) in infants without the DRD2 risk allele than those with the risk allele. At 12 months, infants with the risk allele who were also exposed to maternal sensitivity showed levels of RSA withdrawal comparable to infants who were not at genetic risk. Findings demonstrate the importance of developmental analysis of gene-environment interaction.
http://www.ncbi.nlm.nih.gov/pubmed/18826531

Increased heart rate variability in mice overexpressing the Cu/Zn superoxide dismutase. (2008)
Cu/Zn superoxide dismutase (SOD1) is implicated in various pathological conditions including Down's syndrome, neurodegenerative diseases, and afflictions of the autonomic nervous system (ANS). To assess the SOD1 contribution to ANS dysfunction, especially its influence on cardiac regulation, we studied the heart rate variability (HRV) and cardiac arrhythmias in conscious 12-month-old male and female transgenic mice for the human SOD1 gene (TghSOD1). TghSOD1 mice presented heart rate reduction as compared with control FVB/N individuals. All HRV parameters reflecting parasympathetic activity were increased in TghSOD1. Pharmacological studies confirmed that the parasympathetic tone was exacerbated and the sympathetic pathway was functional in TghSOD1 mice. A high frequency of atrioventricular block and premature ventricular contractions was observed in TghSOD1. By biochemical assays we found that SOD1 activities were multiplied by 9 and 4 respectively in the heart and brainstem of transgenic mice. A twofold decrease in cholinesterase activity was observed in the heart but not in the brainstem. We demonstrate that SOD1 overexpression induces an ANS dysfunction by an exacerbated vagal tone that may be related to impaired cardiac activity of the cholinesterases and may explain the high occurrence of arrhythmias.
http://www.ncbi.nlm.nih.gov/pubmed/18513493

A deletion in the alpha2B-adrenergic receptor gene and autonomic nervous function in central obesity. (2003)
The results of the present study suggest that the 12Glu9 polymorphism of the alpha(2B)-adrenergic receptor gene modulates autonomic nervous function in Finnish nondiabetic men. In the nondiabetic men with the Glu(9)/Glu(9) genotype, the general autonomic tone is depressed, and vagal activity especially becomes impaired with time. Furthermore, this association is accentuated by central obesity.
http://www.ncbi.nlm.nih.gov/pubmed/12917501


Vagus Nerve - why you should care

People who have high vagal tone have been found to be happier, less stressed, and less likely to suffer from depression than those with lower tone. They also have good memories, are better able to focus their attention, and have increased brain-power. They are usually healthier too, as the vagus nerve is involved in insulin production, cardiovascular health, and immune responses. High vagal tone helps your body better regulate blood glucose levels, reducing the likelihood of diabetes, stroke and cardiovascular disease.

Conversely, those with low vagal tone have been shown to suffer more from chronic inflammatory conditions, strokes and cardiovascular problems, depression, diabetes, cognitive impairment and chronic fatigue syndrome. They may have ulcers, constipation and urinary incontinence. They may also be prone to depression, anxiety, mood disorders.


You may need the vagus nerve to understand pathophysiology and to treat diseases. (2012)
Can different pathophysiological mechanisms and risk factors leading to various diseases be linked with altered transmission of signals by one common pathway? The present article provides evidence for the hypothesis that adequate vagal nerve activity reduces the risk of major diseases, via common basic mechanisms and interim risk factors. These diseases include cardiovascular disease, cancer, Alzheimer's disease and the metabolic syndrome. Three basic mechanisms contribute to such illnesses: local oxidative stress and DNA damage, inflammatory reactions and excessive sympathetic responses, all of which are inhibited by vagal nerve activity. Efferent vagal activity that can be non-invasively measured by HRV (heart rate variability), derived from an ECG, is inversely related to all three basic mechanisms, to various risk factors (e.g. diabetes and dyslipidaemia) and, more broadly, to the diseases as well. Finally, vagal activity is proposed to moderate the effects of risk factors on developing such illnesses. By proposing an integrative neurobiological model of major diseases, identifying people at risk for, and treating patients with, such diseases may be done more efficiently. People with low HRV may be identified and subsequently treated by vagus nerve activation to possibly prevent or treat such illnesses. This proposed disease paradigm may have important preventative and therapeutic implications, whose clinical effects need to be investigated.
http://www.ncbi.nlm.nih.gov/pubmed/22150254

Low vagal tone is associated with impaired post stress recovery of cardiovascular, endocrine, and immune markers. (2010)
Confirming our hypothesis, low vagal tone was associated with impaired recovery of cardiovascular, endocrine, and immune markers in healthy males. The data support an inhibitory role of the vagus in the regulation of allostatic systems as described in the neurovisceral integration model. We posit reduced resting HRV as a risk marker for future cardiovascular and other stress-related disease.
http://www.ncbi.nlm.nih.gov/pubmed/20052593

Autonomic Imbalance as a Predictor of Metabolic Risks, Cardiovascular Disease, Diabetes, and Mortality. (2015)
RESULTS: RHR and HRV, along with sex, age, and smoking were significant predictors of high blood pressure, hyperglycemia, and a diagnosis of diabetes within 12 years. RHR and HRV also predicted the development of cardiovascular disease and early mortality for most of the sample. CONCLUSIONS: In this community sample two measures of autonomic imbalance predicted multiple poor metabolic outcomes and mortality, making autonomic imbalance a potentially worthy target for intervention studies to reduce risks for cardiovascular disorders, diabetes, and early death.
http://www.ncbi.nlm.nih.gov/pubmed/26047073

Other References:

http://www.md-health.com/Vagus-Nerve.html

Upward spirals of the heart: Autonomic flexibility, as indexed by vagal tone, reciprocally and prospectively predicts positive emotions and social connectedness (2010)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122270/


Vagus Nerve - it’s effects on inflammation

Of course, inflammation can be useful in helping the body to heal after an injury, for example, but chronic inflammation can damage organs and blood vessels. One of the vagus nerve’s jobs is to reset the immune system and switch off production of proteins that fuel inflammation. Low vagal tone means this regulation is less effective and inflammation can become excessive.


The inflammatory reflex: the role of the vagus nerve in regulation of immune functions (2011)
Experimental studies published in past years have shown an important role of the vagus nerve in regulating immune functions. Afferent pathways of this cranial nerve transmit signals related to tissue damage and immune reactions to the brain stem. After central processing of these signals, activated efferent vagal pathways modulate inflammatory reactions through inhibiting the synthesis and secretion of pro-inflammatory cytokines by immune cells. Therefore, pathways localized in the vagus nerve constitute the afferent and efferent arms of the so-called "inflammatory reflex" that participates in negative feedback regulation of inflammation in peripheral tissues. Activation of efferent pathways of the vagus nerve significantly reduces tissue damage in several models of diseases in experimental animals. Clinical studies also indicate the importance of the vagus nerve in regulating inflammatory reactions in humans. It is suggested that alteration of the inflammatory reflex underlies the etiopathogenesis of diseases characterized by exaggerated production of pro-inflammatory mediators. Therefore, research into the inflammatory reflex may create the basis for developing new approaches in the treatment of diseases with inflammatory components.
http://www.ncbi.nlm.nih.gov/pubmed/22263327

The parasympathetic nervous system as a regulator of mast cell function. (2015)
Often considered as the archetype of neuroimmune communication, much of our understanding of the bidirectional relationship between the nervous and immune systems has come from the study of mast cell-nerve interaction. Mast cells play a role in resistance to infection and are extensively involved in inflammation and subsequent tissue repair. Thus, the relationship between mast cells and neurons enables the involvement of peripheral and central nervous systems in the regulation of host defense mechanisms and inflammation. Recently, with the identification of the cholinergic anti-inflammatory pathway, there has been increased interest in the role of the parasympathetic nervous system in regulating immune responses. Classical neurotransmitters and neuropeptides released from cholinergic and inhibitory NANC neurons can modulate mast cell activity, and there is good evidence for the existence of parasympathetic nerve-mast cell functional units in the skin, lung, and intestine that have the potential to regulate a range of physiological processes.
http://www.ncbi.nlm.nih.gov/pubmed/25388249

The vagus nerve and the inflammatory reflex: wandering on a new treatment paradigm for systemic inflammation and sepsis. (2012)
The central nervous system recognizes peripheral inflammation via afferent vagus nerve signaling. The brain can attenuate peripheral innate immune responses, including pro-inflammatory cytokine production, leukocyte recruitment, and nuclear factor kappa β activation via α7-nicotinic acetylcholine receptor subunit-dependent, T-lymphocyte-dependent, vagus nerve signaling to spleen. This efferent arm of the inflammatory reflex is referred to as the "cholinergic anti-inflammatory pathway." Activation of this pathway via vagus nerve stimulation or pharmacologic α7 agonists prevents tissue injury in multiple models of systemic inflammation, shock, and sepsis.
http://www.ncbi.nlm.nih.gov/pubmed/22913335

Neuroendocrine and Immune Contributors to Fatigue (2010)
Whereas, circulating hormones, such as glucocorticoids, regulate immunity at a systemic level, neural pathways regulate immunity at a local and regional level. The SNS and peripheral nervous system innervate immune organs, where sympathetic influences can be both pro- and anti-inflammatory, depending on the type of adrenergic receptor to which the catecholamine binds [8,9]. Neuropeptides released from peripheral nerves, such as substance P, tend to be proinflammatory [7]. Locally released norepinephrine or circulating epinephrine also affect lymphocyte trafficking, proliferation, function, and cytokine production. With regard to the peripheral nervous system, both afferent and efferent parasympathetic activities have been shown to be immunomodulatory.

Whereas, afferent vagal fibers express IL-1 receptors on paraganglia cells situated in parasympathetic ganglia [12], efferent vagal fibers have been shown to exert anti-inflammatory action via the release of acetylcholine [10, 11]. Therefore, the vagus nerve also serves as a source of negative feedback on the immune system, with the brain being an integral relay station…

…HRV is a term that describes variations of both instantaneous heart rate and the interval between consecutive beats. A prominent circadian variation in HRV, with significant increases during the night and decreases during the day, is observed in healthy individuals. Results of previous studies showed that this increase in nighttime HRV is blunted by acute stress and that decreased HRV is associated with increased overnight urinary cortisol and increased proinflammatory cytokines and acute-phase proteins [105]. Decreased HRV, indicative of reduced parasympathetic-vagal tone, is an independent risk factor for morbidity and mortality.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933136/

Involvement of MAPK/NF-κB Signaling in the Activation of the Cholinergic Anti-Inflammatory Pathway in Experimental Colitis by Chronic Vagus Nerve Stimulation (2013)
Recently, Tracey and colleagues reported the anti-inflammatory effect of vagus nerve stimulation on the systemic inflammatory response to endotoxin. They identified the neural mechanisms of the cholinergic anti-inflammatory pathway (CAP): vagal efferents innervate many of the organs associated with the immune system, including the heart, liver, and gastrointestinal system. Acetylcholine (ACh) released from the vagal efferents modulates immune responses via alpha 7 nicotinic receptors (α7nAchRs) on human macrophages that inhibit NF-κB and, consequently, cytokine (TNF-α, IL-1, etc.) synthesis and release [17-21].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732220/

Differential Patterns and Determinants of Cardiac Autonomic Nerve Dysfunction during Endotoxemia and Oral Fat Load in Humans (2015)
The metabolic homeostasis is regulated by the vagus nerve via controlling heart rate, gastrointestinal motility and secretion, pancreatic endocrine and exocrine secretion, and endogenous glucose production [1,2]. The parasympathetic nervous system (PNS) also controls innate immune responses and inflammation during pathogen invasion and tissue injury. The physiological mechanism through which the PNS regulates immune function and inhibits excessive proinflammatory cytokine production has been termed the “inflammatory reflex” [1–3]. Vagus nerve signaling plays a paramount role in the regulation of feeding behavior and metabolic homeostasis aimed at preserving energy balance and preventing fluctuations in body weight and metabolism [1]. The efferent vagus nerve signaling pathway termed the “cholinergic antiinflammatory pathway” has been corroborated in an animal model of endotoxemia and shock [3–5]. Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases [5], and the myocardial inflammatory response and impairment during experimental endotoxemia are aggravated following vagotomy [6]. The sympathetic nervous system (SNS) plays a dual role in the regulation of inflammation by mediating both pro- and anti-inflammatory activities [4]. Both divisions of the autonomic nervous system (ANS) are activated by immunogenic stimuli and both contribute to modulation of inflammation. The cholinergic anti-inflammatory pathway and the SNS also act synergistically to control inflammation [4].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403853/


Underlying many of these studies are the anti-inflammatory effects of α7 nicotinic ACh receptors on macrophages and immune cells. Vagal stimulation releases acetylcholine, which interacts with alpha7 nicotinic acetylcholine receptors and down-regulates pro-inflammatory cytokine synthesis.


Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases (2013)
In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis, psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine-mediated inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines such as TNF-α. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines. This “cholinergic anti-inflammatory pathway” modulates the immune system through cholinergic mechanisms that act on alpha7 receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory components.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678737/


And of course, we know that inflammation is implicated in neurodegeneration:


Inflammasomes in neuroinflammation and changes in brain function: a focused review (2014)
Recent literature has pointed to the existence of inflammasome-mediated inflammatory pathways in central nervous system (CNS) disorders and associated changes in behavior. Neuroinflammation, which is an innate immune response in the CNS against harmful and irritable stimuli such as pathogens and metabolic toxic waste, as well as to chronic mild stress, is mediated by protein complexes known as inflammasomes. Inflammasomes activate pro-inflammatory caspases 1 and 5, which then cleave the precursor forms of pro-inflammatory cytokines IL-1β, IL-18, and IL-33 into their active forms. These pro-inflammatory cytokines have been shown to promote a variety of innate immune processes associated with infection, inflammation, and autoimmunity, and thereby play an instrumental role in the instigation of neuroinflammation during old age and subsequent occurrence of neurodegenerative diseases, cognitive impairment, and dementia. In particular, NLRP inflammasomes may also have a role in the etiologies of depression, Alzheimer's disease (AD) and in metabolic disorders, such as Type II diabetes, obesity and cardiovascular diseases that have been shown to be co-morbid with psychiatric illnesses.
http://journal.frontiersin.org/article/10.3389/fnins.2014.00315/full

Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases (2013)
A direct correlation has been established between the A-beta-induced neurodegeneration and cytokine production and its subsequent release. In effect, neuroinflammation is responsible for an abnormal secretion of proinflammatory cytokines that trigger signaling pathways that activate brain tau hyperphosphorylation in residues that are not modified under normal physiological conditions [18].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678737/


Vagus Nerve - it’s relationship to disease

Epilepsy

In 1884, J.L. Corning, an American neurologist, proposed treating epilepsy through transcutaneous electrical stimulation. Yep, 1884. Even though it is still not clear exactly how stimulating the vagus nerve controls refractory epilepsy, it does work. (Reference: http://onlinelibrary.wiley.com/doi/10.1113/expphysiol.2012.064543/full) There are many papers on VNS and epilepsy, but here is a good summary.


Vagus nerve stimulation for refractory epilepsy in children: More to VNS than seizure frequency reduction (2008)

The exact mechanism by which VNS modulates seizures is not known. The vagus nerve, comprising 80% afferent fibers originating from the heart, lungs, larynx, pharynx, and gastrointestinal tract, transmits visceral sensory information to the central nervous system. The vagus nerve projects primarily to the nucleus of the solitary tract, which has projections to multiple areas in the forebrain and brainstem, including areas involved in epileptogenesis such as the thalamus, hippocampus, amygdala, and neocortex (Rutecki, 1990; Vonck et al., 2001). Because the right vagus nerve has efferent projections to the sinoatrial node, the left vagus nerve is used for stimulation (Ardell & Randall, 1986). Studies have demonstrated a bilateral increase in blood flow to the thalamus during stimulation that correlates with a decrease in seizure frequency (Henry et al., 1998, 1999). It is postulated that the anticonvulsant effect of VNS may be caused by the release of norepinephrine (McLachlan, 1993; Krahl et al., 1998) or influence on the reticular activating system (McLachlan, 1993). Detailed reviews of animal and human studies on the mechanisms of VNS action are available (Vonck et al., 2001; Henry, 2002).
http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2008.01940.x/full


Gastro-intestinal Disease

Research has found links to Crohn’s Disease and Irritable Bowel Syndrome (IBS), and more specifically IBS with constipation.


Relationship between Vagal Tone, Cortisol, TNF-Alpha, Epinephrine and Negative Affects in Crohn’s Disease and Irritable Bowel Syndrome (2014)
In conclusion, these data argue for an imbalance between the hypothalamus-pituitary-adrenal axis and the vagal tone in CD and IBS patients. Furthermore, they highlight the specific homeostatic link between vagal tone and TNF-alpha in CD and epinephrine in IBS and argue for the relevance of vagus nerve reinforcement interventions in those diseases.

Specifically, the parasympathetic nervous system plays a major role in gastrointestinal homeostasis [14] and is involved in physiological and psychological flexibility in reaction to stress [15], [16], emotional regulation, and stress recovery [17], [18]. Furthermore, the parasympathetic nervous system, through the vagus nerve, modulates the production of pro-inflammatory cytokines such as TNF-alpha [19] through both vagal afferents and efferents activating respectively the HPA axis and the cholinergic anti-inflammatory pathway [9], [20], [21]. TNF-alpha is a key pro-inflammatory cytokine involved in CD and anti-TNF therapy is currently the gold standard in the treatment of IBD patients [22].

The resting vagal tone is strongly involved in the regulation of physiological systems that are important in health and disease and notably those concerning the HPA axis and inflammation [23]. HRV has been previously proposed as an endophenotype marker particularly as a mediator between physiology and behavior [44].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160179/

The autonomic nervous system in functional bowel disorders (2000)
Patients with increased sympathetic activity and low vagal tone tended to have constipation, whereas diarrhoea prone patients primarily showed increased parasympathetic activity.
http://gut.bmj.com/content/47/suppl_4/iv78.full

Autonomic functioning in irritable bowel syndrome measured by heart rate variability: a meta-analysis. (2013)
Impaired parasympathetic functioning and abnormal sympathovagal balance may be involved in the pathogenesis of IBS. Vagal dysfunction is more obvious in the IBS-C subgroup.
http://www.ncbi.nlm.nih.gov/pubmed/23927739


For more details about how exactly the vagus nerve effects inflammation and the gut, this paper is a great review (although very technical).

The vagal innervation of the gut and immune homeostasis (2013)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711371/


This same paper also suggests the vagal effect on both innate and adaptive parts of the immune system.


"Finally, although so far most studies focused on the innate immune system, modulation of the adaptive immune response is to be anticipated, especially as the DCs and macrophages are the key players initiating this process. One study elegantly demonstrated that antibody production against trinitrophenyl-ovalbumin was dependent on vagal innervation indeed suggesting that the adaptive immune system is under cholinergic control.14 If future studies confirm this, the therapeutic and clinical impact may be even larger than assumed so far. Preclinical evidence supporting the potential therapeutic effect of the cholinergic anti-inflammatory pathway has been recently reviewed in great detail."


And lastly, our gut microbiome can influence the vagus nerve.


Vagal pathways for microbiome-brain-gut axis communication. (2014)
There is now strong evidence from animal studies that gut microorganism can activate the vagus nerve and that such activation plays a critical role in mediating effects on the brain and behaviour. The vagus appears to differentiate between non-pathogenic and potentially pathogenic bacteria even in the absence of overt inflammation and vagal pathways mediate signals that can induce both anxiogenic and anxiolytic effects, depending on the nature of the stimulus. Certain vagal signals from the gut can instigate an anti-inflammatory reflex with afferent signals to the brain activating an efferent response, releasing mediators including acetylcholine that, through an interaction with immune cells, attenuates inflammation. This immunomodulatory role of the vagus nerve may also have consequences for modulation of brain function and mood.What is currently lacking are relevant data on the electrophysiology of the system. Certainly, important advances in our understanding of the gut-brain and microbiome- gut-brain axis will come from studies of how distinct microbial and nutritional stimuli activate the vagus and the nature of the signals transmitted to the brain that lead to differential changes in the neurochemistry of the brain and behaviour. Understanding the induction and transmission of signals in the vagus nerve may have important implications for the development of microbial-or nutrition based therapeutic strategies for mood disorders.
http://www.ncbi.nlm.nih.gov/pubmed/24997031


Related to GI function, vagal stimulation reduced food allergy symptoms in mice. Mucosal mast cell degranulation can be inhibited by the effects of both vagal stimulation and nicotine on mast cell α7 nicotinic ACh receptors - and just because trade has reopened with Cuba, don’t take up cigar smoking for a daily nicotine hit, okay?!?


Anti-Allergic Role of Cholinergic Neuronal Pathway via α7 Nicotinic ACh Receptors on Mucosal Mast Cells in a Murine Food Allergy Model (2014)
Vagal stimulation by 2-deoxy-D-glucose and drug treatment with nicotinic ACh receptor (nAChR) agonists (nicotine and α7 nAChR agonist GTS-21) alleviated the allergic symptoms in the FA mice. Nicotine treatment suppressed MMCs hyperplasia, enhanced MPO and upregulated mRNA expression of Th1 and Th2 cytokines in the FA mice colon. MMCs, which are negatively regulated by α7 nAChRs, were often located in close proximity to cholinergic CGRP-immunoreactive nerve fibers in the FA mice colon. The present results reveal that the cholinergic neuroimmune interaction via α7 nAChRs on MMCs is largely involved in maintaining intestinal immune homeostasis and can be a target for a new therapy against mucosal immune diseases with homeostatic disturbances such as FA.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894205/


For more detailed information on how this mechanism works on mast cells, see:


Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex (2013)
The present study identifies stimulation of the hard-wired vagal anti-inflammatory reflex by enteral lipid-rich nutrition as a strong inhibitor of mucosal mast cell reactivity. Since mast cells are recognized as early and pivotal regulators of the innate immune response, these findings support nutritional intervention in patients prone to develop an excessive inflammatory response.
http://ajpgi.physiology.org/content/305/5/G383


And lastly, the vagus nerve influences gut permeability.


Vagus nerve stimulation attenuates intestinal epithelial tight junctions disruption in endotoxemic mice through α7 nicotinic acetylcholine receptors. (2013)
Our results for the first time confirmed that vagus nerve stimulation attenuated the disruption of tight junction in intestinal epithelium in endotoxemic mice, which was mediated through suppressing translocation of nuclear factor κB p65, downregulating myosin light chain kinase, and the α7nAchR may play an important role in this process.
http://www.ncbi.nlm.nih.gov/pubmed/23860583


Memory, cognition and Alzheimer’s Disease

There is research on how the vagus nerve influences memory. There is less research specifically on Alzheimer’s available, but there are some interesting studies suggesting a connection.


The effects of peripheral vagal nerve stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala. (2004)
Vagal nerve stimulation (VNS) is known to improve cognitive processing, presumably by affecting activity in central nervous system structures that process recently acquired information. It has long been assumed that these effects are related to stimulation-induced increases of norepinephrine (NE) release in limbic brain structures. The present study examined this hypothesis by administering VNS at an intensity and duration that improves memory and then measuring fluctuations in NE output in the basolateral amygdala (BLA) with in vivo microdialysis. In Experiment 1, VNS caused a 98% increase in NE output relative to baseline. In Experiment 2, methyl atropine was given 10 min before VNS to assess whether stimulation-induced increases in amygdala NE are mediated by afferent or efferent vagal branches. Methyl atropine did not alter NE release in the BLA in comparison with saline. The significance of these findings in understanding how peripheral neural activity modulates limbic structures to encode and store new information into memory is discussed.
http://www.ncbi.nlm.nih.gov/pubmed/14979784

Enhanced recognition memory following vagus nerve stimulation in human subjects. (1999)
Neuromodulators associated with arousal modulate learning and memory, but most of these substances do not freely enter the brain from the periphery. In rodents, these neuromodulators act in part by initiating neural messages that travel via the vagus nerve to the brain, and electrical stimulation of the vagus enhances memory. We now extend that finding to human verbal learning. We examined word-recognition memory in patients enrolled in a clinical study evaluating the capacity of vagus nerve stimulation to control epilepsy. Stimulation administered after learning significantly enhanced retention. These findings confirm in humans the hypothesis that vagus nerve activation modulates memory formation similarly to arousal.
http://www.ncbi.nlm.nih.gov/pubmed/10195186/

The influence of vagus nerve stimulation on memory. (2006)
We found that VNS had no effect on learning but enhanced consolidation, which led to improved retention. The means by which VNS improves retention is probably related to the increased activity in the nucleus of the tractus solitarius and the locus coeruleus-central adrenergic system that activates the amygdala and increases long-term potentiation in the hippocampus.
http://www.ncbi.nlm.nih.gov/pubmed/16957488/

Cardiac autonomic modulation and cognitive status in Alzheimer's disease. (2010)
The cognitive status and the cardiac sympathovagal modulation appear to be correlated and hypothetically may influence one another in mild to severe Alzheimer's disease. Individuals with more severe cognitive deficiency showed suggestive lower cardiac parasympathetic modulation and trend for higher cardiac sympathetic modulation.
http://www.ncbi.nlm.nih.gov/pubmed/19830511


And there is a study underway for using VNS in TBI: http://www.ncbi.nlm.nih.gov/pubmed/23485054.

There is also an interesting theory about AD, pointing the finger at the nucleus tractus solitarius. The nucleus tractus solitarius is innervated by vagus nerves and integrates various cardiac, respiratory and GI functions. (For more info on the nucleus tractus solitarius see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075317/)


Dysfunctional nucleus tractus solitarius: its crucial role in promoting neuropathogenetic cascade of Alzheimer's dementia--a novel hypothesis. (2012)
The pathophysiological mechanism(s) underlying Alzheimer's disease (AD) still remain unclear, and no disease-modifying or prophylactic therapies are currently available. Unraveling the fundamental neuropathogenesis of AD is an important challenge. Several studies on AD have suggested lesions in a number of CNS areas including the basal forebrain, hippocampus, entorhinal cortex, amygdale/insula, and the locus coeruleus. However, plausible unifying studies on the upstream factors that involve these heterogeneous regions and herald the onset of AD pathogenesis are not available. The current article presents a novel nucleus tractus solitarius (NTS) vector hypothesis that underpins several disparate biological mechanisms and neural circuits, and identifies relevant hallmarks of major presumptive causative factor(s) linked to the NTS, in older/aging individuals. Aging, obesity, infection, sleep apnea, smoking, neuropsychological states, and hypothermia-all activate inflammatory cytokines and oxidative stress. The synergistic impact of systemic proinflammatory mediators activates microglia and promotes neuroinflammation. Acutely, the innate immune response is protective defending against pathogens/toxins; however, when chronic, it causes neuroinflammation and neuronal dysfunction, particularly in brainstem and neocortex. The NTS in the brainstem is an essential multiple signaling hub, and an extremely important central integration site of baroreceptor, chemoreceptor, and a multitude of sensory afferents from gustatory, gastrointestinal, cardiac, pulmonary, and upper airway systems. Owing to persistent neuroinflammation, the dysfunctional NTS exerts deleterious impact on nucleus ambiguus, dorsal motor nucleus of vagus, hypoglossal, parabrachial, locus coeruleus and many key nuclei in the brainstem, and the hippocampus, entorhinal cortex, prefrontal cortex, amygdala, insula, and basal forebrain in the neocortex. The neuronal and synaptic dysfunction emanating from the inflamed NTS may affect its interconnected pathways impacting almost the entire CNS--which is already primed by neuroinflammation, thus promoting cognitive and neuropsychiatric symptoms. The upstream factors discussed here may underpin the neuropathopgenesis of AD. AD pathology is multifactorial; the current perspective underscores the value of attenuating disparate upstream factors--in conjunction with anticholinesterase, anti-inflammatory, immunosuppressive, and anti-oxidant pharmacotherapy. Amelioration of the NTS pathology may be of central importance in countering the neuropathological cascade of AD. The NTS, therefore, may be a potential target of novel therapeutic strategies.
http://www.ncbi.nlm.nih.gov/pubmed/22219130


But at minimum, researchers are looking at vagus nerve measurement as an AD diagnostic, and to distinguish AD from vascular dementia.


Non-invasive measurement of vagus activity in the brainstem - a methodological progress towards earlier diagnosis of dementias? (2007)
In Alzheimer's disease (AD), mild functional disturbances should precede gross structural damage and even more clinical symptoms, possibly by decades. Moreover, alterations in the brainstem are supposed to occur earlier as cortical affections. Based on these considerations, we developed a new method aiming at the measurement of vagal brainstem functioning by means of evoked potentials after electrical stimulation of the cutaneous representation of the vagus nerve in the external auditory channel. In the current study, a first sample of patients with Alzheimer's disease (n = 7) and mild cognitive impairment (n = 3) were investigated (6m, 4f, range from 57 to 78 y, mean age 68.6 years). Vagus somatosensory evoked potentials (VSEP) were characterized by significantly longer latencies as compared to healthy age- and gender-matched controls (p < 0.05). Future large scale studies - also including preclinical stages of AD - have to assess the value of this non-invasive, fast and cheap method in the early diagnosis of neurodegenerative disorders.
http://www.ncbi.nlm.nih.gov/pubmed/17308983

Auricular vagus somatosensory evoked potentials in vascular dementia. (2009)
A new method for the assessment of vagus nerve function has recently been introduced into clinical practice. In the present study we could show that, contrary to our results in Alzheimer's disease (AD), in patients with vascular dementia (VaD) vagus sensory evoked potentials (VSEP) did not show statistically significant differences as compared to healthy controls. Thus, we hypothesize that the new method of VSEP could possibly contribute to a differential diagnosis between early cases of AD and VaD.
http://www.ncbi.nlm.nih.gov/pubmed/19280116


Cardiovascular diseases

The vagus nerve is involved in normal cardiovascular function including heart rate, rhythm and blood pressure. It makes sense that it also impacts disease processes, possibly through its influence on inflammation.


Vagus nerve modulation of inflammation: Cardiovascular implications. (2015)
The vagus nerve modulates inflammatory responses in various organ systems. Emerging evidence indicates that the vagus can have profound and complex effects on cardiovascular function, remodeling, arrhythmias, and mortality by several mechanisms. In heart failure and during ischemia, an adverse inflammatory response can occur. The vagus nerve may modulate cardiovascular disease and outcomes by affecting inflammatory responses. Here, evidence for and components of the vagus inflammatory reflex are reviewed and evidence for and implications of effects of vagus activation on inflammation in the cardiovascular system are considered.
http://www.ncbi.nlm.nih.gov/pubmed/25939778

Vagus-brain communication in atherosclerosis-related inflammation: a neuroimmunomodulation perspective of CAD. (2007)
The current understanding of the pathophysiology of atherosclerosis leading to coronary artery disease (CAD) emphasizes the role of inflammatory mediators. Given the bidirectional communication between the immune and central nervous systems, an important question is whether the brain can be "informed" about and modulate CAD-related inflammation. A candidate communicator and modulator is the vagus nerve. Until now, the vagus nerve has received attention in cardiology mainly due to its role in the parasympathetic cardiovascular response. However, the vagus nerve can also "inform" the brain about peripheral inflammation since its paraganglia have receptors for interleukin-1. Furthermore, its efferent branch has a local anti-inflammatory effect. These effects have not been considered in research on the vagus nerve in CAD or in vagus nerve stimulation trials in CAD. In addition, various behavioural interventions, including relaxation, may influence CAD prognosis by affecting vagal activity. Based on this converging evidence, we propose a neuroimmunomodulation approach to atherogenesis. In this model, the vagus nerve "informs" the brain about CAD-related cytokines; in turn, activation of the vagus (via vagus nerve stimulation, vagomimetic drugs or relaxation) induces an anti-inflammatory response that can slow down the chronic process of atherogenesis.
http://www.ncbi.nlm.nih.gov/pubmed/17101139

Effect of gender on sympathovagal imbalance in prehypertensives. (2012)
It was concluded that vagal inhibition plays an important role in critical alteration of SVI in the genesis of prehypertension, especially in males, and WHR could be a better indicator of SVI in prehypertensives. It was suggested that prehypertensives should improve their vagal tone to restore the sympathovagal homeostasis.
http://www.ncbi.nlm.nih.gov/pubmed/21967020


Metabolic Syndrome and Insulin Resistance

Beyond inflammation, there are many other processes going on in metabolic syndrome including vagal activity (and impact on heart rate and heart rate variability).


Increased sympathetic and decreased parasympathetic activity rather than changes in hypothalamic-pituitary-adrenal axis activity is associated with metabolic abnormalities. (2010)
Our findings suggest that increased sympathetic and decreased parasympathetic nervous system activity is associated with metabolic syndrome, whereas HPA axis activity is not.
http://www.ncbi.nlm.nih.gov/pubmed/20237163/

Reduced heart rate variability correlates with insulin resistance but not with measures of obesity in population undergoing laparoscopic Roux-en-Y gastric bypass. (2010)
Obesity is associated with a pathologic predominance of sympathetic over parasympathetic tone. With respect to the heart, this autonomic dysfunction presents as a decreased heart rate variability (HRV), which has been associated with increased cardiovascular morbidity. Gastric bypass (GB) reduces cardiovascular mortality, and, thus, could beneficially affect the HRV. We sought to identify the factors predictive of HRV in a severely obese population of undergoing GB at a university hospital in the United States. METHODS: The data of all patients presenting for GB were included in a prospective database. The homeostatic model of assessment (HOMA) was used to calculate the insulin resistance and glucose disposition index. A 24-hour Holter monitor was used to assess the HRV. Measurements were repeated at 2 weeks and 6 months postoperatively. The correlations between variables were determined using linear mixed models. RESULTS: We studied 30 patients undergoing GB. All exhibited some degree of reduced HRV that improved postoperatively. The HOMA-insulin resistance inversely correlated with the HRV, and the HOMA-glucose disposition index directly correlated with the parameters of HRV in our longitudinal models. Weight, body mass index, excess body weight, gender, and age did not correlate with HRV. Improvements in HRV correlated with reductions in the average heart rate, underscoring a postoperative increase in relative vagal tone. CONCLUSION: HRV in the severely obese is better predicted by the degree of insulin resistance, than by the degree of obesity, age, or gender. GB led to an improvement in HRV, the magnitude of which correlated with the change in insulin resistance and glucose disposition index, but not with weight loss.
http://www.ncbi.nlm.nih.gov/pubmed/20005785

Metabolic syndrome and short-term heart rate variability in young adults. The cardiovascular risk in young Finns study. (2009)
MetS is associated with lower HRV in young adults. The individual components of MetS are differentially associated with HRV in men and in women. Our results are consistent with lower vagal activity and a possible increase in sympathetic predominance in women with the MetS. This sex difference in vagal activity and sympathovagal balance may partly explain the greater increase in cardiovascular risk associated with MetS in women than in men.
http://www.ncbi.nlm.nih.gov/pubmed/19388964/

Circulating Pancreatic Polypeptide Concentrations Predict Visceral and Liver Fat Content (2014)
Vagal tone has been suggested to influence regional fat deposition. Pancreatic polypeptide (PP) is secreted from the endocrine pancreas under vagal control. We investigated the utility of PP in predicting visceral and liver fat.

Pancreatic polypeptide (PP) is a member of the PP fold peptide family and is secreted postprandially from PP cells of the pancreatic islets of Langerhans. PP has been shown to inhibit food intake, gastric emptying, pancreatic exocrine secretion, and gallbladder contraction (5). PP secretion is thought to be primarily under vagal control (6).

Fasting PP concentrations are a predictor of liver fat…Pancreatic polypeptide concentrations were associated with a number of cardiometabolic risk factors, including low-density lipoprotein cholesterol, TG, and BP. These associations were mediated by visceral and/or liver fat. Unsurprisingly, HOMA2-IR, a surrogate of insulin resistance, was a predictor of hepatic steatosis. Interestingly, however, fasting PP was an independent predictor of liver fat.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333038/


And this is a fairly comprehensive overview of the vagus nerve and immunity as related to obesity and obesity related disease.


The vagus nerve and the inflammatory reflex—linking immunity and metabolism (2012)
Autonomic dysfunction and diminished vagus nerve activity occur frequently in individuals with obesity and type 2 diabetes mellitus. 14–16 A 15-year follow-up study has revealed a strong relationship between autonomic dysfunction and insufficient vagus nerve activity (revealed by impaired heart rate recovery following exercise cessation), impaired glucose homeostasis and development of type 2 diabetes mellitus.17 Together, these preclinical and clinical findings support the hypothesis that diminished vagus nerve signalling in obesity could lead to enhanced inflammation and metabolic complications.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082307/


Autoimmune diseases

It’s clear that autoimmune diseases are related to immune dysfunction. Of course, immune dysfunction is multi-factorial, but vagal pathways are certainly part of the equation.


Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases (2013)
The expression and localization of alpha7 nicotinic receptors in synovial biopsies from patients with rheumatoid arthritis (RA) and psoriatic arthritis have been investigated [95]. Using alpha7-specific antibodies, alpha7-positive cells were detected mainly in synovial lining cells and vessels and were identified as primarily macrophages and fibroblasts, with the majority of these cells expressing the receptor. Alpha7 was also identified at both the mRNA and protein level in cultured fibroblast-like synoviocytes, and the alpha7 agonists nicotine and AR-R17779 reduced TNF-α, IL-6, and IL-8 production by synoviocytes. In other studies, acetylcholine significantly reduced the production of IL-6, the chemokines IL-8, CCL2, CCL3, CCL5, and GM-CSF by IL-1-stimulated synoviocytes, and these effects were blocked by the alpha7 antagonist MLA (methyllycaconitine) or by using alpha7 siRNA to knock down receptor expression [96]. The selective alpha7 agonist PNU-282987 also decreased the production of IL-6 by IL-1-stimulated synoviocytes.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678737/

Vagus nerve stimulation: A new bioelectronics approach to treat rheumatoid arthritis? (2014)
Various observational studies have demonstrated that RA patients have lower vagus nerve tone shown by reduced HRV compared to age-matched controls [∗[51], [52], [53]]. This phenomenon has also been observed in other autoimmune diseases, such as systemic lupus erythematosus [51], ankylosing spondylitis [54], and chronic inflammatory bowel diseases [55]. Parasympathetic activity can be increased by different types of exercise, like cardiac training [56], yoga [57], meditation [58], daily 5-min diaphragmatic breathing [59], and possibly acupuncture [60]. One study showed that low parasympathetic and high sympathetic activity in RA patients predicts a poor therapeutic response to anti-TNF therapy compared to RA patients with a more balanced autonomic nervous system [61]. Taken together, these data show that chronic inflammatory diseases are associated with reduced parasympathetic and increased sympathetic activity.
http://www.bprclinrheum.com/article/S1521-6942(14)00097-7/fulltext

Autonomic nervous tone in vitiligo patients--a case-control study. (2014)
The parameter LFnu, which predominantly represents sympathetic and partly parasympathetic components (23, 24), was significantly higher in vitiligo patients as compared to controls. Additionally, the parasympa­thetic tone, reflected by the HFnu component (23, 24) is reduced in vitiligo patients. Both findings indicate clearly sympathetic dominance and thus, higher vegetative arousal in patients who suffer from vitiligo.
http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1896&html=1

Vagal nerve stimulation improves cerebellar tremor and dysphagia in multiple sclerosis. (2007)
Vagus nerve stimulation (VNS), an adjunctive approach for the treatment of epilepsy, was performed in three multiple sclerosis (MS) patients displaying postural cerebellar tremor (PCT) and dysphagia. Following VNS, improvement of PCT and dysphagia was manifested over a period of two and three months, respectively. In view of the involvement of the main brainstem visceral component of the vagus, the nucleus tractus solitarius (NTS), in modulating central pattern generators (CPGs) linked to both olive complex pathway and swallowing, improvement is likely to be VNS related. The results obtained suggest an additional therapeutic application for VNS and may represent a novel form of treatment in patients with severe MS.
http://www.ncbi.nlm.nih.gov/pubmed/17623740


And perhaps vagal tone explains some of the gender difference in being diagnosed with an autoimmune disease.


Neural aspects of immunomodulation: Focus on the vagus nerve (2010)
In humans, Thayer and Fischer (2009) found that the inverse association between HRV and CRP was 4.4 times greater in females than in males. Both of these studies suggested that these gender differences may have important implications for understanding the disparities in autoimmune disorders between males and females. Thus future research is needed to further clarify the nature of these gender differences in neuroimmunomodulation and their implications for health disparities.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949498/


Stress/Emotion/Behavior

Ever wonder why we get butterflies in our stomachs or you feel sick to your stomach when anxious? It’s the vagus nerve and gut interacting. Signals from the vagus nerve traveling from the gut to the brain have been linked to modulating mood and distinctive types of fear and anxiety.

Alterations in vagal-immune pathway in long-lasting mental stress. (2015)
We studied a potential impact of chronic psychosocial load on the allostatic biomarkers--cardiac vagal activity, inflammation, and oxidative stress in healthy undergraduate students. Continuous resting ECG signals were monitored in a group of 16 female healthy students (age: 23.2±0.2 years, BMI: 20.9±0.5 kg/m2) at two time periods: right after holiday (rest period) and a day before final exams (stress period). Vagal activity was quantified by spectral analysis of heart rate variability at high frequency band (HF-HRV). The immune response was assessed from the level of tumor necrosis factor-alpha (TNF-α) in plasma. In addition, mean RR intervals were evaluated. We found that HF-HRV was significantly reduced and the TNF-α was increased in the stress period compared with the rest period. No significant changes were found in the RR interval. In conclusion, allostatic load induced by stress and the accompanying greater immune response decreased cardiovagal regulation in healthy young subjects. These findings may help understand the pathway by which stress can influence health and disease.
http://www.ncbi.nlm.nih.gov/pubmed/25300681

Cardiac vagal tone predicts attentional engagement to and disengagement from fearful faces. (2013)
The current research examines individual differences in flexible emotional attention. In two experiments, we investigated the relationship between individual differences in cardiac vagal tone and top-down and bottom-up processes associated with emotional attention. To help determine the role of cortical and subcortical mechanisms underlying top-down and bottom-up emotional attention, fearful faces at broad, high, and low spatial frequency were presented as cues that triggered either exogenous or endogenous orienting. Participants with lower heart rate variability (HRV) exhibited faster attentional engagement to low-spatial-frequency fearful faces at short stimulus-onset asynchronies, but showed delayed attentional disengagement from high-spatial-frequency fearful faces at long stimulus-onset asynchronies in contrast to participants with higher HRV. This research suggests that cardiac vagal tone is associated with more adaptive top-down and bottom-up modulation of emotional attention. Implications for various affective disorders, including depression, anxiety disorders, and posttraumatic stress disorder, are discussed.
http://www.ncbi.nlm.nih.gov/pubmed/23914769

Effects of emotion regulation difficulties on the tonic and phasic cardiac autonomic response. (2014)
The HERD [high emotion regulation difficulties] group exhibited inappropriate cardiac vagal recovery after a negative emotion elicitation had ended. Cardiac vagal tone took longer to return to its initial state in the HERD group than in the LERD group. Prolonged cardiac vagal suppression might constitute an early marker of emotion regulation difficulties leading to lower cardiac vagal tone.

People who experience emotion regulation difficulties exhibit inappropriate cardiac vagal recovery after a negative emotion ends. This may reflect an early indicator of vulnerability to psychological disorders or cardiovascular diseases.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108383/


This next article suggests a link between low vagal tone and the impact of Adverse Childhood Experiences (ACEs). You can search the ApoE4.info forums for discussions about ACEs.


Vagal Regulation and Internalizing Psychopathology among Adolescents Exposed to Childhood Adversity (2014)
Vagal tone and regulation are potentially promising markers of reduced vulnerability to the negative mental health consequences of exposure to childhood adversity. Identifying neurobiological markers of vulnerability provides the advantage of not having to rely on self-reported information about emotion, personality, and other dispositional characteristics, for which self-awareness may be poor and reporting biases are prominent (Robinson & Clore, 2002; Thomas & Deiner, 1990). Interventions designed to increase vagal tone and regulation might reduce stress sensitivity and vulnerability to internalizing psychopathology among youths experiencing high degrees of childhood adversity. Vagal tone therefore represents a potentially useful target for intervention. Studies with adults suggest that relaxation training and mindfulness are associated with increased vagal tone (Ditto, Eclache, & Goldman, 2006; Sarang & Telles, 2006; Wu & Lo, 2008).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043866/

Tapping the Vagus Nerve to Help Us Heal

Researchers admit they don’t know exactly what healthy vagal tone looks like. Expect to see more research in the coming years.


Direct Stimulation

Direct electrical stimulation of this nerve has been used in some medical treatments; vagus stimulation appears to benefit people who suffer from depression, and it is also sometimes used to treat epilepsy. For Vagal Nerve Stimulation (VNS), a pacemaker-like device is placed under the skin of the upper chest, and used to send electric impulses to the left vagus nerve in the neck via a lead wire implanted under the skin.

Vagus nerve stimulation…25 years later! What do we know about the effects on cognition? (2014)
VNS therapy was delivered to patients for the first time in 1988. After 25 years, insight in the antiepileptic and antidepressant mechanism of action of VNS has grown steadily. The effects on cognition and especially memory remain controversial. This review provides an elaborate overview of studies addressing cognition and describes potential underlying mechanisms for the reported effects. Short-term VNS has an effect on verbal memory recognition when administered at the correct timing and dosage. Chronic VNS resulted into a positive effect on the cognitive status in an Alzheimer population. Positive effect of chronic VNS in epilepsy or depression patients on global cognitive functioning are less convincing. Neither do the results reveal a negative effect which has major implications for chronic treatment of neurology patients. A cascade of neurochemical processes put in motion by changes in NE concentrations in reaction to stimulation of the vagal nerve may underlie the VNS-induced effects on cognition and memory. In Alzheimer pathology, NE may act as an anti-inflammatory agent on brainstem nuclei.
http://www.ncbi.nlm.nih.gov/pubmed/24858008


Here are some examples of other effects of VNS on the brain.


Vagus nerve stimulation in patients with Alzheimer's disease: Additional follow-up results of a pilot study through 1 year. (2006)
Cognitive-enhancing effects of vagus nerve stimulation (VNS) have been reported during 6 months of treatment in a pilot study of patients with Alzheimer's disease (AD). Data through 1 year of VNS (collected from June 2000 to September 2003) are now reported. METHOD: All patients (N = 17) met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD. Responder rates for the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE) were measured as improvement or absence of decline from baseline. Global change, depressive symptoms, and quality of life were also assessed. Cerebrospinal fluid (CSF) levels for total tau, tau phosphorylated at Thr181 (phosphotau), and Abeta42 were measured by standardized enzyme-linked immunosorbent assay (ELISA). RESULTS: VNS was well tolerated. After 1 year, 7 (41.2%) of 17 patients and 12 (70.6%) of 17 patients improved or did not decline from baseline on the ADAS-cog and MMSE, respectively. Twelve of 17 patients were rated as having no change or some improvement from baseline on the Clinician Interview-Based Impression of Change (CIBIC+). No significant decline in mood, behavior, or quality of life occurred during 1 year of treatment. The median change in CSF tau at 1 year was a reduction of 4.8% (p = .057), with a 5.0% increase in phosphotau (p = .040; N = 14). CONCLUSION: The results of this study support long-term tolerability of VNS among patients with AD and warrant further investigation.
http://www.ncbi.nlm.nih.gov/pubmed/16965193

Effects of vagus nerve stimulation on rat hippocampal progenitor proliferation. (2008)
Vagus nerve stimulation (VNS), used in the treatment of epilepsy, was approved recently for treatment-resistant depression. The mechanisms of action of the VNS anti-depressive effects are not yet fully elucidated. Modulation of hippocampal neurogenesis has been proposed as an important factor in depression pathogenesis. We evaluated the effects of VNS on hippocampal progenitor turnover in the adult rat brain. Rats receiving VNS at the output current of 0.75 mA VNS for 2 days showed a significant 50% increase in dentate gyrus BrdU-incorporation consistent with an increase in progenitor proliferation. Output currents of 0.5 or 1.5 mA yielded non-significant trends for increased BrdU-labeling indicating an inverted U-shaped proliferative dose response to VNS as previously reported for other VNS-induced effects. Specific analysis for progenitor survival revealed no effects by VNS on dentate gyrus BrdU-labeling. These results suggest that VNS induced an increase in the number of available progenitor cells in the adult rat dentate gyrus by a mechanism presumably involving increased progenitor proliferation.
http://www.ncbi.nlm.nih.gov/pubmed/18804463/

Vagal nerve stimulation decreases blood-brain barrier disruption after traumatic brain injury. (2012)
VNS attenuates cerebral vascular permeability and decreases the up-regulation of AQP-4 after TBI. Future studies are needed to assess the mechanisms by which VNS maintains the BBB. (Note, this was a mouse study)
http://www.ncbi.nlm.nih.gov/pubmed/22695423


We’re early in this vagus nerve game. Most VNS studies are mouse or rat studies, but I expect further human studies. Here are some tempting possibilities.


Neuroimmune interaction in the gut: from bench to bedside. (2006)
In summary, our work illustrates that the innervation of the intestine intensely communicates with the immune system. Inflammation activates inhibitory neural pathways whereas vagus nerve stimulation can suppress the immune system, in particular macrophages. These findings have led to the identification of new "targets" for the development of new treatments, not only for postoperative ileus, but possibly also for other gastrointestinal inflammatory diseases.
http://www.ncbi.nlm.nih.gov/pubmed/17313093

The vagal innervation of the gut and immune homeostasis (2013)
Recent evidence suggests that the vagal innervation of the gastrointestinal tract also plays a major role controlling intestinal immune activation. Indeed, VN electrical stimulation potently reduces intestinal inflammation restoring intestinal homeostasis, whereas vagotomy has the reverse effect.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711371/

SINGLE-PULSE AND UNIDIRECTIONAL ELECTRICAL ACTIVATION OF THE CERVICAL VAGUS NERVE REDUCES TUMOR NECROSIS FACTOR IN ENDOTOXEMIA (2015)
The inflammatory reflex is a neural circuit defined by action potentials transmitted in the vagus nerve that regulate cytokine production in the spleen. Detailed mechanistic studies implicate the vagus nerve, the splenic nerve, a T-cell subset that produces acetylcholine under the control of adrenergic signals, and alpha7 nicotinic acetylcholine receptors (α7nAChR). expressed on macrophages. This study defines the vagus nerve fibers that transmit the efferent signal in this pathway, a motor arc of the inflammatory reflex…These results indicate that single-pulse and unidirectional electrical activation of the cervical vagus nerve reduce TNF in endotoxemia.
http://bioelecmed.org/articles/item/2/24

Can vagus nerve stimulation halt or ameliorate rheumatoid arthritis and lupus? (2011)
In view of their similar anti-inflammatory actions, it is proposed that vagal nerve stimulation, alpha7nAChR agonists and EPA and DHA may augment the formation of anti-inflammatory lipid molecules: lipoxins, resolvins, protectins and maresins. This implies that therapies directed at regulation of the cholinergic and alpha7nAChR mediated mechanisms and enhancing the formation of lipoxins, resolvins, protectins and maresins may halt and/or ameliorate rheumatoid arthritis, lupus and other rheumatological conditions.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037330/

Vagal nerve stimulation in prevention and management of coronary heart disease (2011)
Coronary heart disease (CHD) that is due to atherosclerosis is associated with low-grade systemic inflammation. Congestive cardiac failure and arrhythmias that are responsible for mortality in CHD can be suppressed by appropriate vagal stimulation that is anti-inflammatory in nature. Acetylcholine, the principal vagal neurotransmitter, is a potent anti-inflammatory molecule. Polyunsaturated fatty acids (PUFAs) augment acetylcholine release, while acetylcholine can enhance the formation of prostacyclin, lipoxins, resolvins, protectins and maresins from PUFAs, which are anti-inflammatory and anti-arrhythmic molecules. Furthermore, plasma and tissue levels of PUFAs are low in those with CHD and atherosclerosis. Hence, vagal nerve stimulation is beneficial in the prevention of CHD and cardiac arrhythmias.

Wang et al[45] have shown that the vagus nerve can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses, and have termed it as the “cholinergic anti-inflammatory pathway”. The essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals has been identified as the nicotinic acetylcholine receptor α7 subunit that is required for acetylcholine inhibition of macrophage TNF release.

The observation that vagal tone is decreased, sympathetic tone is enhanced, production of IL-6, TNF-α, migration inhibitory factor and HMGB1 is increased, and plasma and tissue concentrations of AA and DHA and their products PGI2, lipoxins, resolvins, protectins and maresins are decreased in CHD, atherosclerosis and cardiac arrhythmias has important therapeutic implications. If this is true, it implies that blockade of α2-adrenoreceptors (blocking these receptor inhibits inflammation injury due to catecholamines[51]), stimulation of the vagus nerve[52] and the nicotinic acetylcholine receptor α7 subunit[45], and administration of AA, DHA, PGI2, lipoxins, resolvins, protectins and maresins, or their stable synthetic analogs, could be of significant benefit in the prevention and management of CHD and cardiac arrhythmias (Figure 1). It is also likely that acetylcholine and VNS enhance the production of anti-inflammatory molecules such as lipoxins, resolvins, protectins and maresins by inducing the release of PUFAs (such as AA, EPA and DHA) from the cell membrane lipid pool.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082733/


Transcutaneous Vagus Nerve Stimulation (tVNS)

Another promising method to stimulate the vagus nerve doesn’t require implantation.


Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. (2014)
tVNS can increase HRV and reduce sympathetic nerve outflow, which is desirable in conditions characterized by enhanced sympathetic nerve activity, such as heart failure. tVNS can therefore influence human physiology and provide a simple and inexpensive alternative to invasive VNS.
http://www.ncbi.nlm.nih.gov/pubmed/25164906

Transcutaneous vagus nerve stimulation boosts associative memory in older individuals. (2015)
We conclude that tVNS is a promising neuromodulatory technique to improve associative memory performance in older individuals, even after a single session. More research is necessary to investigate its underlying neural mechanisms, the impact of varying stimulation parameters, and its applicability in patients with cognitive decline.
http://www.ncbi.nlm.nih.gov/pubmed/25805212

Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study (2014)
100 participants completed the study and were included in data analysis. Two female patients (one in the taVNS group, one in the sham taVNS group) dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. Compared with sham taVNS, taVNS significantly reduced the two-hour glucose tolerance (F(2) = 5.79, p = 0.004). In addition, we found that taVNS significantly decreased (F(1) = 4.21, p = 0.044) systolic blood pressure over time compared with sham taVNS. Compared with the no-treatment control group, patients receiving taVNS significantly differed in measures of FPG (F(2) = 10.62, p < 0.001), 2hPG F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) over the course of the 12 week treatment period.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227038/


Now lets look at some of the things we know are generally good for us. These studies might help explain why we get benefits.


Exercise

Physical activity, by enhancing parasympathetic tone and activating the cholinergic anti-inflammatory pathway, is a therapeutic strategy to restrain chronic inflammation and prevent many chronic diseases (2013)
Chronic diseases are the leading cause of death in the world and chronic inflammation is a key contributor to many chronic diseases. Accordingly, interventions that reduce inflammation may be effective in treating multiple adverse chronic conditions. In this context, physical activity is documented to reduce systemic low-grade inflammation and is acknowledged as an anti-inflammatory intervention. Furthermore, physically active individuals are at a lower risk of developing chronic diseases. However the mechanisms mediating this anti-inflammatory phenotype and range of health benefits are unknown. We hypothesize that the "cholinergic anti-inflammatory pathway" (CAP) mediates the anti-inflammatory phenotype and range of health benefits associated with physical activity. The CAP is an endogenous, physiological mechanism by which acetylcholine from the vagus nerve, interacts with the innate immune system to modulate and restrain the inflammatory cascade. Importantly, higher levels of physical activity are associated with enhanced parasympathetic (vagal) tone and lower levels of C-reactive protein, a marker of low-grade inflammation. Accordingly, physical activity, by enhancing parasympathetic tone and activating the CAP, may be a therapeutic strategy to restrain chronic inflammation and prevent many chronic diseases.
http://www.ncbi.nlm.nih.gov/pubmed/23395411


Probiotics

Modulation of Intestinal Microbiota by the Probiotic VSL#3 Resets Brain Gene Expression and Ameliorates the Age-Related Deficit in LTP (2014)
Our data agree with previous studies which demonstrated that intestinal microbiota modulates brain gene expression and alters the profiles of canonical signaling pathways, neurotransmitter turnover and synaptic-related proteins which, in turn, influence brain development and function [53]. While changes in the expression of genes in the brain might be functionally relevant, the mechanism involved in their regulation by VSL#3 remains to be determined. One possible mechanism mediating the gut-brain communication may be via established neuronal circuits. Recent data have shown that an impact of probiotics on the brain requires the integrity of the vagus nerve and gut microbiota can elicit signals via the vagal nerve to the brain and vice versa [54].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159266/


Omega 3's / Dietary fat

Short-term effects of fish-oil supplementation on heart rate variability in humans: a meta-analysis of randomized controlled trials (2013)
Short-term fish-oil supplementation may favorably influence the frequency domain of heart rate variability, as indicated by an enhanced vagal tone, which may be an important mechanism underlying the antiarrhythmic and other clinical effects of fish oil. http://www.ncbi.nlm.nih.gov/pubmed/23515005

n-3 fatty acids and the risk of sudden cardiac death. Emphasis on heart rate variability (2003)
Furthermore, our data may indicate that the protective effect of n-3 PUFA on SCD found among post-MI patients and healthy subjects is caused by a modulation of autonomic control with increased vagal tone.
http://www.ncbi.nlm.nih.gov/pubmed/14694851

Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve (2005)
The present study shows that high-fat enteral nutrition stimulates CCK-receptors centrally or peripherally by way of the afferent vagus nerve leading to inhibition of the inflammatory response by way of vagal efferents and nicotinic receptors (Fig. 4). Previously, we showed that the beneficial effects of high-fat enteral nutrition on inflammation and intestinal barrier integrity are specific for the amount of lipids in the enteral nutrition, not related to caloric intake and cannot be attributed to formation of endotoxin neutralizing triacylglycerol-rich lipoproteins (5, 6, 16). The finding that high-fat enteral nutrition inhibits inflammation by way of the vagus nerve provides a functional new mechanism for the interaction between nutrition and the immune response and has widespread implications. It was previously unrecognized that nutrition-induced neuro-endocrine signals such as CCK modulate the immune response by way of the efferent vagus nerve. From a teleological point of view it is functional that a state of immune-hyporesponsiveness is created during feeding. In this way an unwanted response to temporally present high amounts of dietary antigens, biological toxins and destructive endogenous lysozymes in the gut lumen is prevented, gut barrier function is preserved and homeostasis maintained…

Based on our findings, high-fat enteral nutrition is potentially therapeutic in various inflammatory disorders such as sepsis and inflammatory bowel disease (IBD) characterized by an inflammatory response in which TNF-α is prominent and intestinal barrier function is impaired. In light of this, a fasted state could be a risk factor for developing a potentially lethal inflammatory response after trauma or injury.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213207/

Lipid-rich enteral nutrition regulates mucosal mast cell activation via the vagal anti-inflammatory reflex (2013)
The present study identifies stimulation of the hard-wired vagal anti-inflammatory reflex by enteral lipid-rich nutrition as a strong inhibitor of mucosal mast cell reactivity. Since mast cells are recognized as early and pivotal regulators of the innate immune response, these findings support nutritional intervention in patients prone to develop an excessive inflammatory response.
http://ajpgi.physiology.org/content/305/5/G383


Acupuncture

Auricular Acupuncture and Vagal Regulation (2010)
In the present study, the relationship between the auricular acupuncture and the vagal regulation has been reviewed. It has been shown that auricular acupuncture plays a role in vagal activity of autonomic functions of cardiovascular, respiratory, and gastrointestinal systems. Mechanism studies suggested that afferent projections from especially the auricular branch of the vagus nerve (ABVN) to the nucleus of the solitary tract (NTS) form the anatomical basis for the vagal regulation of auricular acupuncture. Therefore, we proposed the “auriculovagal afferent pathway” (AVAP): both the autonomic and the central nervous system could be modified by auricular vagal stimulation via projections from the ABVN to the NTS. Auricular acupuncture is also proposed to prevent neurodegenerative diseases via vagal regulation.

There are inconsistent study results related to the treatment effects of auricular acupuncture, which may be related to trial designing, clinical observation measures, the set of sham acupuncture, and statistical analyses [46–48]. In clinical studies, most studies on the clinical observation of auricular acupuncture were not sufficiently convincing. More RCT evaluations of effect of auricular acupuncture should be performed to obtain objective and consistent results. Besides, there are almost 200 auricular acupoints in each ear that represent all parts of the body and many functional areas. It is not easy to locate the acupoint accurately. Therefore, in a clinical trial, the acupuncture operator should be trained well. In experimental studies, anatomical and morphological studies on auricular acupoints and neuroimaging study such as fMRI on the effect of auricular acupuncture should be encouraged to investigate the mechanism of auricular acupuncture.
http://www.hindawi.com/journals/ecam/2012/786839/

Neuroanatomic and Clinical Correspondences: Acupuncture and Vagus Nerve Stimulation (2013)
This analysis demonstrated marked correspondences of the indications for those lateral head and neck acupoints to the clinical effects (beneficial and adverse) documented for the VNS device in the medical literature. This clinical correspondence, in conjunction with the anatomic proximity of the acupoints to the vagus nerve in the lateral neck, strongly suggests that vagus nerve (and hence the autonomic nervous system) stimulation is fundamental in producing the clinical effects of the acupoints. Conclusion: By having anatomic access to the vagus nerve and parasympathetic chain that permits electrical stimulation of those nerves in clinical practice, acupuncture may offer a less costly and safer alternative to implanted VNS devices for treating medically refractory epilepsy, tremor, depression, and pain conditions.
http://www.researchgate.net/publication/259446488_Neuroanatomic_and_Clinical_Correspondences_Acupuncture_and_Vagus_Nerve_Stimulation


Yoga/pranayama

Slow yogic breathing through right and left nostril influences sympathovagal balance, heart rate variability, and cardiovascular risks in young adults. (2014)
For the purpose, they were asked to sit in an easy and steady posture with the head, neck, and trunk erect. They were instructed to bring the right hand up to the nose and close the left nostril (for RNB) or right nostril (for LNB) with the finger and then breathe through one nostril only. During this unilateral breathing the exhalation and inhalation were of equal duration and without any pause. Breathing was diaphragmatic and slow and controlled with no sense of exertion. For both inspiration and expiration, they were asked to count 1 to 5 in their mind (each count was roughly one second) for each phase, so that each respiratory cycle lasted for about 10 s. Thus, about six breathing cycles occurred during 1 min. In this study, following 6-week practice of slow nostril breathing, the LF-HF ratio of LNB group was significantly less and of RNB group was significantly more compared to the control group [Table 2] suggesting that there was sympathetic activation in subjects those who practiced right nostril breathing and parasympathetic activation in those who practiced left nostril breathing, as increase in the LF-HF ratio indicates increased sympathetic and decrease in this ratio indicates the increased vagal activity.[24,30] The increased sympathetic activity in the RNB group was further evidenced by increase in LFnu in these subjects compared to the control group and to their own before the practice value, as LFnu represents sympathetic drive to the heart.[24,30] The increased vagal tone in the LNB group was supported by increase in HFnu in these subjects compared to the control group and to their own before practice value, as HFnu indicates parasympathetic drive of cardiac autonomic control.[24,30] The improvement in vagal tone in the LNB group was further demonstrated by increase in TP and time-domain indices (RMSSD, SDNN, NN50, pNN50) of HRV as TP and time-domain indices in general represent vagal modulation of cardiac functions.[24,30] Further, the BHR of LNB group was significantly decreased compared to their own before practice value and to the values of the control group [Table 1] indicating improvement in vagal tone as resting heart rate is an index of the parasympathetic activity and decrease in the heart rate reflects increased vagal tone.[31]

The exact mechanism of improvement of the vagal activity in the LNB group and sympathetic activity in the RNB group cannot be fully ascertained from this study.

In the yogic system of breathing, the right nostril dominance corresponds to activation of ‘Pingala’, the subtle energy channel of yoga, which is related to sympathetic arousal; the left nostril dominance to ‘Ida’, which is the representative of parasympathetic activation.[33] The nostril dominance at rest is the natural phenomenon of nasal cycle, which is an ultradian rhythm characterized by alternating patency of the left and right nostrils, with a periodicity of 2-8 h.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978938/


And lastly, medical marijuana. I'd suggest more research to see if this is "good" for e4s before you dive in.

Cannabinoids

Tumor necrosis factor activation of vagal afferent terminal calcium is blocked by cannabinoids. (2012)
The early proinflammatory cytokine tumor necrosis factor (TNF) is released in significant quantities by the activated immune system in response to infection, leukemia, autoimmune disorders, and radiation sickness. Nausea, emesis, and anorexia are common features of these disorders. TNF action on vagal afferent terminals in the brainstem is a likely cause of the malaise associated with these disorders. Our previous work has shown that TNF action to excite vagal afferents occurs as a result of sensitization of ryanodine channels in afferent nerve terminals. For millennia, cannabinoids (CB) have been used to combat the visceral malaise associated with chronic disease, although the mechanism of action has not been clear. Previous work in culture systems suggests that CB1 agonists can suppress neurotransmission by downregulating ryanodine channels through a protein kinase A (PKA)-dependent mechanism. Laser confocal calcium imaging methods were used to directly examine effects of CB1 cannabinoid agonists and TNF on visceral afferent signaling in the rat hindbrain. CB1 agonists blocked the effects of TNF to amplify vagal afferent responsiveness; blockade of PKA with H89 also eliminated the TNF amplification effect. These results help to explain the effectiveness of cannabinoids in blocking the malaise generated by TNF-releasing disease processes by opposing effects on ryanodine channels.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342927/


But, too much of a good thing…

Too much of a good thing? Cardiac vagal tone's nonlinear relationship with well-being. (2013)
Individuals with moderate CVT had higher well-being than those with low or high CVT. These results provide the first direct evidence of a nonlinear relationship between CVT and well-being, adding to a growing body of research that has suggested some biological processes may cease being adaptive when they reach extreme levels.
http://www.ncbi.nlm.nih.gov/pubmed/23731433


So, there you go. A birds-eye view of the vagus nerve and it's connection to our health. This is not exhaustive (although I'm exhausted), so feel free to pick your favorite health area and look for more information.