Full title: “Can Acupuncture Bio-Hack the Autonomic Nervous System and Down-Regulate Inflammation?”
ABSTRACT
Research suggests acupuncture down-regulates inflammation. But what are the mechanisms that drive this process? In this essay, I review studies about how inflammation is regulated by the autonomic nervous system and studies that indicate acupuncture may actively participate in the regulation of inflammatory cytokines.
MAKING THE CASE: ACUPUNCTURE MODULATES THE AUTONOMIC NERVOUS SYSTEM
Blue arrows signify the down-regulating effect of acupuncture.1
In the above illustration, the blue lines signify the effects of acupuncture on an inflammatory condition. Disorders such as stress, indigestion, irritability, or pain can indicate the effect of mild inflammation.
Can ‘the inflammatory reflex’ which research indicates rebalances the autonomic nervous system be applied to the acupuncture effect? Does the acupuncture treatment act as a distributed connection that affects both the autonomic nervous system and the immune system?
Recent studies indicate that health is a delicate balance between the autonomic nervous system and cytokine production. Overproduction of cytokines can result in critical and severe disease such as sepsis, rheumatoid arthritis, or ulcerative colitis. Research1 indicates that by stimulating the vagus nerve, cytokine production can be diminished. Sensory input elicited by injury or infection travels along the afferent branch of the vagus nerve to regions of the brainstem, and the brain carries outbound signals that effect the spleen and other regions of the immune system. Some of research by Zhou2 and Torres3 suggests that acupuncture may down-regulate the immune system through the autonomic nervous system.
In an article published in 20004, Dr. Kevin Tracey injected a chemical into a rat brain, which activated the vagus nerve, resulting reduction of tumor necrosis factor (TNF) throughout the body. In that same article, the author describes how in another such experiment, Tracey injected endotoxin in a rat, a pro-inflammatory bacterial toxin typically resulting in body wide inflammation and sepsis. He then electrically stimulated the vagus nerve, reducing TNF, thereby reducing inflammation. He and other research scientists performed a series of experiments on animal models4, demonstrating that the vagus nerve when activated with electrical stimulation affects the spleen’s depository of immune cells. From there, David Felton, a neuroanatomist captured microscopic images of hybrid neuron T-cells synapses, not only in the spleen, but thymus and lymph nodes which responded to sympathetic transmission. Akiko Nakai of Osaka University reported T-Cells, affected by sympathetic stimulation refrained from entering the wider immune system.5 Lorton and Bellinger6 found that sympathetic nerve pathways are modified by immune disorders. There seems to be agreement by scientists that there is no direct neural connection between the vagus nerve and spleen, but vagal stimulation modulates sympathetic activity and the immune system.5
The research, involving the autonomic nervous system, can be utilized by acupuncturists in both treatment design and explanations about treatment effect to doctors and patients. This essay reviews some seminal research not only about how the autonomic nervous system interacts with the immune system, but studies that indicate a place for acupuncture in this research that adjusts inflammation in peripheral tissues.
A BRIEF REVIEW OF THE VAGUS NERVE
The vagus nerve is the key component of the parasympathetic system, comprised of sensory and motor fibers or afferent and efferent pathways. The afferent portion of the vagus nerve is far greater – eighty percent of the vagus. It monitors autonomic activities such as heart rate, blood pressure, breathing, digestion. While the afferent portion is relaying important sensory information to the brain, the efferent fibers, which are cholinergic, are activating parasympathetic activity in the heart, lungs, liver, stomach and upper portion of the large intestine. Afferent fibers project to the nucleus tractus solitaries (visceral, sensory, and taste), while efferent fibers project from the nucleus ambiguous (branchial) and dorsal motor nucleus. While the sensory afferent fibers in the brainstem terminate in the nucleus tractus solitaries, they send fibers that connect either directly or indirectly to different brain regions.7,8 Afferent signaling of the vagus nerve also activates the hypothalamus and other CNS nuclei, which regulate the neuro-hormonal HPA axis. These neurons are associated with glucocorticoid production. The signals are also relayed to the cell bodies of the efferent parasympathetic vagus nerve, which are located the medullary nucleus ambiguus.1
In the heart the baroreceptor reflex is activated by increases in blood pressure, which stimulate stretch receptor in the carotid sinuses and aortic arc. These receptors trigger action potentials transmitted along the vagus nerve to the brainstem and other nuclei, which modulate outgoing blood pressure responses. These include decreased signaling to adrenergic nerves to the heart, reducing contractibility and heart rate, while maintaining blood pressure within a narrow homeostatic range.1
The vagus nerve fibers innervating the upper and middle gastrointestinal tract originate from two nuclei in the brain stem. The nucleus ambiguous nucleus which reaches the larynx and esophagus, and the dorsal motor nucleus of the vagus which reaches the stomach and the descending colon.9 There is some suggestion9 that ‘the macrophages located between the longitudinal and circular muscled layer at the level of the myenteric plexus act as the gatekeepers of the enteric nervous system. The enteric nervous system forms a dense network of nerve cells near many immune cells. Theory suggests the cholinergic tone affects the enteric nervous system, and vagal innervation may modulate the intestinal environment by any immune cell carrying a cholinergic receptor.9
THE SYMPATHETIC IMMUNE RESPONSE
The sympathetic nervous system and the immune system are tightly intertwined. There is a large body of research10 demonstrates the autonomic dysregulation can drive inflammation by inciting the immune system. If the signal from nerve fibers is strong enough or if local inflammation mediators spill into broader circulation such as lymph and blood, the hypothalamus pituitary adrenal (HPA) system and the sympathetic nervous system activates.10
When an antigen enters the body, local immune cells are activated, leading to the release of pro-inflammatory cytokines and chemo-messengers such as the tumor necrosis factor (TNF), Interleukin1 (IL1) or Interleukin6 (IL6).11 Cytokines are small non-antibody proteins secreted by various immune cells including macrophages, T-Cells, B-Cells, dendritic cells, endothelial cells, fibroblasts and stroma cells. Cytokines are not personalized by exposure to antigens like antibodies.11
These chemo-messengers regulate immune response. Critical conditions including sepsis, some cancer, trauma, rheumatoid arthritis, and heart disease12 are the result of an over-response of the immune system. The cytokines, TNF (alpha), Il6, and Il1 are elevated in almost all inflammatory states and recognized targets for treatment in many of the new biologic drugs entering the market.11, 13 The chemo-signals can either excite or lower the thresholds for sensory pain receptors and sensory vagal nerve fibers.
Communication between the brain and immune system toggles between levels of cytokines. For example, in a study14 involving hypertensive medication of menopausal women, reduction in blood pressure down-regulated sympathetic activity, thereby reducing TNF serum levels. In another study15down-regulating the sympathetic system coincided with a reduction in IL-6.10 Other research10 shows that communication between the brain and area of inflammation can be modified by a stroke; doctors and scientists10 have noted other evidence of inflammatory reduction in the region of paralysis of a patient with an inflammatory condition such as rheumatoid arthritis. In patients10 who have had even a minor stroke or poliomyelitis, their immune response is altered on the affected side. In rat models, a symphathectomy leads to a reduction in infection rates.10,16
It has been shown that secondary lymphoid tissue, such as the spleen, is innervated by sympathetic nerve fibers, and nerve terminals within the vicinity of immune cells.10 Immune cells express receptors for neurotransmitters. One such group of transmitters on immune cells has been named adrenoreceptors (AR). There are many subclasses of adrenoceptors on nerve endings and other kinds of tissue, including receptors that activate the immune system by responding to adrenergenic stimulation.17 TNF was the first of many cytokines that was shown to respond to catecholamines that belong AR category.10
Sympathetic nerve endings release not only norepinephrine, but nitrous oxide, neuropeptide y (NPY), and adenosine triphosphate, ATP. While norepinephrine may be the best understood neurotransmitter affecting the immune system, it has also been shown that an NPY antagonist reduces inflammation in rats with chemically induced rheumatoid arthritis.10 Immune cells can be directly affected by the sympathetic nervous system through their own adrenoceptors, or indirectly influenced through flow of blood or lymph, whereby they regulate the production and distribution of lymphocytes, or modulate pro-inflammatory peptides such as substance P elicited from sensory nerve endings.10
The sympathetic nervous system is involved in changes in leukocyte distribution and immune cell recruitment throughout the body. A recent tissue study13, showed that Beta AR’s (beta adrenoceptors) were expressed on non-hematopoietic cells, leading to the expression of endothelial cell adhesion molecules and chemokines; a significant step in accelerating an inflammatory response. This pathway can be a stepping stone toward degenerative disease such as atherosclerosis18,19 or the formation of secondary cancers.13,19 In another study the sympathetic nervous system effected recruitment of monocytes from the spleen during a peritoneal infection.10
Neither cytokines, their receptors, or neurotransmitters behave in a simple digital manner. There is a profound dialectic of cross talk between them6; receptors responding on the surface of immune cells to neurotransmitters, cytokines affecting nerve endings which in turn affect the autonomic nervous system and sensory nerves; output and input juggling a conversation between what is both local and central. There are no simple caveats such as norepinephrine is pro-inflammatory. Neurotransmitters may contradict one another’s messaging, and to add to the mix, the sympathetic nervous system is directing nonimmune cells to reduce the inflammatory process, while redefining input from sensory nervous system.6,10
THE INFLAMMATORY REFLEX: THE VAGUS NERVE GUIDES THE IMMUNE SYSTEM
In this complicated electro-chemical conversation, the vagus nerve plays a prominent role in suppressing inflammatory cytokine chatter. Dr. Tracey has described this phenomena as ‘the inflammatory reflex’.1 The vagus nerve terminates in the celiac ganglion, never reaching the spleen; however, electrical stimulation of the vagus nerve above the celiac ganglion or the splenic nerve significantly inhibits TNF production in the red pulp and marginal zone macrophages of the spleen. Nerve fibers in the spleen that originate in the celiac ganglion are adrenergic, responding to norepinephrine as the primary neurotransmitter. The vagus nerve situated upstream from the sympathetic celiac ganglion, somehow activates nicotinic acetycholine receptors (nACH7) on macrophages that respond to the neurotransmitter acetylcholine which substantially down-regulates TNF.20
Within minutes of Tracey et al. applying electrical stimulation to the vagus nerve, acetycholine levels were elevated, reaching a peak twenty minutes later. These scientists postulated that perhaps lymphocytes synthesize and release the neurotransmitter in response to norepinephrine. They also postulate that these T cells are located not only in the spleen but Peyer’s patches and lymph nodes, widening the influence of vagus nerve signaling.20, 21
Reduced heart rate variability (HRV) is a symptom associated with a rise in cytokine levels. This may be prompted by both Pathogen or Danger Associated Molecular Patterns (PAMP or DAMP).22,23,1 Many acute and chronic inflammatory disease are associated with such molecular patterns and accompanied by a reduction of heart rate variability. These include sepsis24, hemmorhagic shock25, myocardial infarction26,27, rheumatoid arthritis28, or ulcerative colitis29,30, but also conditions like metabolic syndrome or diabetes31. Tracey and his colleagues have shown that by introducing endotoxin into a rat peritoneal cavity, there was a reduction in heart rate variability. Vagal signaling was conjoined to HRV response, and reduced the response of innate immunity.1, 32
Dendritic cells, releasing Interleukin (IL-1Beta) and prostaglandins, are located within vicinity of vagus nerve fibers. Injection of bacterial endotoxin or administration of IL-1Beta, a cytokine, activated afferent vagus neurons. These scientists posit that signals through the afferent vagus nerve reach the nucleus tractus solitaries in the brainstem portion of the medulla. This is where interconnections to the dorsal motor nucleus of the vagus nerve efferent vagus nerves fibers originate. Tracey et al. have demonstrated that there is afferent nerve activity in the thymus and the splenic nerve as a response to interleukin IL-1beta and endotoxin.31,33
Ninety-four percent of TNF released systemically in early phase toxemia in a rodent model originates in the spleen, and has been shown the splenectomy protects against the lethal effects of sepsis.34 Dr. Tracey and colleagues make a case that the spleen is the primary target for signals from the efferent arm of the vagal neurons. Within the celiac plexus ganglia, vagus nerve fibers transmit information through interneurons or postsynaptic cate-cholinergic neurons. While the central nervous system transmits signals from sympathetic chain, accumulating data1,3,21,33 indicates the vagal efferent signaling is required for the inflammatory reflex to occur. The inflammatory reflex response is neither classically parasympathetic nor sympathetic but an amalgamation of neural communication.33,34
Just to review, presently, researchers think the circuitry involving vagus input finishes on cytokine producing macrophages. First neuron is sensory, information goes in the brain; second is efferent (leaves the brain) and cholinergic. The cholinergic efferent branch of the vagus travels near the celiac sympathetic ganglion, which connects to a third adrenegic neuron. This connects to the splenic nerve to deliver norepinephrine to Beta-2 adrenergic receptors expressed on a subset of T-cells capable of secreting acetylcholine. T-cells are acting in place of cholinergic neurons, activating the nACH7 receptors expressed on cytokine producing macrophages. This occurs in marginal zone and red pulp of the spleen. These macrophage nACH7 receptors then suppress cytokine transcription and release.35 The efferent vagus nerve indirectly modulates the immune response.
This illustration describes the inflammatory reflex — the pathway for reducing cytokines by adjusting the inflammatory response in the spleen. Acetylcholine, the major vagal neurotransmitter, diminished the release of TNF and interleukins (IL-1 beta, IL-6 and Il-8).1
It is the vagal efferent signal that activates macrophages that also modifies heart rate variability. The cholinergic response to nACH7 receptors slows the heart rate via the muscaric cholinergic receptors on heart pacemaker cells.36 Vagus response increases the variations between heartbeats. The lack of heart rate variability can be an indicator of autonomic dysregulation. Dr. Tracey and other scientists37 suggest the heart rate variability may qualify as an indicator at who may be at greater risk for high levels of inflammation.
STUDIES THAT DEMONSTRATE ACUPUNCTURE DOWN-REGULATES INFLAMMATION
In recent study by Zhou et al.2 functional dyspepsia and gastric emptying were measured in rat pups before and after auricular electro-acupuncture. Gastric distension or functional dyspepsia was rated by behavior indicating discomfort. Autonomic functions were assessed from the spectral analysis of heart rate variability derived from an electro-cardiogram. Functional dyspepsia diminished in rats treated with auricular electro-acupuncture but gastric emptying was not altered.2
Other avenues were explored by Zhou et al. Two different sets of electrical prescriptions were implemented, indicating that the frequency of electrical stimulation has a consequence on treatment effect. These prescriptions were based on the work of Han et al.38 that demonstrated the combination of two frequencies, 2 hz and 100 hz produced all 4 opioid peptides, enhancing the effect of electrical stimulation. Sun et al.39 used Han’s prescriptions to reduce visceral sensitivity in rats with gastric ulcer. This research of Han and Sun was the basis of Zhou’s choices in choosing frequencies for reducing gastric dyspepsia.
Naloxone was injected intraperitoneally into the rats before electro-acupuncture treatment to examine the opioid mechanism.2 Surprisingly, the drug, an opioid antagonist, did not block the effects of auricular electro-acupuncture on the autonomic function. In a previous study40, Zhou and colleagues determined electro-acupuncture at ST 36 mediated both autonomic and opioid pathways, but also operated independently from the opioid pathway. Naxloxone did not inhibit the treatment effects in this study2; and auricular electro-acupuncture increased vagus nerve activity and improved sympathovagal balance.
Zhou et al. devised two sets of electrical prescriptions. The first was based directly on the work of Han and Sun. This provided intermittent frequency of 2 hz and 100 hz. Besides inducing opioid pathways, Sun had shown this protocol reduced visceral hypersensitivity.39 Another set of parameters were added that had consistently shown to reduce gastric emptying. It consisted of 2 seconds on, 3 seconds off, at 25 hertz.2,40 Interestingly, researchers discussed another study41 in which auricular electro-acupuncture was reported to improve rectal distention induced gastric dysrhythmias.
In another recent animal study at Rutgers University study by Torres, Rosa, and Ulloa, et al.3 demonstrated electrically stimulation of ST 36 (Zu San Li) at 10 Hz, in continuous mode activated the common tibial and peronal branches of the sciatic nerve. In this electro-chemical thread, Zu San Li St 36 by way of the sciatic nerve leads to production of dopamine in the adrenal medulla. These results suggest the production of catecholamines is moderated by the vagus nerve. Dopamine inhibits cytokine production by dopamine (D1) receptors in the medulla indicating another path of vagus nerve interference. As dopamine production can modulate the immune system, animal studies suggest electro-acupuncture at Zu San Li St 36 post-surgically decreases inflammatory cytokines.3
The effects of electro-acupuncture at Zu San Li T 36, describing how by activating the sciatic nerve, systemic inflammation was reduced by vagal activation of a dopamine precursor in the adrenal medulla.3
VAGUS NERVE THERAPY
Electrical devices, often surgically implanted micro cuffs, are now employed in the treatment of epilepsy, depression, and rheumatoid arthritis. Electrical stimulation of the left vagus nerve is an approved therapy for epilepsy. Some studies7 suggest that low amplitude (<1.5mA) and high frequency (20 hertz) stimulation is effective for depression. The device most commonly employed is a battery powered pulse generator that requires a surgical implantation. The generator is inserted subcutaneously in left upper chest wall, while an electrode wire is attached to the left mid-cervical vagus nerve through a second incision in the upper left region of the neck. A handheld computer programs the pulse generator. Unfortunately, stimulation of the mid-cervical vagus nerve may affect the voice, breathing, swallowing and the neck. It also generates uncomfortable sensations of paresthesia in the upper body. Electrical impulses generated at area have a greater effect on the brain since the bulk of nerve fibers are afferent.7
Recently, an Israeli company developed a cuff designed to circumnavigate the vagus nerve. This new design favored activation of vagal efferent fibers that affect cardiac function in the right chest wall. So far, studies7 (preclinical, and phase II) indicate this device is safe. The same cuff was re-engineered for the left side of vagus. Five patients were treated for epilepsy with the newly designed cuff and side effects in the upper region of the body diminished.7 There is some anatomical evidence that the right cervical vagus nerve stimulation has a greater effect on the heart, but treatment for heart failure using such devices has not be particularly successful. The cervical neck area contains abundant sympathetic fibers, particularly the right vagus nerve, indicating both sympathetic and vagus nerves travel in a common trunk. Others posit that transcutaneous stimulation of the vagus nerve in the ear might be a better avenue for treatment, preferentially engaging only the vagus nerve.44
The auriculotemporal, greater auricular and auricular branch of the vagus nerve innervate the ear. The cymba conchae of the ear is innervated exclusively by auricular branch of the vagus nerve. Patients can self-administer treatment directly to the cymba concha. Such a device has already received European government clearance for the treatment of epilepsy and depression. A TENS (transcutaneous electrical nerve stimulator) can also be used to stimulate the cymba concha either unilateral or bilateral.44
Another device includes contact pads that are placed over both branches of the vagus nerve in the region of the upper neck. The intensity of the stimulation is directed by the patient with a handheld device. This design is intended to relieve cluster and migraine headaches. The USDA (FDA) recently approved a similar hand-held device called, gammaCore, for the treatment of cluster headaches in adults. In a small study45 patients were pain-free in 15 minutes.
SetPoint Medical Devices developed by Dr. Tracey and his colleagues initially modified a stimulator designed for the treatment of epilepsy. They have demonstrated the macrophages hit by acetylcholine are unable to produce TNF for up to twenty-four hours. Additionally, vagus nerve fibers require very low electrical stimulation, approximately one eight typically required for epilepsy to respond to a treatment. In 2011, SetPoint Devices5 were tested on human subjects in Amsterdam and at the UK-based pharmaceutical company GlaxoSmithKline. Over the course of several years eighteen people with rheumatoid arthritis enrolled in the study. Twelve participants stated their symptoms improved over six weeks. Lab tests demonstrated the blood levels of inflammatory molecules, such as TNF and IL-6, decreased. Improvements vanished when the devices were shut off for two weeks, but returned when stimulation was restarted.5 Dr. Bruno Bonaz46, a gastroenterologist from Grenoble, was treating seven people with Crohn’s disease. Five people reported fewer symptoms, and endoscopies showed reduced tissue damage. The study was never published. SetPoint is also engaged in a clinical trial for Crohn’s disease.5
Will electro-ceuticals be the next treatment breakthrough? Electrical stimulation of the vagus nerve is an accepted treatment, and medical devices are being marketed in Europe, Israel, and the United States. Glaxo Smith Kline is partnering with Google. US National Institute of Health (NIH) has announced a program called ‘Stimulating Peripheral Activity to Relieve Conditions’; the object — to update neural maps in the abdominal and thoracic cavities.5 Medical researchers already consider treatment of the vagus nerve at the ear or neck with electrical stimulation as a likely therapeutic intervention for irritable bowel disease or rheumatoid arthritis.9,46 These new devices duplicate aspects of the acupuncture experience, but many acupuncturists are in the dark about the why their technique is effective.
CONCLUSION
This research, understanding how the immune system and autonomic nervous system are co-joined, should be part of an acupuncture vocabulary. As acupuncturists, we know that series of acupuncture treatments are an effective tool for improving many conditions, but it is important to be able to describe an underlying mechanism.
More research may be needed to demonstrate the benefit of acupuncture on the autonomic nervous system in stimulating down-regulation. There is evidence that electrical stimulation to the vagus nerve has a positive effect on epilepsy, depression, and headache. The evidence for effecting the vagus nerve in serious conditions such as sepsis, heart disease, diabetes, cancers, colitis, and rheumatoid arthritis, has been demonstrated mostly in animal studies, but there are now a few small breakout studies involving human patients being treated with electrical devices. Theory now indicates that electrical stimulation of the vagus nerve may exert a positive down-regulating influence on body wide inflammation. Furthermore, animal studies indicate electrical acupuncture at certain points on the ear and ST 36 duplicate these effects.
Not only is it important for acupuncturists to understand the effect of acupuncture on the autonomic nervous system and the immune system, but they should also be able to communicate this effect to both their patients and other professionals. While more research is being done and more evidence will accumulate in the future, research science has generously provided us with a convincing umbrella to stand beneath. We must master and define our place in this new paradigm of treatment.
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