2011年7月31日 星期日

E. 心率變異(HRV)與肥胖

E1 心率變異在減肥者及減重後的變化
Heart Rate Variability in Obesity and the Effect of Weight Loss【資料來源:THE AMERICAN JOURNAL OF CARDIOLOGYT (1999)】

D. 自律神經與糖尿病

16 糖尿病患無意識的致命但能治療的情況沒有症狀的發展
Most Diabetes Patients Unaware of Deadly but Treatable Condition that Develops Without Symptoms, Survey Says【資料來源:malattiemetaboliche (2001)】

C. 自律神經與癌症

C1 交感神經是誘發原發性乳癌轉移的開關
The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer【資料來源:Cancer Research (2010)】

C2 神經內分泌調控癌症的進程
Neuroendocrine modulation of cancer progression【資料來源:Brain, Behavior, and Immunity (2009)】

C3 迷走神經是否可以在臨床上腫瘤發生前;通知大腦並調控它?
Does the vagus nerve inform the brain about preclinical tumours and modulate them?【資料來源:Lancet Oncol (2005)】

C4 心率變異是什麼?它會被腫瘤壞死因子減弱嗎?
What Is “Heart Rate Variability” and Is It Blunted by Tumor Necrosis Factor?【資料來源:Chest (2003)】

C5 以神經,內分泌和免疫系統之互動,作為經由大腦監視及調控腫瘤生成的基礎
Interactions between nervous, endocrine and immune systems as a base for monitoring and modulating the tumorigenesis by the brain【資料來源:Seminars in Cancer Biology (2008) 】

C6 發炎與癌症:它們之間關聯多深?
Inflammation and cancer: How hot is the link?【資料來源:Biochemical Pharmacology (2006)】

C7 癌症之機制:為什麼癌症與發炎有關?
Why Cancer and Inflammation?【資料來源:Yale Journal of Biology and Medicine (2006)】

C8 大腦與癌症之間的發展
The Developing Brain and Cancer【資料來源:The George Washington University (2011)】

B. 自律神經與發炎

B1 迷走神經與發炎的反應的關係
Vagal tone and the inflammatory reflex【資料來源:CLEVEL AND CLINIC JOURNAL OF MEDICINE(2009)】

B2 發炎反應
The inflammatory reflex【資料來源:NATURE(2002)】

B3 神經系統調節發炎細胞素及心率變異
Nervous system regulation of inflammation, cytokines, and heart rate variability

B4 心率變異是發炎的脈搏,副交感神經的抗發炎路徑及治療上的應用
The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy【資料來源:Journal of Internal Medicine (2011)】

B5 副交感抗發炎路徑的生理及免疫學
Physiology and immunology of the cholinergic antiinflammatory pathway【資料來源:The Journal of Clinical Investigation (2007)】

A. 自律神經基礎文獻

A1 心率變異:測量的標準,生理上的解釋,及臨床應用
Heart rate variability:Standards of measurement, physiological interpretation, and clinical use【資料來源:European Heart Journal (1996) 】

A2 九二一大地震時突然變化的心率變異
Sudden Changes in Heart Rate Variability During the 1999 Taiwan Earthquake 【資料來源:The American Journal of Cardiology (2001)】

A3 九一一事件期間的心率變異
Heart Rate Variability During the Week of September 11, 2001【資料來源:JAMA (2002)】

A4 交感神經 -- 兩個超級系統大腦及免疫系統的介面
The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System【資料來源:Pharmacol Rev (2000)】

2011年7月29日 星期五

Neural Control of Immunity

The immune system protects against invasive pathogens through the production of pro-inflammatory cytokines, which initiates a cascade of events to promote tissue repair. However, excessive or unrestrained release of pro-inflammatory cytokines can result in a range of chronic inflammatory conditions and disease states.


自律神經失調 HRV檢測及治療衛教手冊

編了一本自律神經失調 HRV檢測及治療衛教手冊


2011年7月28日 星期四

Most Diabetes Patients Unaware of Deadly but Treatable Condition that Develops Without Symptoms, Survey Says


According to the results of a national survey released today, ninety-two percent of the estimated 16 million Americans with diabetes have never heard of diabetic autonomic neuropathy, an often deadly but treatable condition that can develop for years without symptoms.

Also according to the survey, eighty-three percent of people with diabetes are unaware of a non-invasive procedure called heart rate variability testing. Physicians are more able to detect the presence of diabetic autonomic dysfunction when they augment their clinical evaluation with the information provided by heart rate variability testing. However, while it is estimated that diabetic autonomic neuropathy may affect more than twenty-five percent of people with diabetes, only two percent of survey respondents said that they have ever been tested for the condition.


Sudden Changes in Heart Rate Variability During the 1999 Taiwan Earthquake

Jin-Long Huang, MD, Chuen-Wang Chiou, MD, Chih-Tai Ting, MD, PhD, Ying-Tsung Chen, MD, and Shih-Ann Chen, MD

The acute stress of major natural disasters, such as an earthquake, may alter biochemical data,1 affect the psychological state,2 and may be associated with increased cardiovascular mortality.1–9 Although alterations of autonomic tone are hypothesized to be the link between such environmental stressors and mortality, autonomic tone, as reflected by heart rate variability
(HRV), has never been measured during an earthquake. The earthquake that struck the Nan-Tou
area, in the central part of Taiwan, at 1:47 A.M. on September 21, 1999, Richter scale 7.3, was one of the strongest earthquakes ever recorded in a major city in Taiwan. We studied patients who were equipped with Holter electrocardiographic monitors to investigate the effect of an earthquake on the autonomic system.


Heart Rate Variability During the Week of September 11, 2001

Rachel Lampert, MD;     Suzanne J. Baron, BA;     Craig A. McPherson, MD;     Forrester A. Lee, MD

To the Editor: Catastrophes such as war or earthquake are known to result in increased incidence of sudden cardiac death among survivors, but the physiological mechanisms remain unknown.1​-2 The events of September 11, 2001, produced psychological distress among large numbers of people who were not physically affected by them. We hypothesized that such stress may lead to autonomic dysfunction, which may be reflected in changes in heart rate variability (HRV). Diminished HRV is associated with an increased incidence of cardiovascular and sudden death in patients both with and without coronary artery disease (CAD).


We measured HRV in 12 patients at the Yale-New Haven Hospital who wore 24-hour ambulatory heart monitors during the week of September 11, as well as 12 in control patients who had worn monitors in the preceding 2 months. Control patients were matched for age (within 10 years), sex, presence of CAD or congestive heart failure, and diabetes. Two patients in each group were using β-blockers. Indications for monitoring included palpitations (4 cases, 4 controls), history of or risk for arrhythmia (6 cases, 5 controls), and syncope (2 cases, 3 controls). All patients had been scheduled for heart monitoring prior to September 11. This study was approved by the Yale Human Investigation Committee.Frequency domain indices of HRV were analyzed using standard power spectrum analysis methods. After editing the R-R interval file to remove ectopic beats and noise, gaps were estimated by interpolated linear splines (recordings with >20% interpolation excluded). The heart rate power spectrum was computed through Fast Fourier Transform and integrated over 5 discrete frequency bands, with high frequency defined as 0.15 to 0.40 Hz.3 Indices of HRV were log-normalized and compared by paired t test.


The logarithm of high-frequency power (a measure of parasympathetic tone) was lower in the subjects monitored after September 11 than in controls (5.54 vs 6.23, P = .047). High-frequency power was lower in 9 of the 12 cases compared with their controls (P = .045). Mean heart rate did not differ between groups (R-R interval: 857 milliseconds [cases] vs 829 milliseconds [controls], P = .64). 


We found a decrease in parasympathetic tone during the week of September 11, 2001, which may represent a physiological perturbation among individuals exposed to large-scale psychological stress. Unlike previous studies in which subjects were directly affected by war or natural disaster,1-2 the stress experienced by subjects in our study was purely psychological. It is not yet known whether there was increased cardiac mortality or morbidity as a result of the September 11 attacks. Mental stress can induce coronary ischemia2 and can facilitate lethal arrhythmias.5 These changes in cardiac blood flow and rhythm may in turn be caused by alterations in autonomic nervous system function.6 Our data demonstrate that the September 11 attacks may have produced similarly decreased parasympathetic output, which may increase susceptibility to lethal arrhythmias.7

2011年7月27日 星期三

Heart Rate Variability in Obesity and the Effect of Weight Loss

Kristjan Karason, MD, Henning Mølgaard, MD, PhD, John Wikstrand, MD, PhD, and
Lars Sjo¨stro¨m, MD, PhD

To investigate the effects of obesity and weight loss on cardiovascular autonomic function, we examined 28 obese patients referred for weight-reducing gastroplasty, 24 obese patients who received dietary recommendations, and 28 lean subjects. Body weight, blood pressure, and 24-hour urinary norepinephrine excretion were measured, and time and frequency domain indexes of heart rate variability (HRV) were obtained from 24-hour Holter recordings. A measure of long-term HRV, the SD of all normal RR intervals (SDANN), was used as an index of sympathetic activity and the high-frequency (HF) component of the frequency domain, reflecting
short-term HRV, as an estimate of vagal activity. All 3 study groups were investigated at baseline, and the 2 obese groups were reexamined at 1-year follow-up. Obese patients had higher blood pressure, higher urinary norepinephrine excretion, and attenuated SDANN
and HF values than lean subjects (p <0.01). Obese patients treated with surgery had a mean weight loss of 32 kg (28%), whereas the obese group treated with dietary recommendations remained weight stable (p <0.001). At follow-up the weight-loss group displayed decreases in blood pressure and norepinephrine excretion and showed increments in SDANN and HF values. These changes were significantly greater than those observed in the obese control group (p <0.05). Our findings suggest that obese patients have increased sympathetic
activity and a withdrawal of vagal activity and that these autonomic disturbances improve after weight loss. Q1999 by Excerpta Medica, Inc.


What Is “Heart Rate Variability” and Is It Blunted by Tumor Necrosis Factor?

David R. Murray

In the 18th century, Albrecht von Haller1 made the initial observation that the beat of a healthy heart is not absolutely regular. Heart rate and rhythm are governed by the intrinsic automaticity of the sinoatrial node and the modulating influence of the autonomic nervous system. Vagal tone dominates under resting conditions,2 and rhythmic variations in heart rate are largely dependent on vagal modulation.3 The vagal and sympathetic nervous system constantly interact. The stimulation of the vagal afferent fibers leads to the reflex excitation of vagal efferent activity and the inhibition of sympathetic efferent activity.4 The opposite reflex events are mediated by the stimulation of sympathetic afferent activity.5 Central oscillators (ie, vasomotor and respiratory centers) and peripheral oscillators (ie, oscillation in arterial pressure and respiratory movements) can further modulate the efferent sympathetic and vagal activities that are directed to the sinus
node.6 These oscillators generate rhythmic fluctuations in efferent neural discharge that are manifested as short-term and long-term oscillation in beat-to-beat intervals and periodic heart rates.6 Heart rate variability (HRV) is a conventionally accepted term that is used to characterize these heart rate fluctuations. The analysis of HRV permits inferences to be made about the
state and function of the central oscillators, autonomic efferent activity, humoral factors, and the sinus node.


The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer

Erica K. Sloan, Saul J. Priceman, Benjamin F. Cox, Stephanie Yu, Matthew A. Pimentel, Veera Tangkanangnukul, Jesusa M.G. Arevalo, Kouki Morizone, Breanne D.W. Karanikolas, Lily Wu, Anil K. Sood, and Steven W. Cole


Metastasis to distant tissues is the chief driver of breast caner-related mortality, but little is known about the systemic physiologic dynamics that regulate this process. To investigate the role of neuroendocrine activation in cancer progression, we used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer. Stress-induced neuroendocrine activation had a negligible effect on growth of the promary tumor but induced a 30-fold increase in metastasis to distant tissues including the lymph nodes and lung. These effects were mediated by B-adrenergic signaling, which increased the infiltration of CD11b'F4/80' macrophages into primary tumor parenchyma and thereby induced a prometastic gene expression signature accompanied by indications of M2 macrophage differentiation. Pharmacologic activation of B-adrenergic signaling induced similar effects, and treatment of stressed animals with the B-antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues. The effects of stress on distant metastasis were also inhibited by in vivo macrophage suppression using the CSF-1 receptor kinase inhibitor GW2580. These findings identify activation of the sympathetic nervous system as a novel neural regulator of breast cancer metastasis and suggest new strategies for antimetastic therapies the target the B-adrenergic induction of prometastatic gene expression in primary breast cancers.


2011年7月26日 星期二


  1. 發炎、消炎及癌症之產生與發展
  2. 自律神經失調 HRV檢測及治療衛教手冊
  3. 廿一世紀癌症防治大突破 – 自律神經調控法


                                 … 都是自律神經的事

July 2011


Interactions between nervous, endocrine and immune systems as a base for monitoring and modulating the tumorigenesis by the brain

Boris Mravec , Yori Gidron , Ivan Hulin


The interactions between the nervous, endocrine and immune systems are studied intensively. The communication between immune and cancer cells, and multilevel and bi-directional interactions between the nervous and immune systems constitute the basis for a hypothesis assuming that
the brain might monitor and modulate the processes associated with the genesis and progression of cancer. The aim of this article is to describe the data supporting this hypothesis.


Physiology and immunology of the cholinergic antiinflammatory pathway

Kevin J. Tracey


Cytokine production by the immune system contributes importantly to both health and disease. The nervous system, via an inflammatory reflex of the vagus nerve, can inhibit cytokine release and thereby prevent tissue injury and death. The efferent neural signaling pathway is termed the cholinergic antiinflammatory pathway. Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases. Stimulation of the vagus nerve prevents the damaging effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury,
hemorrhagic shock, arthritis, and other inflammatory syndromes. Herein is a review of this physiological, functional anatomical mechanism for neurological regulation of cytokine-dependent disease that begins to define an immunological homunculus.


Does the vagus nerve inform the brain about preclinical tumours and modulate them?

Yori Gidron, Hugh Perry, Martin Glennie


The inflammatory microenvironment is thought to play a pivotal part in tumorigenesis. But, can the brain be informed about peripheral preclinical cancer cells? Can it modulate tumour development? One of the key routes for information to reach the brain from visceral regions is through the vagus nerve. Yet, patients with ulcers who have had a vagotomy have been shown to die from cancer more frequently than do those who have not had this procedure, and surgical and chemical vagotomy attenuates tumour-induced anorexia and leads to enhanced tumour progression. We therefore postulate that the vagus nerve participates in informing the brain about tumorigenesis by
transmiting information to the brain about tumour-associated proinflammatory cytokines. Furthermore, activation of the vagus could slow tumorigenesis by suppression of peripheral proinflammatory cytokines.


The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy

J. M. Huston & K. J. Tracey


Huston JM, Tracey KJ (Department of Surgery, Division of General Surgery, Trauma, Surgical Critical Care, and Burns, Stony Brook University Medical Center, Health Sciences Center, Stony Brook; and Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset; NY, USA). The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway, and implications for therapy (Key Symposium). J Intern Med 2011; 269: 45–53.

Biological therapeutics targeting TNF, IL-1 and IL-6 arewidelyused for treatment of rheumatoidarthritis, inflammatory bowel disease and a growing list of other syndromes, often with remarkable success. Nowadvances inneurosciencehave collidedwiththis therapeutic approach, perhaps rendering possible the development of nerve stimulators to inhibit cytokines. Action potentials transmitted in the vagus nerve culminate in the release of acetylcholine that blocks cytokine production by cells expressing acetylcholine receptors. The molecular mechanism of this cholinergic anti-inflammatory pathway is attributable to signal transduction by the nicotinic alpha 7
acetylcholine receptor subunit, a regulator of the intracellular signals that control cytokine  transcription and translation. Favourable preclinical data support the possibility that nerve stimulatorsmay be added to the future therapeutic armamentarium, possibly replacing somedrugs to inhibit cytokines.

Keywords: heart rate variability, inflammation, neuroimmunology, therapeutics, vagus nerve stimulation.

瞄準TNF,IL-1,IL-6之生物治療法對類風濕性發炎,發炎性腸胃炎及其他炎症都有意想不到的效果。神經科學之最新進展更推高其可能性,使到用神經刺激方法來抑制細胞激素之產生是一種可行之治療方法。在迷走神經所發之位能會使其釋出乙醯膽鹼,細胞中之乙醯膽鹼接受器會在接受乙醯膽鹼後便會阻斷細胞激素之產生。這些接受器就是叫做尼古丁α-7分子 --- 一個調整細胞激素之分子。正面的臨床前的數據支持下面所說的一個可能性;即神經刺激可代替藥物來抑制細胞激素的產生。


The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System



The brain and the immune system are the two major adaptive systems of the body. During an
immune response the brain and the immune system “talk to each other” and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/ neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic
nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the b2-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-a, and interferon-g by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as
IL-10 and transforming growth factor-b. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune
responses, through induction of IL-1, tumor necrosis factor-a, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes,
and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective a2- and b2-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic
fatigue syndrome.


Neuroendocrine modulation of cancer progression

Guillermo N. Armaiz-Pena , Susan K. Lutgendorf , Steve W. Cole , Anil K. Sood


Clinical and animal studies now support the notion that psychological factors such as stress, chronic depression, and lack of social support might promote tumor growth and progression. Recently, cellular and molecular studies have started to identify biological processes that could mediate such effects. This review provides a mechanistic understanding of the relationship between biological and behavioral influences in cancer and points to more comprehensive behavioral and pharmacological approaches for better patient outcomes.



2011年7月24日 星期日

Nervous system regulation of inflammation, cytokines, and heart rate variability

As readers here know, inflammation is a fundamental factor in chronic disease and accelerated
aging (neurodegeneration). A functional approach to treatment requires an objective understanding of how this system is working for each patient. Here are several of the many
studies that illustrate how nervous system function and inflammation can be evaluated with heart
rate variability (HRV) analysis and cytokine (‘messenger molecules’ of inflammation) levels.

The practical focus is on restoring parasympathetic nervous system
(PNS) activity which inhibits inflammation. (PNS resources decline with disease, stress and age
resulting in a state of ‘sympathetic nervous system dominance’.) This paper just published in the
journal Shock shows how autonomic nervous system activity (sympathetic and parasympathetic)
as measured by HRV corresponds to inflammatory cytokine activity, in this case when stimulated
by endotoxins (poisons produced by bacterial infections):

“Autonomic inputs from the sympathetic and parasympathetic nervous systems, as
measured by heart rate variability (HRV), have been reported to correlate to the…
responses to infectious challenge… In addition, parasympathetic/vagal activity has
been shown experimentally to exert anti-inflammatory effects via attenuation of
splanchnic tissue TNF-α [cytokine] production. We sought… to determine if baseline
HRV parameters correlated with endotoxin-mediated circulating cytokine responses.”

They documented a strong correspondence regardless of gender, body mass index and resting
heart rate:

“…we found a significant correlation of several baseline HRV parameters…on TNF-α
release after endotoxin exposure.”

This is not a new observation. An interesting study published a few years
ago in the journal Psychosomatic Medicine documents the HRV expression of autonomic activity in response to an inflammatory challenge and its correspondence to cytokine production. They begin by noting that:

“…the autonomic nervous system plays a key role in regulating the magnitude of immune responses to inflammatory stimuli. Signaling by the parasympathetic system inhibits the production of proinflammatory cytokines by activated monocytes/macrophages and thus decreases local and systemic inflammation.”

They examined the relationship of HRV to lipopolysaccharide-induced production of the
inflammatory cytokines interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-{alpha}, and IL-10.
What did the data show?

“Consistent with animal findings, higher derived estimates of vagal activity measured during paced respiration* were associated with lower production of the proinflammatory cytokines TNF-{alpha} and IL-6…These associations persisted after controlling for demographic and health characteristics, including age, gender, race, years of education, smoking, hypertension, and white blood cell count.”

Their conclusion has profound implications for the biological mechanism by which stress causes

“These data provide initial human evidence that vagal activity is inversely related to inflammatory competence, raising the possibility that vagal regulation of immune reactivity may represent a pathway linking psychosocial factors to risk for inflammatory disease.”

How might this show up in heart disease? This paper published not long ago in the journal Brain, Behavior, and Immunity investigates the links between HRV, inflammatory cytokines, coronary heart disease and depression:

“Studies show negative correlations between heart rate variability (HRV) and inflammatory markers [less variability = more inflammation]…We investigated links between short-term HRV and inflammatory markers in relation to depression in acute coronary syndrome (ACS) patients.”

They measured C-reactive protein (CRP), interleukin-6 (IL-6, a cytokine), depression symptoms
and heart rate variability determinants of autonomic function. What did their data show?

“…all HRV measures were negatively and significantly associated with both inflammatory markers…HRV independently accounted for at least 4% of the variance in CRP in the depressed, more than any factor except BMI.”

Interestingly, they also noted that:

“Relationships between measures of inflammation and autonomic function are stronger among depressed than non-depressed cardiac patients. Interventions targeting regulation of both autonomic control and inflammation may be of particular importance.”

The research of another group published in the Journal of Critical Care used sepsis as their model.

“The aim of the study was to investigate possible associations between different heart
rate variability (HRV) indices and various biomarkers of inflammation in 45 septic

They examined the correlation between HRV, C-reactive protein, and the cytokines interleukin 6
and interleukin 10:

“Our data suggest that low HRV and sympathovagal balance during septic shock are associated with both an increased hyperinflammatory and antiinflammatory response.”

The antiinflammatory response corresponds to high HRV and interleukin-10, the cytokine that is
also increased by vitamin D.

How can we reduce inflammation by increasing HRV and reducing inflammatory cytokines? There are numerous methods; one is to increase cholinergic activity in the nervous system (parasympathetic activity mediated by the neurotransmitter acetylcholine). We can increase this with natural precursor support for acetylcholine. This study published recently in the Journal of Internal Medicine shows the connection between vagal parasympathetic function (as shown by HRV), inflammatory cytokines, cholinergic activity and rheumatoid arthritis:

“The central nervous system regulates innate immunity in part via the cholinergic  anti-inflammatory pathway, a neural circuit that transmits signals in the vagus nerve that suppress pro-inflammatory cytokine production…Vagus nerve activity is significantly suppressed in patients with autoimmune diseases, including rheumatoid arthritis (RA). It has been suggested that stimulating the cholinergic anti-inflammatory pathway may be beneficial to patients…”

They found that increasing cholinergic signaling in stimulated whole blood cultures suppressed
cytokine production in rheumatoid arthritis patients whose vagal activity was deficient:

“These findings suggest that it is possible to pharmacologically target the α7nAChR dependent control of cytokine release in RA patients with suppressed vagus nerve activity.”

In a functional medicine practice, of course, we use natural acetylcholine precursors.

This is a drop in the bucket, but here’s one more fascinating paper published recently in the journal Brain, Behavior, and Immunity that shows how acetylcholine activity in the brain (the upper level of autonomic regulation) controls systemic cytokine levels through vagal function:
“The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release…Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks…Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF [cytokine] production during endotoxemia.”

They demonstrated that inhibiting the breakdown of acetylcholine† markedly reduced proinflammatory serum TNF levels through the resulting increasing vagus nerve signaling which
prevented inflammatory damage. What do they conclude from their research?

“These findings show that inhibition of brain acetylcholinesterase [that breaks down acetylcholine] suppresses systemic inflammation through a central…mediated and
vagal…dependent mechanism. Our data also indicate that a clinically used centrallyacting
acetylcholinesterase inhibitor† can be utilized to suppress abnormal inflammation to therapeutic advantage.”

* There are numerous therapies to reduce inflammation by increasing parasympathetic function.
Breathing is a powerful stimulus to the autonomic nervous system. We train breathing with
biofeedback while simultaneously monitoring for CO2 (capnography) and coherence in HRV to hit the physiological “sweet spot”.

† Agents that inhibit the breakdown of neurotransmitters including reuptake inhibitors do not
restore the body’s ability to make its own. Precursor therapy provides the natural ingredients that have been depleted or are insufficient to meet genetic needs so neurotransmitters can be
increased naturally.

The inflammatory reflex

Kevin J. Tracey

Laboratory of Biomedical Science, North Shore-LIJ Research Institute, 350 Community Drive, Manhasset, New York 11030, USA (e-mail: kjtracey@sprynet.com)

Inflammation is a local, protective response to microbial invasion or injury. It must be fine-tuned and
regulated precisely, because deficiencies or excesses of the inflammatory response cause morbidity and shorten lifespan. The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded our understanding of how the nervous system modulates immune responses. The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible ‘hard-wired’ neural systems.

“The mind has great influence over the body, and maladies often have their origin there.” Molière (1622–1673).

survival is impossible without vigilant defence against attack and injury. The innate immune
system continuously surveys the body for the presence of invaders. When it encounters an
attack, it involuntarily sets in motion a discrete, localized inflammatory response to thwart most
pathogenic threats. The magnitude of the inflammatory response is crucial: insufficient responses result in immunodeficiency, which can lead to infection and cancer; excessive responses cause morbidity and mortality in diseases such as rheumatoid arthritis, Crohn’s disease, atherosclerosis, diabetes, Alzheimer’s disease, multiple sclerosis, and cerebral and myocardial ischaemia. If inflammation spreads into the bloodstream, as occurs in septic shock syndrome, sepsis, meningitis and severe trauma, the inflammatory responses can be more
dangerous than the original inciting stimulus. Homeostasis and health are restored when inflammation is limited by anti-inflammatory responses that are redundant, rapid, reversible, localized, adaptive to changes in input and integrated by the nervous system.



2011年7月22日 星期五

Vagal tone and the inflammatory reflex

Professor, Department of Psychology,
The Ohio State University, Columbus, OH
Mannheim Institute of Public Health, Social and Preventive Medicine,
Mannheim Medical Faculty, Heidelberg University,
Mannheim, Germany

Inhibition of sympathoexcitatory circuits is influenced by cerebral structures and mediated via vagal mechanisms. Studies of pharmacologic blockade of the prefrontal cortex together with neuroimaging studies support the role of the right hemisphere in parasympathetic control of the heart via its connection with the right vagus nerve. Neural mechanisms also regulate infl ammation; vagus nerve activity inhibits macrophage activation and the synthesis of tumor necrosis factor in the reticuloendothelial system through the release of acetylcholine. Data
suggest an association between heart rate variability and infl ammation that may support the concept of a cholinergic anti-infl ammatory pathway.

The neurovisceral integration model of cardiac vagal tone integrates autonomic, attentional,
and affective systems into a functional and structural network. This neural network can be indexed by heart rate variability (HRV). High HRV is associated with greater prefrontal inhibitory
tone. A lack of inhibition leads to undifferentiated threat responses to environmental challenges.



2011年7月21日 星期四

Heart rate variability:Standards of measurement, physiological interpretation, and clinical use

European Heart Journal (1996) 17, 354–381

Heart rate variability

Standards of measurement, physiological interpretation, and clinical use

Task Force of The European Society of Cardiology and The North American
Society of Pacing and Electrophysiology (Membership of the Task Force listed in
the Appendix)

The last two decades have witnessed the recognition of a significant relationship between the autonomic nervous system and cardiovascular ortality, including sudden cardiac death[1–4]. Experimental evidence for an association between a propensity for lethal arrhythmias and signs of either increased sympathetic or reduced vagal activity has encouraged the development of quantitative markers of autonomic activity.

Heart rate variability (HRV) represents one of the most promising such markers. The apparently easy derivation of this measure has popularized its use. As many commercial devices now provide automated measurement of HRV, the cardiologist has been provided with a seemingly simple tool for both research and clinical studies[5]. However, the significance and meaning of the many different measures of HRV are more complex than generally appreciated and there is a potential for incorrect conclusions and for excessive or unfounded extrapolations.

Recognition of these problems led the European Society of Cardiology and the North American Society of Pacing and Electrophysiology to constitute a Task Force charged with the responsibility of developing appropriate standards. The specific goals of this Task Force were to: standardize nomenclature and develop definitions of terms; specify standard methods of measurement; define physiological and pathophysiological correlates; describe currently appropriate clinical applications, and identify areas for future research.

In order to achieve these goals, the members of the Task Force were drawn from the fields of mathematics, engineering, physiology, and clinical medicine. The standards and proposals offered in this text should not limit further development but, rather, should allow appropriate comparisons, promote circumspect interpretations, and lead to further progress in the field.

The phenomenon that is the focus of this report is the oscillation in the interval between consecutive heart beats as well as the oscillations between consecutive instantaneous heart rates. ‘Heart Rate Variability’ has become the conventionally accepted term to describe variations of both instantaneous heart rate and RR intervals. In order to describe oscillation in consecutive cardiac cycles, other terms have been used in the literature,
for example cycle length variability, heart period variability, RR variability and RR interval tachogram, and they more appropriately emphasize the fact that it is the interval between consecutive beats that is being analysed rather than the heart rate per se. However, these terms have not gained as wide acceptance as HRV, thus we will use the term HRV in this document.