Kategoriarkiv: Forskning og artikler

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Caloric restriction may reverse age-related autonomic decline in humans

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Nevner hvordan kalorifattig diett (som f.eks. faste) påvirke vagusnerven.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598611/

Caloric restriction (CR) retards aging in laboratory rodents. No information is available on the effects of long-term CR on physiologic markers of aging and longevity in humans. Heart rate variability (HRV) is a marker for cardiac autonomic functioning. The progressive decline in HRV with aging and the association of higher HRV with better health outcomes are well established. Heart rate variability assessment is a reliable tool by which the effects of CR on autonomic function can be assessed. Time- and frequency-domain analyses compared 24-h HRV in 22 CR individuals aged 35–82 years and 20 age-matched controls eating Western diets (WD). The CR group was significantly leaner than the WD group. Heart rate was significantly lower, and virtually, all HRV values were significantly higher in the CR group than in the WD group (P < 0.002). Heart rate variability in the CR individuals was comparable with published norms for healthy individuals 20 years younger. In addition, when differences in HRAUTHOR: Please define HR. and HRV between CR and WD were compared with previously published changes in HRV induced in healthy adults given atenolol, percent differences in each measure were generally similar in direction and magnitude and suggested declines in sympathetic and increases in parasympathetic modulation of HR and increased circadian variability associated with CR. These findings provide evidence that CR has direct systemic effects that counter the expected age-associated changes in autonomic function so that HRV indexes in CR individuals are similar to those of individuals 20 years younger eating WDs.

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You may need the vagus nerve to understand pathophysiology and to treat diseases

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Denne studien gir en omfattende gjennomgang av hvordan stimulering av vagusnerven kan være viktig å fokusere på i behandling av forskjellige sykdommer.
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.
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Voluntarily produced increases in heart rate variability modulate autonomic effects of endotoxin induced systemic inflammation: an exploratory study.

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Denne viser hvordan HRV biofeedback øker vagus funksjon og demper symptomer på endotoxin-indusert betennelse, noe som ofte brukes i studier på systemisk inflammasjon. De så ingen endring på betennelsesmarkørene i denne, kanskje fordi den bare var på noen timer, men de så stor bedring av symptomer hos de som gjorde HRV biofeedback pust.

http://www.ncbi.nlm.nih.gov/pubmed/20635134

Exposure of healthy people to lipopolysaccharide (LPS; endotoxin) produces a pro-inflammatory response, subjective symptoms, and decreased heart rate variability (HRV). Given the efficacy of HRV biofeedback (BF) for treating asthma, the large autonomic effects of HRV BF, and the link between vagus nerve activity and inflammation, we hypothesized that HRV BF would dampen the acute manifestations of systemic inflammation induced by LPS challenge. Healthy participants age 18-40 were randomly assigned to four-one-hour training sessions of either HRV BF (n = 6) or a control 15/min paced breathing condition (n = 5) prior to acute experimentally induced LPS exposure. Participants were coached to do the procedures for 10 min each at five hourly time points after LPS injection, and then 2 h later. Subjective symptoms, HRV parameters, and plasma cytokine levels were measured at each time point, 2 h afterward, and the following morning. Participants were able to perform the procedures both during four pre-exposure training sessions and while experiencing LPS-induced symptoms. The HRV BF group showed significant attenuation of the LPS-induced decline in HRV for the 6 h following LPS exposure, suggesting that HRV BF decreased autonomic dysfunction produced by LPS-induced inflammation. HRV BF also reduced symptoms of headache and eye sensitivity to light, but did not affect LPS-induced levels of pro-inflammatory cytokines or symptoms of nausea, muscle aches, or feverishness. Further evaluation of HRV BF appears to be warranted among patients with inflammatory conditions.

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RR Interval Variability Is Inversely Related to Inflammatory Markers: The CARDIA Study

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Bekrefter at svak vagus gir økt betennelse. Stor studie som inkluderte over 750 deltakere.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892756/

Recent evidence reveals that the immune system is under the direct control of the vagus nerve via the “cholinergic anti-inflammatory pathway.” Stimulation of vagus nerve activity significantly inhibits cytokine levels in animal models, and cholinergic agents inhibit cytokine release by human macrophages. Moreover, when vagus nerve activity is decreased or absent, cytokines are overproduced. Atherosclerosis is an inflammatory disease characterized by elevated levels of CRP and IL-6, but the relationship between cardiac vagal activity and cytokine levels in healthy humans is not well understood. Here we measured RR interval variability, an index of cardiac vagal modulation, and CRP and IL-6 in 757 subjects participating in a subset of the year 15 data collection in the CARDIA study of the evolution of risk factors in young adults. Univariate analysis revealed that all indices of RRV were strongly and inversely related to IL-6 (log pg/mL b= −0.08 and −0.17 for HF and LF power, P < 0.001 respectively) and CRP (log mg/L b = −0.14 and −0.26 for HF and LF power, P < 0.001 respectively) levels. In the multivariate model including gender, race, age, smoking, physical activity, SBP, BMI, and disease, the inverse relationship between RRV and inflammatory markers, although slightly attenuated, remained significant. These findings are consistent with the hypothesis that diminished descending vagal anti-inflammatory signals can allow cytokine overproduction in humans.

To our knowledge, these are the first results demonstrating inverse relationships between inflammatory markers and indices of cardiac autonomic regulation in a large sample of healthy young adults. These findings are consistent with evidence from animal studies indicating that the cholinergic anti-inflammatory pathway counter-regulates inflammation.

It now appears that in our data from the CARDIA study of heart disease in young adults there is an inverse relationship between low frequency RR interval variability and the inflammatory markers IL-6 and CRP, even after control of relevant covariates and cardioactive medications or hypertension or diabetes, which is consistent with the hypothesis of a cholinergic anti-inflammatory pathway that regulates inflammation in humans.

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Behavioural modification of the cholinergic anti-inflammatory response to C-reactive protein in patients with hypertension

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Denne beskriver hvordan regulering av pusten kan påvirke vagus nerven til å dempe betennelser og redusere CRP (en betennelsesmarkør) i blodet.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2012.02523.x/full

Objectives.  A central hypothesis of the cholinergic anti-inflammatory reflex model is that innate immune activity is inhibited by the efferent vagus. We evaluated whether changes in markers of tonic or reflex vagal heart rate modulation following behavioural intervention were associated inversely with changes in high-sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6).

Design.  Subjects diagnosed with hypertension (n = 45, age 35–64 years, 53% women) were randomized to an 8-week protocol of behavioural neurocardiac training (with heart rate variability biofeedback) or autogenic relaxation. Assessments before and after intervention included pro-inflammatory factors (hsCRP, IL-6), markers of vagal heart rate modulation [RR high-frequency (HF) power within 0.15–0.40 Hz, baroreflex sensitivity and RR interval], conventional measures of lipoprotein cholesterol and 24-h ambulatory systolic and diastolic blood pressure.

Results.  Changes in hsCRP and IL-6 were not associated with changes in lipoprotein cholesterol or blood pressure. After adjusting for anti-inflammatory drugs and confounding factors, changes in hsCRP related inversely to changes in HF power (β =−0.25±0.1, P = 0.02), baroreflex sensitivity (β = −0.33±0.7, P = 0.04) and RR interval (β = −0.001 ± 0.0004, P = 0.02). Statistically significant relationships were not observed for IL-6.

Conclusions.  Changes in hsCRP were consistent with the inhibitory effect of increased vagal efferent activity on pro-inflammatory factors predicted by the cholinergic anti-inflammatory reflex model. Clinical trials for patients with cardiovascular dysfunction are warranted to assess whether behavioural interventions can contribute independently to the chronic regulation of inflammatory activity and to improved clinical outcomes.

Chronic low-grade inflammation contributes to the development of experimental and clinical hypertension [1–3], and it increases the risk for myocardial infarction, stroke and sudden cardiac death [4]. C-reactive protein (CRP) is an established index of systemic inflammation. It is produced chiefly by hepatocytes under the regulation of a cascade of pro-inflammatory cytokines [tumour necrosis factor-α (TNF-α), interleukin-1ß [IL-1ß] and IL-6] that are expressed in response to conditions that include vascular injury and infection. In addition, CRP is produced by human coronary artery smooth muscle cells following exposure to pro-inflammatory cytokines [5], which suggests that it may contribute independently to endothelial dysfunction and atherogenesis [6].

Clinical trials that have attempted to modify vagal efferent activity by means of aerobic exercise [17, 18], resistance exercise [19] or device-guided vagal nerve stimulation [20–22] have yet to demonstrate consequent reduction in pro-inflammatory activity that is independent of confounding factors such as anti-inflammatory medications.

Subjects received four weekly and two biweekly 1-h sessions of behavioural neurocardiac training or autogenic relaxation, as described previously [23]. Home practice sessions complemented the laboratory-based training. All sessions began with a 10-min review of cognitive-behavioural guidelines for managing daily stress [25].

At the completion of each task, subjects were trained to cognitively disengage from negative or aroused affect and to focus attention on slowing respiration (within their comfort zone) to 10-s cycles (6 breaths min−1). During each countering exercise, subjects were guided by the use of biofeedback to increase RR spectral power at approximately 0.1 Hz, as shown on a biofeedback display of the RR power spectrum (0.003–0.5 Hz) and breaths min−1.

The major finding of this study is that following an 8-week protocol of behavioural neurocardiac training or autogenic relaxation amongst patients with hypertension, change in hsCRP was associated independently and inversely with changes in tonic and reflex vagal heart rate modulation as measured by RR high-frequency power (ms2 per Hz), baroreflex sensitivity (ms per mmHg) and lengthening of the RR interval (ms). A statistical trend in the data suggested a similar inverse association between changes in IL-6 and RR high-frequency power.

A central hypothesis of the cholinergic anti-inflammatory reflex model is that the innate immune response is regulated, in part, by rapid and localized efferent activity of the vagus nerve. Previous reviews have identified the functional anatomy and neural mechanisms of this model [10, 29, 30]. In brief, efferent fibres of the vagus nerve comprise a neural anti-inflammatory pathway that culminates in the release of acetylcholine in proximate sites where pro-inflammatory factors have been expressed. Acetylcholine has been shown to bind to subunit α7 of nicotinic acetylcholine receptors on cytokine-producing immune cells [30]. This inhibits the activation of NF-κB and the subsequent expression of a pro-inflammatory cascade that includes TNF-α, IL-6 and CRP [10].

To our knowledge, the present proof of principle study involving hypertensive patients provides the most direct evaluation of whether augmentation of tonic or reflex vagal heart rate modulation, in this instance by a behavioural intervention, attenuates independently pro-inflammatory activity as assessed by hsCRP and IL-6. It is noteworthy that the present findings were observed following only modest changes in markers of vagal HR modulation. Previous behavioural trials of heart rate variability biofeedback or relaxation [32–34] have reported a small but statistically significant increase in vagal HR modulation. Similarly, behavioural training is associated with a modest, but statistically significant decrease in proinflammatory factors, including hsCRP and IL-6 [35], although heart rate variability biofeedback failed to reduce other inflammatory factors following experimental administration of an endotoxin (lipopolysaccharide) [36].

In sum, the present findings support the model of a cholinergic anti-inflammatory reflex when pro-inflammatory activity is measured by hsCRP. Clinical trial evidence has demonstrated that behavioural interventions can significantly augment vagal heart rate modulation or cardiovagal baroreflex gain through the use of relaxation training and biofeedback [32–34].

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Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

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Viser hvordan tarmbakterier påvirker vagusnerven. Mus som har fått vagusnerven fjernet opplevde ingen av de stress-,  angst,  og depresjonsreduserende effektene av Lactobacillus Rhamnosus tilskudd. Dette viser hvor viktig vagusnerven er i kommunikasjonen mellom hjerne og tarmsystem.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179073/

ABSTRACT

There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABAB1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus(JB-1) reduced GABAAα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABAAα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut–brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.

There is increasing evidence suggesting an interaction between the intestinal microbiota, the gut, and the central nervous system (CNS) in what is recognized as the microbiome–gut–brain axis (1–4). Studies in rodents have implicated dysregulation of this axis in functional bowel disorders, including irritable bowel syndrome. Indeed, visceral perception in rodents can be affected by alterations in gut microbiota (5). Moreover, it has been shown that the absence and/or modification of the gut microflora in mice affects the hypothalamic–pituitary–adrenal (HPA) axis response to stress (6, 7) and anxiety behavior (8, 9), which is important given the high comorbidity between functional gastrointestinal disorders and stress-related psychiatric disorders, such as anxiety and depression (10). In addition, pathogenic bacteria in rodents can induce anxiety-like behaviors, which are mediated via vagal afferents (9, 11).

Accumulating clinical evidence suggests that probiotics can modulate the stress response and improve mood and anxiety symptoms in patients with chronic fatigue and irritable bowel syndrome (15, 16). One such organism isLactobacillus rhamnosus (JB-1), which has been demonstrated to modulate the immune system because it prevents the induction of IL-8 by TNF-α in human colon epithelial cell lines (T84 and HT-29) (17) and modulates inflammation through the generation of regulatory T cells (18). Moreover, it inhibits the cardio–autonomic response to colorectal distension (CRD) in rats (19), reduces CRD-induced dorsal root ganglia excitability (20), and affects small intestine motility (21).

Stress-induced levels of corticosterone are significantly lower in L. rhamnosus(JB-1)-fed mice compared with broth fed control animals (###P < 0.001).

Furthermore, in this study we observed that L. rhamnosus (JB-1) administration reduces the stress-induced elevation in corticosterone, suggesting that the impact of the Lactobacillus on the CNS has an important effect at a physiological level. Alterations in the HPA axis have been linked to the development of mood disorders and have been shown to affect the composition of the microbiota in rodents (26). Our data are in line with previous studies showing that subchronic or chronic treatment with antidepressants can prevent forced swim stress-induced increases in plasma corticosterone in both mice and rats (27). Moreover, it has been shown that alterations in HPA axis modulation can be reversed by treatment with Lactobacillus andBifidobacterium (28, 29).

The vagus nerve plays a major role in communicating changes in the gastrointestinal tract to the CNS (3). In the present study, Vx prevented the anxiolytic and antidepressant effects of L. rhamnosus (JB-1) and also the changes in GABAAα2 and GABAAα1 mRNAs in the amygdala (SI Materials and Methods), as well as GABAAα1mRNA in the hippocampus.

Moreover, vagus nerve stimulation has been described as a successful approach to treat some (44), but not all (45), patients with treatment-resistant depression, which further suggests the importance of the vagus nerve in the modulation of behavior.

 Nonetheless, our data conclusively demonstrate that a potential probiotic can robustly alter brain neurochemistry and behavior relevant to anxiety- and depression-related behavior in mice.

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Heartbeat Synchronizes With Respiratory Rhythm Only Under Specific Circumstances

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Dette er et svar på en studie hvor de viser at HRV er høyest ved 0.1 Hz (6 pust/min).

http://journal.publications.chestnet.org/article.aspx?articleid=1082860

we determined that the phase relationship between heart rate and respiration was 0° only at a respiratory frequency of approximately 0.1 Hz, in which the target frequency heart rate variability also was highest (Fig 1 ).

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Kritikk til polyvagal teorien og mye viktig om vagus-pust forbindelsen

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Svært viktig studie som forteller om alle aspekter ved vagus nervens og pustens relasjon. Nevner at det ikke er en direkte relasjon, og at det blir ikke riktig å si at RSA/HRV er en direkte intdikasjon på vagus nervens funksjon. Mange faktorer spiller inn. Sier også at vagus fyrer av like mye, men når pustefrekvensen synker blir signalene sterkere i løpet av den lange utpusten. Nevner også at i individet er det tydelig sammenheng mellom pust og HRV, men mellom forskjellige individer er det store forskjeller. Nevner også at vagus nerven fyrer av når CO2 øker for øke gassutvekslingen mellom blod og luft.

http://www.ncbi.nlm.nih.gov/pubmed/17081672

Mer fra studien er her.

Abstract

Respiratory sinus arrhythmia (RSA, or high-frequency heart-rate variability) is frequently employed as an index of cardiac vagal tone or even believed to be a direct measure of vagal tone. However, there are many significant caveats regarding vagal tone interpretation:

1. Respiratory parameters can confound relations between RSA and cardiac vagal tone.

2. Although intraindividual relations between RSA and cardiac vagal control are often strong, interindividual associations may be modest.

3. RSA measurement is profoundly influenced by concurrent levels of momentary physical activity, which can bias estimation of individual differences in vagal tone.

4. RSA magnitude is affected by beta-adrenergic tone.

5. RSA and cardiac vagal tone can dissociate under certain circumstances.

6. The polyvagal theory contains evolution-based speculations that relate RSA, vagal tone and behavioral phenomena.

We present evidence that the polyvagal theory does not accurately depict evolution of vagal control of heart-rate variability, and that it ignores the phenomenon of cardiac aliasing and disregards the evolution of a functional role for vagal control of the heart, from cardiorespiratory synchrony in fish to RSA in mammals. Unawareness of these issues can lead to misinterpretation of cardiovascular autonomic mechanisms. On the other hand, RSA has been shown to often provide a reasonable reflection of cardiac vagal tone when the above-mentioned complexities are considered. Finally, a recent hypothesis is expanded upon, in which RSA plays a primary role in regulation of energy exchange by means of synchronizing respiratory and cardiovascular processes during metabolic and behavioral change.

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Evoked Pain Analgesia in Chronic Pelvic Pain Patients using Respiratory-gated Auricular Vagal Afferent Nerve Stimulation

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I medisinsk sammenheng benyttes ofte elektrisk stimuli i øret for å styrke vagusnerven gjennom dens forbindelse til huden i øret. I denne studien viser de at vagus nerven stimuleres best om man synkroniserer stimulien med utpust. Denne kobler altså medisinsk stimuli med pustens stimuli. Men de har ingen oppmerksomhet på mulighetene ved å senke pustefrekvens samtidig.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376238/

Chronic pain disorders such as CPP are in great need of effective, non-pharmacological options for treatment. RAVANS (Respiratory-gated Auricular Vagal Afferent Nerve Stimulation) produced promising anti-nociceptive effects for QST outcomes reflective of the noted hyperalgesia and central sensitization in this patient population. Future studies should evaluate longer-term application of RAVANS to examine its effects on both QST outcomes and clinical pain.

The analgesic mechanisms of VNS have not been fully elucidated, but are likely mediated by afferent (not efferent) input to supraspinal brain regions [16]. Vagal afference is relayed to the nucleus tractus solitarious (NTS) in the medullary brainstem. Importantly, the NTS also receives somatosensory afference via the auricular branch of the vagus (ABV) nerve from specific portions of the auricle [17]. ABV afference is transmitted to both the NTS [17] and the spinal trigeminal nucleus (SpV) [18], by neurons located in the superior (jugular) ganglion of the vagus nerve. Respiration can modulate NTS activity directly (the lungs are innervated by the vagus nerve) and indirectly. In regard to the latter, inspiration increases venous return to the thorax, which increases arterial pressure, and hence vagal (and glossopharyngeal n.) afference to the NTS via aortic and carotid baroreceptors, respectively [19]. The NTS then inhibits efferent vagal outflow to the heart [20, 21], leading to a transient inspiratory tachycardia with every breath. This feedback loop is termed “respiratory sinus arrhythmia” [22]. Hence, the dorsal medullary vagal system operates in tune with respiration, and we propose that supplying vagal afferent stimulation gated to the exhalation phase of respiration (i.e. when thoracic baroreceptor afference does not enter the NTS), will optimize t-VNS therapy (see Figure 1 for schematic). Furthermore, such intermittent, irregular stimulation (i.e., varying with respiration) will also mitigate classical neuronal adaptation/accomodation, which can occur with continuous stimulation of NTS neurons [23].