Autonomic regulation and vagal tone

Autonomy of autonomic dysfunction in major depression.: Objective: To investigate cardiac autonomic dysfunction in patients with major depressive disorder (MDD). Research in this area has faced several limitations because of the heterogeneity of the disease, the influence of medication, and methodological shortcomings. Methods: Participants were 75 patients suffering from an acute recurrent episode of MDD and 75 matched controls. All participants were assessed at baseline for linear and nonlinear parameters of heart rate variability, QT variability a

Non-invasive vagus nerve stimulation acutely improves spontaneous cardiac baroreflex sensitivity in healthy young men: A randomized placebo-controlled trial.: Background: Despite positive outcomes of transcutaneous vagus nerve stimulation (tVNS) via the auricular branch of the vagus nerve (ABVN), the mechanisms underlying these outcomes remain unclear. Additionally, previous studies have not been controlled the possible placebo effects of tVNS. Objective: To test the hypothesis that tVNS acutely improves spontaneous cardiac baroreflex sensitivity (cBRS) and autonomic modulation, and that these effects are specific to stimulation of ABVN. Methods: Thir

Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity.: Background: Vagus nerve stimulation (VNS) is currently used to treat refractory epilepsy and is being investigated as a potential therapy for a range of conditions, including heart failure, tinnitus, obesity and Alzheimer's disease. However, the invasive nature and expense limits the use of VNS in patient populations and hinders the exploration of the mechanisms involved. Objective: We investigated a non-invasive method of VNS through electrical stimulation of the auricular branch of the vagus n

Effects of transcutaneous vagus nerve stimulation in individuals aged 55 years or above: potential benefits of daily stimulation.: Ageing is associated with attenuated autonomic function. Transcutaneous vagal nerve stimulation (tVNS) improved autonomic function in healthy young participants. We therefore investigated the effects of a single session of tVNS (studies 1 and 2) and tVNS administered daily for two weeks (study 3) in volunteers aged ≥ 55 years. tVNS was performed using modified surface electrodes on the tragus and connected to a transcutaneous electrical nerve stimulation (TENS) machine. Study 1: participants (n=

Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity.: Background: The parasympathetic nervous system, whose main neural substrate is the vagus nerve, exerts a fundamental antinociceptive role and influences gastrointestinal sensori-motor function. Our research question was to whether combined electrical and physiological modulation of vagal tone, using transcutaneous electrical vagal nerve stimulation (t-VNS) and deep slow breathing (DSB) respectively, could increase musculoskeletal pain thresholds and enhance gastroduodenal motility in healthy sub

Sex differences in healthy human heart rate variability: A meta-analysis.: The present meta-analysis aimed to quantify current evidence on sex differences in the autonomic control of the heart, indexed by measures of heart rate variability (HRV) in healthy human subjects. An extensive search of the literature yielded 2020 titles and abstracts, of which 172 provided sufficient reporting of sex difference in HRV. Data from 63,612 participants (31,970 females) were available for analysis. Meta-analysis yielded a total of 1154 effect size estimates (k) across 50 different

Cardiac parasympathetic regulation: respective associations with cardiorespiratory fitness and training load.

The objective of this study was to establish the separate associations between parasympathetic modulations of the heart [evaluated through heart rate (HR) variability (HRV) indexes and postexercise HR recovery (HRR) indexes] with cardiorespiratory fitness and training load. We have measured cardiorespiratory fitness through peak oxygen consumption (Vo2 max) and estimated weekly training load with the Baecke sport score in 55 middle-aged individuals (30.8 +/- 1.8 yr, body mass index 24.5 +/- 0.4 kg/m2). HRV indexes were analyzed at rest under controlled breathing, and HRR was estimated from HR curve fitting after maximal exercise or from measurements of the number of beats recovered at 60 s after exercise. Multiple linear regressions were used to investigate the separate relationships between vagal-related HRV indexes and Vo2 max and Baecke scores. On the basis of their Vo2 max and Baecke…

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The effects of respiratory sinus arrhythmia biofeedback on heart rate variability and posttraumatic stress disorder symptoms: a pilot study.

Recent studies have found a significant association between PTSD and low heart rate variability (HRV), a biomarker of autonomic dysregulation. Research indicates that respiratory sinus arrhythmia (RSA) biofeedback increases HRV while reducing related pathological symptoms. This controlled pilot study compared RSA biofeedback to progressive muscle relaxation (PMR) as adjunctive interventions for 38 persons with PTSD symptoms in a residential treatment facility for a substance use disorder. Both groups were assessed at pre-intervention and 4-week post-intervention. Group x time interactions revealed significantly greater reductions in depressive symptoms and increases in HRV indices for the RSA group. Both groups significantly reduced PTSD and insomnia symptoms and a statistical trend was observed for reduced substance craving for the RSA group. Increases in HRV were significantly associat…

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The role of vagal function in the risk for cardiovascular disease and mortality.

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. The understanding of the risk factors for CVD may yield important insights into the prevention, etiology, course, and treatment of this major public health concern. We review the evidence for the role of vagal function in the risk for cardiovascular disease and mortality. Using a broad range of indicators of vagal function including resting heart rate, heart rate recovery, heart rate variability, and baroreflex sensitivity we show that decreased vagal function is associated with an increased risk for morbidity and mortality. These effects are independent of traditional risk factors. Moreover, we show that decreased vagal function is associated with both traditional and emerging risk factors as well as modifiable and non-modifiable risk factors. Most importantly, we provide evidence to support the notion …

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The efficacy and safety of transcutaneous auricular vagus nerve stimulation in patients with mild cognitive impairment: A double blinded randomized clinical trial.

Background: There are 9.9 million new cases of dementia in the world every year. Short-term conversion rate from mild cognitive impairment (MCI) to dementia is between 20% and 40%, but long-term in 5-10 years ranges from 60% to 100%. It is particularly important to prevent or prolong the development of MCI into dementia. Both auriculotherapy and vagus nerve stimulation are effective on improving cognitive functions. However, there is no double blinded randomized clinical trial to support the effectiveness of transcutaneous electrical stimulation of auricular acupoints in patients with MCI. Methods: This randomized controlled trial involved patients with MCI, aged from 55 to 75 years old. Patients were randomly allocated to transcutaneous auricular vagus nerve stimulation (taVNS) group or sham taVNS group. In the taVNS group, two auricular acupoints were stimulated, including heart (conch…

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Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review.

Background: Electrical stimulation of the auricular branch of the vagus nerve (ABVN) via transcutaneous auricular vagus nerve stimulation (taVNS) may influence afferent vagal networks. There have been 5 prior taVNS/fMRI studies, with inconsistent findings due to variability in stimulation targets and parameters. Objective: We developed a taVNS/fMRI system to enable concurrent electrical stimulation and fMRI acquisition to compare the effects of taVNS in relation to control stimulation. Methods: We enrolled 17 healthy adults in this single-blind, crossover taVNS/fMRI trial. Based on parameters shown to affect heart rate in healthy volunteers, participants received either left tragus (active) or earlobe (control) stimulation at 500 μs 25 HZ for 60 s (repeated 3 times over 6 min). Whole brain fMRI analysis was performed exploring the effect of: active stimulation, control stimulation, and t…

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Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02).

Background: Various brain stimulation techniques are in use to treat epilepsy. These methods usually require surgical implantation procedures. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive technique to stimulate the left auricular branch of the vagus nerve at the ear conch. Objective: We performed a randomized, double-blind controlled trial (cMPsE02) to assess efficacy and safety of tVNS vs. control stimulation in patients with drug-resistant epilepsy. Methods: Primary objective was to demonstrate superiority of add-on therapy with tVNS (stimulation frequency 25 Hz, n = 39) versus active control (1 Hz, n = 37) in reducing seizure frequency over 20 weeks. Secondary objectives comprised reduction in seizure frequency from baseline to end of treatment, subgroup analyses and safety evaluation. Results: Treatment adherence was 84% in the 1 Hz group and 88% in the 25 Hz group…

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Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder.

Background: Depression is the most common form of mental disorder in community and health care settings and current treatments are far from satisfactory. Vagus nerve stimulation (VNS) is a Food and Drug Administration approved somatic treatment for treatment-resistant depression. However, the involvement of surgery has limited VNS only to patients who have failed to respond to multiple treatment options. Transcutaneous VNS (tVNS) is a relatively new, noninvasive VNS method based on the rationale that there is afferent/efferent vagus nerve distribution on the surface of the ear. The safe and low-cost characteristics of tVNS have the potential to significantly expand the clinical application of VNS. Methods: In this study, we investigated how tVNS can modulate the default mode network (DMN) functional connectivity (FC) in mild or moderate major depressive disorder (MDD) patients. Forty-nin…

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Vagus Nerve Stimulation and the Cardiovascular System.

The vagus nerve plays an important role in maintaining physiological homeostasis, which includes reflex pathways that regulate cardiac function. The link between vagus nerve activity and the high-frequency component of heart rate variability (HRV) has been well established, correlating with vagal tone. Recently, vagus nerve stimulation (VNS) has been investigated as a therapeutic for a multitude of diseases, such as treatment-resistant epilepsy, rheumatoid arthritis, Crohn's disease, and asthma. Because of the vagus nerve's innervation of the heart, VNS has been identified as a potential therapy for cardiovascular disorders, such as cardiac arrest, acute myocardial infarction, and stroke. Here, we review the current state of preclinical and clinical studies, as well as the potential application of VNS in relation to the cardiovascular system.

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TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation): A Randomized Clinical Trial.

Objectives: This study was a sham-controlled, double-blind, randomized clinical trial to examine the effect of chronic low level tragus stimulation (LLTS) in patients with paroxysmal AF. Background: Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve at the tragus (LLTS) acutely suppresses atrial fibrillation (AF) in humans, but the chronic effect remains unknown. Methods: LLTS (20 Hz, 1 mA below the discomfort threshold) was delivered using an ear clip attached to the tragus (active arm) (n = 26) or the ear lobe (sham control arm) (n = 27) for 1 h daily over 6 months. AF burden over 2-week periods was assessed by noninvasive continuous electrocardiogram monitoring at baseline, 3 months, and 6 months. Five-minute electrocardiography and serum were obtained at each visit to measure heart rate variability and inflammatory cytokines, respectively. Resu…

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Biofeedback on heart rate variability in cardiac rehabilitation: practical feasibility and psycho-physiological effects.

Objective: Biofeedback is a self-regulation therapy by which the patient learns how to optimize the functioning of his autonomic nervous system. It has been applied to patients with various cardiovascular disorders. The purpose of this study was to investigate the practical feasibility and the psychophysiological effects of biofeedback applied to heart rate variability (HRV biofeedback) in order to increase cardiac coherence in coronary artery disease (CAD) patients participating in a cardiac rehabilitation programme. Methods and results: In this randomised and controlled study, 31 CAD patients were randomly assigned to an experimental or to a control group. The experimental group participated in a programme of 10 sessions of cardiac coherence biofeedback training, in addition to the rehabilitation programme. The control group participated in the usual cardiac rehabilitation programme on…

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Voluntarily produced increases in heart rate variability modulate autonomic effects of endotoxin induced systemic inflammation: an exploratory study.

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 …

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A systematic review and meta-analysis of heart rate variability in epilepsy and antiepileptic drugs.

Purpose: Epilepsy is associated with near-fatal and fatal arrhythmias, and sudden unexpected death in epilepsy (SUDEP) is partly related to cardiac events. Dysfunction of the autonomous nervous system causes arrhythmias and, although previous studies have investigated the effects of epilepsy on the autonomic control of the heart, the results are still mixed regarding whether imbalance of sympathetic, vagal, or both systems is present in epilepsy, and also the importance of anticonvulsant treatment on the autonomic system. Therefore, we aimed to investigate epilepsy and its treatment impact on heart rate variability (HRV), assessed by sympathetic and parasympathetic activity expressed as low-frequency (LF) and high-frequency (HF) power spectrum, respectively. Method: We performed a systematic review from the first date available to July 2011 in Medline and other databases; key search term…

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Impact of depression and antidepressant treatment on heart rate variability: a review and meta-analysis.

Background: Depression is associated with an increase in the likelihood of cardiac events; however, studies investigating the relationship between depression and heart rate variability (HRV) have generally focused on patients with cardiovascular disease (CVD). The objective of the current report is to examine with meta-analysis the impact of depression and antidepressant treatment on HRV in depressed patients without CVD. Methods: Studies comparing 1) HRV in patients with major depressive disorder and healthy control subjects and 2) the HRV of patients with major depressive disorder before and after treatment were considered for meta-analysis. Results: Meta-analyses were based on 18 articles that met inclusion criteria, comprising a total of 673 depressed participants and 407 healthy comparison participants. Participants with depression had lower HRV (time frequency: Hedges' g = -.301, p…

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Relaxation training assisted by heart rate variability biofeedback: Implication for a military predeployment stress inoculation protocol.

Decreased heart rate variability (HRV) is associated with posttraumatic stress disorder (PTSD) and depression symptoms, but PTSD's effects on the autonomic stress response and the potential influence of HRV biofeedback in stress relaxation training on improving PTSD symptoms are not well understood. The objective of this study was to examine the impact of a predeployment stress inoculation training (PRESTINT) protocol on physiologic measures of HRV in a large sample of the military population randomly assigned to experimental HRV biofeedback-assisted relaxation training versus a control condition. PRESTINT altered the parasympathetic regulation of cardiac activity, with experimental subjects exhibiting greater HRV, that is, less arousal, during a posttraining combat simulation designed to heighten arousal. Autonomic reactivity was also found to be related to PTSD and self-reported use of…

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Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial.

Objective: ANTHEM-HF evaluated a novel autonomic regulation therapy (ART) via either left or right vagus nerve stimulation (VNS) in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Methods and results: Sixty subjects (New York Heart Association [NYHA] functional class II-III, left ventricular ejection fraction (LVEF) ≤ 40%, left ventricular end-diastolic diameter ≥ 50 mm to < 80 mm) receiving optimal pharmacologic therapy were randomized at 10 sites. VNS systems were randomly implanted on the left (n = 31) or right (n = 29) side. All patients were successfully implanted and 59 were titrated over 10 weeks to a well tolerated stimulation intensity. One patient died 3 days after an embolic stroke that occurred during implantation. Common device-related adverse events after VNS titration were transient mild dysphonia, cough, and oropharyngeal pain, which were similar f…

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Resting respiratory sinus arrhythmia is associated with tonic positive emotionality.

Resting respiratory sinus arrhythmia (RSAREST) indexes important aspects of individual differences in emotionality. In the present investigation, the authors address whether RSAREST is associated with tonic positive or negative emotionality, and whether RSAREST relates to phasic emotional responding to discrete positive emotion-eliciting stimuli. Across an 8-month, multiassessment study of first-year university students (n = 80), individual differences in RSAREST were associated with positive but not negative tonic emotionality, assessed at the level of personality traits, long-term moods, the disposition toward optimism, and baseline reports of current emotional states. RSAREST was not related to increased positive emotion, or stimulus-specific emotion, in response to compassion-, awe-, or pride-inducing stimuli. These findings suggest that resting RSA indexes aspects of a person's toni…

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Toward understanding respiratory sinus arrhythmia: relations to cardiac vagal tone, evolution and biobehavioral functions.

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 p…

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Vagal tone: effects on sensitivity, motility, and inflammation.

The vagus nerve (VN) is a key element of the autonomic nervous system. As a mixed nerve, the VN contributes to the bidirectional interactions between the brain and the gut, i.e., the brain-gut axis. In particular, after integration in the central autonomic network of peripheral sensations such as inflammation and pain via vagal and spinal afferents, an efferent response through modulation of preganglionic parasympathetic neurons of the dorsal motor nucleus of the vagus and/or preganglionic sympathetic neurons of the spinal cord is able to modulate gastrointestinal nociception, motility, and inflammation. A low vagal tone, as assessed by heart rate variability, a marker of the sympatho-vagal balance, is observed in functional digestive disorders and inflammatory bowel diseases. To restore a normal vagal tone appears as a goal in such diseases. Among the therapeutic tools, such as drugs ta…

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A 12-month pilot study outcomes of vagus nerve stimulation in Crohn's disease.

Background: The vagus nerve has anti-inflammatory properties. We aimed to investigate vagus nerve stimulation (VNS) as a new therapeutic strategy targeting an intrinsic anti-inflammatory pathway in a pilot study in Crohn's disease patients. The main objectives addressed the questions of long-term safety, tolerability, and anti-inflammatory effects of this therapy. This study is the continuation of previous reported findings at 6 months. Methods: Nine patients with moderate active disease underwent VNS. An electrode wrapped around the left cervical vagus nerve was continuously stimulated over 1 year. Clinical, biological, endoscopic parameters, cytokines (plasma, gut), and mucosal metabolites were followed-up. Key results: After 1 year of VNS, five patients were in clinical remission and six in endoscopic remission. C-reactive protein (CRP) and fecal calprotectin decreased in six and five…

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Daily heart rate variability biofeedback training decreases locus coeruleus MRI contrast in younger adults in a randomized clinical trial.

As an arousal hub region in the brain, the locus coeruleus (LC) has bidirectional connections with the autonomic nervous system. Magnetic resonance imaging (MRI)-based measures of LC structural integrity have been linked to cognition and arousal, but less is known about factors that influence LC structure and function across time. Here, we tested the effects of heart rate variability (HRV) biofeedback, an intervention targeting the autonomic nervous system, on LC MRI contrast and sympathetic activity. Younger and older participants completed daily HRV biofeedback training for five weeks. Those assigned to an experimental condition performed biofeedback involving slow, paced breathing designed to increase heart rate oscillations, whereas those assigned to a control condition performed biofeedback to decrease heart rate oscillations. At the pre- and post-training timepoints, LC contrast wa…

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Methods for Heart Rate Variability Biofeedback (HRVB): A Systematic Review and Guidelines.

Heart Rate Variability Biofeedback (HRVB) has been widely used to improve cardiovascular health and well-being. HRVB is based on breathing at an individual's resonance frequency, which stimulates respiratory sinus arrhythmia (RSA) and the baroreflex. There is, however, no methodological consensus on how to apply HRVB, while details about the protocol used are often not well reported. Thus, the objectives of this systematic review are to describe the different HRVB protocols and detect methodological concerns. PsycINFO, CINALH, Medline and Web of Science were searched between 2000 and April 2021. Data extraction and quality assessment were based on PRISMA guidelines. A total of 143 studies were finally included from any scientific field and any type of sample. Three protocols for HRVB were found: (i) "Optimal RF" (n = 37), each participant breathes at their previously detected RF; (ii) "I…

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Should heart rate variability be "corrected" for heart rate? Biological, quantitative, and interpretive considerations.

Metrics of heart period variability are widely used in the behavioral and biomedical sciences, although somewhat confusingly labeled as heart rate variability (HRV). Despite their wide use, HRV metrics are usually analyzed and interpreted without reference to prevailing levels of cardiac chronotropic state (i.e., mean heart rate or mean heart period). This isolated treatment of HRV metrics is nontrivial. All HRV metrics routinely used in the literature exhibit a known and positive relationship with the mean duration of the interval between two beats (heart period): as the heart period increases, so does its variability. This raises the question of whether HRV metrics should be "corrected" for the mean heart period (or its inverse, the heart rate). Here, we outline biological, quantitative, and interpretive issues engendered by this question. We provide arguments that HRV is neither unifo…

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Neurophysiological Approach by Self-Control of Your Stress-Related Autonomic Nervous System with Depression, Stress and Anxiety Patients.

Background: Heart Rate Variability Biofeedback (HRVB) is a treatment in which patients learn self-regulation of a physiological dysregulated vagal nerve function. While the therapeutic approach of HRVB is promising for a variety of disorders, it has not yet been regularly offered in a mental health treatment setting. Aim: To provide a systematic review about the efficacy of HRV-Biofeedback in treatment of anxiety, depression, and stress related disorders. Method: Systematic review in PubMed and Web of Science in 2020 with terms HRV, biofeedback, Post-Traumatic Stress Disorder (PTSD), depression, panic disorder, and anxiety disorder. Selection, critical appraisal, and description of the Random Controlled Trials (RCT) studies. Combined with recent meta-analyses. Results: The search resulted in a total of 881 studies. After critical appraisal, nine RCTs have been selected as well as two oth…

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Heart rate variability and experimentally induced pain in healthy adults: a systematic review.

Background: Reactivity of the autonomic nervous system to experimental pain stimuli has been extensively studied using measures of heart rate and blood pressure. Heart rate variability (HRV) attempts to tease out the relative contributions of sympathetic and parasympathetic activity in the autonomic control of the heart and may therefore be more appropriate to investigate autonomic response to short-term nociceptive stimulation in detail. The current evidence on HRV and experimentally induced pain has not yet been synthesized within a systematic review. Method: English articles indexed in PubMed, EMBASE, Psyndex, PsycINFO, CINAHL and the Cochrane Library were reviewed for eligibility under pre-specified inclusion criteria. Studies were included when they reported empirical work on autonomic response (specifically, HRV) to experimentally induced pain in healthy adults. The method of pain …

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Autonomic nervous system activity and workplace stressors--a systematic review.

Aim: This systematic review evaluates and summarizes the evidence of the association between psychosocial work environment as indicated by several work-stress models such as Job-Demand-Control (JDC), Effort-Reward-Imbalance (ERI), or Organizational Justice (OJ) and autonomic nervous system (ANS) function as indexed by heart rate variability (HRV). Method: We conducted a systematic literature search following the PRISMA-Statement in eleven databases including Medline, Web of Science and PsycINFO to address medical as well as psychological aspects of the relation between psychosocial work-stress models and HRV. Results: We identified 19 publications with a total of 8382 employees from ten countries reporting data from the years 1976-2008. Overall, nine of all studies report a negative and significant association between vagally-mediated HRV and measures of stress at work, while eight of al…

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