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

Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve: a noninvasive approach to treat the initial phase of atrial fibrillation.

Background: We studied the effects of transcutaneous electrical stimulation at the tragus, the anterior protuberance of the outer ear, for inhibiting atrial fibrillation (AF). Objective: To develop a noninvasive transcutaneous approach to deliver low-level vagal nerve stimulation to the tragus in order to treat cardiac arrhythmias such as AF. Methods: In 16 pentobarbital anesthetized dogs, multielectrode catheters were attached to pulmonary veins and atria. Three tungsten-coated microelectrodes were inserted into the anterior right ganglionated plexi to record neural activity. Tragus stimulation (20 Hz) in the right ear was accomplished by attaching 2 alligator clips onto the tragus. The voltage slowing the sinus rate or atrioventricular conduction was used as the threshold for setting the low-level tragus stimulation (LL-TS) at 80% below the threshold. At baseline, programmed stimulatio…

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Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation.

Background: Transcutaneous low-level tragus electrical stimulation (LLTS) suppresses atrial fibrillation (AF) in canines. Objectives: This study examined the antiarrhythmic and anti-inflammatory effects of LLTS in humans. Methods: Patients with paroxysmal AF who presented for AF ablation were randomized to either 1 h of LLTS (n = 20) or sham control (n = 20). Attaching a flat metal clip onto the tragus produced LLTS (20 Hz) in the right ear (50% lower than the voltage slowing the sinus rate). Under general anesthesia, AF was induced by burst atrial pacing at baseline and after 1 h of LLTS or sham treatment. Blood samples from the coronary sinus and the femoral vein were collected at those time points and then analyzed for inflammatory cytokines, including tumor necrosis factor alpha and C-reactive protein, using a multiplex immunoassay. Results: There were no differences in baseline char…

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Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model.

Background: Autonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, contributes to the progression of heart failure (HF). Although the therapeutic benefits of sympathetic inhibition with beta-blockers in HF are clear, the role of increased vagal tone in this setting has been less studied. We have investigated the impact of enhancing vagal tone (achieved through chronic cervical vagus nerve stimulation, [VNS]) on HF development in a canine high-rate ventricular pacing model. Methods and results: Fifteen dogs were randomized into control (n=7) and VNS (n=8) groups. All dogs underwent 8 weeks of high-rate ventricular pacing (at 220 bpm for the first 4 weeks to develop HF and another 4 weeks at 180 bpm to maintain HF). Concomitant VNS, at an intensity reducing sinus rate approximately 20 bpm, was delivered together with the ventricular pacing in the VNS group. At…

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Low-frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes.

Power spectral analysis of heart rate variability has often been used to assess cardiac autonomic function; however, the relationship of low-frequency (LF) power of heart rate variability to cardiac sympathetic tone has been unclear. With or without adjustment for high-frequency (HF) power, total power or respiration, LF power seems to provide an index not of cardiac sympathetic tone but of baroreflex function. Manipulations and drugs that change LF power or LF:HF may do so not by affecting cardiac autonomic outflows directly but by affecting modulation of those outflows by baroreflexes.

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Autonomic alterations and cardiac changes in epilepsy.

Studies with heart rate variability have revealed interictal autonomic alterations in patients with epilepsy. In addition, epilepsy is frequently associated with ictal tachycardia or bradycardia, which sometimes precedes the onset of seizures. Ictal tachycardia is sometimes associated with electrocardiography (ECG) morphologic changes and ictal bradycardia often progresses to asystole. Such cardiac manifestations of seizures have been hypothesized as possible causes for sudden unexplained death in epilepsy (SUPEP). The present review relates to interictal and ictal cardiac manifestations of epilepsy with focus on heart rate, heart rate variability, and ECG changes. Aspects of the supporting mechanisms are discussed and attention is drawn to the interaction between central and peripheral effects, interictal autonomic conditions, ictal autonomic discharges, and administration of antiepilep…

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Autonomic nerve activity and atrial fibrillation.

This review focuses on the importance of autonomic nervous system (ANS) activity in the induction of paroxysmal atrial fibrillation (PAF). Clinical studies suggest that both sympathetic and parasympathetic nervous systems are important in mediating PAF. Consistent with that hypothesis, heart rate variability analyses showed that sympathovagal imbalance is present before the onset of PAF episodes. The importance of the ANS in PAF is further supported by animal experiments and recent clinical studies showing that vagal denervation enhances the efficacy of circumferential pulmonary vein ablation in preventing AF recurrence. In vitro studies show that ANS activation facilitates early afterdepolarization and triggered activity by simultaneously prolonging the intracellular calcium (Ca(i)) transient (sympathetic effect) and shortening the action potential duration (parasympathetic effect). By …

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Effect of a Biofeedback Intervention on Heart Rate Variability in Individuals With Panic Disorder: A Randomized Controlled Trial.

Objective: Some individuals with panic disorder (PD) display reduced heart rate variability (HRV), which may result in an increased risk of cardiovascular mortality. Heart rate variability-biofeedback (HRV-BF) training has been shown to improve the modulation of the autonomic activity. Therefore, this randomized controlled trial was conducted to investigate the effect of a 4-week HRV-BF intervention in individuals with PD. HRV-BF training improved the modulation of the autonomic activity. Therefore, with this randomized controlled trial, we aimed to investigate the effect of a 4-week HRV-BF intervention in people with PD. Methods: Thirty-six women and 16 men with PD (mean age = 35.85 [15.60] years) were randomly allocated either to HRV-BF with 0.1-Hz breathing as intervention group or to HRV-Sham-BF as active control group. HRV-BF was performed for 4 weeks, whereas HRV was measured both …

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Effects of Heart Rate Variability Biofeedback in Patients With Acute Ischemic Stroke: A Randomized Controlled Trial.

Background: Autonomic dysfunction, cognitive impairment, and psychological distress are associated with poorer prognosis in patients with acute ischemic stroke (AIS). Heart rate variability (HRV) biofeedback (BF) improves autonomic dysfunction, cognitive impairment, and psychological distress in other patient populations, but its effect in patients with AIS is still unclear. Objective: This study investigated the effects of an HRVBF intervention on autonomic function, cognitive impairment, and psychological distress in patients with AIS. Method: In this randomized, controlled, single-blind trial, patients with AIS were randomly assigned to the experimental or control group. The experimental group received four HRVBF training sessions. The control group received usual care. Repeated measures of HRV, mini-mental status examination (MMSE), and Hospital Anxiety and Depression Scales (HADS) w…

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Symptom Management Among Cancer Survivors: Randomized Pilot Intervention Trial of Heart Rate Variability Biofeedback.

Chronic cancer-related symptoms (stress, fatigue, pain, depression, insomnia) may be linked with sympathetic nervous system over-activation and autonomic imbalance. Decreased heart rate variability (HRV) is an indicator of autonomic dysregulation that is commonly observed among cancer survivors. HRV biofeedback (HRVB) training induces HRV coherence, which maximizes HRV and facilitates autonomic and cardiorespiratory homeostasis. This randomized, wait-list-controlled, pilot intervention trial tested the hypothesis that HRVB can improve HRV coherence and alleviate cancer-related symptoms. The intervention group (n = 17) received 4-6 weekly HRVB training sessions until participants demonstrated skill acquisition. Controls (n = 17) received usual care. Outcomes assessed at baseline and follow-up included 15-min HRV recordings (HRV Coherence Ratio), and symptoms of: stress, distress, post-tra…

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Effectiveness of emWave biofeedback in improving heart rate variability reactivity to and recovery from stress.

The current study examined the efficacy of heart rate variability (HRV) biofeedback using emWave, a publicly available biofeedback device, to determine whether training affected physiological tone and stress responses. Twenty-seven individuals aged 18-30 years were randomized to a treatment or no-treatment control group. Treatment participants underwent 4-8 sessions of emWave intervention, and all participants attended pre-treatment and post-treatment assessment sessions during which acute stressors were administered. Physiological data were collected at rest, during stress, and following stress. emWave treatment did not confer changes in tonic measures of HRV or in HRV recovery following stress. However, treatment participants exhibited higher parasympathetic responses (i.e., pNN50) during stress presentations at the post-treatment session than their control counterparts. No treatment e…

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Psychophysiological investigations in depersonalization disorder and effects of electrodermal biofeedback.

Previous studies investigating depersonalization disorder (DPD) report a lower baseline skin conductance level (SCL) and attenuated skin conductance response (SCR) to emotive stimuli. We hypothesized that increasing physiological arousal levels via electrodermal biofeedback may ameliorate disembodiment and emotional numbing symptomatology. Real-time versus sham biofeedback yielded a significant SCL increase after just 3 real-time biofeedback sessions in healthy volunteers. Subsequently, a randomized controlled biofeedback trial was administered with DPD patients. Findings were not replicated as SCL tended to fall, curiously more substantially in the real-time condition, concomitant with increased low- and high-frequency heart rate variability. To further investigate abnormal autonomic regulation in DPD, we compared basal autonomic activity between patients and healthy volunteers and foun…

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Moderating laboratory adaptation with the use of a heart-rate variability biofeedback device (StressEraser).

Difficulty sleeping is a common problem with laboratory polysomnograms. This affects both polysomnograms that are used as a clinical tool to investigate sleep pathology or as an outcome variable in research. The goal of this study was to use a handheld biofeedback device (StressEraser) to improve sleep quality in the laboratory. Ten subjects without a history of sleep disorders were randomly assigned to either a StressEraser or no-treatment control condition. A sleep disturbance scale derived from sleep efficiency, REM latency, minutes of stage 1 sleep, and wake after sleep onset was created to evaluate the differences between these groups. Subjects in the StressEraser group had significantly lower scores on the sleep disturbance scale compared to the no-treatment control group (p = 0.003). Sleep latency was not improved. In conclusion, the StressEraser significantly improved sleep quali…

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Heart rate variability is enhanced in controls but not maladaptive perfectionists during brief mindfulness meditation following stress-induction: A stratified-randomized trial.

Heart rate variability (HRV) is a vagal nerve-mediated biomarker of cardiac function used to investigate chronic illness, psychopathology, stress and, more recently, attention-regulation processes such as meditation. This study investigated HRV in relation to maladaptive perfectionism, a stress-related personality factor, and mindfulness meditation, a stress coping practice expected to elevate HRV, and thereby promote relaxation. Maladaptive perfectionists (n=21) and Controls (n=39) were exposed to a lab-based assessment in which HRV was measured during (1) a 5-minute baseline resting phase, (2) a 5-minute cognitive stress-induction phase, and (3) a post-stress phase. In the post-stress phase, participants were randomly assigned to a 10-minute audio-instructed mindfulness meditation condition or a 10-minute rest condition with audio-description of mindfulness meditation. Analyses reveale…

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The autonomic brain: an activation likelihood estimation meta-analysis for central processing of autonomic function.

The autonomic nervous system (ANS) is of paramount importance for daily life. Its regulatory action on respiratory, cardiovascular, digestive, endocrine, and many other systems is controlled by a number of structures in the CNS. While the majority of these nuclei and cortices have been identified in animal models, neuroimaging studies have recently begun to shed light on central autonomic processing in humans. In this study, we used activation likelihood estimation to conduct a meta-analysis of human neuroimaging experiments evaluating central autonomic processing to localize (1) cortical and subcortical areas involved in autonomic processing, (2) potential subsystems for the sympathetic and parasympathetic divisions of the ANS, and (3) potential subsystems for specific ANS responses to different stimuli/tasks. Across all tasks, we identified a set of consistently activated brain regions…

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The effects of transcutaneous vagus nerve stimulation on conditioned fear extinction in humans.

A critical component of the treatment for anxiety disorders is the extinction of fear via repeated exposure to the feared stimulus. This process is strongly dependent on successful memory formation and consolidation. Stimulation of the vagus nerve enhances memory formation in both animals and humans. The objective of this study was to assess whether transcutaneous stimulation of the vagus nerve (tVNS) can accelerate extinction memory formation and retention in fear conditioned humans. To assess fear conditioning and subsequent fear extinction, we assessed US expectancy ratings, fear potentiated startle responses and phasic heart rate responses. We conducted a randomized controlled trial in thirty-one healthy participants. After fear conditioning participants were randomly assigned to receive tVNS or sham stimulation during the extinction phase. Retention of extinction memory was tested 2…

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Influence of age and gender on autonomic regulation of heart.

Heart rate variability (HRV) is a non-invasive method to measure cardiac autonomic function. Impairments in HRV have been proposed as independent risk factor for increased cardiac mortality and morbidity. Cardio protective phenomenon in females has been hypothesized to be due to differential autonomic tone. Age related loss of vagal control has been reported as predisposing factor for the development of cardiovascular disease. In this study we assessed effect of age and gender on autonomic regulation of heart in healthy volunteers. HRV data of 189 subjects (114 males and 75 females) were analyzed in time and frequency domains using customized program. Artifact free 5 min electrocardiogram segment was used for analysis. It was ensured that none of the subject had medical illness such as diabetes, hypertension, thyroid disorders, cardiac disorders, diseases potentially related with autonom…

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Autonomic dysfunction and heart rate variability in depression.

Depression occurs in people of all ages across all world regions; it is the second leading cause of disability and its global burden increased by 37.5% between 1990 and 2010. Autonomic changes are often found in altered mood states and appear to be a central biological substrate linking depression to a number of physical dysfunctions. Alterations of autonomic nervous system functioning that promotes vagal withdrawal are reflected in reductions of heart rate variability (HRV) indexes. Reduced HRV characterizes emotional dysregulation, decreased psychological flexibility and defective social engagement, which in turn are linked to prefrontal cortex hypoactivity. Altogether, these pieces of evidence support the idea that HRV might represent a useful endophenotype for psychological/physical comorbidities, and its routine application should be advised to assess the efficacy of prevention/inte…

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Interaction between heart rate and heart rate variability.

Heart rate variability (HRV) is significantly associated with average heart rate (HR), therefore, HRV actually provides information on two quantities, that is, on HR and its variability. It is difficult to conclude which of these two plays a principal role in the HRV clinical value, or in other words, what is the HR contribution to the clinical significance of HRV. Moreover, the association between HRV and HR is both a physiological phenomenon and a mathematical one. The physiological HRV dependence on HR is determined by the autonomic nervous system activity, but the mathematical one is caused by the nonlinear relationship between RR interval and HR. By employing modification methods of the HRV and HR relationship, it is possible to investigate the HR contribution to the HRV clinical value. Recent studies have shown that the removal of the HR impact on HRV makes HRV more predictive for …

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Beyond heart rate variability: vagal regulation of allostatic systems.

The autonomic nervous system (ANS) plays a role in a wide range of somatic and mental diseases. Whereas the role of the ANS in the regulation of the cardiovascular system seems evident, its role in the regulation of other systems associated with allostasis is less clear. Using a model of neurovisceral integration we describe how the ANS and parasympathetic tone in particular may be associated with the regulation of allostatic systems associated with glucose regulation, hypothalamic-pituitary-adrenal (HPA) axis function, and inflammatory processes. Decreased vagal function and heart rate variability (HRV) were shown to be associated with increased fasting glucose and hemoglobin A1c levels, increased overnight urinary cortisol, and increased proinflammatory cytokines and acute-phase proteins. All of these factors have been associated with increased allostatic load and poor health. Thus, va…

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Transcutaneous vagus nerve stimulation (tVNS) enhances conflict-triggered adjustment of cognitive control.

Response conflicts play a prominent role in the flexible adaptation of behavior as they represent context-signals that indicate the necessity for the recruitment of cognitive control. Previous studies have highlighted the functional roles of the affectively aversive and arousing quality of the conflict signal in triggering the adaptation process. To further test this potential link with arousal, participants performed a response conflict task in two separate sessions with either transcutaneous vagus nerve stimulation (tVNS), which is assumed to activate the locus coeruleus-noradrenaline (LC-NE) system, or with neutral sham stimulation. In both sessions the N2 and P3 event-related potentials (ERP) were assessed. In line with previous findings, conflict interference, the N2 and P3 amplitude were reduced after conflict. Most importantly, this adaptation to conflict was enhanced under tVNS c…

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Transcutaneous Vagus Nerve Stimulation Combined with Robotic Rehabilitation Improves Upper Limb Function after Stroke.

The efficacy of standard rehabilitative therapy for improving upper limb functions after stroke is limited; thus, alternative strategies are needed. Vagus nerve stimulation (VNS) paired with rehabilitation is a promising approach, but the invasiveness of this technique limits its clinical application. Recently, a noninvasive method to stimulate vagus nerve has been developed. The aim of the present study was to explore whether noninvasive VNS combined with robotic rehabilitation can enhance upper limb functionality in chronic stroke. Safety and efficacy of this combination have been assessed within a proof-of-principle, double-blind, semirandomized, sham-controlled trial. Fourteen patients with either ischemic or haemorrhagic chronic stroke were randomized to robot-assisted therapy associated with real or sham VNS, delivered for 10 working days. Efficacy was evaluated by change in upper …

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A prospective, multicenter study of cardiac-based seizure detection to activate vagus nerve stimulation.

Purpose: This study investigates the performance of a cardiac-based seizure detection algorithm (CBSDA) that automatically triggers VNS (NCT01325623). Methods: Thirty-one patients with drug resistant epilepsy were evaluated in an epilepsy monitoring unit (EMU) to assess algorithm performance and near-term clinical benefit. Long-term efficacy and safety were evaluated with combined open and closed-loop VNS. Results: Sixty-six seizures (n=16 patients) were available from the EMU for analysis. In 37 seizures (n=14 patients) a ≥ 20% heart rate increase was found and 11 (n=5 patients) were associated with ictal tachycardia (iTC, 55% or 35 bpm heart rate increase, minimum of 100 bpm). Multiple CBSDA settings achieved a sensitivity of ≥ 80%. False positives ranged from 0.5 to 7.2/h. 27/66 seizures were stimulated within ± 2 min of seizure onset. In 10/17 of these seizures, where triggered VNS o…

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Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial.

Background: Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium-glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. Methods: This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency-to-high-frequency (LF/HF) ratio from baseline to 24 weeks. Sec…

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Self-regulatory biofeedback training: an intervention to reduce school burnout and improve cardiac functioning in college students.

With the detrimental relationship between school burnout and physiological and cognitive functioning now well documented, interventions to ameliorate school burnout symptomology are needed. This study examined the effectiveness of a self-regulatory biofeedback intervention program (Heart Rate Variability Coherence Biofeedback Training [HRVCB]) in contrast to a protocol demonstrated to produce cognitive and physiological improvements (a high intensity interval training protocol [HIIT]) as well as a wait-list control condition at decreasing school burnout in an American collegiate sample (N = 90). Intervention training was conducted over a 4-week span (three sessions per week) with accompanying baseline and post-intervention assessments. In addition to measurements of school burnout and negative affect (depression and anxiety), intervention influences on cognition (via a serial subtraction…

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L-Theanine reduces psychological and physiological stress responses.

L-Theanine is an amino acid contained in green tea leaves which is known to block the binding of L-glutamic acid to glutamate receptors in the brain. Because the characteristics of L-Theanine suggest that it may influence psychological and physiological states under stress, the present study examined these possible effects in a laboratory setting using a mental arithmetic task as an acute stressor. Twelve participants underwent four separate trials: one in which they took L-Theanine at the start of an experimental procedure, one in which they took L-Theanine midway, and two control trials in which they either took a placebo or nothing. The experimental sessions were performed by double-blind, and the order of them was counterbalanced. The results showed that L-Theanine intake resulted in a reduction in the heart rate (HR) and salivary immunoglobulin A (s-IgA) responses to an acute stress…

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