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

Repeatedly pairing vagus nerve stimulation with a movement reorganizes primary motor cortex.

Although sensory and motor systems support different functions, both systems exhibit experience-dependent cortical plasticity under similar conditions. If mechanisms regulating cortical plasticity are common to sensory and motor cortices, then methods generating plasticity in sensory cortex should be effective in motor cortex. Repeatedly pairing a tone with a brief period of vagus nerve stimulation (VNS) increases the proportion of primary auditory cortex responding to the paired tone (Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake J, Sudanagunta SP, Borland MS, Kilgard MP. 2011. Reversing pathological neural activity using targeted plasticity. Nature. 470:101-104). In this study, we predicted that repeatedly pairing VNS with a specific movement would result in an increased representation of that movement in primary motor cortex. To test this hypothesis, we paired VNS with movements …

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The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study.

Background: Brainstem-focused mechanisms supporting transcutaneous auricular VNS (taVNS) effects are not well understood, particularly in humans. We employed ultrahigh field (7T) fMRI and evaluated the influence of respiratory phase for optimal targeting, applying our respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique. Hypothesis: We proposed that targeting of nucleus tractus solitarii (NTS) and cardiovagal modulation in response to taVNS stimuli would be enhanced when stimulation is delivered during a more receptive state, i.e. exhalation. Methods: Brainstem fMRI response to auricular taVNS (cymba conchae) was assessed for stimulation delivered during exhalation (eRAVANS) or inhalation (iRAVANS), while exhalation-gated stimulation over the greater auricular nerve (GANctrl, i.e. earlobe) was included as control. Furthermore, we evaluated cardiovagal response …

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Infant stress reactivity and prenatal alcohol exposure.

Background: Animal studies have shown that prenatal alcohol exposure (PAE) is linked to alterations in the stress response systems. To date, little is known about the impact of PAE on stress systems in human infants. The current study examined PAE effects on the stress response, as evidenced by the activation of the limbic-hypothalamic-pituitary-adrenal (L-HPA) axis and autonomic system and changes in negative affect during a social-emotional challenge in human infants. We also examined whether the effects of PAE on infant responsiveness differed in boys and girls. Methods: Measures of cortisol, heart rate, and negative affect were obtained during a modified version of Tronick's still-face procedure, a standardized developmental paradigm used to study emotion and stress regulation. Our sample included fifty-five 5- to 7-month-old infants whose mothers were enrolled in an alcohol interven…

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Effects of maternal sleep position on fetal and maternal heart rate patterns using overnight home fetal ECG recordings.

Objective: To assess the effects of maternal position on maternal and fetal heart rate and heart rate variability (HRV) in healthy late gestation pregnancies using non-invasive techniques during overnight studies. Methods: In an observational study of women between 34 and 36 weeks of pregnancy conducted from September 1, 2013, to March 31, 2014, at Columbia University Medical Center, New York, US, maternal and fetal ECG recordings and position monitoring were undertaken through the night in the woman's own home. These data were used for time domain analyses of fetal and maternal heart rate and HRV. Results: Forty-two women were recruited to the study which showed that maternal position affected maternal heart rate (MHR), with left side sleeping associated with lower heart rate (left vs right P=0.017, left vs supine P=0.027) and higher overall HRV (left vs right P=0.032). MHR showed signi…

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An open source benchmarked toolbox for cardiovascular waveform and interval analysis.

Objective: This work aims to validate a set of data processing methods for variability metrics, which hold promise as potential indicators for autonomic function, prediction of adverse cardiovascular outcomes, psychophysiological status, and general wellness. Although the investigation of heart rate variability (HRV) has been prevalent for several decades, the methods used for preprocessing, windowing, and choosing appropriate parameters lacks consensus among academic and clinical investigators. Moreover, many of the important steps are omitted from publications, preventing reproducibility. Approach: To address this, we have compiled a comprehensive and open-source modular toolbox for calculating HRV metrics and other related variability indices, on both raw cardiovascular time series and RR intervals. The software, known as the PhysioNet Cardiovascular Signal Toolbox, is implemented in …

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Comparison of Heart-Rate-Variability Recording With Smartphone Photoplethysmography, Polar H7 Chest Strap, and Electrocardiography.

Purpose: To establish the validity of smartphone photoplethysmography (PPG) and heart-rate sensor in the measurement of heart-rate variability (HRV). Methods: 29 healthy subjects were measured at rest during 5 min of guided breathing and normal breathing using smartphone PPG, a heart-rate chest strap, and electrocardiography (ECG). The root mean sum of the squared differences between R-R intervals (rMSSD) was determined from each device. Results: Compared to ECG, the technical error of estimate (TEE) was acceptable for all conditions (average TEE CV% [90% CI] = 6.35 [5.13; 8.5]). When assessed as a standardized difference, all differences were deemed "trivial" (average standard difference [90% CI] = 0.10 [0.08; 0.13]). Both PPG- and heart-rate-sensor-derived measures had almost perfect correlations with ECG (R = 1.00 [0.99; 1.00]). Conclusion: Both PPG and heart-rate sensors provide an a…

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Validity of the Polar V800 heart rate monitor to measure RR intervals at rest.

Purpose: To assess the validity of RR intervals and short-term heart rate variability (HRV) data obtained from the Polar V800 heart rate monitor, in comparison to an electrocardiograph (ECG). Method: Twenty participants completed an active orthostatic test using the V800 and ECG. An improved method for the identification and correction of RR intervals was employed prior to HRV analysis. Agreement of the data was assessed using intra-class correlation coefficients (ICC), Bland-Altman limits of agreement (LoA), and effect size (ES). Results: A small number of errors were detected between ECG and Polar RR signal, with a combined error rate of 0.086 %. The RR intervals from ECG to V800 were significantly different, but with small ES for both supine corrected and standing corrected data (ES <0.001). The bias (LoA) were 0.06 (-4.33 to 4.45 ms) and 0.59 (-1.70 to 2.87 ms) for supine and standin…

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Validity of (Ultra-)Short Recordings for Heart Rate Variability Measurements.

Objectives: In order to investigate the applicability of routine 10s electrocardiogram (ECG) recordings for time-domain heart rate variability (HRV) calculation we explored to what extent these (ultra-)short recordings capture the "actual" HRV. Methods: The standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences (RMSSD) were measured in 3,387 adults. SDNN and RMSSD were assessed from (ultra)short recordings of 10s(3x), 30s, and 120s and compared to 240s-300s (gold standard) measurements. Pearson's correlation coefficients (r), Bland-Altman 95% limits of agreement and Cohen's d statistics were used as agreement analysis techniques. Results: Agreement between the separate 10s recordings and the 240s-300s recording was already substantial (r = 0.758-0.764/Bias = 0.398-0.416/d = 0.855-0.894 for SDNN; r = 0.853-0.862/Bias = 0.079-0.096/d = 0.…

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How accurate is pulse rate variability as an estimate of heart rate variability? A review on studies comparing photoplethysmographic technology with an electrocardiogram.

Background: The usefulness of heart rate variability (HRV) as a clinical research and diagnostic tool has been verified in numerous studies. The gold standard technique comprises analyzing time series of RR intervals from an electrocardiographic signal. However, some authors have used pulse cycle intervals instead of RR intervals, as they can be determined from a pulse wave (e.g. a photoplethysmographic) signal. This option is often called pulse rate variability (PRV), and utilizing it could expand the serviceability of pulse oximeters or simplify ambulatory monitoring of HRV. Methods: We review studies investigating the accuracy of PRV as an estimate of HRV, regardless of the underlying technology (photoplethysmography, continuous blood pressure monitoring or Finapresi, impedance plethysmography). Results/conclusions: Results speak in favor of sufficient accuracy when subjects are at re…

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Depression, comorbid anxiety disorders, and heart rate variability in physically healthy, unmedicated patients: implications for cardiovascular risk.

Context: There is evidence that heart rate variability (HRV) is reduced in major depressive disorder (MDD), although there is debate about whether this effect is caused by medication or the disorder per se. MDD is associated with a two to fourfold increase in the risk of cardiac mortality, and HRV is a robust predictor of cardiac mortality; determining a direct link between HRV and not only MDD, but common comorbid anxiety disorders, will point to psychiatric indicators for cardiovascular risk reduction. Objective: To determine in physically healthy, unmedicated patients whether (1) HRV is reduced in MDD relative to controls, and (2) HRV reductions are driven by MDD alone, comorbid generalized anxiety disorder (GAD, characterized by anxious anticipation), or comorbid panic and posttraumatic stress disorders (PD/PTSD, characterized by anxious arousal). Design, setting, and patients: A cas…

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A comparison of photoplethysmography and ECG recording to analyse heart rate variability in healthy subjects.

Measures of heart rate variability (HRV) are widely used to assess autonomic nervous system (ANS) function. The signal from which they are derived requires accurate determination of the interval between successive heartbeats; it can be recorded via electrocardiography (ECG), which is both non-invasive and widely available. However, methodological problems inherent in the recording and analysis of ECG traces have motivated a search for alternatives. Photoplethysmography (PPG) constitutes another means of determining the timing of cardiac cycles via continuous monitoring of changes in blood volume in a portion of the peripheral microvasculature. This technique measures pulse waveforms, which in some instances may prove a practical basis for HRV analysis. We investigated the feasibility of using earlobe PPG to analyse HRV by applying the same analytic process to PPG and ECG recordings made …

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Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers.

Accumulating evidence suggests that obstructive sleep apnea is associated with alterations in glucose metabolism. Although the pathophysiology of metabolic dysfunction in obstructive sleep apnea is not well understood, studies of murine models indicate that intermittent hypoxemia has an important contribution. However, corroborating data on the metabolic effects of intermittent hypoxia on glucose metabolism in humans are not available. Thus the primary aim of this study was to characterize the acute effects of intermittent hypoxia on glucose metabolism. Thirteen healthy volunteers were subjected to 5 h of intermittent hypoxia or normoxia during wakefulness in a randomized order on two separate days. The intravenous glucose tolerance test (IVGTT) was used to assess insulin-dependent and insulin-independent measures of glucose disposal. The IVGTT data were analyzed using the minimal model …

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Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction.

Aims: To determine whether risk stratification tests can predict serious arrhythmic events after acute myocardial infarction (AMI) in patients with reduced left ventricular ejection fraction (LVEF < or = 0.40). Methods and results: A total of 5869 consecutive patients were screened in 10 European centres, and 312 patients (age 65 +/- 11 years) with a mean LVEF of 31 +/- 6% were included in the study. Heart rate variability/turbulence, ambient arrhythmias, signal-averaged electrocardiogram (SAECG), T-wave alternans, and programmed electrical stimulation (PES) were performed 6 weeks after AMI. The primary endpoint was ECG-documented ventricular fibrillation or symptomatic sustained ventricular tachycardia (VT). To document these arrhythmic events, the patients received an implantable ECG loop-recorder. There were 25 primary endpoints (8.0%) during the follow-up of 2 years. The strongest pr…

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Validity of the polar S810 heart rate monitor to measure R-R intervals at rest.

Purpose: This study was conducted to compare R-R intervals and the subsequent analysis of heart rate variability (HRV) obtained from the Polar S810 heart rate monitor (HRM) (Polar Electro Oy) with an electrocardiogram (ECG) (Physiotrace, Estaris, Lille, France) during an orthostatic test. Methods: A total of 18 healthy men (age: 27.1 +/- 1.9 yr; height: 1.82 +/- 0.06 m; mass 77.1 +/- 7.7 kg) performed an active orthostatic test during which R-R intervals were simultaneously recorded with the HRM and the ECG recorder The two signals were synchronized and corrected before a time domain analysis, the fast Fourier transform (FFT) and a Poincaré plot analysis. Bias and limits of agreement (LoA), effect size (ES), and correlation coefficients were calculated. Results: R-R intervals were significantly different in the supine and standing position between the ECG and the HRM uncorrected and corr…

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Vagus nerve stimulation in patients with Alzheimer's disease: Additional follow-up results of a pilot study through 1 year.

Background: Cognitive-enhancing effects of vagus nerve stimulation (VNS) have been reported during 6 months of treatment in a pilot study of patients with Alzheimer's disease (AD). Data through 1 year of VNS (collected from June 2000 to September 2003) are now reported. Method: All patients (N = 17) met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD. Responder rates for the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE) were measured as improvement or absence of decline from baseline. Global change, depressive symptoms, and quality of life were also assessed. Cerebrospinal fluid (CSF) levels for total tau, tau phosphorylated at Thr181 (phosphotau), and Abeta42 were measured by standardized enzyme-…

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Beyond HIV Shame: Effects of Self-Forgiveness in Improving Mental Health in HIV-Positive Individuals in Poland.

Guided by the bio-psycho-socio-spiritual approach, this randomized controlled trial assessed the efficacy of a self-forgiveness intervention among 60 HIV-positive individuals in Poland. Participants underwent a 90-min "Restore: The Journey Toward Self-Forgiveness" session, in contrast to a wait-list control group. The intervention significantly enhanced self-forgiveness, spirituality, mental well-being, and heart rate variability in response to a cognitive stressor (i.e., a mental arithmetic challenge). Significant effects were observed in both between-group and within-subject comparisons. These results support the incorporation of self-forgiveness into psychological rehabilitation programs for HIV to improve quality of life and health outcomes.

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The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus.

Background: Individuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity. Methods: Blood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4-6 mmol/L) and hyperglycaemia (blood glucose 9-11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily). Res…

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Heart rate and heart rate variability in panic, social anxiety, obsessive-compulsive, and generalized anxiety disorders at baseline and in response to relaxation and hyperventilation.

It remains unclear if diminished high frequency heart rate variability (HF-HRV) can be found across anxiety disorders. HF-HRV and heart rate (HR) were examined in panic (PD), generalized anxiety (GAD), social anxiety (SAD), and obsessive-compulsive disorder (OCD) relative to healthy controls at baseline and during anxiety stressors. All disorders evidenced diminished baseline HF-HRV relative to controls. Baseline HRV differences were maintained throughout relaxation. For hyperventilation, PD and GAD demonstrated greater HR than controls. Psychotropic medication did not account for HF-HRV differences except in OCD. Age and sex evidenced multiple main effects. Findings suggest that low baseline HF-HRV represents a common index for inhibitory deficits across PD, GAD, and SAD, which is consistent with the notion of autonomic inflexibility in anxiety disorders. Elevated HR responses to hyperv…

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Cardiovascular, electrodermal, and respiratory response patterns to fear- and sadness-inducing films.

Responses to fear- and sadness-inducing films were assessed using a broad range of cardiovascular (heart rate, T-wave amplitude, low- and high-frequency heart rate variability, stroke volume, preejection period, left-ventricular ejection time, Heather index, blood pressure, pulse amplitude and transit time, and finger temperature), electrodermal (level, response rate, and response amplitude), and respiratory (rate, tidal volume and its variability, inspiratory flow rate, duty cycle, and end-tidal pCO(2)) measures. Subjective emotional experience and facial behavior (Corrugator Supercilii and Zygomaticus Major EMG) served as control measures. Results indicated robust differential physiological response patterns for fear, sadness, and neutral (mean classification accuracy 85%). Findings are discussed in terms of the fight-flight and conservation-withdrawal responses and possible limitation…

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Characteristics of resonance in heart rate variability stimulated by biofeedback.

As we previously reported, resonant frequency heart rate variability biofeedback increases baroreflex gain and peak expiratory flow in healthy individuals and has positive effects in treatment of asthma patients. Biofeedback readily produces large oscillations in heart rate, blood pressure, vascular tone, and pulse amplitude via paced breathing at the specific natural resonant frequency of the cardiovascular system for each individual. This paper describes how resonance properties of the cardiovascular system mediate the effects of heart rate variability biofeedback. There is evidence that resonant oscillations can train autonomic reflexes to provide therapeutic effect. The paper is based on studies described in previous papers. Here, we discuss the origin of the resonance phenomenon, describe our procedure for determining an individual's resonant frequency, and report data from 32 adult…

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Autonomic dysfunction in dementia.

Background: There are no studies of autonomic function comparing Alzheimer's disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Aims: To assess cardiovascular autonomic function in 39 patients with AD, 30 with VAD, 30 with DLB, 40 with PDD and 38 elderly controls by Ewing's battery of autonomic function tests and power spectral analysis of heart rate variability. To determine the prevalence of orthostatic hypotension and autonomic neuropathies by Ewing's classification. Results: There were significant differences in severity of cardiovascular autonomic dysfunction between the four types of dementia. PDD and DLB had considerable dysfunction. VAD showed limited evidence of autonomic dysfunction and in AD, apart from orthostatic hypotension, autonomic functions were relatively unimpaired. PDD showed consistent impairment of both pa…

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Manipulation of the inflammatory reflex as a therapeutic strategy.

The cholinergic anti-inflammatory pathway is the efferent arm of the inflammatory reflex, a neural circuit through which the CNS can modulate peripheral immune responses. Signals communicated via the vagus and splenic nerves use acetylcholine, produced by Choline acetyltransferase (ChAT)+ T cells, to downregulate the inflammatory actions of macrophages expressing α7 nicotinic receptors. Pre-clinical studies using transgenic animals, cholinergic agonists, vagotomy, and vagus nerve stimulation have demonstrated this pathway's role and therapeutic potential in numerous inflammatory diseases. In this review, we summarize what is understood about the inflammatory reflex. We also demonstrate how pre-clinical findings are being translated into promising clinical trials, and we draw particular attention to innovative bioelectronic methods of harnessing the cholinergic anti-inflammatory pathway f…

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Vagus nerve stimulation (VNS) therapy update.

Epilepsy affects millions of people worldwide. Approximately one-third have pharmacoresistant epilepsy, and of these, the majority are not candidates for epilepsy surgery. Vagus nerve stimulation (VNS) therapy has been an option to treat pharmacoresistant seizures for 30 years. In this update, we will review the clinical data that support the device's efficacy in children, adolescents, and adults. We will also review its side-effect profile, quality of life and cost benefits, and the impact the device has on sudden unexpected death in epilepsy (SUDEP). We will then discuss candidate selection and provide guidance on dosing and future models. Vagus nerve stimulation therapy is an effective treatment for many seizure types and epilepsy syndromes with a predictable and benign side-effect profile that supports its role as the most commonly prescribed device to treat pharmacoresistant epileps…

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The vagus afferent network: emerging role in translational connectomics.

Vagus nerve stimulation (VNS) is increasingly considered for the treatment of intractable epilepsy and holds potential for the management of a variety of neuropsychiatric conditions. The emergence of the field of connectomics and the introduction of large-scale modeling of neural networks has helped elucidate the underlying neurobiology of VNS, which may be variably expressed in patient populations and related to responsiveness to stimulation. In this report, the authors outline current data on the underlying neural circuitry believed to be implicated in VNS responsiveness in what the authors term the "vagus afferent network." The emerging role of biomarkers to predict treatment effect is further discussed and important avenues for future work are highlighted.

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Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation.

Brain and viscera interplay within the autonomic nervous system where the vagus nerve (VN), containing approximately 80% afferent and 20% efferent fibres, plays multiple key roles in the homeostatic regulations of visceral functions. Recent data have suggested the anti-inflammatory role of the VN. This vagal function is mediated through several pathways, some of them still debated. The first one is the anti-inflammatory hypothalamic-pituitary-adrenal axis which is stimulated by vagal afferent fibres and leads to the release of cortisol by the adrenal glands. The second one, called the cholinergic anti-inflammatory pathway, is mediated through vagal efferent fibres that synapse onto enteric neurons which release acetylcholine (ACh) at the synaptic junction with macrophages. ACh binds to α-7-nicotinic ACh receptors of those macrophages to inhibit the release of tumour necrosis (TNF)α, a pr…

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