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

Two-year outcome of vagus nerve stimulation in treatment-resistant depression.

One of the major goals of antidepressant treatment is a sustained response and remission of depressive symptoms. Some of the previous studies of vagus nerve stimulation (VNS) have suggested antidepressant effects. Our naturalistic study assessed the efficacy and the safety of VNS in 74 European patients with therapy-resistant major depressive disorder. Psychometric measures were obtained after 3, 12, and 24 months of VNS. Mixed-model repeated-measures analysis of variance revealed a significant reduction (P < or = 0.05) at all the 3 time points in the 28-item Hamilton Rating Scale for Depression (HRSD28) score, the primary outcome measure. After 2 years, 53.1% (26/49) of the patients fulfilled the response criteria (> or =50% reduction in the HRSD28 scores from baseline) and 38.9% (19/49) fulfilled the remission criteria (HRSD28 scores < or = 10). The proportion of patients who fulfilled…

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Vagus nerve stimulation for refractory epilepsy in children: More to VNS than seizure frequency reduction.

Purpose: Vagus nerve stimulation (VNS) is used increasingly as adjunctive therapy for refractory epilepsy. Studies of VNS in children report mainly seizure frequency reduction as a measure of efficacy and clinical details are often scanty. We report our experience with VNS in children with refractory epilepsy and emphasize the positive effects of VNS in terms of seizure severity. Methods: We reviewed 26 consecutive children who had VNS with a minimum follow-up period of 18 months. We examined their clinical characteristics, seizure types, seizure frequency, epilepsy syndrome diagnosis, and response to VNS in terms of seizure frequency and seizure severity. Results: Fifty-four percent of patients responded to VNS with >or=50% seizure frequency reduction. Patients with Lennox-Gastaut syndrome (LGS) and tonic seizures had a higher responder rate; 78% (seven of nine patients) (p < 0.01). Sta…

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Charting the perfect storm: emerging biological interfaces between stress and stroke.

A growing body of evidence demonstrates that psychosocial stress is an important and often underestimated risk factor for cardiovascular disease such as myocardial infarction and stroke. In this article, we map out major biological interfaces between stress, stress-related psychiatric disorders, and stroke, placing special emphasis on the fact that stress and psychiatric disorders may be both cause and consequence of cardiovascular disease. Apart from high-risk lifestyle habits such as smoking and lack of exercise, neuroendocrine dysregulation, alterations of the hemostatic system, increased oxidative stress, and inflammatory changes have been implicated in stress-related endothelial dysfunction. Heart rate provides another useful and easily available measure that reflects the complex interplay of vascular morbidity and psychological distress. Importantly, heart rate is emerging as a val…

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Vagus nerve stimulation exerts cardioprotection against myocardial ischemia/reperfusion injury predominantly through its efferent vagal fibers.

Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against myocardial ischemia/reperfusion (I/R) injury. However, whether the cardioprotection of VNS is mainly due to direct activation through its ipsilateral efferent fibers (motor) rather than indirect effects mediated by the afferent fibers (sensory) have not been clearly understood. We hypothesized that VNS exerts cardioprotection predominantly through its efferent vagal fibers. Thirty swine (30-35 kg) were randomized into five groups: I/R no VNS (I/R), and left mid-cervical VNS with both vagal trunks intact (LC-VNS), with left vagus nerve transection (LtVNX), with right vagus nerve transection (RtVNX) and with atropine pretreatment (Atropine), respectively. VNS was applied at the onset of ischemia (60 min) and continued until the end of reperfusion (120 min). Cardiac function, infarct size, arrhythmia score, myoca…

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Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control.

Key points: The evoked cardiac response to bipolar cervical vagus nerve stimulation (VNS) reflects a dynamic interaction between afferent mediated decreases in central parasympathetic drive and suppressive effects evoked by direct stimulation of parasympathetic efferent axons to the heart. The neural fulcrum is defined as the operating point, based on frequency-amplitude-pulse width, where a null heart rate response is reproducibly evoked during the on-phase of VNS. Cardiac control, based on the principal of the neural fulcrum, can be elicited from either vagus. Beta-receptor blockade does not alter the tachycardia phase to low intensity VNS, but can increase the bradycardia to higher intensity VNS. While muscarinic cholinergic blockade prevented the VNS-induced bradycardia, clinically relevant doses of ACE inhibitors, beta-blockade and the funny channel blocker ivabradine did not alter …

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Vagus nerve stimulation for depression: efficacy and safety in a European study.

Background: Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression. Method: An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically. Results: The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (> or = 50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates r…

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TRPA1 channels mediate cold temperature sensing in mammalian vagal sensory neurons: pharmacological and genetic evidence.

Cold thermoreceptors have been described in different territories of the vagus nerve. Application of cold temperature to these visceral afferents can evoke major protective reflexes and thermoregulatory responses. However, virtually nothing is known about the transduction mechanisms underlying cold sensitivity in vagal afferents. Here, we investigated the effects of cold stimulation on intracellular calcium responses and excitability of cultured vagal sensory neurons in the rat nodose ganglion. A large fraction of vagal neurons were activated by cold, with a mean threshold of approximately 24 degrees C. Cooling was accompanied by development of a small inward current and the firing of action potentials. Most cold-sensitive neurons were also activated by heat and capsaicin, suggesting a nociceptive function. The pharmacological response to TRPM8 and TRPA1 agonists and antagonists suggeste…

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Long-term results with vagus nerve stimulation in children with pharmacoresistant epilepsy.

Purpose: To retrospectively review our experience with VNS in pediatric patients with pharmacoresistant epilepsy and examine the seizure-frequency outcome and rates of discontinuation in two age groups: adolescent and pre-adolescent children. Results: Complete pre- and post-VNS data were available for 46/49 patients. Median age at implantation was 12.1 (range 2.3-17.9) and median duration of epilepsy 8.0 (1.9-16.9) years. Twenty-one patients (45.6%) were under 12 years at the time of surgery. Median follow-up was 2 years; follow-up exceeded 4 years in 9/46 patients. As compared to baseline, median seizure-frequency reduction in the setting of declining numbers was 56% at 3 months, 50% at 6, 63% at 12, 83% at 24 and 74% at 36 months. When a last observation carried forward analysis was employed median seizure-frequency reduction in the range of 60% was observed at 1, 2 and 3 years post-VN…

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Heart rate variability in elite triathletes, is variation in variability the key to effective training? A case comparison.

Measures of an athlete's heart rate variability (HRV) have shown potential to be of use in the prescription of training. However, little data exists on elite athletes who are regularly exposed to high training loads. This case study monitored daily HRV in two elite triathletes (one male: 22 year, VO2max 72.5 ml kg min(-1); one female: 20 year, VO2max 68.2 ml kg min(-1)) training 23 ± 2 h per week, over a 77-day period. During this period, one athlete performed poorly in a key triathlon event, was diagnosed as non-functionally over-reached (NFOR) and subsequently reactivated the dormant virus herpes zoster (shingles). The 7-day rolling average of the log-transformed square root of the mean sum of the squared differences between R-R intervals (Ln rMSSD), declined towards the day of triathlon event (slope = -0.17 ms/week; r2 = -0.88) in the NFOR athlete, remaining stable in the control (slo…

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Comparison of three mobile devices for measuring R-R intervals and heart rate variability: Polar S810i, Suunto t6 and an ambulatory ECG system.

The first aim of this study was to compare an ambulatory five-lead ECG system with the commercially available breast belt measuring devices; Polar S810i and Suunto t6, in terms of R-R interval measures and heart rate variability (HRV) indices. The second aim was to compare different HRV spectral analysis methods. Nineteen young males (aged between 22 and 31 years, median 24 years) underwent simultaneous R-R interval recordings with the three instruments during supine and sitting rest, moderate dynamic, and moderate to vigorous static exercise of the upper and lower limb. For each subject, 17 R-R interval series of 3-min length were extracted from the whole recordings and then analyzed in frequency domain using (1) a fast Fourier transform (FFT), (2) an autoregressive model (AR), (3) a Welch periodogram (WP) and (4) a continuous wavelet transform (CWT). Intra-class correlation coefficient…

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Salivary alpha-amylase stress reactivity across different age groups.

tract Salivary alpha-amylase (sAA) increases rapidly in response to psychosocial stress in young adults, but no direct comparisons between different age groups across the life span have been made. Secretion of sAA and cortisol was assessed in children, young adults, and older adults after exposure to the Trier Social Stress Test. Additionally, cardiovascular activity was measured in both adult groups. Older adults showed attenuated sAA, heart rate (HR), and heart rate variability (HRV) responses. Furthermore, we found higher sAA but lower cortisol at baseline as well as lower sAA and cortisol responses in children. Age x sex interactions were observed only for cortisol with higher responses in older male participants. No associations between the parameters were found. These results implicate sAA as an alternative or additional sympathetic stress marker throughout the life span, with mark…

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Modeling multisystem biological risk in young adults: The Coronary Artery Risk Development in Young Adults Study.

Although much prior research has focused on identifying the roles of major regulatory systems in health risks, the concept of allostatic load (AL) focuses on the importance of a more multisystems view of health risks. How best to operationalize allostatic load, however, remains the subject of some debate. We sought to test a hypothesized metafactor model of allostatic load composed of a number of biological system factors, and to investigate model invariance across sex and ethnicity. Biological data from 782 men and women, aged 32-47, from the Oakland, CA and Chicago, IL sites of the Coronary Artery Risk Development in Young Adults Study (CARDIA) were collected as part of the Year 15exam in 2000. These include measures of blood pressure, metabolic parameters (glucose, insulin, lipid profiles, and waist circumference), markers of inflammation (interleukin-6, C-reactive protein, and fibrin…

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Bioindicators in the MIDUS national study: protocol, measures, sample, and comparative context.

Objectives: Midlife in the United States (MIDUS) is a national study of health and aging among individuals aged 25 to 74 at baseline (1995-1996). Longitudinal survey assessments (2004-2005), were followed by biological assessments on a subsample (aged 35-85).To facilitate public use, we describe the protocol, measures, and sample. Method: Respondents traveled to clinics for a 2-day data-collection protocol that included fasting blood specimens, 12-hr urine specimen, medical history, physical exam, bone densitometry, and a laboratory challenge (heart rate variability, blood pressure, respiration, salivary cortisol). Results: Response rates for the biological protocol (N = 1,255) were 39.3% or 43.1% (adjusting for those who could not be located or contacted). Reasons for nonparticipation were travel, family obligations, and being too busy. Respondents were comparable to the recruitment poo…

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Cardiac iodine-123 metaiodobenzylguanidine imaging predicts sudden cardiac death independently of left ventricular ejection fraction in patients with chronic heart failure and left ventricular systolic dysfunction: results from a comparative study with signal-averaged electrocardiogram, heart rate variability, and QT dispersion.

Objectives: We prospectively compared the predictive value of cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging for sudden cardiac death (SCD) with that of the signal-averaged electrocardiogram (SAECG), heart rate variability (HRV), and QT dispersion in patients with chronic heart failure (CHF). Background: Cardiac MIBG imaging predicts prognosis of CHF patients. However, the long-term predictive value of MIBG imaging for SCD in this population remains to be elucidated. Methods: At entry, cardiac MIBG imaging, SAECG, 24-h Holter monitoring, and standard 12-lead electrocardiography (ECG) were performed in 106 consecutive stable CHF outpatients with a radionuclide left ventricular ejection fraction (LVEF) <40%. The cardiac MIBG washout rate (WR) was obtained from MIBG imaging. Furthermore, the time and frequency domain HRV parameters were calculated from 24-h Holter recordings, and…

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Validity and reliability of short-term heart-rate variability from the Polar S810.

Purpose: : To assess the validity and the reliability of short-term resting heart-rate variability (HRV) measures obtained using the Polar S810 heart-rate monitor and accompanying software. Methods: : Measures of HRV were obtained from 5-min R to R wave (RR) interval data for 19 males and 14 females during 10 min of quiet rest on three separate occasions at 1-wk intervals using the Polar S810. Criterion measures of HRV were obtained simultaneously using the CardioPerfect (CP; Medical Graphics Corporation, St Paul, MN) 12-lead ECG module. Measures of validity of the Polar S810 were estimated by regression analysis, and measures of reliability of both devices were estimated by analysis of change scores. Measures of the SD of normal-to-normal intervals (SDNN), the root mean square of successive differences (RMSSD), and the low-frequency (LF) and the high-frequency (HF) spectral power and th…

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A pilot study on the effects of heart rate variability biofeedback in patients with depression and in healthy subjects.

Decreased vagal activity and increased sympathetic arousal have been proposed as major contributors to the increased risk of cardiovascular mortality in patients with depression. It was aim of the present study to assess the feasibility of using heart rate variability (HRV) biofeedback to treat moderate to severe depression. This was an open-label study in which 14 patients with different degrees of depression (13 f, 1 m) aged 30 years (18-47; median; range) and 12 healthy volunteers attended 6 sessions of HRV biofeedback over two weeks. Another 12 healthy subjects were observed under an active control condition. At follow up BDI was found significantly decreased (BDI 6; 2-20; median 25%-75% quartile) as compared to baseline conditions (BDI 22;15-29) in patients with depression. In addition, depressed patients had reduced anxiety, decreased heart rate and increased HRV after conduction o…

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Psychosocial, hemostatic, and inflammatory correlates of delayed poststress blood pressure recovery.

Objective: Delayed poststress cardiovascular recovery has been associated with cardiovascular disease risk. This study assessed relationships between systolic blood pressure (BP) recovery, psychosocial risk factors, and delayed recovery of inflammatory and hemostatic variables. Method: Data were analyzed from 228 middle-aged men and women from the Whitehall Psychobiology study who performed color/word and mirror-tracing tasks. Systolic BP recovery was assessed as the difference between baseline and levels recorded 40 to 45 minutes poststress. Associations were analyzed with socioeconomic markers (grade of employment, education, income), psychosocial factors (social isolation, hostility, mental health, financial strain), and recovery of heart rate, heart rate variability, von Willebrand factor, factor VIII clotting activity, plasma fibrinogen, and plasma viscosity. Results: Systolic BP wa…

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Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study.

Background: Decreased vagal activity after myocardial infarction results in reduced heart-rate variability and increased risk of death. To distinguish between vagal and sympathetic factors that affect heart-rate variability, we used a signal-processing algorithm to separately characterise deceleration and acceleration of heart rate. We postulated that diminished deceleration-related modulation of heart rate is an important prognostic marker. Our prospective hypotheses were that deceleration capacity is a better predictor of risk than left-ventricular ejection fraction (LVEF) and standard deviation of normal-to-normal intervals (SDNN). Methods: We quantified heart rate deceleration capacity by assessing 24-h Holter recordings from a post-infarction cohort in Munich (n=1455). We blindly validated the prognostic power of deceleration capacity in post-infarction populations in London, UK (n=…

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Access to Vagal Projections via Cutaneous Electrical Stimulation of the Neck: fMRI Evidence in Healthy Humans.

Background: Stimulation of the vagus nerve via implanted electrodes is currently used to treat refractory epilepsy and depression. Recently, a non-invasive approach to vagal stimulation has demonstrated similar beneficial effects, but it remains unclear whether these effects are mediated via activation of afferent vagal fibers. Objective: The present study was designed to ascertain whether afferent vagal projections can be accessed non-invasively by transcutaneous electrical stimulation of the antero-lateral surface of the neck, which overlies the course of the vagus nerve. Methods: Thirteen healthy subjects underwent 2 fMRI scans in one session. Transcutaneous electrical stimulation was applied for 2 min to the right postero-lateral surface of the neck during scan #1 (control condition, sternocleidomastoid stimulation: "SCM") and to the right antero-lateral surface of the neck during sc…

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The Microbiome-Gut-Brain Axis in Health and Disease.

Gut microbes are capable of producing most neurotransmitters found in the human brain. Evidence is accumulating to support the view that gut microbes influence central neurochemistry and behavior. Irritable bowel syndrome is regarded as the prototypic disorder of the brain-gut-microbiota axis that can be responsive to probiotic therapy. Translational studies indicate that certain bacteria may have an impact on stress responses and cognitive functioning. Manipulating the gut microbiota with psychobiotics, prebiotics, or even antibiotics offers a novel approach to altering brain function and treating gut-brain axis disorders, such as depression and autism.

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Relationships between features of autonomic cardiovascular control and cognitive performance.

The study investigated relationships between autonomic cardiovascular control and attentional performance. In 60 healthy subjects R-wave to pulse interval (RPI), respiratory sinus arrhythmia (RSA), heart rate variability in the mid-frequency (MF) band and sensitivity of the cardiac baroreflex (BRS) were assessed at rest and during a visual attention test. All parameters decreased markedly during test execution. Lower values of resting BRS predicted increased performance. On-task RPI, RSA, MF power and BRS were inversely related to attentional functioning, with RSA accounting for the largest portion of test score variance. The inverse association between resting BRS and performance is discussed as reflecting the bottom-up modulation of cerebral function by baroreceptor activity. The results concerning the on-task measures suggest that a pattern of cardiovascular adjustment including enhan…

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Cardiac vagal tone is associated with social engagement and self-regulation.

The polyvagal theory (Porges, 2007) represents a biobehavioral model that relates autonomic functioning to self-regulation and social engagement. The aim of the two presented studies was to test the proposed association of cardiac vagal tone (CVT), assessed via resting high-frequency heart rate variability (respiratory sinus arrhythmia, RSA), with coping, emotion-regulation, and social engagement in young adults. In Study 1 (retrospective self-report), RSA was positively associated with engagement coping (situation control, response control, positive self-instructions, social-support seeking) and aspects of social well-being. In Study 2 (ecological momentary assessment), for 28 days following the initial assessment, RSA predicted less use of disengagement strategies (acceptance and avoidance) for regulating negative emotions and more use of socially adaptive emotion-regulation strategies…

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An introduction into autonomic nervous function.

The results of many medical measurements are directly or indirectly influenced by the autonomic nervous system (ANS). For example pupil size or heart rate may demonstrate striking moment-to-moment variability. This review intends to elucidate the physiology behind this seemingly unpredictable system. The review is split up into: 1. The peripheral ANS, parallel innervation by the sympathetic and parasympathetic branches, their transmitters and co-transmitters. It treats questions like the supposed sympatho/vagal balance, organization in plexuses and the 'little brains' that are active like in the enteric system or around the heart. Part 2 treats ANS-function in some (example-) organs in more detail: the eye, the heart, blood vessels, lungs, respiration and cardiorespiratory coupling. Part 3 poses the question of who is directing what? Is the ANS a strictly top-down directed system or is i…

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Ictal tachycardia: the head-heart connection.

Epileptic seizures can lead to changes in autonomic function affecting the sympathetic, parasympathetic, and enteric nervous systems. Changes in cardiac signals are potential biomarkers that may provide an extra-cerebral indicator of ictal onset in some patients. Heart rate can be measured easily when compared to other biomarkers that are commonly associated with seizures (e.g., long-term EEG), and therefore it has become an interesting parameter to explore for detecting seizures. Understanding the prevalence and magnitude of heart rate changes associated with seizures, as well as the timing of such changes relative to seizure onset, is fundamental to the development and use of cardiac based algorithms for seizure detection. We reviewed 34 articles that reported the prevalence of ictal tachycardia in patients with epilepsy. Scientific literature supports the occurrence of significant inc…

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Neural correlates of heart rate variability during emotion.

The vagal (high frequency [HF]) component of heart rate variability (HRV) predicts survival in post-myocardial infarction patients and is considered to reflect vagal antagonism of sympathetic influences. Previous studies of the neural correlates of vagal tone involved mental stress tasks that included cognitive and emotional elements. To differentiate the neural substrates of vagal tone due to emotion, we correlated HF-HRV with measures of regional cerebral blood flow (rCBF) derived from positron emission tomography (PET) and (15)O-water in 12 healthy women during different emotional states. Happiness, sadness, disgust and three neutral conditions were each induced by film clips and recall of personal experiences (12 conditions). Inter-beat intervals derived from electrocardiographic recordings during the 60-second scans were spectrally-analyzed, generating 12 separate measures of HF-HRV…

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