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

The Microbiome-Gut-Brain Axis and Resilience to Developing Anxiety or Depression under Stress.

Episodes of depression and anxiety commonly follow the experience of stress, however not everyone who experiences stress develops a mood disorder. Individuals who are able to experience stress without a negative emotional effect are considered stress resilient. Stress-resilience (and its counterpart stress-susceptibility) are influenced by several psychological and biological factors, including the microbiome-gut-brain axis. Emerging research shows that the gut microbiota can influence mood, and that stress is an important variable in this relationship. Stress alters the gut microbiota and plausibly this could contribute to stress-related changes in mood. Most of the reported research has been conducted using animal models and demonstrates a relationship between gut microbiome and mood. The translational evidence from human clinical studies however is rather limited. In this review we ex…

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Studying brain-regulation of immunity with optogenetics and chemogenetics; A new experimental platform.

The interactions between the brain and the immune system are bidirectional. Nevertheless, we have far greater understanding of how the immune system affects the brain than how the brain affects immunity. New technological developments such as optogenetics and chemogenetics (using DREADDs; Designer Receptors Exclusively Activated by Designer Drugs) can bridge this gap in our understanding, as they enable an unprecedented mechanistic and systemic analysis of the communication between the brain and the immune system. In this review, we discuss new experimental approaches for revealing neuronal circuits that can participate in regulation of immunity. In addition, we discuss methods, specifically optogenetics and chemogenetics, that enable targeted neuronal manipulation to reveal how different brain regions affect immunity. We describe how these techniques can be used as an experimental platf…

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Low-amplitude, left vagus nerve stimulation significantly attenuates ventricular dysfunction and infarct size through prevention of mitochondrial dysfunction during acute ischemia-reperfusion injury.

Background: Right cervical vagus nerve stimulation (VNS) provides cardioprotective effects against acute ischemia-reperfusion injury in small animals. However, inconsistent findings have been reported. Objective: To determine whether low-amplitude, left cervical VNS applied either intermittently or continuously imparts cardioprotection against acute ischemia-reperfusion injury. Methods: Thirty-two isoflurane-anesthetized swine (25-30 kg) were randomized into 4 groups: control (sham operated, no VNS), continuous-VNS (C-VNS; 3.5 mA, 20 Hz), intermittent-VNS (I-VNS; continuously recurring cycles of 21-second ON, 30-second OFF), and I-VNS + atropine (1 mg/kg). Left cervical VNS was applied immediately after left anterior descending artery occlusion (60 minutes) and continued until the end of reperfusion (120 minutes). The ischemic and nonischemic myocardium was harvested for cardiac mitochon…

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Breaking the cycle: cognitive behavioral therapy and biofeedback training in a case of cyclic vomiting syndrome.

The present article presents a case of cognitive behavioral therapy (CBT) along with heart rate variability (HRV) biofeedback training for the treatment of a medication unresponsive 13-year-old boy with cyclic vomiting syndrome (CVS). CVS is characterized by recurring stereotypic episodes of vomiting, interspersed with asymptomatic periods. Triggers for vomiting include anticipatory anxiety related to school examinations, family conflicts, and birthday parties as well as infectious diseases, and certain foods. Current treatment design addressed two pivotal etiological factors: autonomic dysregulation and anticipatory anxiety. Treatment outcome suggests that vomiting episodes may be successfully prevented by aiding the patient to identify and manage precipitant psychological stressors, to regulate HRV patterns, and gain a renewed sense of bodily control and self-efficacy. Further research…

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Use of a portable biofeedback device to improve insomnia in a combat zone, a case report.

Insomnia is a common problem in situations of stress. Some forms of stress, however, may contraindicate the use of traditional, pharmacological interventions. Working in a combat zone is such a situation. Alternative means of improving sleep are clearly needed for Service Members. We report a case involving a medical provider who was serving in a military, emergency-services facility in Iraq, and who presented with anxiety, depressed mood, and insomnia. Symptoms were sub-threshold for major depressive disorder or acute stress disorder. Mood and anxiety symptoms responded to traditional therapy techniques, but problems with insomnia remained. The patient was given a portable biofeedback device that employs an infrared sensor photoplethysmograph to measure heart rate variability (HRV) from peripheral finger pulse. One week later, sleep was significantly improved. Symptom improvement lasted…

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Fear balance is maintained by bodily feedback to the insular cortex in mice.

How does the brain maintain fear within an adaptive range? We found that the insular cortex acts as a state-dependent regulator of fear that is necessary to establish an equilibrium between the extinction and maintenance of fear memories in mice. Whereas insular cortex responsiveness to fear-evoking cues increased with their certainty to predict harm, this activity was attenuated through negative bodily feedback that arose from heart rate decelerations during freezing. Perturbation of body-brain communication by vagus nerve stimulation disrupted the balance between fear extinction and maintenance similar to insular cortex inhibition. Our data reveal that the insular cortex integrates predictive sensory and interoceptive signals to provide graded and bidirectional teaching signals that gate fear extinction and illustrate how bodily feedback signals are used to maintain fear within a funct…

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Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies.

Heart rate is under the precise control of the autonomic nervous system. However, the wiring of peripheral neural circuits that regulate heart rate is poorly understood. Here, we develop a clearing-imaging-analysis pipeline to visualize innervation of intact hearts in 3D and employed a multi-technique approach to map parasympathetic and sympathetic neural circuits that control heart rate in mice. We identify cholinergic neurons and noradrenergic neurons in an intrinsic cardiac ganglion and the stellate ganglia, respectively, that project to the sinoatrial node. We also report that the heart rate response to optogenetic versus electrical stimulation of the vagus nerve displays different temporal characteristics and that vagal afferents enhance parasympathetic and reduce sympathetic tone to the heart via central mechanisms. Our findings provide new insights into neural regulation of heart …

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Respiratory effects on experimental heat pain and cardiac activity.

Objective: Slow deep breathing has been proposed as an effective method to decrease pain. However, experimental studies conducted to validate this claim have not been carried out. Design: We measured thermal pain threshold and tolerance scores from 20 healthy adults during five different conditions, namely, during natural breathing (baseline), slow deep breathing (6 breaths/minute), rapid breathing (16 breaths/minute), distraction (video game), and heart rate (HR) biofeedback. We measured respiration (rate and depth) and HR variability from the electrocardiogram (ECG) output and analyzed the effects of respiration on pain and HR variability using time and frequency domain measures of the ECG. Results: Compared with baseline, thermal pain threshold was significantly higher during slow deep breathing (P = 0.002), HR biofeedback (P < 0.001), and distraction (P = 0.006), whereas thermal pain…

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Induction of c-Fos and DeltaFosB immunoreactivity in rat brain by Vagal nerve stimulation.

Vagus nerve stimulation (VNS) is used as therapy for treatment-resistant depression or epilepsy. This study used immunohistochemistry for biomarkers of short-term (c-Fos) and long-term (DeltaFosB) neuronal activation to map regions in brain that are activated by acute (2 h) or chronic (3 weeks) VNS in conscious Sprague-Dawley rats. Electrodes (Cyberonics Inc.) were implanted on the left vagus nerve and 1 week after surgery, stimulation began using parameters employed clinically (one burst of 20 Hz, 250 micros pulse width, 0.25 mA stimulation for 30 s every 5 min). Radio telemetry transmitters were used for monitoring blood pressure, heart rate, activity, and respiratory rate during VNS; neither acute nor chronic VNS significantly affected these parameters. Acute VNS significantly increased c-Fos staining in the nucleus of the solitary tract, paraventricular nucleus of the hypothalamus, p…

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Neural Pathway for Gut Feelings: Vagal Interoceptive Feedback From the Gastrointestinal Tract Is a Critical Modulator of Anxiety-like Behavior.

Background: Anxiety disorders are associated with an altered perception of the body's internal state. Therefore, understanding the neuronal basis of interoception can foster novel anxiety therapies. In rodents, the feeding status bidirectionally modulates anxiety-like behavior but how the sensing of gastrointestinal state affects anxiety remains unclear. Methods: We combined chemogenetics, neuropharmacology, and behavioral approaches in male and female rats to test whether vagal afferents terminating in the gastrointestinal tract mediate feeding-induced tuning of anxiety. Using saporin-based lesions and transcriptomics, we investigated the chronic impact of this gut-brain circuit on anxiety-like behavior. Results: Both feeding and selective chemogenetic activation of gut-innervating vagal afferents increased anxiety-like behavior. Conversely, chemogenetic inhibition blocked the increase …

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Postingestive Modulation of Food Seeking Depends on Vagus-Mediated Dopamine Neuron Activity.

Postingestive nutrient sensing can induce food preferences. However, much less is known about the ability of postingestive signals to modulate food-seeking behaviors. Here we report a causal connection between postingestive sucrose sensing and vagus-mediated dopamine neuron activity in the ventral tegmental area (VTA), supporting food seeking. The activity of VTA dopamine neurons increases significantly after administration of intragastric sucrose, and deletion of the NMDA receptor in these neurons, which affects bursting and plasticity, abolishes lever pressing for postingestive sucrose delivery. Furthermore, lesions of the hepatic branch of the vagus nerve significantly impair postingestive-dependent VTA dopamine neuron activity and food seeking, whereas optogenetic stimulation of left vagus nerve neurons significantly increases VTA dopamine neuron activity. These data establish a nece…

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Genetic Identification of Vagal Sensory Neurons That Control Feeding.

Energy homeostasis requires precise measurement of the quantity and quality of ingested food. The vagus nerve innervates the gut and can detect diverse interoceptive cues, but the identity of the key sensory neurons and corresponding signals that regulate food intake remains unknown. Here, we use an approach for target-specific, single-cell RNA sequencing to generate a map of the vagal cell types that innervate the gastrointestinal tract. We show that unique molecular markers identify vagal neurons with distinct innervation patterns, sensory endings, and function. Surprisingly, we find that food intake is most sensitive to stimulation of mechanoreceptors in the intestine, whereas nutrient-activated mucosal afferents have no effect. Peripheral manipulations combined with central recordings reveal that intestinal mechanoreceptors, but not other cell types, potently and durably inhibit hung…

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A Neural Circuit for Gut-Induced Reward.

The gut is now recognized as a major regulator of motivational and emotional states. However, the relevant gut-brain neuronal circuitry remains unknown. We show that optical activation of gut-innervating vagal sensory neurons recapitulates the hallmark effects of stimulating brain reward neurons. Specifically, right, but not left, vagal sensory ganglion activation sustained self-stimulation behavior, conditioned both flavor and place preferences, and induced dopamine release from Substantia nigra. Cell-specific transneuronal tracing revealed asymmetric ascending pathways of vagal origin throughout the CNS. In particular, transneuronal labeling identified the glutamatergic neurons of the dorsolateral parabrachial region as the obligatory relay linking the right vagal sensory ganglion to dopamine cells in Substantia nigra. Consistently, optical activation of parabrachio-nigral projections …

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Effects of A Brief Resonance Frequency Breathing Exercise on Heart Rate Variability and Inhibitory Control in the Context of Generalised Anxiety Disorder.

Generalised anxiety disorder (GAD) is associated with cognitive and physiological symptoms including uncontrollable worry, inhibitory control deficits, and low heart rate variability (HRV). Literature linking HRV and inhibition in GAD is predominantly correlational. The present experiment investigated whether HRV has a causal role in maintaining inhibitory control. Participants (N = 135, 111 female) aged 18-37 reporting high levels of symptoms associated with GAD (GAD-7 scores ≥ 10; Penn State Worry Questionnaire scores ≥ 56) were assigned to an experimental or active control condition and completed baseline measures of HRV, respiration rate, and inhibitory control. The experimental condition completed resonance frequency breathing (RFB) training, and the control condition practiced breathing at their mean breathing rate before repeating the inhibitory control assessment. Participants al…

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Psychophysiological effects of slow-paced breathing at six cycles per minute with or without heart rate variability biofeedback.

Heart rate variability (HRV) biofeedback, referring to slow-paced breathing (SPB) realized while visualizing a heart rate, HRV, and/or respiratory signal, has become an adjunct treatment for a large range of psychologic and medical conditions. However, the underlying mechanisms explaining the effectiveness of HRV biofeedback still need to be uncovered. This study aimed to disentangle the specific effects of HRV biofeedback from the effects of SPB realized alone. In total, 112 participants took part in the study. The parameters assessed were emotional (valence, arousal, and control) and perceived stress intensity as self-report variables and the root mean square of the successive differences (RMSSD) as a physiologic variable. A main effect of condition was found for emotional valence only, valence being more positive overall in the SPB-HRVB condition. A main effect of time was observed fo…

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Effects of heart rate variability biofeedback training in athletes exposed to stress of university examinations.

Introduction: Heart rate variability biofeedback (HRV-BFB) training, a method whereby one controls an unusually low breathing rate to reach cardiac coherence, has been shown to reduce anxiety and improve cardiac autonomic markers in diseased people, but much less is known about HRV-BFB benefits in healthy people. Here we investigated potential benefits in young competitors experiencing stress during university examinations as well as persistence of benefits after HRV-BFB training cessation. Methods: A group of sports students (n = 12) practiced 5-min HRV-BFB training twice a day for 5-weeks using URGOfeel® (URGOTECH) and was compared to a control group (n = 6). University examinations occurred immediately after HRV-BFB training (Exam1), then 12-weeks later (Exam2). Anxiety markers and cardiac autonomic markers were assessed at baseline, Exam1 and Exam2. Principal Component Analyses (PCA)…

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Adding HRV biofeedback to psychotherapy increases heart rate variability and improves the treatment of major depressive disorder.

Heart rate variability (HRV) is a significant marker of health outcomes with decreased HRV predicting increased disease risk. HRV is decreased in major depressive disorder (MDD) but existing treatments for depression do not return heart rate variability to normal levels even with successful treatment of depression. Heart rate variability biofeedback (HRVB) increases heart rate variability but no studies to date have examined whether combining HRVB with psychotherapy improves outcome in MDD treatment. The present study used a randomized controlled design to compare the effects of HRVB combined with psychotherapy on MDD relative to a psychotherapy treatment as usual group and to a non-depressed control group. The HRVB+psychotherapy group showed a larger increase in HRV and a larger decrease in depressive symptoms relative to the other groups over a six-week period, whereas the psychotherap…

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Vagal Tone and Children's Delay of Gratification: Differential Sensitivity in Resource-Poor and Resource-Rich Environments.

Children from different socioeconomic backgrounds have differing abilities to delay gratification, and impoverished children have the greatest difficulties in doing so. In the present study, we examined the role of vagal tone in predicting the ability to delay gratification in both resource-rich and resource-poor environments. We derived hypotheses from evolutionary models of children's conditional adaptation to proximal rearing contexts. In Study 1, we tested whether elevated vagal tone was associated with shorter delay of gratification in impoverished children. In Study 2, we compared the relative role of vagal tone across two groups of children, one that had experienced greater impoverishment and one that was relatively middle-class. Results indicated that in resource-rich environments, higher vagal tone was associated with longer delay of gratification. In contrast, high vagal tone i…

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Roots and Benefits of Costly Giving: Children Who Are More Altruistic Have Greater Autonomic Flexibility and Less Family Wealth.

Altruism, although costly, may promote well-being for people who give. Costly giving by adults has received considerable attention, but less is known about the possible benefits, as well as biological and environmental correlates, of altruism in early childhood. In the current study, we present evidence that children who forgo self-gain to help other people show greater vagal flexibility and higher subsequent vagal tone than children who do not, and children from less wealthy families behave more altruistically than those from wealthier families. These results suggest that (a) altruism should be viewed through a biopsychosocial lens, (b) the influence of privileged contexts on children's willingness to make personal sacrifices for others emerges early, and (c) altruism and healthy vagal functioning may share reciprocal relations in childhood. When children help others at a cost to themse…

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Mindfulness meditation, well-being, and heart rate variability: a preliminary investigation into the impact of intensive Vipassana meditation.

Mindfulness meditation has beneficial effects on brain and body, yet the impact of Vipassana, a type of mindfulness meditation, on heart rate variability (HRV) - a psychophysiological marker of mental and physical health - is unknown. We hypothesised increases in measures of well-being and HRV, and decreases in ill-being after training in Vipassana compared to before (time effects), during the meditation task compared to resting baseline (task effects), and a time by task interaction with more pronounced differences between tasks after Vipassana training. HRV (5-minute resting baseline vs. 5-minute meditation) was collected from 36 participants before and after they completed a 10-day intensive Vipassana retreat. Changes in three frequency-domain measures of HRV were analysed using 2 (Time; pre- vs. post-Vipassana)× 2 (Task; resting baseline vs. meditation) within subjects ANOVA. These m…

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A wearable respiratory biofeedback system based on generalized body sensor network.

Wearable medical devices have enabled unobtrusive monitoring of vital signs and emerging biofeedback services in a pervasive manner. This article describes a wearable respiratory biofeedback system based on a generalized body sensor network (BSN) platform. The compact BSN platform was tailored for the strong requirements of overall system optimizations. A waist-worn biofeedback device was designed using the BSN. Extensive bench tests have shown that the generalized BSN worked as intended. In-situ experiments with 22 subjects indicated that the biofeedback device was discreet, easy to wear, and capable of offering wearable respiratory trainings. Pilot studies on wearable training patterns and resultant heart rate variability suggested that paced respirations at abdominal level and with identical inhaling/exhaling ratio were more appropriate for decreasing sympathetic arousal and increasin…

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The development of regulatory functions from birth to 5 years: insights from premature infants.

This study examined physiological, emotional, and attentional regulatory functions as predictors of self-regulation in 125 infants followed 7 times from birth to 5 years. Physiological regulation was assessed by neonatal vagal tone and sleep-wake cyclicity; emotion regulation by response to stress at 3, 6, and 12 months; and attention regulation by focused attention and delayed response in the 2nd year. Executive functions, behavior adaptation, and self-restraint were measured at 5 years. Regulatory functions showed stability across time, measures, and levels. Structural modeling demonstrated both mediated paths from physiological to self-regulation through emotional and attentional processes and direct continuity between vagal tone and each level of regulation. Results support the coherence of the regulation construct and are consistent with neurobiological models on self and consciousn…

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Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral and neural responses to threat.

Stress-related disorders such as depression and anxiety are characterized by enhanced negative emotion and physiological dysfunction. Whilst elevated activity within area 25 of the subgenual anterior cingulate cortex (sgACC/25) has been implicated in these illnesses, it is unknown whether this over-activity is causal. By combining targeted intracerebral microinfusions with cardiovascular and behavioral monitoring in marmosets, we show that over-activation of sgACC/25 reduces vagal tone and heart rate variability, alters cortisol dynamics during stress and heightens reactivity to proximal and distal threat. 18F-FDG PET imaging shows these changes are accompanied by altered activity within a network of brain regions including the amygdala, hypothalamus and dorsolateral prefrontal cortex. Ketamine, shown to have rapid antidepressant effects, fails to reverse elevated arousal to distal threa…

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Continuous intraoperative vagus nerve stimulation for identification of imminent recurrent laryngeal nerve injury.

Background: Conventional intraoperative nerve monitoring, predicated on intermittent stimulation, can predict recurrent laryngeal nerve (RLN) palsy only after the damage has been done. Methods: Fifty-two patients (52 nerves at risk) who underwent continuous intraoperative nerve monitoring (CIONM) for thyroid surgery via vagus nerve stimulation had their electromyographic (EMG) tracings recorded and correlated with surgical maneuvers and postoperative RLN function. Results: There was 1 imminent loss of signal (LOS) with intraoperative signal recovery and there were 4 losses of signal with corresponding unilateral transient RLN palsy. When EMG amplitude decreased >50% and EMG latency increased >10%, LOS and postoperative RLN palsy were noted in 4 of 8 patients (50%) who had multiple combined events. In 9 of 13 patients (70%) who developed adverse EMG changes, modification of the causative …

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A Validation of Six Wearable Devices for Estimating Sleep, Heart Rate and Heart Rate Variability in Healthy Adults.

The primary aim of this study was to examine the validity of six commonly used wearable devices, i.e., Apple Watch S6, Garmin Forerunner 245 Music, Polar Vantage V, Oura Ring Generation 2, WHOOP 3.0 and Somfit, for assessing sleep. The secondary aim was to examine the validity of the six devices for assessing heart rate and heart rate variability during, or just prior to, night-time sleep. Fifty-three adults (26 F, 27 M, aged 25.4 ± 5.9 years) spent a single night in a sleep laboratory with 9 h in bed (23:00-08:00 h). Participants were fitted with all six wearable devices-and with polysomnography and electrocardiography for gold-standard assessment of sleep and heart rate, respectively. Compared with polysomnography, agreement (and Cohen's kappa) for two-state categorisation of sleep periods (as sleep or wake) was 88% (κ = 0.30) for Apple Watch; 89% (κ = 0.35) for Garmin; 87% (κ = 0.44) …

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