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

Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: long-term outcomes and predictors of response.

Objective: The goal of this study was to assess the efficacy and safety of vagus nerve stimulation in a consecutive series of adults and children with treatment-resistant epilepsy (TRE). Methods: In this retrospective review of a prospectively created database of 436 consecutive patients who underwent vagus nerve stimulator implantation for TRE between November 1997 and April 2008, there were 220 (50.5%) females and 216 (49.5%) males ranging in age from 1 to 76 years at the time of implantation (mean: 29.0 ± 16.5). Thirty-three patients (7.6%) in the primary implantation group had inadequate follow-up (<3 months from implantation) and three patients had early device removal because of infection and were excluded from seizure control outcome analyses. Results: Duration of vagus nerve stimulation treatment varied from 10 days to 11 years (mean: 4.94 years). Mean seizure frequency significa…

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Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases.

Object: The authors undertook this study to analyze the efficacy of vagus nerve stimulation (VNS) in a large consecutive series of children 18 years of age and younger with treatment-resistant epilepsy and compare the safety and efficacy in children under 12 years of age with the outcomes in older children. Methods: The authors retrospectively reviewed 141 consecutive cases involving children (75 girls and 66 boys) with treatment-resistant epilepsy in whom primary VNS implantation was performed by the senior author between November 1997 and April 2008 and who had at least 1 year of follow-up since implantation. The patients' mean age at vagus nerve stimulator insertion was 11.1 years (range 1-18 years). Eighty-six children (61.0%) were younger than 12 years at time of VNS insertion (which constitutes off-label usage of this device). Results: Follow-up was complete for 91.8% of patients a…

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Chronic vagus nerve stimulation decreased weight gain, food consumption and sweet craving in adult obese minipigs.

Chronic vagus nerve stimulation (VNS) is known to influence food intake and body weight in animals and humans. The aim of our work was to evaluate the effects of long-term VNS in adult obese minipigs. Eight minipigs were fed ad libitum a Western diet to cause obesity, after which half of the animals were implanted with bilateral vagal electrodes connected to constant current stimulators (2mA, 30Hz, 500-μs pulse, ON 30s, OFF 5min). The other animals were implanted with sham devices. Animals were weighed weekly and their daily consumption was measured. Still 14 weeks after surgery, VNS animals (70.3±3.3kg, P>0.10) did not significantly gain weight compared to sham animals (80.6±8.0kg, P<0.05). Furthermore, food consumption decreased in VNS animals (-18%, P<0.02) compared to sham animals (+1%, P>0.10). When subjected to a three-choice meal test (high-fat vs. high-carbohydrates vs. balanced …

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Vagal nerve stimulation protects against burn-induced intestinal injury through activation of enteric glia cells.

The enteric nervous system may have an important role in modulating gastrointestinal barrier response to disease through activation of enteric glia cells. In vitro studies have shown that enteric glia activation improves intestinal epithelial barrier function by altering the expression of tight junction proteins. We hypothesized that severe injury would increase expression of glial fibrillary acidic protein (GFAP), a marker of enteric glial activation. We also sought to define the effects of vagal nerve stimulation on enteric glia activation and intestinal barrier function using a model of systemic injury and local gut mucosal involvement. Mice with 30% total body surface area steam burn were used as model of severe injury. Vagal nerve stimulation was performed to assess the role of parasympathetic signaling on enteric glia activation. In vivo intestinal permeability was measured to asse…

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Individual differences in some (but not all) medial prefrontal regions reflect cognitive demand while regulating unpleasant emotion.

The present study investigated the premise that individual differences in autonomic physiology could be used to specify the nature and consequences of information processing taking place in medial prefrontal regions during cognitive reappraisal of unpleasant pictures. Neural (blood oxygenation level-dependent functional magnetic resonance imaging) and autonomic (electrodermal [EDA], pupil diameter, cardiac acceleration) signals were recorded simultaneously as twenty-six older people (ages 64-66 years) used reappraisal to increase, maintain, or decrease their responses to unpleasant pictures. EDA was higher when increasing and lower when decreasing compared to maintaining. This suggested modulation of emotional arousal by reappraisal. By contrast, pupil diameter and cardiac acceleration were higher when increasing and decreasing compared to maintaining. This suggested modulation of cognit…

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A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders.

Background: Vagus nerve stimulation (VNS) is an effective anticonvulsant device and has shown antidepressant effects in chronic treatment resistant depression. Because the vagus nerve sends information to brain regions important in anxiety regulation (locus coeruleus, orbitofrontal cortex, insula, hippocampus and amygdala), this pathway might be involved in perceiving or manifesting various somatic and cognitive symptoms that characterize anxiety disorders. On the basis of this reasoning and reports of anxiolytic effects of VNS in patients treated for epilepsy and depression, we organized an open-label pilot acute trial of adjunctive VNS on top of stable medications, followed by long-term follow-up, to assess the safety and potential efficacy of VNS for patients with treatment resistant anxiety disorders. Methods: Eleven adult outpatients with treatment resistant obsessive-compulsive dis…

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Does repressive coping promote resilience? Affective-autonomic response discrepancy during bereavement.

Traditional theories of coping emphasize the value of attending to and expressing negative emotion while recovering from traumatic life events. However, recent evidence suggests that the tendency to direct attention away from negative affective experience (i.e., repressive coping) may promote resilience following extremely aversive events (e.g., the death of a spouse). The current study extends this line of investigation by showing that both bereaved and nonbereaved individuals who exhibited repressive coping behavior--as measured by the discrepancy between affective experience and sympathetic nervous system response--had fewer symptoms of psychopathology, experienced fewer health problems and somatic complaints, and were rated as better adjusted by close friends than those who did not exhibit repressive coping. Results are discussed in terms of recent developments in cognitive and neuro…

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Genetic dissection of behavioural and autonomic effects of Delta(9)-tetrahydrocannabinol in mice.

Marijuana and its main psychotropic ingredient Delta(9)-tetrahydrocannabinol (THC) exert a plethora of psychoactive effects through the activation of the neuronal cannabinoid receptor type 1 (CB1), which is expressed by different neuronal subpopulations in the central nervous system. The exact neuroanatomical substrates underlying each effect of THC are, however, not known. We tested locomotor, hypothermic, analgesic, and cataleptic effects of THC in conditional knockout mouse lines, which lack the expression of CB1 in different neuronal subpopulations, including principal brain neurons, GABAergic neurons (those that release gamma aminobutyric acid), cortical glutamatergic neurons, and neurons expressing the dopamine receptor D1, respectively. Surprisingly, mice lacking CB1 in GABAergic neurons responded to THC similarly as wild-type littermates did, whereas deletion of the receptor in a…

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Sex differences in response to a panicogenic challenge procedure: an experimental evaluation of panic vulnerability in a non-clinical sample.

Epidemiological studies show that women are twice as likely as men to develop panic disorder (PD) during their lifetimes. Data from retrospective studies also suggest that women are more distressed by panic and other negative emotional states than men, and that this tendency may precede the development of PD. The present prospective study sought to expand this work by evaluating sex differences in the predisposition to panic in individuals without PD or other forms of psychopathology. Participants (N=96; 52 women) were exposed to 12 panicogenic inhalations of 20% CO2-enriched air while physiological (e.g., heart rate, electrodermal response, Frontalis EMG) and self-report (e.g., subject distress, fear, frequency and severity of DSM-IV panic symptoms) response domains were monitored. As expected, magnitude of autonomic responding failed to reliably discriminate between women and men. Yet,…

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Autonomic and neuroendocrine responses to a psychosocial stressor in adults with autistic spectrum disorder.

Objective of the study was to replicate in adults our previous findings of decreased heart rate and normal endocrine responses to stress in autistic children and to elucidate the discrepancy between autonomic and endocrine stress responses by including epinephrine, norepinephrine, oxytocin and vasopressin measurements. Ten autistic spectrum disorder (ASD) adults were compared to 14 healthy controls in their response to a psychosocial stressor (public speaking). ASD patients showed decreased heart rate, but normal cortisol responses, consistent with our prior findings in children. No differences in norepinephrine, epinephrine, oxytocin or vasopressin responses to stress were found. However, in contrast to previous findings in low functioning autistic children, ASD adults showed increased basal oxytocin levels, which may be related to developmental factors.

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Maternal Immune Activation During the Third Trimester Is Associated with Neonatal Functional Connectivity of the Salience Network and Fetal to Toddler Behavior.

Prenatal maternal immune activation (MIA) is associated with altered brain development and risk of psychiatric disorders in offspring. Translational human studies of MIA are few in number. Alterations of the salience network have been implicated in the pathogenesis of the same psychiatric disorders associated with MIA. If MIA is pathogenic, then associated abnormalities in the salience network should be detectable in neonates immediately after birth. We tested the hypothesis that third trimester MIA of adolescent women who are at risk for high stress and inflammation is associated with the strength of functional connectivity in the salience network of their neonate. Thirty-six women underwent blood draws to measure interleukin-6 (IL-6) and C-reactive protein (CRP) and electrocardiograms to measure fetal heart rate variability (FHRV) at 34-37 weeks gestation. Resting-state imaging data we…

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Mind-wandering and alterations to default mode network connectivity when listening to naturalistic versus artificial sounds.

Naturalistic environments have been demonstrated to promote relaxation and wellbeing. We assess opposing theoretical accounts for these effects through investigation of autonomic arousal and alterations of activation and functional connectivity within the default mode network (DMN) of the brain while participants listened to sounds from artificial and natural environments. We found no evidence for increased DMN activity in the naturalistic compared to artificial or control condition, however, seed based functional connectivity showed a shift from anterior to posterior midline functional coupling in the naturalistic condition. These changes were accompanied by an increase in peak high frequency heart rate variability, indicating an increase in parasympathetic activity in the naturalistic condition in line with the Stress Recovery Theory of nature exposure. Changes in heart rate and the pe…

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Electroencephalogram and electrocardiograph assessment of mental fatigue in a driving simulator.

Mental fatigue is a contributing factor to some serious transportation crashes. In this study, we measured mental fatigue in drivers using electroencephalogram (EEG) and electrocardiograph (ECG). Together, thirteen healthy subjects performed a continuous simulated driving task for 90 min with simultaneous ECG and multi-channel EEG recording of each subject. Several important physiological parameters were investigated using preprocessed ECG and EEG signals. The results show that the EEG alpha and beta, the relative power, the amplitude of P300 wave of event-related potential (ERP), the approximated entropy of the ECG, and the lower and upper bands of power of heart rate variability (HRV) are significantly different before and after finishing the driving task (p<0.05). These metrics are possible indices for measuring simulated driving mental fatigue.

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Caloric restriction: powerful protection for the aging heart and vasculature.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Research has shown that the majority of the cardiometabolic alterations associated with an increased risk of CVD (e.g., insulin resistance/type 2 diabetes, abdominal obesity, dyslipidemia, hypertension, and inflammation) can be prevented, and even reversed, with the implementation of healthier diets and regular exercise. Data from animal and human studies indicate that more drastic interventions, i.e., calorie restriction with adequate nutrition (CR), may have additional beneficial effects on several metabolic and molecular factors that are modulating cardiovascular aging itself (e.g., cardiac and arterial stiffness and heart rate variability). The purpose of this article is to review the current knowledge on the effects of CR on the aging of the cardiovascular system and CVD risk in rodent…

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Resilience Training Program Reduces Physiological and Psychological Stress in Police Officers.

Research suggests that police work is among the most stressful occupations in the world and officers typically suffer a variety of physiological, psychological, and behavioral effects and symptoms. Officers operating under severe or chronic stress are likely to be at greater risk of error, accidents, and overreactions that can compromise their performance, jeopardize public safety, and pose significant liability costs to the organization. Therefore, this study explored the nature and degree of physiological activation typically experienced of officers on the job and the impact of the Coherence Advantage resilience and performance enhancement training on a group of police officers from Santa Clara County, California. Areas assessed included vitality, emotional well-being, stress coping and interpersonal skills, work performance, workplace effectiveness and climate, family relationships, a…

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Changes in heart rate and blood pressure during nocturnal hot flashes associated with and without awakenings.

Hot flashes (HFs) are a hallmark of menopause in midlife women. They are beyond bothersome symptoms, having a profound impact on quality of life and wellbeing, and are a potential marker of cardiovascular (CV) disease risk. Here, we investigated the impact on CV functioning of single nocturnal HFs, considering whether or not they were accompanied by arousals or awakenings. We investigated changes in heart rate (HR, 542 HFs), blood pressure (BP, 261 HFs), and pre-ejection period (PEP, 168 HFs) across individual nocturnal physiological HF events in women in the menopausal transition or post-menopause (age: 50.7 ± 3.6 years) (n = 86 for HR, 45 for BP, 27 for PEP). HFs associated with arousals/awakenings (51.1%), were accompanied by an increase in systolic (SBP; ~6 mmHg) and diastolic (DBP; ~5 mmHg) BP and HR (~20% increase), sustained for several minutes. In contrast, HFs occurring in undis…

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Exploring Emotional Recovery From Anger in Individuals With Borderline Personality Disorder: The Role of Respiratory Sinus Arrhythmia as a Potential Physiological Mechanism.

Difficulties in emotional regulation are central to borderline personality disorder (BPD), which is characterized by heightened emotional reactivity and prolonged recovery from anger, often exacerbated by rumination. In this study, we examine the role of respiratory sinus arrhythmia (RSA) as a vital indicator of parasympathetic nervous system activity in BPD patients exposed to anger-inducing films. We recruited 35 BPD patients and 35 healthy controls, collecting self-reported emotional symptoms and physiological data during baseline, induction, recovery, and relaxation sessions. The findings revealed that BPD participants exhibited significantly slower RSA recovery from anger, underscoring its critical role in emotional regulation. Furthermore, relaxation techniques were found to enhance emotional recovery, suggesting that lower parasympathetic activation during anger makes individuals …

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Awe Sparks Prosociality in Children.

Rooted in the novel and the mysterious, awe is a common experience in childhood, but research is almost silent with respect to the import of this emotion for children. Awe makes individuals feel small, thereby shifting their attention to the social world. Here, we studied the effects of art-elicited awe on children's prosocial behavior toward an out-group and its unique physiological correlates. In two preregistered studies (Study 1: N = 159, Study 2: N = 353), children between 8 and 13 years old viewed movie clips that elicited awe, joy, or a neutral (control) response. Children who watched the awe-eliciting clip were more likely to spend their time on an effortful task (Study 1) and to donate their experimental earnings (Studies 1 and 2), all toward benefiting refugees. They also exhibited increased respiratory sinus arrhythmia, an index of parasympathetic nervous system activation ass…

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Intergenerational transmission of emotion dysregulation: Part I. Psychopathology, self-injury, and parasympathetic responsivity among pregnant women.

The World Health Organization recently reported that maternal mental health is a major public health concern. As many as one in four women suffer from psychiatric disorders at some point during pregnancy or the first postpartum year. Furthermore, self-injurious thoughts and behaviors (SITBs) represent one of the leading causes of death among women during this time. Thus, efforts to identify women at risk for serious forms of psychopathology and especially for SITBs are of utmost importance. Despite this urgency, current single-diagnostic approaches fail to recognize a significant subset of women who are vulnerable to perinatal stress and distress. The current study was among the first to investigate emotion dysregulation-a multilevel, transdiagnostic risk factor for psychopathology-and its associations with stress, distress, and SITBs in a sample of pregnant women (26-40 weeks gestation)…

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Culture and the socialization of child cardiovascular regulation at school entry in the US.

The measurement of cardiovascular functioning targets an important bridge between social conditions and differential well-being. Nevertheless, the biocultural, psychosocial processes that link human ecology to cardiovascular function in children remain inadequately characterized. Childrearing practices shaped by parents' cultural beliefs should moderate children's affective responses to daily experience, and hence their psychophysiology. The present study concerns interactions among family ecology, the normative social challenge of entry into kindergarten, and parasympathetic (vagal) cardiac regulation in US middle-class children (N = 30). Although parents believed children must be protected from overscheduling to reduce stress and improve socio-emotional adaptation, maternal rather than child schedules predicted parasympathetic regulation during a nonthreatening social engagement task f…

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Heart rate variability biofeedback: how and why does it work?

In recent years there has been substantial support for heart rate variability biofeedback (HRVB) as a treatment for a variety of disorders and for performance enhancement (Gevirtz, 2013). Since conditions as widely varied as asthma and depression seem to respond to this form of cardiorespiratory feedback training, the issue of possible mechanisms becomes more salient. The most supported possible mechanism is the strengthening of homeostasis in the baroreceptor (Vaschillo et al., 2002; Lehrer et al., 2003). Recently, the effect on the vagal afferent pathway to the frontal cortical areas has been proposed. In this article, we review these and other possible mechanisms that might explain the positive effects of HRVB.

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Multiple areas of the cerebral cortex influence the stomach.

The central nervous system both influences and is influenced by the gastrointestinal system. Most research on this gut-brain connection has focused on how ascending signals from the gut and its microbiome alter brain function. Less attention has focused on how descending signals from the central nervous system alter gut function. Here, we used retrograde transneuronal transport of rabies virus to identify the cortical areas that most directly influence parasympathetic and sympathetic control of the rat stomach. Cortical neurons that influence parasympathetic output to the stomach originated from the rostral insula and portions of medial prefrontal cortex, regions that are associated with interoception and emotional control. In contrast, cortical neurons that influence sympathetic output to the stomach originated overwhelmingly from the primary motor cortex, primary somatosensory cortex, …

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I Keep a Close Watch on This Heart of Mine: Increased Interoception in Insomnia.

Study objectives: Whereas both insomnia and altered interoception are core symptoms in affective disorders, their neural mechanisms remain insufficiently understood and have not previously been linked. Insomnia Disorder (ID) is characterized by sensory hypersensitivity during wakefulness and sleep. Previous studies on sensory processing in ID addressed external stimuli only, but not interoception. Interoceptive sensitivity can be studied quantitatively by measuring the cerebral cortical response to one's heartbeat (heartbeat-evoked potential, HEP). We here investigated whether insomnia is associated with increased interoceptive sensitivity as indexed by the HEP amplitude. Methods: Sixty-four participants aged 21-70 years were recruited through www.sleepregistry.nl including 32 people suffering from ID and 32 age- and sex-matched controls without sleep complaints. HEPs were obtained from …

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Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study.

Background: Vagus nerve stimulation has been successfully used as a treatment strategy for epilepsy and affective disorders for years. Transcutaneous vagus nerve stimulation (tVNS) is a new non-invasive method to stimulate the vagus nerve, which has been shown to modulate neuronal activity in distinct brain areas. Objectives: Here we report effects of tVNS on cardiac function from a pilot study, which was conducted to evaluate the feasibility and safety of tVNS for the treatment of chronic tinnitus. Methods: Twenty-four patients with chronic tinnitus underwent treatment with tVNS over 3-10 weeks in an open single-armed pilot study. Safety criteria and practical usability of the neurostimulating device were to investigate by clinical examination and electrocardiography at baseline and at several visits during and after tVNS treatment (week 2, 4, 8, 16, and 24). Results: Two adverse cardia…

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True or false? Memory is differentially affected by stress-induced cortisol elevations and sympathetic activity at consolidation and retrieval.

Adrenal stress hormones released in response to acute stress may yield memory-enhancing effects when released post-learning and impairing effects at memory retrieval, especially for emotional memory material. However, so far these differential effects of stress hormones on the various memory phases for neutral and emotional memory material have not been demonstrated within one experiment. This study investigated whether, in line with their effects on true memory, stress and stress-induced adrenal stress hormones affect the encoding, consolidation, and retrieval of emotional and neutral false memories. Participants (N=90) were exposed to a stressor before encoding, during consolidation, before retrieval, or were not stressed and then were subjected to neutral and emotional versions of the Deese-Roediger-McDermott word list learning paradigm. Twenty-four hours later, recall of presented wo…

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