Showing papers on "Autonomic nervous system published in 2017"

Neurological consequences of obesity

Abstract: Summary The high prevalence of obesity is associated with an enormous medical, social, and economic burden. The metabolic dysfunction, dyslipidaemia, and inflammation caused by obesity contribute to the development of a wide variety of disorders and effects on the nervous system. In the CNS, mild cognitive impairment can be attributed to obesity-induced alterations in hippocampal structure and function in some patients. Likewise, compromised hypothalamic function and subsequent defects in maintaining whole-body energy balance might be early events that contribute to weight gain and obesity development. In the peripheral nervous system, obesity-driven alterations in the autonomic nervous system prompt imbalances in sympathetic–parasympathetic activity, while alterations in the sensory–somatic nervous system underlie peripheral polyneuropathy, a common complication of diabetes. Pharmacotherapy and bariatric surgery are promising interventions for people with obesity that can improve neurological function. However, lifestyle interventions via dietary changes and exercise are the preferred approach to combat obesity and reduce its associated health risks.

The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract.

Abstract: The vagus nerve (VN) is the longest nerve of the organism and a major component of the parasympathetic nervous system which constitutes the autonomic nervous system (ANS), with the sympathetic nervous system. There is classically an equilibrium between the sympathetic and parasympathetic nervous systems which is responsible for the maintenance of homeostasis. An imbalance of the ANS is observed in various pathologic conditions. The VN, a mixed nerve with 4/5 afferent and 1/5 efferent fibers, is a key component of the neuro-immune and brain-gut axes through a bidirectional communication between the brain and the gastrointestinal (GI) tract. A dual anti-inflammatory role of the VN is observed using either vagal afferents, targeting the hypothalamic-pituitary-adrenal axis, or vagal efferents, targeting the cholinergic anti-inflammatory pathway. The sympathetic nervous system and the VN act in synergy, through the splenic nerve, to inhibit the release of tumor necrosis factor-alpha (TNFα) by macrophages of the peripheral tissues and the spleen. Because of its anti-inflammatory effect, the VN is a therapeutic target in the treatment of chronic inflammatory disorders where TNFα is a key component. In this review, we will focus on the anti-inflammatory role of the VN in inflammatory bowel diseases (IBD). The anti-inflammatory properties of the VN could be targeted pharmacologically, with enteral nutrition, by VN stimulation (VNS), with complementary medicines or by physical exercise. VNS is one of the alternative treatments for drug resistant epilepsy and depression and one might think that VNS could be used as a non-drug therapy to treat inflammatory disorders of the GI tract, such as IBD, irritable bowel syndrome, and postoperative ileus, which are all characterized by a blunted autonomic balance with a decreased vagal tone.

The Role of the Autonomic Nervous System in the Pathophysiology of Obesity.

Abstract: Obesity is reaching epidemic proportions globally and represents a major cause of comorbidities, mostly related to cardiovascular disease. The autonomic nervous system dysfunction has a two-way relationship with obesity. Indeed, alterations of the autonomic nervous system might be involved in the pathogenesis of obesity, acting on different pathways. On the other hand, the excess weight induces autonomic nervous system dysfunction, which may be involved in the haemodynamic and metabolic alterations that increase the cardiovascular risk of obese individuals, i.e.hypertension, insulin resistance and dyslipidemia. This article will review current evidence about the role of the autonomic nervous system in short-term and long-term regulation of energy homeostasis. Furthermore, an increased SNS activity has been demonstrated in obese patients, particularly in the muscle vasculature and in the kidneys, possibily contributing to increased cardiovascular risk. Selective leptin resistance, obstructive sleep apnea syndrome, hyperinsulinemia and low ghrelin levels are possible mechanisms underlying sympathetic activation in obesity. Weight loss is able to reverse metabolic and SNS alterations associated with obesity. Given the crucial role of autonomic dysfunction in the pathophysiology of obesity and its cardiovascular complications, vagal nerve modulation and sympathetic inhibition may serve as therapeutic targets in this condition.

Autonomic dysreflexia after spinal cord injury: Systemic pathophysiology and methods of management.

Abstract: Traumatic spinal cord injury (SCI) has widespread physiological effects beyond the disruption of sensory and motor function, notably the loss of normal autonomic and cardiovascular control. Injury at or above the sixth thoracic spinal cord segment segregates critical spinal sympathetic neurons from supraspinal modulation which can result in a syndrome known as autonomic dysreflexia (AD). AD is defined as episodic hypertension and concomitant baroreflex-mediated bradycardia initiated by unmodulated sympathetic reflexes in the decentralized cord. This condition is often triggered by noxious yet unperceived visceral or somatic stimuli below the injury level and if severe enough can require immediate medical attention. Herein, we review the pathophysiological mechanisms germane to the development of AD, including maladaptive plasticity of neural circuits mediating abnormal sympathetic reflexes and hypersensitization of peripheral vasculature that collectively contribute to abnormal hemodynamics after SCI. Further, we discuss the systemic effects of recurrent AD and pharmacological treatments used to manage such episodes. Contemporary research avenues are then presented to better understand the relative contributions of underlying mechanisms and to elucidate the effects of recurring AD on cardiovascular and immune functions for developing more targeted and effective treatments to attenuate the development of this insidious syndrome following high-level SCI.

Lipid Processing in the Brain: A Key Regulator of Systemic Metabolism

Abstract: Metabolic disorders, particularly aberrations in lipid homeostasis, such as obesity, type 2 diabetes mellitus (T2D), and hypertriglyceridemia often manifest together as the Metabolic Syndrome (MetS). Despite major advances in our understanding of the pathogenesis of these disorders, the prevalence of the MetS continues to rise. It is becoming increasingly apparent that intermediary metabolism within the central nervous system (CNS) is a major contributor to the regulation of systemic metabolism. In particular, lipid metabolism within the brain is tightly regulated to maintain neuronal structure and function, and may signal-nutrient status to modulate metabolism in key peripheral tissues such as the liver. There is now a growing body of evidence to suggest that fatty acid-sensing in hypothalamic neurons via accumulation of fatty acids (FA) or FA metabolites may signal nutritional sufficiency and may decrease hepatic glucose production, lipogenesis and VLDL-TG secretion. In addition, recent studies have highlighted the existence of liver-related neurons that have the potential to direct such signals through parasympathetic and sympathetic nervous system activity. However, to date whether these liver-related neurons are FA-sensitive remain to be determined. The findings discussed in this review underscore the importance of the autonomic nervous system in the regulation of systemic metabolism, and highlight the need for further research to determine the key features of FA-neurons, which may serve as novel therapeutic targets for the treatment of metabolic disorders.

An introduction into autonomic nervous function.

Abstract: 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 its organization bottom-up? Finally, it is concluded that the 'noisy numbers' in medical measurements, caused by ANS variability, are part and parcel of how the system works. This topical review is a one-man's undertaking and may possibly give a biased view. The author has explicitly indicated in the text where his views are not (yet) supported by facts, hoping to provoke discussion and instigate new research.

Heart–Brain Axis: Effects of Neurologic Injury on Cardiovascular Function

Abstract: A complex interaction exists between the nervous and cardiovascular systems. A large network of cortical and subcortical brain regions control cardiovascular function via the sympathetic and parasympathetic outflow. A dysfunction in one system may lead to changes in the function of the other. The effects of cardiovascular disease on the nervous system have been widely studied; however, our understanding of the effects of neurological disorders on the cardiovascular system has only expanded in the past 2 decades. Various pathologies of the nervous system can lead to a wide range of alterations in function and structure of the cardiovascular system ranging from transient and benign electrographic changes to myocardial injury, cardiomyopathy, and even cardiac death. In this article, we first review the anatomy and physiology of the central and autonomic nervous systems in regard to control of the cardiovascular function. The effects of neurological injury on cardiac function and structure will be summarized, and finally, we review neurological disorders commonly associated with cardiovascular manifestations.

Cardiac Signals Are Independently Associated with Temporal Discounting and Time Perception

Abstract: Cardiac signals reflect the function of the autonomic nervous system and have previously been associated with a range of self-regulatory behaviours such as emotion regulation and memory recall. It is unknown whether cardiac signals may also be associated with self-regulation in the temporal domain, in particular impulsivity. We assessed both decision impulsivity (temporal discounting) and time perception impulsivity (duration reproduction) in 120 participants while they underwent electrocardiography in order to test whether cardiac signals were related to these two aspects of impulsivity. We found that over the entire period of task performance, individuals with higher heart rates had a tendency toward lower discount rates, supporting previous research that has associated sympathetic responses with decreased impulsivity. We also found that low-frequency components of heart rate variability were associated with a less accurate perception of time, suggesting that time perception may be modulated by autonomic nervous system function. Overall, these findings constitute preliminary evidence that autonomic function plays an important role in both decision impulsivity and time perception.

Autonomic Dysfunction after Mild Traumatic Brain Injury.

Abstract: A mild traumatic brain injury (mTBI) is a complex pathophysiologic process that has a systemic effect on the body aside from solely an impairment in cognitive function. Dysfunction of the autonomic nervous system (ANS) has been found to induce abnormalities in organ systems throughout the body, and may contribute to cardiovascular dysregulation and increased mortality. Autonomic dysfunction, also known as dysautonomia, has been studied in moderate and severe TBI, and has emerged as a major contributing factor in the symptomatology in mTBI as well. Analysis of the ANS has been studied through changes in heart rate variability (HRV), pupillary dynamics, eye pressure, and arterial pulse wave in those with mild TBI. Graded exercise testing has been studied as both a method of diagnosis and as a means of recovery in those with mild TBI, especially in those with persistent symptoms. Given the studies showing persistence of autonomic dysfunction after symptomatic resolution of concussions, further research is needed to establish return to play protocols.

Effects of Short Forest Bathing Program on Autonomic Nervous System Activity and Mood States in Middle-Aged and Elderly Individuals.

Abstract: The present study investigated changes in autonomic nervous system activity and emotions after a short (2 h) forest bathing program in the Xitou Nature Education Area (XNEA), Taiwan. One hundred and twenty-eight (60.0 ± 7.44 years) middle-aged and elderly participants were recruited. Physiological responses, pulse rate, systolic and diastolic blood pressure, heart rate variability (HRV), and psychological indices were measured before and after the program. We observed that pulse rate, systolic and diastolic blood pressure were significantly lower after the program, which indicated physiological benefits from stress recovery. The Profile of Mood States negative mood subscale scores of “tension-anxiety”, “anger-hostility”, “fatigue-inertia”, “depression-dejection”, and “confusion-bewilderment” were significantly lower, whereas the positive mood subscale score of “vigor-activity” was higher. Furthermore, participants exhibited significantly lower anxiety levels according to the State-Trait Anxiety Inventory. However, changes in sympathetic and parasympathetic nerve activity were nonsignificant. Our study determined that the short forest bathing program is a promising therapeutic method for enhancing heart rate and blood pressure functions as well as an effective psychological relaxation strategy for middle-aged and elderly individuals.

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis.

Abstract: Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune-mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so-called cholinergic anti-inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL-6 production and improved RA disease severity, even in some patients with therapy-resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.

Autonomic nervous system involvement in pulmonary arterial hypertension.

Abstract: Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Autonomic nervous system involvement in the pathogenesis of PAH has been demonstrated several years ago, however the extent of this involvement is not fully understood. PAH is associated with increased sympathetic nervous system (SNS) activation, decreased heart rate variability, and presence of cardiac arrhythmias. There is also evidence for increased renin-angiotensin-aldosterone system (RAAS) activation in PAH patients associated with clinical worsening. Reduction of neurohormonal activation could be an effective therapeutic strategy for PAH. Although therapies targeting adrenergic receptors or RAAS signaling pathways have been shown to reverse cardiac remodeling and improve outcomes in experimental pulmonary hypertension (PH)-models, the effectiveness and safety of such treatments in clinical settings have been uncertain. Recently, novel direct methods such as cervical ganglion block, pulmonary artery denervation (PADN), and renal denervation have been employed to attenuate SNS activation in PAH. In this review, we intend to summarize the multiple aspects of autonomic nervous system involvement in PAH and overview the different pharmacological and invasive strategies used to target autonomic nervous system for the treatment of PAH.

The Central Nervous System and Bone Metabolism: An Evolving Story

Abstract: Our understanding of the control of skeletal metabolism has undergone a dynamic shift in the last two decades, primarily driven by our understanding of energy metabolism. Evidence demonstrating that leptin not only influences bone cells directly, but that it also plays a pivotal role in controlling bone mass centrally, opened up an investigative process that has changed the way in which skeletal metabolism is now perceived. Other central regulators of bone metabolism have since been identified including neuropeptide Y (NPY), serotonin, endocannabinoids, cocaine- and amphetamine-regulated transcript (CART), adiponectin, melatonin and neuromedin U, controlling osteoblast and osteoclast differentiation, proliferation and function. The sympathetic nervous system was originally identified as the predominant efferent pathway mediating central signalling to control skeleton metabolism, in part regulated through circadian genes. More recent evidence points to a role of the parasympathetic nervous system in the control of skeletal metabolism either through muscarinic influence of sympathetic nerves in the brain or directly via nicotinic receptors on osteoclasts, thus providing evidence for broader autonomic skeletal regulation. Sensory innervation of bone has also received focus again widening our understanding of the complex neuronal regulation of bone mass. Whilst scientific advance in this field of bone metabolism has been rapid, progress is still required to understand how these model systems work in relation to the multiple confounders influencing skeletal metabolism, and the relative balance in these neuronal systems required for skeletal growth and development in childhood and maintaining skeletal integrity in adulthood.

Alterations in cardiac autonomic control in spinal cord injury

Abstract: A spinal cord injury (SCI) interferes with the autonomic nervous system (ANS). The effect on the cardiovascular system will depend on the extent of damage to the spinal/central component of ANS. The cardiac changes are caused by loss of supraspinal sympathetic control and relatively increased parasympathetic cardiac control. Decreases in sympathetic activity result in heart rate and the arterial blood pressure changes, and may cause arrhythmias, in particular bradycardia, with the risk of cardiac arrest in those with cervical or high thoracic injuries. The objective of this review is to give an update of the current knowledge related to the alterations in cardiac autonomic control following SCI. With this purpose the review includes the following subheadings: 2. Neuro-anatomical plasticity and cardiac control 2.1 Autonomic nervous system and the heart 2.2 Alteration in autonomic control of the heart following spinal cord injury 3. Spinal shock and neurogenic shock 3.1 Pathophysiology of spinal shock 3.2 Pathophysiology of neurogenic shock 4. Autonomic dysreflexia 4.1 Pathophysiology of autonomic dysreflexia 4.2 Diagnosis of autonomic dysreflexia 5. Heart rate/electrocardiography following spinal cord injury 5.1 Acute phase 5.2 Chronic phase 6. Heart rate variability 6.1 Time domain analysis 6.2 Frequency domain analysis 6.3 QT-variability index 6.4 Nonlinear (fractal) indexes 7. Echocardiography 7.1 Changes in cardiac structure following spinal cord injury 7.2 Changes in cardiac function following spinal cord injury 8. International spinal cord injury cardiovascular basic data set and international standards to document the remaining autonomic function in spinal cord injury.

Chronic interfacing with the autonomic nervous system using carbon nanotube (CNT) yarn electrodes.

Abstract: The ability to reliably and safely communicate chronically with small diameter (100–300 µm) autonomic nerves could have a significant impact in fundamental biomedical research and clinical applications. However, this ability has remained elusive with existing neural interface technologies. Here we show a new chronic nerve interface using highly flexible materials with axon-like dimensions. The interface was implemented with carbon nanotube (CNT) yarn electrodes to chronically record neural activity from two separate autonomic nerves: the glossopharyngeal and vagus nerves. The recorded neural signals maintain a high signal-to-noise ratio (>10 dB) in chronic implant models. We further demonstrate the ability to process the neural activity to detect hypoxic and gastric extension events from the glossopharyngeal and vagus nerves, respectively. These results establish a novel, chronic platform neural interfacing technique with the autonomic nervous system and demonstrate the possibility of regulating internal organ function, leading to new bioelectronic therapies and patient health monitoring.

Long Term High Fat Diet Treatment: An Appropriate Approach to Study the Sex-Specificity of the Autonomic and Cardiovascular Responses to Obesity in Mice.

Abstract: Obesity-related cardiovascular disease (CVD) involves increased sympathetic activity in men and male animals. Although women exhibit increased visceral fat, metabolic disorders, inflammation and CVD with obesity, whether body weight gain affects autonomic control of cardiovascular function in females remain unknown. Due to the lack of adequate model to mimic the human pathology, this study aimed to develop a murine model, which would allow studying the sex-specificity of the response of the autonomic nervous system to obesity and identifying the origin of potential sex-differences. We tested the hypothesis that sexual dimorphisms in the autonomic response to obesity disappear in mice matched for changes in body weight, metabolic and inflammatory disorders. Male and female C57Bl/6 mice were submitted to control (CD) or high fat diet (HFD) for 24 weeks. Female mice gained more adipose mass and lost more lean mass than males but reached similar visceral adipose mass and body weight, as males, at the end of the diet. 24 weeks of HFD matched male and female mice for visceral adiposity, glycaemia, plasma insulin, lipids and inflammatory cytokines levels, demonstrating the suitability of the model to study human pathology. HFD did not elevate BP, but similarly increased heart rate (HR) in males (CD: 571±9 vs. HFD: 631±14 bpm, P<0.05) and females (CD: 589±19 vs. HFD: 642±6 bpm, P<0.05). Indices of autonomic control of BP and HR were obtained by measuring BP and HR response to ganglionic blockade, β-adrenergic and muscarinic receptors antagonists. HFD increased vascular but reduced cardiac sympathetic drive in males (CD: -43±4 and HFD: -60±7% drop in BP, P<0.05). HFD did not alter females’ vascular or cardiac sympathetic drive. HFD specifically reduced aortic α-adrenergic constriction in males and lowered HR response to muscarinic receptor antagonism in females. These data suggest that obesity-associated increases in HR could be caused by a reduced cardiac vagal tone in females, while HR increases in males may compensate for the reduced vascular adrenergic contractility to preserve baseline BP. These data suggest that obesity impairs autonomic control of cardiovascular function in males and females, via sex-specific mechanisms and independent of fat distribution, metabolic disorder or inflammation.

Targets and End Points in Cardiac Autonomic Denervation Procedures

Abstract: Background—Autonomic denervation is an alternative approach for patients with symptomatic bradycardia. No consensus exists on the critical targets and end points of the procedure. The aim of this s...

Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha.

Abstract: The vagus nerve is a central component of cholinergic anti-inflammatory pathways. We sought to evaluate the effect of bilateral transcutaneous cervical vagal nerve stimulation (t-VNS) on validated parameters of autonomic tone and cytokines in 20 healthy subjects. 24 hours after t-VNS, there was an increase in cardiac vagal tone and a reduction in tumor necrosis factor-α in comparison to baseline. No change was seen in blood pressure, cardiac sympathetic index or other cytokines. These preliminary data suggest that t-VNS exerts an autonomic and a subtle antitumor necrosis factor-α effect, which warrants further evaluation in larger controlled studies.

The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice.

Abstract: Objectives Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice. Methods The actions of GLP-1R agonists were examined on the control of HR in wild type mice (WT) and in mice with cardiomyocyte-selective disruption of the GLP-1R ( Glp1r CM−/− ). Complimentary studies examined the effects of GLP-1R agonists in mice co-administered propranolol or atropine. The direct effects of GLP-1R agonism on HR and ventricular developed pressure were examined in isolated perfused mouse hearts ex vivo, and atrial depolarization was quantified in mouse hearts following direct application of liraglutide to perfused atrial preparations ex vivo. Results Doses of liraglutide and lixisenatide that were equipotent for acute glucose control rapidly increased HR in WT and Glp1r CM−/− mice in vivo. The actions of liraglutide to increase HR were more sustained relative to lixisenatide, and diminished in Glp1r CM−/− mice. The acute chronotropic actions of GLP-1R agonists were attenuated by propranolol but not atropine. Neither native GLP-1 nor lixisenatide increased HR or developed pressure in perfused hearts ex vivo. Moreover, liraglutide had no direct effect on sinoatrial node firing rate in mouse atrial preparations ex vivo. Despite co-localization of HCN4 and GLP-1R in primate hearts, HCN4-directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart. Conclusions GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner.

Mechanisms underpinning sympathetic nervous activity and its modulation using transcutaneous vagus nerve stimulation

Abstract: New Findings •What is the topic of this review? This review briefly considers what modulates sympathetic nerve activity and how it may change as we age or in pathological conditions. It then focuses on transcutaneous vagus nerve stimulation, a method of neuromodulation in autonomic cardiovascular control. •What advances does it highlight? The review considers the pathways involved in eliciting the changes in autonomic balance seen with transcutaneous vagus nerve stimulation in relationship to other neuromodulatory techniques. The autonomic nervous system, consisting of the sympathetic and parasympathetic branches, is a major contributor to the maintenance of cardiovascular variables within homeostatic limits. As we age or in certain pathological conditions, the balance between the two branches changes such that sympathetic activity is more dominant, and this change in dominance is negatively correlated with prognosis in conditions such as heart failure. We have shown that non-invasive stimulation of the tragus of the ear increases parasympathetic activity and reduces sympathetic activity and that the extent of this effect is correlated with the baseline cardiovascular parameters of different subjects. The effects could be attributable to activation of the afferent branch of the vagus and, potentially, other sensory nerves in that region. This indicates that tragus stimulation may be a viable treatment in disorders where autonomic activity to the heart is compromised.

Vagal-immune interactions involved in cholinergic anti-inflammatory pathway.

Abstract: Inflammation and other immune responses are involved in the variety of diseases and disorders. The acute response to endotoxemia includes activation of innate immune mechanisms as well as changes in autonomic nervous activity. The autonomic nervous system and the inflammatory response are intimately linked and sympathetic and vagal nerves are thought to have anti-inflammation functions. The basic functional circuit between vagus nerve and inflammatory response was identified and the neuroimmunomodulation loop was called cholinergic anti-inflammatory pathway. Unique function of vagus nerve in the anti-inflammatory reflex arc was found in many experimental and pre-clinical studies. They brought evidence on the cholinergic signaling interacting with systemic and local inflammation, particularly suppressing immune cells function. Pharmacological/electrical modulation of vagal activity suppressed TNF-alpha and other proinflammatory cytokines production and had beneficial therapeutic effects. Many questions related to mapping, linking and targeting of vagal-immune interactions have been elucidated and brought understanding of its basic physiology and provided the initial support for development of Tracey´s inflammatory reflex. This review summarizes and critically assesses the current knowledge defining cholinergic anti-inflammatory pathway with main focus on studies employing an experimental approach and emphasizes the potential of modulation of vagally-mediated anti-inflammatory pathway in the treatment strategies.

Non-invasive Vagal Nerve Stimulation Effects on Hyperarousal and Autonomic State in Patients with Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury: Preliminary Evidence.

Abstract: Posttraumatic stress disorder (PTSD) is a reaction to trauma that results in a chronic perception of threat, precipitating mobilization of the autonomic nervous system, and may be reflected by chronic disinhibition of limbic structures. A common injury preceding PTSD in veterans is mild traumatic brain injury (mTBI). This may be due to the vulnerability of white matter in these networks and such damage may affect treatment response. We evaluated transcutaneous vagal nerve stimulation (tVNS), a non-invasive, low-risk approach that may alter the functions of the limbo-cortical and peripheral networks underlying the hyperarousal component of PTSD and thus improve patient health and well-being. In this single visit pilot study evaluating the impact of tVNS in 22 combat veterans, we used a between subjects design in people with either PTSD with preceding mTBI or healthy controls. Participants were randomized into stimulation or sham groups and completed a posturally-modulated autonomic assessment and emotionally-modulated startle paradigm. The primary measures used were respiratory sinus arrhythmia (high frequency heart rate variability) during a tilt-table procedure derived from an electrocardiogram, and skin conductance changes in response to acoustic startle while viewing emotional images (International Affective Picture System). The stimulation was well tolerated and resulted in improvements in vagal tone and moderation of autonomic response to startle, consistent with modulation of autonomic state and response to stress in this population. Our results suggest that tVNS affects systems underlying emotional dysregulation in this population and therefore should be further evaluated and developed as a potential treatment tool for these patients.

Differential contribution of POMC and AgRP neurons to the regulation of regional autonomic nerve activity by leptin.

Abstract: Objectives The autonomic nervous system is critically involved in mediating the control by leptin of many physiological processes. Here, we examined the role of the leptin receptor (LepR) in proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in mediating the effects of leptin on regional sympathetic and parasympathetic nerve activity. Methods We analyzed how deletion of the LepR in POMC neurons (POMCCre/LepRfl/fl mice) or AgRP neurons (AgRPCre/LepRfl/fl mice) affects the ability of leptin to increase sympathetic and parasympathetic nerve activity. We also studied mice lacking the catalytic p110α or p110β subunits of phosphatidylinositol-3 kinase (PI3K) in POMC neurons. Results Leptin-evoked increase in sympathetic nerve activity subserving thermogenic brown adipose tissue was partially blunted in mice lacking the LepR in either POMC or AgRP neurons. On the other hand, loss of the LepR in AgRP, but not POMC, neurons interfered with leptin-induced sympathetic nerve activation to the inguinal fat depot. The increase in hepatic sympathetic traffic induced by leptin was also reduced in mice lacking the LepR in AgRP, but not POMC, neurons whereas LepR deletion in either AgRP or POMC neurons attenuated the hepatic parasympathetic nerve activation evoked by leptin. Interestingly, the renal, lumbar and splanchnic sympathetic nerve activation caused by leptin were significantly blunted in POMCCre/LepRfl/fl mice, but not in AgRPCre/LepRfl/fl mice. However, loss of the LepR in POMC or AgRP neurons did not interfere with the ability of leptin to increase sympathetic traffic to the adrenal gland. Furthermore, ablation of the p110α, but not the p110β, isoform of PI3K from POMC neurons eliminated the leptin-elicited renal sympathetic nerve activation. Finally, we show trans-synaptic retrograde tracing of both POMC and AgRP neurons from the kidneys. Conclusions POMC and AgRP neurons are differentially involved in mediating the effects of leptin on autonomic nerve activity subserving various tissues and organs.

Combined effect of prefrontal transcranial direct current stimulation and a working memory task on heart rate variability.

Abstract: Prefrontal cortex activity has been associated with changes to heart rate variability (HRV) via mediation of the cortico-subcortical pathways that regulate the parasympathetic and sympathetic branches of the autonomic nervous system. Changes in HRV due to altered prefrontal cortex functioning can be predicted using the neurovisceral integration model, which suggests that prefrontal hyperactivity increases parasympathetic tone and decreases contributions from the sympathetic nervous system. Working memory (WM) tasks and transcranial direct current stimulation (tDCS) have been used independently to modulate brain activity demonstrating changes to HRV in agreement with the model. We investigated the combined effects of prefrontal tDCS and a WM task on HRV. Bifrontal tDCS was administered for 15 minutes at 2mA to 20 participants in a sham controlled, single-blind study using parallel groups. A WM task was completed by participants at three time points; pre-, during-, and post-tDCS, with resting state data collected at similar times. Frequency-domain HRV was computed for high frequency (HF; 0.15–0.4Hz) and low frequency (LF; 0.04–0.15Hz) power reflecting parasympathetic and sympathetic branch activity, respectively. Response time on the WM task, but not accuracy, improved from baseline to during-tDCS and post-tDCS with sham, but not active, stimulation. HF-HRV was significantly increased in the active tDCS group compared to sham, lasting beyond cessation of stimulation. Additionally, HF-HRV showed a task-related reduction in power during performance on the WM task. Changes in LF-HRV were moderately inversely correlated (r > 0.4) with changes in WM accuracy during and following tDCS compared to baseline levels. Stimulation of the prefrontal cortex resulted in changes to the parasympathetic branch of the nervous system in agreement with a linearly additive interpretation of effects. Sympathetic activity was not directly altered by tDCS, but was correlated with changes in WM performance. This suggests that the parasympathetic and sympathetic branches respond differentially due to similar, but distinct neural pathways. Given the ease of HRV data collection, studies of prefrontal tDCS would benefit from collection of this data as it provides unique insight into tDCS effects resulting from propagation through brain networks.