Neuromodulation has recently received a great deal of attention among academic institutions, government funding agents and industries. This mini-review focuses on methods and applications as well as mechanisms of various neuromodulation methods in treating functional diseases of the upper gastrointestinal tract. First, the methods of various neuromodulation are introduced, including direct electrical stimulation at various peripheral nerves, such as the vagus nerve, sacral nerve and spinal cord, direct gastrointestinal electrical stimulation and noninvasive/transcutaneous electrical stimulation. Then, literature search was performed on the clinical applications of these neuromodulation methods for treating gastroesophageal reflux disease, functional dyspepsia and gastroparesis. Due to nature of the mini-review, the search results are selectively presented based on the expert opinions. Finally, a perspective is provided based on the author's own experience in this field of research.

Although the autonomic nervous system has an evident impact on cardiac electrophysiology and radiofrequency ablation (RFA) is the conventional technique for treating persistent atrial fibrillation, the specific effects of RFA have been insufficiently studied to date. Here, we investigated whether RFA affects neurohumoral transmitter levels and myocardial 123I-metaiodobenzylguanidine (123I-MIBG) uptake. To perform this task, we compared two groups of patients with acquired valvular heart disease: patients who had undergone surgical AF ablation and patients with sinus rhythm. The decrease in norepinephrine (NE) level in the coronary sinus had a direct association with the heart-to-mediastinum ratio (p = 0.02) and a negative correlation with 123I-MIBG uptake defects (p = 0.01). The NE level decreased significantly after the main surgery, both in patients with AF (p = 0.0098) and sinus rhythm (p = 0.0039). Furthermore, the intraoperative difference between the norepinephrine levels in the ascending aorta and coronary sinus (ΔNE) of -400 pg/mL was determined as a cut-off value to evaluate RFA efficacy, as denervation failed in all patients with ΔNE < -400 pg/mL. Hence, ΔNE can be utilized to predict the efficacy of the "MAZE-IV" procedure and to assess the risk of AF recurrence after RFA.

Spinal cord injury (SCI) results in severe cardiovascular dysfunction due to the disruption of supraspinal control. Autonomic dysreflexia (AD), an uncontrolled rise in blood pressure in response to peripheral stimuli including common bowel routine, digital anorectal stimulation (DARS), reduces the quality of life, and increases morbidity and mortality. Recently, spinal cord stimulation (SCS) has emerged as a potential intervention to mitigate unstable blood pressure following SCI. The objective of this case series was to test the real-time effect of epidural SCS (eSCS) at the lumbosacral spinal cord, the most common implant location, on mitigating AD in individuals with SCI. We recruited three individuals with cervical and upper thoracic motor-complete SCI who have an implanted epidural stimulator. We demonstrated that eSCS can reduce the elevation in blood pressure and prevent DARS-induced AD. The blood pressure variability analysis indicated that eSCS potentially reduced vascular sympathetic nervous system activity during DARS, compared to without eSCS. This case series provides evidence to support the use of eSCS to prevent AD episodes during routine bowel procedures, improving the quality of life for individuals with SCI and potentially reducing cardiovascular risks.

The clinical importance of autoantibodies against the ganglionic acetylcholine receptor (gAChR) remains to be fully elucidated. We aimed to identify the clinical characteristics of autoimmune autonomic ganglionopathy (AAG) in patients with gAChR autoantibodies. For this cohort investigation, serum samples were obtained from patients with AAG between 2012 and 2018 in Japan. We measured the levels of autoantibodies against gAChRα3 and gAChRβ4 and evaluated clinical features, as well as assessing the laboratory investigation results among the included patients. A total of 179 patients tested positive for antibodies, including 116 gAChRα3-positive, 13 gAChRβ4-positive, and 50 double antibody-positive patients. Seropositive AAG patients exhibited widespread autonomic dysfunction. Extra-autonomic manifestations including sensory disturbance, central nervous system involvement, endocrine disorders, autoimmune diseases, and tumours were present in 118 patients (83%). We observed significant differences in the frequencies of several autonomic and extra-autonomic symptoms among the three groups. Our 123I-metaiodobenzylguanidine myocardial scintigraphy analysis of the entire cohort revealed that the heart-to-mediastinum ratio had decreased by 80%. The present study is the first to demonstrate that patients with AAG who are seropositive for anti-gAChRβ4 autoantibodies exhibit unique autonomic and extra-autonomic signs. Decreased cardiac uptake occurred in most cases, indicating that 123I- metaiodobenzylguanidine myocardial scintigraphy may be useful for monitoring AAG. Therefore, our findings indicate that gAChRα3 and gAChRβ4 autoantibodies cause functional changes in postganglionic fibres in the autonomic nervous system and extra-autonomic manifestations in seropositive patients with AAG.

Environmental contamination has exposed humans to various metal agents, including mercury. It has been determined that mercury is not only harmful to the health of vulnerable populations such as pregnant women and children, but is also toxic to ordinary adults in various ways. For many years, mercury was used in a wide variety of human activities. Nowadays, the exposure to this metal from both natural and artificial sources is significantly increasing. Recent studies suggest that chronic exposure, even to low concentration levels of mercury, can cause cardiovascular, reproductive, and developmental toxicity, neurotoxicity, nephrotoxicity, immunotoxicity, and carcinogenicity. Possible biological effects of mercury, including the relationship between mercury toxicity and diseases of the cardiovascular system, such as hypertension, coronary heart disease, and myocardial infarction, are being studied. As heart rhythm and function are under autonomic nervous system control, it has been hypothesized that the neurotoxic effects of mercury might also impact cardiac autonomic function. Mercury exposure could have a long-lasting effect on cardiac parasympathetic activity and some evidence has shown that mercury exposure might affect heart rate variability, particularly early exposures in children. The mechanism by which mercury produces toxic effects on the cardiovascular system is not fully elucidated, but this mechanism is believed to involve an increase in oxidative stress. The exposure to mercury increases the production of free radicals, potentially because of the role of mercury in the Fenton reaction and a reduction in the activity of antioxidant enzymes, such as glutathione peroxidase. In this review we report an overview on the toxicity of mercury and focus our attention on the toxic effects on the cardiovascular system.

Mechanisms behind development of premature ventricular contraction (PVC)-induced cardiomyopathy remain unclear. PVCs may adversely modulate the autonomic nervous system to promote development of heart failure. Afferent neurons in the inferior vagal (nodose) ganglia transduce cardiac activity and modulate parasympathetic output. Effects of PVCs on cardiac parasympathetic efferent and vagal afferent neurotransmission are unknown. The purpose of this study was to evaluate effects of PVCs on vagal afferent neurotransmission and compare these effects with a known powerful autonomic modulator, myocardial ischemia. In 16 pigs, effects of variably coupled PVCs on heart rate variability (HRV) and vagal afferent neurotransmission were evaluated. Direct nodose neuronal recordings were obtained in vivo, and cardiac-related afferent neurons were identified based on their response to cardiovascular interventions, including ventricular chemical and mechanical stimuli, left anterior descending (LAD) coronary artery occlusion, and variably coupled PVCs. On HRV analysis before versus after PVCs, parasympathetic tone decreased (normalized high frequency: 83.6 ± 2.8 to 72.5 ± 5.3; P < 0.05). PVCs had a powerful impact on activity of cardiac-related afferent neurons, altering activity of 51% of neurons versus 31% for LAD occlusion (P < 0.05 vs. LAD occlusion and all other cardiac interventions). Both chemosensitive and mechanosensitive neurons were activated by PVCs, and their activity remained elevated even after cessation of PVCs. Cardiac afferent neural responses to PVCs were greater than any other intervention, including ischemia of similar duration. These data suggest that even brief periods of PVCs powerfully modulate vagal afferent neurotransmission, reflexly decreasing parasympathetic efferent tone.NEW & NOTEWORTHY Premature ventricular contractions (PVCs) are common in many patients and, at an increased burden, are known to cause heart failure. This study determined that PVCs powerfully modulate cardiac vagal afferent neurotransmission (exerting even greater effects than ventricular ischemia) and reduce parasympathetic efferent outflow to the heart. PVCs activated both mechano- and chemosensory neurons in the nodose ganglia. These peripheral neurons demonstrated adaptation in response to PVCs. This study provides additional data on the potential role of the autonomic nervous system in PVC-induced cardiomyopathy.

Complex neurodevelopmental disorders need multi-disciplinary treatment approaches for optimal care. The clinical effectiveness of treatments is limited in patients with rare genetic syndromes with multisystem morbidity. Emotional and behavioural dysregulation is common across many neurodevelopmental disorders. It can manifest in children across multiple diagnostic groups, including those on the autism spectrum and in rare genetic syndromes such as Rett Syndrome (RTT). There is, however a remarkable scarcity in the literature on the impact of the autonomic component on emotional and behavioural regulation in these disorders, and on the longer-term outcomes on disorder burden.RTT is a debilitating and often life-threatening disorder involving multiple overlapping physiological systems. Autonomic dysregulation otherwise known as dysautonomia is a cardinal feature of RTT characterised by an imbalance between the sympathetic and parasympathetic arms of the autonomic nervous system. Unlocking the autonomic component of emotional and behavioural dysregulation would be central in reducing the impairment seen in patients with RTT. In this vein, Emotional, Behavioural and Autonomic Dysregulation (EBAD) would be a useful construct to target for treatment which could mitigate burden and improve the quality of life of patients.RTT can be considered as a congenital dysautonomia and because EBAD can give rise to impairments occurring in multiple overlapping physiological systems, understanding these physiological responses arising out of EBAD would be a critical part to consider when planning treatment strategies and improving clinical outcomes in these patients. Biometric guided pharmacological and bio-feedback therapy for the behavioural and emotional aspects of the disorder offers an attracting perspective to manage EBAD in these patients. This can also allow for the stratification of patients into clinical trials and could ultimately help streamline the patient care pathway for optimal outcomes.The objectives of this review are to emphasise the key issues relating to the management of EBAD in patients with RTT, appraise clinical trials done in RTT from the perspective of autonomic physiology and to discuss the potential of EBAD as a target for clinical trials.

The autonomic nervous system (ANS) is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common observation among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] in the acute and chronic phases of the disease is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Because abnormalities in the ANS can contribute to each of these symptoms, herein a review of autonomic dysfunction in SARS-COV-2 infection is provided to guide diagnostic testing, patient care and research initiatives. The autonomic nervous system is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common collection of signs and symptoms among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Abnormalities in the autonomic nervous system (ANS) can contribute to each of these identifiers, potentially offering a unifying pathobiology for acute, subacute and the long-term sequelae of SARS-CoV-2 infection (PASC) and a target for intervention.

Pulmonary vein isolation (PVI) modulates the intrinsic cardiac autonomic nervous system (ANS). We evaluated the impact of PVI on 5 non-invasive autonomic tests.

Individuals with spinal cord injury (SCI) have significant autonomic nervous system dysfunction. However, despite recent findings postulated to support that spinal cord stimulation improves dynamic autonomic regulation, limited scope of previous testing means the true effects remain unknown.

Background The natural history of autonomic alterations following catheter ablation of drug-refractory paroxysmal atrial fibrillation is poorly defined, largely because of the historical reliance on non-invasive intermittent rhythm monitoring for outcome ascertainment. Methods and Results The study included 346 patients with drug-refractory paroxysmal atrial fibrillation undergoing pulmonary vein isolation using contemporary advanced-generation ablation technologies. All patients underwent insertion of a Reveal LINQ (Medtronic) implantable cardiac monitor before ablation. The implantable cardiac monitor continuously recorded physical activity, heart rate variability (measured as the SD of the average normal-to-normal), daytime heart rate, and nighttime heart rate. Longitudinal autonomic data in the 2-month period leading up to the date of ablation were compared with the period from 91 to 365 days following ablation. Following ablation there was a significant decrease in SD of the average normal-to-normal (mean difference versus baseline of 19.3 ms; range, 12.9-25.7; P<0.0001), and significant increases in daytime and nighttime heart rates (mean difference versus baseline of 9.6 bpm; range, 7.4-11.8; P<0.0001, and 7.4 bpm; range, 5.4-9.3; P<0.0001, respectively). Patients free of arrhythmia recurrence had significantly faster daytime (11±11 versus 8±12 bpm, P=0.001) and nighttime heart rates (8±9 versus 6±8 bpm, P=0.049), but no difference in SD of the average normal-to-normal (P=0.09) compared with those with atrial fibrillation recurrence. Ablation technology and cryoablation duration did not influence these autonomic nervous system effects. Conclusions Pulmonary vein isolation results in significant sustained changes in the heart rate parameters related to autonomic function. These changes are correlated with procedural outcome and are independent of the ablation technology used. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01913522.

A critical mechanism in atrial fibrillation (AF) is cardiac autonomic nerve remodeling (ANR). MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. Numerous miRNAs are involved in diseases of the nervous and cardiovascular systems.

Intestinal microbiota are critical for health with changes associated with diverse human diseases. Research suggests that altered intestinal microbiota can profoundly affect brain function. However, whether altering brain function directly affects the microbiota is unknown. Since it is currently unclear how brain injury induces clinical complications such as infections or paralytic ileus, key contributors to prolonged hospitalization and death post-stroke, we tested in mice the hypothesis that brain damage induced changes in the intestinal microbiota. Experimental stroke altered the composition of caecal microbiota, with specific changes in Peptococcaceae and Prevotellaceae correlating with the extent of injury. These effects are mediated by noradrenaline release from the autonomic nervous system with altered caecal mucoprotein production and goblet cell numbers. Traumatic brain injury also caused changes in the gut microbiota, confirming brain injury effects gut microbiota. Changes in intestinal microbiota after brain injury may affect recovery and treatment of patients should appreciate such changes.

The pathophysiology of fibromyalgia (FM) involves many mechanisms including central nervous system sensitization theory, autonomic nervous system (ANS) dysfunction, and recently small fiber neuropathy. While the small fiber neuropathy itself can cause ANS dysfunction and neuropathic pain (NP), it is still unknown whether ANS problems have an association with severity of disease and NP in patients with FM. The aim of this study was to evaluate ANS dysfunction in FM patients and to explore possible associations of ANS dysfunction with disease severity and NP.

The aim of the study was to develop a method for diagnosing pre-nosological changes in the electrophysiological state of the myocardium in patients with somatoform dysfunction of the autonomic nervous system (SDANS) and risk factors for cardiovascular diseases using the ECG dispersion mapping method.

In addition to the metabolic effects in diabetes, glucagon-like peptide 1 receptor (GLP-1R) agonists lead to a small but substantial increase in heart rate (HR). However, the GLP-1R actions on the autonomic nervous system (ANS) in diabetes remain debated. Therefore, this meta-analysis evaluates the effect of GLP-1R agonist on measures of ANS function in diabetes.

Vascular dysregulation refers to the regulation of blood flow that is not adapted to the needs of the respective tissue. We distinguish primary vascular dysregulation (PVD, formerly called vasospastic syndrome) and secondary vascular dysregulation (SVD). Subjects with PVD tend to have cold extremities, low blood pressure, reduced feeling of thirst, altered drug sensitivity, increased pain sensitivity, prolonged sleep onset time, altered gene expression in the lymphocytes, signs of oxidative stress, slightly increased endothelin-1 plasma level, low body mass index and often diffuse and fluctuating visual field defects. Coldness, emotional or mechanical stress and starving can provoke symptoms. Virtually all organs, particularly the eye, can be involved. In subjects with PVD, retinal vessels are stiffer and more irregular, and both neurovascular coupling and autoregulation capacity are reduced while retinal venous pressure is often increased. Subjects with PVD have increased risk for normal-tension glaucoma, optic nerve compartment syndrome, central serous choroidopathy, Susac syndrome, retinal artery and vein occlusions and anterior ischaemic neuropathy without atherosclerosis. Further characteristics are their weaker blood-brain and blood-retinal barriers and the higher prevalence of optic disc haemorrhages and activated astrocytes. Subjects with PVD tend to suffer more often from tinnitus, muscle cramps, migraine with aura and silent myocardial ischaemic and are at greater risk for altitude sickness. While the main cause of vascular dysregulation is vascular endotheliopathy, dysfunction of the autonomic nervous system is also involved. In contrast, SVD occurs in the context of other diseases such as multiple sclerosis, retrobulbar neuritis, rheumatoid arthritis, fibromyalgia and giant cell arteritis. Taking into consideration the high prevalence of PVD in the population and potentially linked pathologies, in the current article, the authors provide recommendations on how to effectively promote the field in order to create innovative diagnostic tools to predict the pathology and develop more efficient treatment approaches tailored to the person.

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.

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent lung diseases worldwide. COPD patients show major dysfunction in cardiac autonomic modulation due to sustained hypoxaemia, which has been significantly related to higher risk of cardiovascular disease. Obstructive sleep apnoea syndrome (OSAS) is a frequent comorbidity in COPD patients. It has been found that patients suffering from both COPD and OSAS simultaneously, the so-called overlap syndrome, have notably higher morbidity and mortality. Heart rate variability (HRV) has demonstrated to be useful to assess changes in autonomic functioning in different clinical conditions. However, there is still little scientific evidence on the magnitude of changes in cardiovascular dynamics elicited by the combined effect of both respiratory diseases, particularly during sleep, when apnoeic events occur. In this regard, we hypothesised that a non-linear analysis is able to provide further insight into long-term dynamics of overnight cardiovascular modulation. Accordingly, this study is aimed at assessing the usefulness of sample entropy (SampEn) to distinguish changes in overnight pulse rate variability (PRV) recordings among three patient groups while sleeping: COPD, moderate-to-severe OSAS, and overlap syndrome. In order to achieve this goal, a population composed of 297 patients were studied: 22 with COPD alone, 213 showing moderate-to-severe OSAS, and 62 with COPD and moderate-to-severe OSAS simultaneously (COPD+OSAS). Cardiovascular dynamics were analysed using pulse rate (PR) recordings from unattended pulse oximetry carried out at patients' home. Conventional time- and frequency- domain analyses were performed to characterise sympathetic and parasympathetic activation of the nervous system, while SampEn was applied to quantify long-term changes in irregularity. Our analyses revealed that overnight PRV recordings from COPD+OSAS patients were significantly more irregular (higher SampEn) than those from patients with COPD alone (0.267 [0.210-0.407] vs. 0.212 [0.151-0.267]; p < 0.05) due to recurrent apnoeic events during the night. Similarly, COPD + OSAS patients also showed significantly higher irregularity in PRV during the night than subjects with OSAS alone (0.267 [0.210-0.407] vs. 0.241 [0.189-0.325]; p = 0.05), which suggests that the cumulative effect of both diseases increases disorganization of pulse rate while sleeping. On the other hand, no statistical significant differences were found between COPD and COPD + OSAS patients when traditional frequency bands (LF and HF) were analysed. We conclude that SampEn is able to properly quantify changes in overnight cardiovascular dynamics of patients with overlap syndrome, which could be useful to assess cardiovascular impairment in COPD patients due to the presence of concomitant OSAS.

Background: After a Stroke, there is an autonomic nervous system (ANS) changes. Transcranial Direct Current Stimulation (tDCS) can promote the reorganization of the affected circuits. Objective: To evaluate the effects of tDCS applied before a session of physical activity on the treadmill, in the modulation of the autonomic nervous system of post-stroke patients. Methodology: Cross-over study, were randomized 12 adult hemiparetic subjects in 2 groups, Group 1 (active tDCS before exercise on the treadmill) and Group 2 (sham tDCS before exercise on the treadmill). Stimulation times were 20 min; treadmill time was 20 min. The heart rate variability (HRV) and Variability of Systolic Blood Pressure (VSBP) were evaluated for 15 min, in 3 periods (pre and post tDCS and during exercise recovery on the treadmill). Results: There was no difference in the VSBP and the HRV between the groups, compared with the baseline data; however, in the intragroup analysis, the parasympathetic modulation after active tDCS increased by 18% over baseline by the RMSSD with IC 95% (-7.85 to -0.34). In group 1, the post-tDCS active and post-exercise periods presented a value of variance above baseline, indicating a better prognosis. In group 2, there was a significant reduction of 38% of Variance values (p = 0.003) after tDCS sham. Conclusion: tDCS does not generate immediate effects on HRV and VSBP, except for intragroup comparison, which has greater participation in parasympathetic modulation in the group receiving active tDCS.