The purpose of the current study was twofold. First, to determine the intraindividual variability of sweat rate per gland for a given skin location during exercise in the heat. Second, to determine the relative importance of intrinsic vs. extrinsic factors as the source of the intraindividual variability in the sweat rate per gland. Sweat rate of individual eccrine glands on the forearm was measured following pilocarpine iontophoresis and during exercise in the heat. In five participants during exercise in the heat, the measured sweat rate for individual forearm eccrine glands (n = 500) ranged from 0.5 nL/gland/min to 16 nL/gland/min, or over a 30-fold difference. The mean (SD) intraindividual coefficient of variation in sweat rate per gland was 36 (5)% and 49 (10)% (p = 0.008) following pilocarpine iontophoresis and during exercise in the heat, respectively. Such results suggest that intrinsic factors (i.e., sweat gland size and cholinergic sensitivity) contribute approximately three times more than extrinsic factors (i.e., sweat gland nerve fiber density and threshold amplitude) towards explaining the large intra-person variability in sweat rate per gland seen during exercise in the heat.

An imbalance between cardiovascular parasympathetic and sympathetic activity towards sympathetic predominance has been implicated in the pathogenesis of treatment-resistant arterial hypertension and heart failure. Arterial baroreceptors control efferent cardiovascular autonomic activity and have, therefore, been recognized as potential treatment targets. Baroreflex activation therapy through electrical carotid sinus stimulation is a device-based approach to modulate cardiovascular autonomic activity. Electrical carotid sinus stimulation lowered blood pressure in various hypertensive animal models and improved cardiac remodeling and survival in preclinical models of heart failure. In human mechanistic profiling studies, electrical carotid sinus stimulation lowered blood pressure through sympathetic inhibition with substantial inter-individual variability. The first-generation device reduced blood pressure in controlled and uncontrolled clinical trials. Controlled clinical trials proving efficacy in blood pressure reduction in patients with hypertension do not exist for the currently available second-generation carotid sinus stimulator. Investigations in heart failure patients showed improved symptoms, quality of life, and natriuretic peptide biomarkers. Electrical carotid sinus stimulation is an interesting technology to modulate cardiovascular autonomic control. However, controlled trials with hard clinical endpoints are required.

Chronic Fatigue Syndrome (CFS) is a complex and perplexing medical disorder primarily characterized by persistent and debilitating fatigue, often accompanied by a constellation of symptoms, including weakness, dyspnea, arthromyalgia, sore throat, and disrupted sleep patterns. CFS is defined by its persistent or recurrent manifestation for a minimum duration of six months, marked by an enduring and unrelenting fatigue that remains refractory to rest. In recent decades, this condition has garnered significant attention within the medical community. While the precise etiology of CFS remains elusive, it is postulated to be multifactorial. CFS is potentially associated with various contributory factors such as infections, chronic stress, genetic predisposition, immune dysregulation, and psychosocial influences. The pathophysiological underpinnings of CFS encompass viral infections, immune system dysregulation, neuroendocrine aberrations, heightened oxidative stress, and perturbations in gut microbiota. Presently, clinical management predominantly relies on pharmaceutical interventions or singular therapeutic modalities, offering alleviation of specific symptoms but exhibiting inherent limitations. Traditional Chinese Medicine (TCM) interventions have emerged as a promising paradigm, demonstrating notable efficacy through their multimodal, multi-target, multi-pathway approach, and holistic regulatory mechanisms. These interventions effectively address the lacunae in contemporary medical interventions. This comprehensive review synthesizes recent advancements in the understanding of the etiological factors, pathophysiological mechanisms, and interventional strategies for CFS, drawing from a corpus of domestic and international literature. Its aim is to furnish valuable insights for clinicians actively involved in diagnosing and treating CFS, as well as for pharmaceutical researchers delving into innovative drug development pathways. Moreover, it seeks to address the intricate challenges confronted by clinical practitioners in managing this incapacitating condition.

The following is a narrative review of the fundamentals of optogenetics. It focuses on the advantages and constraints of manipulating the autonomic nervous system by modifying the pathophysiological characteristics that arise in different diseases. Although the use of this technique is currently experimental, we will discuss improvements that have been implemented and identify the necessary measures for potential preclinical translation in the control of the cardiac autonomic nervous system.

Interoception entails perceiving or being aware of the internal state of the body, playing a pivotal role in regulating processes such as heartbeat, digestion, glucose metabolism, and respiration. The carotid body (CB) serves as an interoceptive organ, transmitting information to the brain via its sensitive nerve, the carotid sinus nerve, to maintain homeostasis. While traditionally known for sensing oxygen, carbon dioxide, and pH levels, the CB is now recognized to possess additional interoceptive properties, detecting various mediators involved in blood pressure regulation, inflammation, and glucose homeostasis, among other physiological functions. Furthermore, in the last decades CB dysfunction has been linked to diseases like sleep apnea, essential hypertension, and diabetes. In this review manuscript, we make a concise overview of the traditional interoceptive functions of the CB, acting as a sensor for oxygen levels, carbon dioxide levels, and pH, and introduce the novel interoceptive properties of the CB related to vascular, glucose and energy regulation. Additionally, we revise the contribution of the CB to the onset and progression of metabolic diseases, delving into the potential dysfunction of its interoceptive metabolic functions as a contributing factor to pathophysiology. Finally, we postulate the use of therapeutic interventions targeting the metabolic interoceptive properties of the CB as a potential avenue for addressing metabolic diseases.

Catheter based renal denervation has recently been FDA approved for the treatment of hypertension. Traditionally, the anti-hypertensive effects of renal denervation have been attributed to the ablation of the efferent sympathetic renal nerves. In recent years the role of the afferent sensory renal nerves in the regulation of blood pressure has received increased attention. In addition, afferent renal denervation is associated with reductions in sympathetic nervous system activity. This suggests that reductions in sympathetic drive to organs other than the kidney may contribute to the non-renal beneficial effects observed in clinical trials of catheter based renal denervation. In this review we will provide an overview of the role of the afferent renal nerves in the regulation of renal function and the development of pathophysiologies, both renal and non-renal. We will also describe the central projections of the afferent renal nerves, to give context to the responses seen following their ablation and activation. Finally, we will discuss the emerging role of the kidney as an interoceptive organ. We will describe the potential role of the kidney in the regulation of interoceptive sensitivity and in this context, speculate on the possible pathological consequences of altered renal function.

Plasma levels of the catecholamine norepinephrine (NE) has emerged as a useful tool to help differentiate pre- and post-ganglionic disorders in patients with cardiovascular autonomic failure (AF). However, data on intrasubject reliability in individuals with these conditions are limited. We evaluated the intrasubject reproducibility of supine plasma NE levels drawn across two consecutive time points under controlled conditions during head-up table testing in a large cohort of patients with alpha-synucleinopathies and both pre- and post-ganglionic cardiovascular AF.

Significant volume is pooled in veins in humans and the amount is dramatically altered by various physiological stresses and diseases. Several animal and human studies demonstrated that limb venous distension evoked significant increases in blood pressure and sympathetic nerve activity (venous distension reflex, VDR). VDR has attracted much attention because of its potential to explain the still unknown mechanism of autonomic dysfunction in several diseases, which would lead to a new treatment approach. This mini review discusses accumulated evidence of VDR at this point and what should be investigated in the future to apply the current understanding of VDR in clinical practice.

The nadir pressure responses to cardiac cycles absent of muscle sympathetic nerve activity (MSNA) bursts (or non-bursts) are typically reported in studies quantifying sympathetic transduction, but the information gained by studying non-bursts is unclear. We tested the hypothesis that longer sequences of non-bursts (≥8 cardiac cycles) would be associated with a greater nadir diastolic blood pressure (DBP) and that better popliteal artery function would be associated with an augmented reduction in DBP.

Urinary bladder dysfunction might be related to disturbances at different levels of the micturition reflex arc. The current study aimed to further develop and evaluate a split bladder model for detecting and analysing relaxatory signalling in the rat urinary bladder. The model allows for discrimination between effects at the efferent and the afferent side of the innervation. In in vivo experiments, the stimulation at a low frequency (1 Hz) of the ipsilateral pelvic nerve tended to evoke relaxation of the split bladder half (contralateral side; -1.0 ± 0.4 mN; n = 5), in contrast to high frequency-evoked contractions. In preparations in which the contralateral pelvic nerve was cut the relaxation occurred at a wider range of frequencies (0.5-2 Hz). In separate experiments, responses to 1 and 2 Hz were studied before and after intravenous injections of propranolol (1 mg/kg IV). The presence of propranolol significantly shifted the relaxations into contractions. Also, electrical stimulation of the ipsilateral pudendal nerve evoked relaxations of similar magnitude as for the pelvic stimulations, which were also affected by propranolol. In control in vitro experiments, substances with β-adrenoceptor agonism, in contrast to a selective α-agonist, evoked relaxations. The current study shows that the split bladder model can be used for in vivo studies of relaxations. In the model, reflex-evoked sympathetic responses caused relaxations at low intensity stimulation. The involvement of β-adrenoceptors is supported by the sensitivity to propranolol and by the in vitro observations.

Para-sympathetic vagal activation has profound influence on heart rate and other cardiovascular parameters. We tested the hypothesis that transcutaneous Vagal Nerve Stimulation (tVNS) through the auricular branch of the vagus nerve would attenuate the normal sympathetic response to central blood volume reduction by lower body negative pressure (LBNP).

Syncope is a transient loss of consciousness resulting from cerebral hypoperfusion. Vasovagal syncope (VVS) is a form of orthostatic intolerance (OI). Its clinical signs such as dizziness and hypotension may mimic symptoms of adrenal insufficiency. The objective of this study was to evaluate the adrenal gland function in patients with vasovagal syncope after stimulation with synthetic adrenocorticotropic hormone (ACTH).

Pupillary unrest in ambient light (PUAL) describes the fluctuation of pupil diameter observed in normal, awake subjects under typical levels of indoor light. PUAL becomes low to absent in young healthy subjects during opioid intoxication. We sought to determine the age-related distribution of PUAL values in a random sample of ambulatory participants.

Rodent studies demonstrated specialized sodium chloride (NaCl) sensing neurons in the circumventricular organs, which mediate changes in sympathetic nerve activity, arginine vasopressin, thirst, and blood pressure. However, the neural pathways involved in NaCl sensing in the human brain are incompletely understood. The purpose of this pilot study was to determine if acute hypernatremia alters the functional connectivity of NaCl-sensing regions of the brain in healthy young adults. Resting-state fMRI scans were acquired in 13 participants at baseline and during a 30 min hypertonic saline infusion (HSI). We used a seed-based approach to analyze the data, focusing on the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) as regions of interest (ROIs). Blood chemistry and perceived thirst were assessed pre- and post-infusion. As expected, serum sodium increased from pre- to post-infusion in the HSI group. The primary finding of this pilot study was that the functional connectivity between the SFO and a cluster within the OVLT increased from baseline to the late-phase of the HSI. Bidirectional connectivity changes were found with cortical regions, with some regions showing increased connectivity with sodium-sensing regions while others showed decreased connectivity. Furthermore, the functional connectivity between the SFO and the posterior cingulate cortex (a control ROI) did not change from baseline to the late-phase of the HSI. This finding indicates a distinct response within the NaCl sensing network in the human brain specifically related to acute hypernatremia that will need to be replicated in large-scale studies.

The SARS-CoV-2 pandemic has left millions of individuals with a host of post-viral symptoms that can be debilitating and persist indefinitely. To date there are no definitive tests or treatments for the collection of symptoms known as "Long COVID" or Post-acute sequelae of COVID-19 (PASC). Following our initial case report detailing improvement of Long COVID symptoms after sequential bilateral stellate ganglion blockade (SGB), we performed a retrospective chart analysis study on individuals treated with the same protocol over the course of six months (2021-2022) in our clinic. Patients self-reported symptoms on a 10-point scale as part of optional patient follow-up using an online survey. After one month or more following treatment, patients reported striking reductions in Fatigue, Worsening of Symptoms following Mental and Physical Activity, Memory Problems, Problems Concentrating, Sleep Problems, Anxiety, and Depression. Loss of Taste and Loss of Smell in some individuals did not respond to treatment, likely indicating structural damage following infection. This study suggests that neuromodulation may provide relief of Long COVID symptoms for at least a subset of individuals, and provides support for prospective studies of this potential treatment.

Tributyltin (TBT) is a biocide used in the formulation of antifouling paints and it is highly harmful. Despite the ban, the compound persists in the environment, contaminating marine foodstuffs and household products. Therefore, considering the route of exposure to the contaminant, the gastrointestinal tract (GIT) acts as an important barrier against harmful substances and is a potential biomarker for understanding the consequences of these agents. This work aimed to evaluate histological and neuronal alterations in the duodenum of male Wistar rats that received 20 ng/g TBT and 600 ng/g via gavage for 30 consecutive days. After the experimental period, the animals were euthanized, and the duodenum was intended for neuronal histochemistry (total and metabolically active populations) and histological routine (morphometry and histopathology). The results showed more severe changes in neuronal density and intestinal morphometry in rats exposed to 20 ng/g, such as total neuronal density decrease and reduction of intestinal layers. In rats exposed to 600 ng/g of TBT, it was possible to observe only an increase in intraepithelial lymphocytes. We conclude that TBT can be more harmful to intestinal homeostasis when consumed in lower concentrations.

Unilateral nociceptive stimulation is associated with subtle signs of pupil asymmetry that may reflect lateralized activity in the locus coeruleus. To explore drivers of this pupil asymmetry, electrical stimuli, delivered alone or 200 ms before or after an acoustic startle stimulus, were administered to one ankle under four experimental conditions: with or without a 1.6 s anticipatory period, or while the forearm ipsilateral or contralateral to the electrical stimulus was heated tonically to induce moderate pain (15 healthy participants in each condition). Pupil diameter was measured at the start of each trial, at stimulus delivery, and each second for 5 s after stimulus delivery. At the start of the first trial, the pupil ipsilateral to the side on which electric shocks were later delivered was larger than the contralateral pupil. Both pupils dilated robustly during the anticipatory period and dilated further during single- and dual-stimulus trials. However, pupil asymmetry persisted throughout the experiment. Tonically-applied forearm heat-pain modulated the pupillary response to phasic electrical stimuli, with a slight trend for dilatation to be greater contralateral to the forearm being heated. Together, these findings suggest that focusing anxiously on the expected site of noxious stimulation was associated with dilatation of the ipsilateral pupil whereas phasic nociceptive stimuli and psychological arousal triggered bilateral pupillary dilatation. It was concluded that preparatory cognitive activity rather than phasic afferent nociceptive input is associated with pupillary signs of lateralized activity in the locus coeruleus.

This review considers interoceptive signalling from the heart and coronary circulation. Vagal and cardiac sympathetic afferent sensory nerve endings are distributed throughout the atria, ventricles (mainly left), and coronary artery. A small proportion of cardiac receptors attached to thick myelinated vagal afferents are tonically active during the cardiac cycle. Dependent upon location, these mechanoreceptors detect fluctuations in atrial volume and coronary arterial perfusion. Atrial volume and coronary arterial signals contribute to beat-to-beat feedback control and physiological homeostasis. Most cardiac receptors are attached to thinly myelinated or nonmyelinated C fibres, many of which are unresponsive to the cardiac cycle. Of these, there are many chemically sensitive cardiac receptors which are activated during myocardial stress by locally released endogenous substances. In contrast, some tonically inactive receptors become activated by irregular ventricular wall mechanics or by distortion of the ischaemic myocardium. Furthermore, some are excited both by chemical mediators of ischaemia and wall abnormalities. Reflex responses arising from cardiac receptors attached to thinly myelinated or nonmyelinated are complex. Impulses that project centrally through vagal afferents elicit sympathoinhibition and hypotension, whereas impulses travelling in cardiac sympathetic afferents and spinal pathways elicit sympathoexcitation and hypertension. Two opposing cardiac reflexes may provide a mechanism for fine-tuning a composite haemodynamic response during myocardial stress. Sympathetic afferents provide the primary pathway for transmission of cardiac nociception to the central nervous system. However, activation of sympathetic afferents may increase susceptibility to life-threatening arrhythmias. Notably, the cardiac sympathetic afferent reflex predominates in pathophysiological states including hypertension and heart failure.

Social stress is a major risk factor for comorbid conditions including cardiovascular disease and depression. While women exhibit 2-3× the risk for these stress-related disorders compared to men, the mechanisms underlying heightened stress susceptibility among females remain largely unknown. Due to a lack in understanding of the pathophysiology underlying stress-induced comorbidities among women, there has been a significant challenge in developing effective therapeutics. Recently, a causal role for inflammation has been established in the onset and progression of comorbid cardiovascular disease/depression, with women exhibiting increased sensitivity to stress-induced immune signaling. Importantly, reduced vagal tone is also implicated in stress susceptibility, through a reduction in the vagus nerve's well-recognized anti-inflammatory properties. Thus, examining therapeutic strategies that stabilize vagal tone during stress may shed light on novel targets for promoting stress resilience among women. Recently, accumulating evidence has demonstrated that physical activity exerts cardio- and neuro-protective effects by enhancing vagal tone. Based on this evidence, this mini review provides an overview of comorbid cardiovascular and behavioral dysfunction in females, the role of inflammation in these disorders, how stress may impart its negative effects on the vagus nerve, and how exercise may act as a preventative. Further, we highlight a critical gap in the literature with regard to the study of females in this field. This review also presents novel data that are the first to demonstrate a protective role for voluntary wheel running over vagal tone and biomarkers of cardiac dysfunction in the face of social stress exposure in female rats.

Reported orthostatic hypotension (OH) prevalence in Parkinson's disease (PD) varies widely, with few studies evaluating specifically neurogenic-OH (nOH). The ratio of orthostatic heart rate (HR) to systolic blood pressure (SBP) change (Δ) is a valid screening method to stratify nOH/non-nOH but has had minimal epidemiologic application.

Respiratory interoception is one of the internal bodily systems that is comprised of different types of somatic and visceral sensations elicited by different patterns of afferent input and respiratory motor drive mediating multiple respiratory modalities. Respiratory interoception is a complex system, having multiple afferents grouped into afferent clusters and projecting into both discriminative and affective centers that are directly related to the behavioral assessment of breathing. The multi-afferent system provides a spectrum of input that result in the ability to interpret the different types of respiratory interceptive sensations. This can result in a response, commonly reported as breathlessness or dyspnea. Dyspnea can be differentiated into specific modalities. These respiratory sensory modalities lead to a general sensation of an Urge-to-Breathe, driven by a need to compensate for the modulation of ventilation that has occurred due to factors that have affected breathing. The multiafferent system for respiratory interoception can also lead to interpretation of the sensory signals resulting in respiratory related sensory experiences, including the Urge-to-Cough and Urge-to-Swallow. These behaviors are modalities that can be driven through the differentiation and integration of multiple afferent input into the respiratory neural comparator. Respiratory sensations require neural somatic and visceral interoceptive elements that include gated attention and detection leading to respiratory modality discrimination with subsequent cognitive decision and behavioral compensation. Studies of brain areas mediating cortical and subcortical respiratory sensory pathways are summarized and used to develop a model of an integrated respiratory neural network mediating respiratory interoception.