The autonomic nervous system regulates cardiovascular function essential for homeostasis, and its impairment contributes to disorders including neurogenic orthostatic hypotension, postural orthostatic tachycardia syndrome, and syncope. Quantifying cardiovascular autonomic physiology is therefore paramount in both clinical and research settings to support diagnosis, to mechanistically interrogate autonomic control during physiological challenge, and to test new treatments. As many autonomic abnormalities are expressed through changes in cardiac timing, blood pressure control, and hemodynamic redistribution, cardiovascular monitoring remains a cornerstone of autonomic phenotyping. In this review, we synthesize and compare technologies used to measure key cardiovascular signals relevant to autonomic function, spanning cardiac electrical activity (ECG-derived rhythm and R-R intervals for heart rate/heart rate variability), vascular pressure (intermittent versus beat-to-beat, and central versus peripheral blood pressure), and flow/volume surrogates that inform redistribution and cardiac output dynamics. Within each domain, we consider measurement approaches across invasiveness tiers, from highly invasive and implantable methods to less invasive tools and emerging wearable modalities, highlighting what each method directly measures versus estimates and the implications for interpretation. This continuum increasingly enables longer-duration and ambulatory assessments, creating opportunities to link symptoms to physiology, track dynamic treatment responses, and extend autonomic phenotyping beyond laboratories and hospitals, while highlighting ongoing needs for accuracy, robustness, calibration, and long-term stability in everyday environments.

The purpose of this manuscript is to review all of the experimental studies on the effects of intraluminal HCl on defined esophageal reflexes. Intraluminal presence of HCl in the esophagus activates the slowly adapting touch sensitive mechanoreceptors of the mucosa, which are necessary for the esophageal phase of swallowing to always follow the pharyngeal phase. Intraluminal HCl sensitizes and activates the slowly adapting touch/tension mechanoreceptors of the mucosa which stimulate the pharyngeal phase of swallowing, and activate contractions of the esophagus orad of the stimulus in the striated muscle esophagus. Intraluminal HCl also sensitizes and activates the rapidly adapting mucosal mechanoreceptors which mediate relaxation of the upper esophageal sphincter. Intraluminal HCl sensitizes the slowly adapting mechanoreceptors of the muscularis that stimulate contraction of the upper esophageal sphincter, or the mechanosensitive motor neurons that relax the lower esophageal sphincter. Intraluminal HCl has greater effects on mechanoreceptors closer to the lumen. The effects of HCl on the above reflexes occur with low doses over short periods of time whereas higher doses and longer application times inhibit the esophageal mechanoreceptors and associated reflex responses. The esophagus also has chemoreceptors which are activated by HCl that cause contraction of the small airways, increase airway mucous secretion, and salivary secretion, all of which defend against the effects of supra-esophageal reflux. Therefore, the esophagus is well designed with built in defense mechanisms against normal exposure of the esophagus to HCl, however, high levels of HCl can be very destructive to esophageal receptors and their reflex responses.

Gastrointestinal (GI) symptoms are frequent in disorders that involve the autonomic nervous system (ANS) or the enteric neuromuscular apparatus. Although dysfunction may occur anywhere along the alimentary tract, gastric manifestations are often the most clinically visible 'end-organ' expression of autonomic disease because they drive nausea, vomiting, early satiety, postprandial distress, malnutrition risk, and impaired drug absorption. In this invited review, we summarize the organization of the GI neuromuscular apparatus, emphasizing how intrinsic (enteric) circuitry and extrinsic sympathetic and parasympathetic pathways cooperate to regulate gastrointestinal functions. We then link common symptom clusters (dysphagia, gastroparesis, intestinal pseudo-obstruction, constipation, diarrhea, and fecal incontinence) to likely neuroanatomic levels and review autonomic test batteries and motility studies that help characterize dysfunction. Finally, we discuss neurologic and systemic diseases in which autonomic and enteric involvement produce prominent gastric and broader GI phenotypes. These include cerebrovascular and cortical neurodegenerative disorders, Parkinson's disease, structural and inflammatory brainstem syndromes, primary autonomic failure and hereditary dysautonomia, postural orthostatic tachycardia syndrome, spinal cord disorders (including multiple sclerosis), peripheral neuropathies such as diabetes mellitus and amyloidosis, paraneoplastic and autoimmune autonomic neuropathies, and selected neuromuscular and myopathic conditions.

Chronic intestinal and colonic pseudo-obstruction (CIPO) represent a severe and heterogeneous group of gastrointestinal motility disorders with symptoms of bowel obstruction in the absence of a mechanical cause. Neurological and neuromuscular diseases are among the most important etiological factors, caused by dysfunction of the enteric nervous system, extrinsic autonomic pathways and intestinal smooth muscle. However, intestinal dysmotility in these conditions remains frequently under-recognized leading to delayed diagnosis and substantial morbidity. In this review, we detailed the CIPO-related spectrum of clinical presentations and highlighted features that may suggest an underlying neurogenic or neuromuscular substrate. A structured diagnostic approach is outlined, integrating imaging, physiological testing and targeted investigations to detect enteric neuro-muscular impairment. Also, we examined the main pathophysiological mechanisms linking neurological diseases to intestinal dysmotility, including enteric neuropathies, extrinsic autonomic dysfunction, mitochondrial disorders, visceral myopathies and mixed phenotypes. Particular emphasis was placed on immune-mediated enteric neuropathies, which are of special clinical relevance because they may be affected and potentially reversed via immunomodulatory therapy. Management requires a multidisciplinary approach combining nutritional support, pharmacological/interventional strategies and treatment of complications. Identification of gastrointestinal involvement in neurology-related CIPO is critical to better understand underlying mechanisms and improve management of this challenging condition.

Gastrointestinal involvement is common in Parkinson's disease (PD) and symptoms related to gastrointestinal dysfunction may feature prominently, impact on quality of life and compromise nutrition. While all components of the gastrointestinal tract may be involved, drooling, dysphagia and constipation are the most common symptoms. Various factors contribute to the etiology of gastrointestinal dysfunction in PD and include the involvement of skeletal muscles in the oropharynx, pelvic floor and external anal sphincters in the motor dysfunctions that typify this movement disorder, an associated autonomic neuropathy and the presence of Lewy bodies and other pathological hallmarks of PD in the enteric nervous system. In assessing gastrointestinal symptoms in PD, one must also be mindful of the effects of anti-Parkinsonian medications. The latter observation together with reports of the development of gastrointestinal symptoms, such as constipation, decades before the onset of the classical neurological features of the disorder led to the hypothesis, that, in some individuals, the PD process may originate in the gut and ascend via the vagus nerve to the central nervous system. We review the clinical presentation, prognosis and complications of common gastrointestinal problems in PD and present an approach to their assessment and management. Interactions between gastrointestinal issues, the typical motor features of PD and common co-morbidities are discussed. For several of these problems, the evidence base for therapies directed specifically to the PD patient is thin and reliance continues to be placed on data derived from the management of these symptoms and syndromes in non-PD patients.

Interoception is the process by which the nervous system senses and regulates the body's internal state to maintain homeostasis. Interoceptive processes in the gastrointestinal tract are carried out by multiple levels of sensory-motor control that are organized into hierarchical neural circuits, with different levels of command being engaged under various circumstances. The enteric nervous system provides local intrinsic control, initiating and sustaining functions like peristalsis and secretory reflexes. To coordinate motility and secretions across distant regions of the gut, the ENS recruits postganglionic neurons in prevertebral ganglia through intestinofugal sensory input. For higher control, the central nervous system becomes engaged via vagal and spinal pathways, which exhibit functional segregation for parallel processing of information. Vagal pathways regulate feeding behavior and metabolism, while lumbosacral (LS) spinal pathways are key for the conscious, voluntary control of defecation. Conversely, the thoracolumbar (TL) spinal pathways appear to serve as an 'alert system,' becoming engaged during inflammation, infection, or chronic stress and contributing to visceral pain and pathological hypersensitivity. Emerging research confirms that individual neural pathways express distinct receptors, respond to different sensory modalities, target unique CNS regions, and drive different motor and behavioral responses. By synthesizing key findings from foundational studies with results from more recent reports using modern approaches, this review aims to dissect the neural pathways of the gut-brain axis, detail their physiological roles in interoception, and explore how their dysfunction relates to visceral hypersensitivity, pathological interoceptive awareness, and other GI-related symptoms.

Sympathetic preganglionic neurons (SPNs) distribute signals across paravertebral ganglia, yet the reliability of spike propagation along their predominantly unmyelinated axons remains poorly defined. We examined temperature- and activity-dependent modulation of SPN axonal conduction in an ex vivo adult mouse thoracic sympathetic-chain preparation. Population compound action potentials (CAP) responses were evoked by supramaximal T10 ventral-root stimulation and recorded from the interganglionic nerve (IGN), which contains pathways that branch within the paravertebral chain, and the splanchnic nerve, presumed to project unbranching axons toward prevertebral ganglia. After scaling for temperature-dependent changes in conduction velocity and spike waveform, CAP magnitude at 36 °C was approximately 50% lower than at 22 °C, with preferential reduction of slower-conducting components. Reductions occurred in both pathways, indicating a shared vulnerability of small unmyelinated axons, whereas evidence for an additional branching-associated vulnerability was strongest during repetitive activation. Activity dependence was assessed using 20-s trains at 5 and 20 Hz. At 22 °C, slower-conducting components showed marked frequency-dependent depression that was greater in the IGN. Observed loss of individual units without change in spike amplitude support CAP depression as due to conduction block. At 36 °C, depression of slow components was not statistically detectable, faster-conducting components facilitated at 20 Hz, and several responses showed post-train potentiation. These differences may reflect temperature-dependent filtering of vulnerable slow-conducting axons rather than uniform changes in frequency-following properties. Thus, SPN axonal conduction is strongly modulated by temperature and activation history. Preferential vulnerability of slower-conducting, likely small-diameter axons identifies conduction reliability as a vulnerable site in sympathetic output.

One of the most troublesome non-motor symptoms in Parkinson's disease is urinary dysfunction. The mechanisms involved in how nigrostriatal neurodegeneration leads to these symptoms are poorly understood. In this study, we have investigated the effects of unilateral 6-OHDA lesioning on local smooth muscle responses of rat urinary bladder tissues. Tissue contractile and relaxatory responses to electrical field stimulation and direct muscarinic (methacholine), purinergic (ATP) and adrenergic (noradrenaline) receptor agonists were investigated using in vitro organ bath experiments. The 6-OHDA-lesioned animals displayed a general reduction in bladder contractility, as well as decreased noradrenaline-induced relaxatory response compared to saline-injected animals. These changes were accompanied by reduced expression of muscarinic M3 and β3-adrenergic receptor proteins, the main functional receptors mediating contractile and relaxatory responses, respectively, in urinary bladder smooth muscle. Further, ATP-induced purinergic responses were increased when normalized to tissue weight and maximum contraction response to high K[+] Krebs solution. No changes were, however, seen in purinergic receptor protein expression in the 6-OHDA animals. Our data demonstrate that selective central dopamine loss in the nigrostriatal pathway alters the local smooth muscle function and histology in the urinary bladder. This study gives clues on the local mechanisms behind the troublesome urinary bladder symptoms observed in Parkinson's disease.

To investigate cardiovascular and hemodynamic responses in both static and dynamic motion stimuli in persons with Postural Orthostatic Tachycardia Syndrome (POTS) and chronic mild traumatic brain injury (mTBI), participants with POTS and mTBI (n = 10) were compared to healthy controls (n = 10). Both cohorts underwent static head-up-tilt tests and dynamic tilt-translation sled tests, with oscillatory interaural axis translation coupled with simultaneous roll tilt in various combinations to alter otolithic stimulation and investigate vestibular-mediated influences. Continuous cardiovascular metrics included heart rate (HR), blood pressure (BP), stroke volume (SV), and cardiac output (CO). During static head-up-tilts, the POTS-mTBI group had greater HR increases (padj = 0.025), whereas there were no group differences for BP, SV, and CO. Responses to dynamic motion stimuli varied depending on the motion profile. For the profile consisting of oscillations in roll tilt, the POTS-mTBI group had greater responses in BP (padj = 0.025). For the cancel motion profile, designed to alter hydrostatic pressure gradients along the body axis while producing no shear force stimulation to the otoliths, the POTS-mTBI group had greater responses in BP (padj = 0.044). In a 20° static tilt, there were no differences between cohorts, while a ± 20° dynamic tilt had larger responses in HR (p = 0.020), BP (p = 0.022), and CO (p = 0.045) in the POTS-mTBI group. Potential vestibular-mediated mechanisms in cardiovascular regulation may be impacted in patients with POTS and mTBI, investigated here by quantifying dynamic motion responses.

In the gastrointestinal tract, spinal afferent and sympathetic efferent neurons are key regulators of motility, secretion, and sensation. Strong colocalization of the afferent markers calcitonin gene-related peptide (CGRP) and TRPV1 is established in mouse gut. However, the expression of these markers in sympathetic axons-identifiable by immunoreactivity for tyrosine hydroxylase (TH), the rate-limiting enzyme for noradrenaline synthesis- has not yet been characterized in the colon. Using multiple-label immunohistochemistry, we quantified the coexistence of CGRP, TRPV1, and TH in varicose axons in the myenteric plexus of the mouse proximal and mid colon. Approximately half of CGRP-immunoreactive (IR) varicosities were also TRPV1-IR in the proximal (48.5 ± 3.5) and mid colon (50.3 ± 3.5) and the great majority of TRPV1-IR varicosities were CGRP-IR in the proximal (87 ± 1.1) and mid colon (90 ± 3.3). In the proximal and mid colon, TH-IR varicosities were neither CGRP- or TRPV1-IR, and the converse was also true; CGRP- and TRPV1-IR varicosities were not TH-IR. Our observations reveal that while CGRP and TRPV1 expression largely occurs together in axons in the proximal and mid colon, there is a population of CGRP axons that do not express TRPV1. In varicose axons, TH expression is mutually exclusive from expression of CGRP and TRPV1. Together, the results support the notion that CGRP together with TRPV1 and TH serve as respective "neurochemical markers" to distinguish spinal afferents from sympathetic efferents in the murine GI tract.