Auricular transcutaneous vagus nerve stimulation (atVNS) has been proposed to modulate cognitive control by sharpening gain processes via potential increase in norepinephrine (NE) and gamma-aminobutyric acid (GABA) levels. Yet, its impact on the core mechanisms of action control remains unclear. According to the Binding and Retrieval in Action Control (BRAC) framework, flexible behavior relies on integrating stimulus and response features into event-files and their subsequent retrieval. Here, we investigated whether atVNS alters stimulus-response (S-R) binding in a manner consistent with the proposed modulation of the signal-to-noise ratio of perceptual-motor representations. In a randomized single-blind design, healthy participants received active or sham atVNS while performing a standard binding task. Behavioral analyses revealed robust S-R binding effects across groups. Critically, the active atVNS group showed significantly larger S-R binding effects in reaction times than the sham group. To determine in which cognitive subprocesses this behavioral modulation was expressed, we applied drift diffusion modeling (DDM). Consistent with gain-control accounts, atVNS enhanced S-R binding effects in the drift rate, consistent with a modulation of evidence accumulation across task conditions. These findings provide the first DDM-based evidence that atVNS-related differences in integration and/or retrieval processes central to BRAC may be expressed in the accumulation of task-relevant evidence. Taken together, the results suggest that atVNS modulates S-R binding effects, potentially through changes in event-file integration and/or retrieval, thereby offering a theoretical link between neurochemical gain modulation and action control.

Postural orthostatic tachycardia syndrome is a chronic autonomic disorder with limited effective treatment therapy. Non-invasive transcutaneous vagus nerve stimulation has emerged as a promising intervention that improves autonomic balance and has anti-inflammatory properties. This systematic search and narrative synthesis brings together all available clinical evidence including landmark studies from 2025 to 2026 unavailable to all prior reviews and advances novel arguments to guide future trial design. We searched in 5 databases (PubMed, Embase, Cochrane, Scopus and Web of science) from inception to March 2026 to extract studies evaluating the role of tVNS in treatment of POTS following the PRISMA 2020 guidelines. Because of the small number of clinically and methodologically heterogeneous studies, findings were combined by narrative synthesis rather than meta-analysis, and reported in line with the Synthesis Without Meta-analysis (SWiM) guideline. A total of 105 patients with POTS from 3 primary studies (Stavrakis et al. (2024), Wang et al. (2025), Shiffer et al. (2026) were included in this review. Across the studies, tVNS consistently reduced orthostatic tachycardia and improved multiple autonomic parameters, with reductions in GPCR autoantibodies, inflammatory markers, and the emerging biomarker NPY. Patient-reported symptoms improved in two studies that reported them. These outcomes sustained up to 1-2 years. In this systematic review, we found that tVNS is safe, non-invasive and consistently effective in reducing the orthostatic tachycardia and improving autonomic indices in POTS patients and may contribute to disease modification.

Chronic bladder inflammation and psychological stress are key contributors to lower urinary tract dysfunction and pelvic pain, yet the molecular stress responses engaged across bladder tissues and associated neural pathways remain poorly defined. Heat shock proteins (HSPs), critical regulators of cellular stress adaptation, may differentially respond to peripheral injury versus psychogenic stress. Using cyclophosphamide (CYP)-induced cystitis of varying duration, acute stress and repeated variate stress (RVS) paradigms in mice, we examined time-, tissue-, and segment-specific regulation of Hsp60, Hsp70, and Hsp90 transcripts across the urothelium, detrusor, dorsal root ganglia (DRG), and lumbosacral spinal cord. CYP-induced cystitis elicited a rapid, transient induction of all three Hsps examined in the urothelium and detrusor at 4 h, followed by normalization with longer duration of CYP-induced cystitis. In contrast, sensory (DRG) and central (spinal cord) responses were highly structured: sacral (S1) DRG showed early Hsp induction, whereas lumbar DRG and spinal cord segments exhibited delayed suppression of select Hsps during chronic cystitis. Psychogenic stress produced fundamentally different patterns. Longer duration RVS (2w, 4w), but not acute stress, caused progressive and sustained suppression of Hsp expression in the bladder, with earlier onset in the urothelium than detrusor. In contrast, longer duration RVS increased Hsp expression in select DRG and spinal cord segments, particularly L2, L6 DRG and L1, S1 spinal cord, with biphasic regulation. Together, these findings demonstrate that inflammatory and psychogenic stressors engage distinct, tissue-specific heat shock responses across bladder-neural pathways, revealing differential molecular responses that may underlie bladder dysfunction and pelvic pain.

General anesthetics enable invasive experimentation but can affect cardiovascular and respiratory physiology, biasing preclinical outcomes. We compared five anesthetic regimens in adult male Wistar rats, tribromoethanol (TBE, 250 mg/kg i.p.), chloral hydrate (CH, 400 mg/kg i.p.), ketamine-xylazine (KX, 80/10 mg/kg i.p.), thiopental (TP, 80 mg/kg i.p.), and isoflurane (ISO, 4% induction, 2% maintenance), to investigate integrated cardiorespiratory and biochemical markers. Femoral arterial catheterization allowed continuous blood pressure (BP) and derived heart rate (HR) recordings, while ventilation was assessed through pletysmography at baseline (awake), during induction, and early recovery phases of anesthesia. Variability was evaluated in the time and frequency domains, including HR, systolic blood pressure (SBP), and spontaneous baroreflex sensitivity. In an independent cohort of rats, butyrylcholinesterase (BChE), CK-MB, cTnI, and LDH were measured. Baseline BP was unchanged by TBE and TP, whereas all anesthetics affected HR. Minute ventilation and breathing frequency were reduced with all agents, while tidal volume decreased with KX and TBE only. LDH and cTnI were unaffected, BChE was reduced by KX, TBE, and ISO, and CK-MB increased with CH and KX. Variability analysis showed that all anesthetics depressed pulse-interval and SBP variability and shifted spectral power toward higher frequencies, while baroreflex sensitivity and effectiveness were consistently reduced. During early recovery, KX and TP restored most variability indices, whereas CH, TBE, and ISO showed continued suppression of these indices. These findings highlight distinct profiles of cardiovascular depression and biomarker responses across anesthetics and underscore the importance of accounting for autonomic variability when selecting different anesthetics in experimental protocols.

Inspiratory muscle training (IMT) is a respiratory based intervention capable of increasing maximal inspiratory pressure (MIP) and modulating cardiovascular autonomic control. This systematic review and meta-analysis aimed to synthesize and quantitatively evaluate the effects of IMT on cardiorespiratory interactions and autonomic outcomes. Clinical trials assessing MIP and autonomic markers, including heart rate variability (HRV), spontaneous baroreflex sensitivity (BRS), and muscle sympathetic nerve activity (MSNA), were included. Searches were conducted in PubMed, Scopus, and Europe PMC up to June 2025. Risk of bias was evaluated using the Risk of Bias 2 tool, and random effects meta-analyses were performed. Twelve clinical studies involving 274 participants were included in the quantitative synthesis. IMT protocols varied in duration and intensity. IMT significantly increased MIP, corresponding to an approximate 41% improvement compared with 9% in control groups. Subgroup analyses demonstrated consistent effects across training durations and intensities. Regarding autonomic outcomes, IMT increased the high frequency normalized component of HRV, indicating enhanced vagal mediated cardiac modulation, with no observed heterogeneity. In addition, two studies demonstrated reductions in MSNA following IMT, whereas no significant effects were observed for BRS. Approximately 62.5% of studies were classified as low risk of bias, and no high-risk studies were identified. IMT improves inspiratory muscle strength and enhances cardiac vagal modulation, supporting its role as a non-pharmacological strategy to modulate cardiovascular autonomic control. The review was registered in PROSPERO CRD420251021003.

Orthostatic hypotension is characterized by the reduced ability to compensate for a decrease in blood pressure upon standing and is prevalent among elderly populations as well as many pathophysiological conditions. Orthostatic hypotension is also associated with the development of mild cognitive impairment, cognitive decline, and dementia. While associations have been observed between the presence of orthostatic hypotension and impaired cognitive performance, few studies have assessed cognitive function in both supine and upright postures in individuals with orthostatic hypotension. We conducted a systematic review to examine the influence of upright posture on cognitive function in orthostatic hypotension. The review was registered with Prospero (CRD42025649093), and the following databases were searched from inception to 16 December 2024: Ovid Medline, Embase, Cochrane Central Register of Controlled Trials, APA PsychINFO, CINAHL, and Web of Science. Eight studies which met our inclusion criteria of cognitive function testing completed in both postures underwent data extraction. All pathophysiological conditions were considered, however, only studies that included subgroups with isolated or concurrent orthostatic hypotension, that also reported findings specific to that group, were included. Our findings suggest that cognitive function is worse in upright posture compared to supine posture in individuals with orthostatic hypotension across several cognitive domains (global function, attention and processing speed, executive function, language, memory and learning, visuospatial skills). Further research is required to elucidate relationships between posture and cognition and address several limitations such as the variety of head-up tilt angles, duration of supine and upright conditions, restricting ambulation between conditions, and use of appropriate statistical analysis.

Spinal afferents relay sensory information and regulate cardioprotective reflexes. These afferent signals go to cell bodies in the dorsal root ganglia (DRG) and ultimately to the central nervous system. However, the morphology and distribution of spinal afferent terminals in the heart have not been well delineated. This is partly due to challenges, including limited surgical access to the upper thoracic DRGs, tissue thickness, and tracer options. In this study, we injected tracer dextran biotin (DB) into the left DRG (C8-T3) of male Sprague-Dawley rats (3-5 months). After 16 days, the animals were sacrificed, and the left and right ventricles were separated from the rest of the heart. Next, these samples were stained with diaminobenzidine and mounted for visualization under brightfield microscopy. DB-labeled axons were identified and digitally traced using the Neurolucida system. Our findings showed that spinal afferent neurons of the left DRG project individual axons that enter the ventricles from the base. These axons are distributed across various regions within both ventricles. While these axons are present in the epicardial and myocardial layers, they were not identified in the endocardial layer. Within the epicardial and myocardial layers, spinal afferents form extensive terminal arborizations and make presumptive contact with cardiac muscle, blood vessels, and adipose tissue. This investigation marks the first anterograde characterization of spinal afferent axon terminal distribution and morphology in flat-mount preparations of whole rat ventricles.

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.