Biomechanical increase in cervical esophageal wall tension during peristalsis.

During pharyngeal phase of swallowing, circumferential tension of the cervical esophagus (CTE) increases caused by a biomechanical process of laryngeal elevation pulling the cervical esophagus orad. The esophagus contracts longitudinally during esophageal peristalsis, therefore, we hypothesized that CTE increases during esophageal peristalsis by a biomechanical process. We investigated this hypothesis using 28 decerebrate cats instrumented with electromyographic (EMG) electrodes on the pharynx and esophagus, and esophageal manometry. We recorded CTE, distal esophageal longitudinal tension (DET), and orad laryngeal tension (OLT) using strain gauges. Peristalsis was stimulated by injecting saline into esophagus or nasopharynx. We investigated the effects of transecting the pharyngo-esophageal nerve (PEN), hypoglossal nerve (HG), or administering (10 mg/kg iv) hexamethonium (HEX). We found that the durations of CTE and DET increased and OLT decreased simultaneously during the total extent of esophageal peristalsis. CTE duration was highly correlated with DET but not esophageal EMG or manometry. The peak magnitudes of the DET and CTE were highly correlated. After HEX administration, peristalsis in the distal esophagus did not occur, and the duration of the CTE response decreased. PEN transection blocked the occurrence of cricopharyngeal or cervical esophageal response during peristalsis but had no significant effect on the CTE response. HG transection had no significant effect on CTE. We conclude that there is a significant CTE increase, independent of laryngeal elevation or esophageal muscle contraction, which occurs during esophageal peristalsis. This response is a biomechanical process caused by esophageal shortening that occurs during esophageal longitudinal contraction of esophageal peristalsis.NEW & NOTEWORTHY Circumferential tension of cervical esophagus (CTE) increases during esophageal peristalsis. CTE response is correlated with distal longitudinal tension on cervical esophagus during esophageal peristalsis but not laryngeal elevation or esophageal muscle contraction. CTE response is not blocked by transection of motor innervation of laryngeal elevating muscles or proximal esophagus but is temporally reduced after hexamethonium administration. We conclude that the CTE response is a biomechanical effect caused by longitudinal esophageal contraction during esophageal peristalsis.

The effects of simulated gastroesophageal reflux on infant pig oropharyngeal feeding physiology.

The neural connectivity among the oral cavity, pharynx, and esophagus is a critical component of infant feeding physiology. Central integration of oral and pharyngeal afferents alters motor outputs to structures that power swallowing, but the potential effects of esophageal afferents on preesophageal feeding physiology are unclear. These effects may explain the prevalence of oropharyngeal dysphagia in infants suffering from gastroesophageal reflux (GER), though the mechanism underlying this relationship remains unknown. Here we use the validated infant pig model to assess the impacts of simulated GER on preesophageal feeding parameters. We used high-speed videofluoroscopy and electromyography to record bottle-feeding before and following the infusion of a capsaicin-containing solution into the lower esophagus. Sucking parameters were minimally affected by capsaicin exposure, such that genioglossus activity was unchanged and tongue kinematics were largely unaffected. Aspects of the pharyngeal swallow were altered with simulated GER, including increased thyrohyoid muscle activity, increased excursions of the hyoid and thyroid per swallow, decreased swallow frequency, and increased bolus sizes. These results suggest that esophageal afferents can elicit changes in pharyngeal swallowing. In addition, decreased swallowing frequency may be the mechanism by which esophageal pathologies induce oropharyngeal dysphagia. Although recent work indicates that oral or pharyngeal capsaicin may improve dysphagia symptoms, the decreased performance following esophageal capsaicin exposure highlights the importance of designing sensory interventions based upon neurophysiology and the mechanisms underlying disordered feeding. This mechanistic approach requires comprehensive data collection across the entirety of the feeding process, which can be achieved using models such as the infant pig.NEW & NOTEWORTHY Simulated gastroesophageal reflux (GER) in an infant pig model resulted in significant changes in pharyngeal swallowing, which suggests that esophageal afferents are centrally integrated to alter motor outputs to the pharynx. In addition, decreased swallow frequency and increased bolus sizes may be underlying mechanisms by which esophageal pathologies induce oropharyngeal dysphagia. The infant pig model used here allows for a mechanistic approach, which can facilitate the design of intervention strategies based on neurophysiology.

Ginger Constituent 6-Shogaol Attenuates Vincristine-Induced Activation of Mouse Gastroesophageal Vagal Afferent C-Fibers.

Chemotherapeutic agent-induced nausea and vomiting are the severe adverse effects that are induced by their stimulations on the peripheral and/or central emetic nerve pathways. Even though ginger has been widely used as an herbal medicine to treat emesis, mechanisms underlying its neuronal actions are still less clear. The present study aimed to determine the chemotherapeutic agent vincristine-induced effect on gastroesophageal vagal afferent nerve endings and the potential inhibitory role of ginger constituent 6-shogaol on such response. Two-photon neuron imaging studies were performed in ex vivo gastroesophageal-vagal preparations from Pirt-GCaMP6 transgenic mice. Vincristine was applied to the gastroesophageal vagal afferent nerve endings, and the evoked calcium influxes in their intact nodose ganglion neuron somas were recorded. The responsive nodose neuron population was first characterized, and the inhibitory effects of 5-HT3 antagonist palonosetron, TRPA1 antagonist HC-030031, and ginger constituent 6-shogaol were then determined. Vincristine application at gastroesophageal vagal afferent nerve endings elicited intensive calcium influxes in a sub-population of vagal ganglion neurons. These neurons were characterized by their positive responses to P2X2/3 receptor agonist α,ß-methylene ATP and TRPA1 agonist cinnamaldehyde, suggesting their nociceptive placodal nodose C-fiber neuron lineages. Pretreatment with TRPA1 selective blocker HC-030031 inhibited vincristine-induced calcium influxes in gastroesophageal nodose C-fiber neurons, indicating that TRPA1 played a functional role in mediating vincristine-induced activation response. Such inhibitory effect was comparable to that from 5-HT3 receptor antagonist palonosetron. Alternatively, pretreatment with ginger constituent 6-shogaol significantly attenuated vincristine-induced activation response. The present study provides new evidence that chemotherapeutic agent vincristine directly activates vagal nodose nociceptive C-fiber neurons at their peripheral nerve endings in the upper gastrointestinal tract. This activation response requires both TRPA1 and 5-HT3 receptors and can be attenuated by ginger constituent 6-shogaol.

Mast cell effects on esophageal smooth muscle and their potential role in eosinophilic esophagitis and achalasia.

Mast cells and eosinophils are the key effector cells of allergic disorders. Although most studies on eosinophilic esophagitis (EoE), an allergic disorder of the esophagus, have focused on the role of eosinophils, recent studies suggest a major role for mast cells in causing the clinical manifestations of this disease. Cellular and animal studies have demonstrated that mast cells can cause esophageal muscle cells to proliferate and differentiate into a more contractile phenotype, and that mediators released by degranulating mast cells such as tryptase and histamine can activate smooth muscle contraction pathways. Thus, activated mast cells in the esophageal muscularis propria might cause esophageal motility abnormalities, including the failure of lower esophageal sphincter relaxation typical of achalasia. In addition, mast cells have been implicated in the pathogenesis of a number of neurodegenerative disorders of the central nervous system such as Alzheimer's and Parkinson's diseases, because degranulating mast cells release proinflammatory and cytotoxic mediators capable of damaging neurons. Such mast cell degranulation in the myenteric plexus of the esophagus could cause the loss of enteric neurons that characterizes achalasia. In this report, we review the molecular mechanisms of esophageal smooth muscle contraction, and how mast cells products might affect that muscle and cause neurodegeneration in the esophagus. Based on these data, we present our novel, conceptual model for an allergy-induced form of achalasia mediated by mast cell activation in the esophageal muscularis propria.

Assessment of esophageal body peristaltic work using functional lumen imaging probe panometry.

The goal of this study was to conceptualize and compute measures of "mechanical work" done by the esophagus using data generated during functional lumen imaging probe (FLIP) panometry and compare work done during secondary peristalsis among patients and controls. Eighty-five individuals were evaluated with a 16-cm FLIP during sedated endoscopy, including asymptomatic controls (n = 14) and those with achalasia subtypes I, II, and III (n = 15, each); gastroesophageal reflux disease (GERD; n = 13); eosinophilic esophagitis (EoE; n = 9); and systemic sclerosis (SSc; n = 5). The FLIP catheter was positioned to have its distal segment straddling the esophagogastric junction (EGJ) during stepwise distension. Two metrics of work were assessed: "active work" (during bag volumes ≤ 40 mL where contractility generates substantial changes in lumen area) and "work capacity" (for bag volumes ≥ 60 mL when contractility cannot substantially alter the lumen area). Controls showed median [interquartile range (IQR)] of 7.3 (3.6-9.2) mJ of active work and 268.6 (225.2-332.3) mJ of work capacity. Patients with all achalasia subtypes, GERD, and SSc showed lower active work done than controls (P ≤ 0.003). Patients with achalasia subtypes I and II, GERD, and SSc had lower work capacity compared with controls (P < 0.001, 0.004, 0.04, and 0.001, respectively). Work capacity was similar between controls and patients with achalasia type III and EoE. Mechanical work of the esophagus differs between healthy controls and patient groups with achalasia, EoE, SSc, and GERD. Further studies are needed to fully explore the utility of this approach, but these work metrics would be valuable for device design (artificial esophagus), to measure the efficacy of peristalsis, to gauge the physiological state of the esophagus, and to comment on its pumping effectiveness.NEW & NOTEWORTHY Functional lumen imaging probe (FLIP) panometry assesses esophageal response to distension and provides a simultaneous assessment of pressure and dimension during contractility. This enables an objective assessment of "mechanical work" done by the esophagus. Eighty-five individuals were evaluated, and two work metrics were computed for each subject. Controls showed greater values of work compared with individuals with achalasia, gastroesophageal reflux disease (GERD), and systemic sclerosis (SSc). These values can quantify the mechanical behavior of the distal esophagus and assist in the estimation of muscular integrity.

Deoxycholic acid activates and sensitizes vagal nociceptive afferent C-fibers in guinea pig esophagus.

Bile acid reflux in the esophagus plays a role in the pathogenesis of certain esophageal disorders, where it can induce esophageal pain and heartburn. The present study aimed to determine whether bile acid, deoxycholic acid (DCA), directly activates and sensitizes esophageal vagal nociceptive afferent C-fiber subtypes. DCA-elicited effects on vagal nodose and jugular neurons were studied by calcium imaging. Its effects on esophageal-labeled nodose and jugular neurons were then determined by patch-clamp recording. At nodose and jugular C-fiber nerve endings in the esophagus, DCA-evoked action potentials (APs) were compared by extracellular single-unit recordings in ex vivo esophageal-vagal preparations. DCA application induced calcium influxes in nodose and jugular neurons and elicited inward currents in esophageal-labeled nodose and jugular neurons. In the presence of DCA, the current densities elicited by capsaicin were enhanced in those labeled neurons. Consistently, DCA perfusion at nerve terminals in the esophagus evoked APs in about 50% of esophageal nodose and jugular C-fibers. In DCA-sensitive C-fibers, DCA perfusion also sensitized the fibers such that the subsequent response to capsaicin was amplified. Collectively, these results provide new evidence that DCA directly activates and sensitizes nociceptive nodose and jugular C-fibers in the esophagus. Such activation and sensitization effects may contribute to bile acid-induced esophageal nociceptive symptoms that are refractory to proton-pump inhibitor therapy.NEW & NOTEWORTHY Bile acid reflux in the esophagus can induce pain and heartburn in certain esophageal disorders, but the underlying neuronal mechanism is still unclear. The present study demonstrated that bile acid, deoxycholic acid (DCA), directly activates esophageal vagal afferent nodose and jugular nociceptive C-fibers and sensitizes their response to capsaicin. Such effects may contribute to bile acid-induced esophageal nociceptive symptoms that refractory to proton-pump inhibitors (PPIs) therapy.

Effect of low-threshold versus high-threshold genitalia stimuli on the cystometry parameters in male rats.

The cross talk between external genitalia and urinary bladder could be used as part of management to certain pathological conditions affecting urinary bladder. Since urinary bladder function is also affected by pathologies of other organs (e.g., colon and esophagus), the effect of genitalia stimuli on parameters of bladder function in normal or under different pathological conditions needs to be characterized. Cystometry recordings in male rats were used to examine the effect of low-threshold (LT) and high-threshold (HT) stimulation of the scrotum and penis on urinary bladder function. These effects were studied in intact, colon irritation (CI), and esophagus irritation (EI) groups. Although HT penile stimulation had a significant inhibitory effect on micturition reflex in all groups, CI hypersensitized the penile-bladder inhibitory reflex. In addition, LT penile stimulation had a significant inhibitory effect on micturition, which was significant in CI group only. On the other hand, HT penile stimulation in CI group significantly increased the timing parameters of cystometry. Whereas LT and HT penile stimuli in EI group had a significantly increasing effect on all pressure parameters of cystometry. The scrotal stimuli had minimal effect on bladder function in all groups except for HT scrotal stimulation in the CI group, where it had a significant inhibitory effect on micturition reflex and significantly increased the maximum pressure and pressure amplitude of micturition cycles. These results show that CI and EI exacerbate the effects of genitalia stimuli, especially penile stimuli, on urinary bladder function.

Contribution of tetrodotoxin-sensitive, voltage-gated sodium channels (NaV1) to action potential discharge from mouse esophageal tension mechanoreceptors.

Action potentials depend on voltage-gated sodium channels (NaV1s), which have nine α subtypes. NaV1 inhibition is a target for pathologies involving excitable cells such as pain. However, because NaV1 subtypes are widely expressed, inhibitors may inhibit regulatory sensory systems. Here, we investigated specific NaV1s and their inhibition in mouse esophageal mechanoreceptors-non-nociceptive vagal sensory afferents that are stimulated by low threshold mechanical distension, which regulate esophageal motility. Using single fiber electrophysiology, we found mechanoreceptor responses to esophageal distension were abolished by tetrodotoxin. Single-cell RT-PCR revealed that esophageal-labeled TRPV1-negative vagal neurons expressed multiple tetrodotoxin-sensitive NaV1s: NaV1.7 (almost all neurons) and NaV1.1, NaV1.2, and NaV1.6 (in ∼50% of neurons). Inhibition of NaV1.7, using PF-05089771, had a small inhibitory effect on mechanoreceptor responses to distension. Inhibition of NaV1.1 and NaV1.6, using ICA-121341, had a similar small inhibitory effect. The combination of PF-05089771 and ICA-121341 inhibited but did not eliminate mechanoreceptor responses. Inhibition of NaV1.2, NaV1.6, and NaV1.7 using LSN-3049227 inhibited but did not eliminate mechanoreceptor responses. Thus, all four tetrodotoxin-sensitive NaV1s contribute to action potential initiation from esophageal mechanoreceptors terminals. This is different to those NaV1s necessary for vagal action potential conduction, as demonstrated using GCaMP6s imaging of esophageal vagal neurons during electrical stimulation. Tetrodotoxin-sensitive conduction was abolished in many esophageal neurons by PF-05089771 alone, indicating a critical role of NaV1.7. In summary, multiple NaV1 subtypes contribute to electrical signaling in esophageal mechanoreceptors. Thus, inhibition of individual NaV1s would likely have minimal effect on afferent regulation of esophageal motility.

Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus.

Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.

Anatomical variation and distribution of the vagus nerve in the esophageal hiatus: a cross-sectional study of post-mortem cases in Uganda.

PURPOSE: Vagus nerve injuries during gastroesophageal surgery may cause significant symptoms due to loss of vagal anti-inflammatory and neuromodulator function. Many previous studies have shown high anatomical variability of the vagus nerve at the esophageal hiatus, but information on its variability in Uganda specifically and Africa in general is scanty. This study provides a reliable and detailed description of the anatomical variation and distribution of the vagus nerve in the esophageal hiatus region of post-mortem cases in Uganda. METHODS: This was an analytical cross-sectional survey of 67 unclaimed post-mortem cases. Data collection used a pretested data collection form. Data were entered into Epi-Info version 6.0 data base then exported into STATA software 13.0 for analysis. RESULTS: The pattern of the anterior vagal trunk structures at the esophageal hiatus was: single trunk [65.7%]; biplexus [20.9%]; triplexus [8.9%] and double-but-not-connected trunks [4.5%]. The pattern of the posterior trunk structures were: single trunk [85.1%]; biplexus 10.4% and triplexus [4.5%]. There was no statistically significant gender difference in the pattern of vagal fibres. There was no major differences in the pattern from comparable British studies. CONCLUSION: The study confirmed high variability in the distribution of the vagus nerve at the esophageal hiatus, unrelated to gender differences. Surgeons must consider and identify variants of vagal innervation when carrying out surgery at the gastroesophageal junction to avoid accidental vagal injuries. Published surgical techniques for preserving vagal function are valid in Uganda.

Changes in specific esophageal neuromechanical wall states are associated with conscious awareness of a solid swallowed bolus in healthy subjects.

Esophageal neuromechanical wall states are the physical manifestations of circular muscle inhibition and contraction resulting from neural inputs and leading to bolus propulsion. A novel method infers esophageal neuromechanical wall states through simultaneous determination of pressure and diameter in vivo using impedance manometry. We hypothesized that changes in esophageal neuromechanical wall states relate to conscious awareness of esophageal bolus passage ("bolus perception"). Seven healthy participants were selected for perception of solid bolus passage and were compared with seven healthy participants with no conscious awareness of solid bolus passage. Participants were studied using impedance manometry (MMS Solar, Unisensor, 20 Hz). Subjects swallowed ten 5-ml liquid and ten 2-cm square saline-soaked bread boluses and rated bolus perception using a visual analog scale. Esophageal neuromechanical wall states were calculated and analyzed. Proportions of time spent in states with and without luminal distension were compared using a two-proportions Z-test. Bolus perception was associated with neuromechanical wall states corresponding to luminal distension more frequently than matching states without distension in the proximal esophagus (P < 0.001) and transition zone (P < 0.001), whereas there were no differences for the distal esophagus. In healthy volunteers, perceived swallows relate to changes in esophageal neuromechanical wall states in the proximal esophagus. We postulate that these changes relate to bolus retention and summation of active and passive wall tension activating intramural tension receptors.NEW & NOTEWORTHY This study explores esophageal neuromechanical wall states derived from changes in pressure and impedance-derived distension in relation to conscious awareness of esophageal solid bolus transit in healthy volunteers. There are increases in neuromechanical wall states indicative of esophageal distension in healthy volunteers with conscious awareness of bolus transit as compared with unaware individuals. Bolus-based esophageal distension is postulated as a mechanism for esophageal symptoms such as dysphagia.

Stimulus intensity-dependent recruitment of NaV1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus.

We investigated voltage-gated sodium channel (NaV1) subunits that regulate action potential initiation in the nerve terminals of vagal nodose C-fibers innervating the esophagus. Extracellular single fiber recordings were made from the nodose C-fibers, with mechanically sensitive nerve terminals in the isolated innervated guinea pig esophagus. NaV1 inhibitors were selectively delivered to the tissue-containing nerve terminals. Graded esophageal distention was used for mechanical stimulation. The NaV1.7 inhibitor PF-05089771 nearly abolished action potential initiation in response to low levels of esophageal distention but only partially inhibited the response to higher levels of esophageal distention. The PF-05089771-insensitive component of the response progressively increased (up to ≈50%) with increasing esophageal distention and was abolished by tetrodotoxin (TTX). In addition to NaV1.7, nodose C-fiber [transient receptor potential channel-vanilloid subfamily member 1 (TRPV1)-positive] neurons retrogradely labeled from the esophagus expressed mRNA for multiple TTX-sensitive NaV1s. The group NaV1.1, NaV1.2, and NaV1.3 inhibitor ICA-121431 inhibited but did not abolish the PF-05089771-insensitive component of the response to high level of esophageal distention. However, combination of ICA-121431 with compound 801, which also inhibits NaV1.7 and NaV1.6, nearly abolished the response to the high level of esophageal distention. Our data indicate that the action potential initiation in esophageal nodose C-fibers evoked by low (innocuous) levels of esophageal distention is mediated by NaV1.7. However, the response evoked by higher (noxious) levels of esophageal distention has a progressively increasing NaV1.7-independent component that involves multiple TTX-sensitive NaV1s. The stimulus intensity-dependent recruitment of NaV1s may offer novel opportunities for strategic targeting of NaV1 subunits for inhibition of nociceptive signaling in visceral C-fibers.NEW & NOTEWORTHY We report that pharmacologically distinguishable voltage-gated sodium channels (NaV1) mediate action potential initiation at low (innocuous) versus high (noxious) intensity of esophageal distention in nerve terminals of vagal nodose C-fibers. Action potential initiation at low intensity is entirely dependent on NaV1.7; however, additional tetrodotoxin (TTX)-sensitive NaV1s are recruited at higher intensity of distention. This is the first demonstration that NaV1s underlying action potential initiation in visceral C-fibers depend on the intensity of the stimulus.

Vagus Nerves Provide a Robust Afferent Innervation of the Mucosa Throughout the Body of the Esophagus in the Mouse.

The vagal afferent nerves regulate swallowing and esophageal motor reflexes. However, there are still gaps in the understanding of vagal afferent innervation of the esophageal mucosa. Anatomical studies found that the vagal afferent mucosal innervation is dense in the upper esophageal sphincter area but rare in more distal segments of the esophagus. In contrast, electrophysiological studies concluded that the vagal afferent nerve fibers also densely innervate mucosa in more distal esophagus. We hypothesized that the transfection of vagal afferent neurons with adeno-associated virus vector encoding green fluorescent protein (AAV-GFP) allows to visualize vagal afferent nerve fibers in the esophageal mucosa in the mouse. AAV-GFP was injected into the vagal jugular/nodose ganglia in vivo to sparsely label vagal afferent nerve fibers. The esophageal tissue was harvested 4-6 weeks later, the GFP signal was amplified by immunostaining, and confocal optical sections of the entire esophagi were obtained. We found numerous GFP-labeled fibers in the mucosa throughout the whole body of the esophagus. The GFP-labeled mucosal fibers were located just beneath the epithelium, branched repeatedly, had mostly longitudinal orientation, and terminated abruptly without forming terminal structures. The GFP-labeled mucosal fibers were concentrated in random areas of various sizes in which many fibers could be traced to a single parental axon. We conclude that the vagus nerves provide a robust afferent innervation of the mucosa throughout the whole body of the esophagus in the mouse. Vagal mucosal fibers may contribute to the sensing of intraluminal content and regulation of swallowing and other reflexes.

Interplay of spinal and vagal pathways on esophageal acid-related anterior cingulate cortex functional networks in rats.

Esophageal acid sensory signals are transmitted by both vagal and spinal pathways to the cerebral cortex. The influence and interplay of these pathways on esophageal acid-related functional connectivity has been elusive. Our aim was to evaluate the esophageal acid exposure-related effect on the anterior cingulate cortex (ACC) functional connectivity networks using functional MRI-guided functional connectivity MRI (fcMRI) analysis. We studied six Sprague-Dawley rats for fcMRI experiments under dexmedetomidine hydrochloride anesthesia. Each rat was scanned for 6 min before and after esophageal hydrochloric acid infusion (0.1 N, 0.2 ml/min). The protocol was repeated before and after bilateral cervical vagotomy on the same rat. Seed-based fcMRI analysis was used to examine ACC networks and acid-induced network alterations. Three-factor repeated-measures ANOVA analysis among all four subgroups revealed that the interaction of acid infusion and bilateral vagotomy was mainly detected in the hypothalamus, insula, left secondary somatosensory cortex, left parietal cortex, and right thalamus in the left ACC network. In the right ACC network, this interaction effect was detected in the caudate putamen, insula, motor, primary somatosensory cortex, secondary somatosensory cortex, and thalamic regions. These regions in the ACC networks showed decreased intranetwork connectivity due to acid infusion. However, after bilateral vagotomy, intranetwork connectivity strength inversed and became stronger following postvagotomy acid infusion. Signals transmitted through both the vagal nerve and spinal nerves play a role in esophageal acid-related functional connectivity of the ACC. The vagal signals appear to dampen the acid sensation-related functional connectivity of the ACC networks. NEW & NOTEWORTHY These studies show that esophageal acid-induced brain functional connectivity changes are vagally mediated and suggest that signals transmitted through both the vagal nerve and spinal nerves play a role in esophageal acid-related functional connectivity of the anterior cingulate cortex. This paper focuses on the development of a novel rat functional MRI model fostering improved understanding of acid-related esophageal disorders.

Characterization and mechanism of the esophago-esophageal contractile reflex of the striated muscle esophagus.

An esophago-esophageal contractile reflex (EECR) of the cervical esophagus has been identified in humans. The aim of this study was to characterize and determine the mechanisms of the EECR. Cats (n = 35) were decerebrated, electrodes were placed on pharynx and cervical esophagus, and esophageal motility was recorded using manometry. All areas of esophagus were distended to locate and quantify the EECR. The effects of esophageal perfusion of NaCl or HCl, vagus nerve or pharyngoesophageal nerve (PEN) transection, or hexamethonium administration (5 mg/kg iv) were determined. We found that distension of the esophagus at all locations activated EECR rostral to stimulus only. EECR response was greatest when the esophagus 2.5-11.5 cm from cricopharyngeus (CP) was distended. HCl perfusion activated repetitively an EECR-like response of the proximal esophagus only within 2 min, and after ~20 min EECR was inhibited. Transection of PEN blocked or inhibited EECR 1-7 cm from CP, and vagotomy blocked EECR at all locations. Hexamethonium blocked EECR at 13 and 16 cm from CP but sensitized its activation at 1-7 cm from CP. EECR of the entire esophagus exists, which is directed in the orad direction only. EECR of striated muscle esophagus is mediated by vagus nerve and PEN and inhibited by mechanoreceptors of smooth muscle esophagus. EECR of smooth muscle esophagus is mediated by enteric nervous system and vagus nerve. Activation of EECR of the striated muscle esophagus is initially sensitized by HCl exposure, which may have a role in prevention of supraesophageal reflux.NEW & NOTEWORTHY An esophago-esophageal contractile reflex (EECR) exists, which is directed in the orad direction only. EECR of the proximal esophagus can appear similar to and be mistaken for secondary peristalsis. The EECR of the striated muscle is mediated by the vagus nerve and pharyngoesophageal nerve and inhibited by mechanoreceptor input from the smooth muscle esophagus. HCl perfusion initially sensitizes activation of the EECR of the striated muscle esophagus, which may participate in prevention of supraesophageal reflux.

Gastroesophageal reflux disease and atrial fibrillation: Insight from autonomic cardiogastric neural interaction.

BACKGROUND: The relationship between gastroesophageal reflux disease (GERD) and atrial fibrillation (AF) has been previously reported. However, the detailed mechanism remains unknown. In this study, we investigated the effects of acid reflux on the intrinsic cardiac autonomic nervous system, atrial/ventricular electrophysiology, and AF inducibility. METHODS: Eighteen rabbits were randomized into three groups: acid reflux (group 1, n = 6), control (group 2, n = 6), and acid reflux with periesophageal vagal blockade (group 3, n = 6). Atrial and ventricular effective refractory periods (ERPs) and AF inducibility were checked at baseline and then hourly until 5 hours after the experiment. RESULTS: Three hours after the experiment, atrial ERP prolongation was noted in groups 2 and 3 (P < .05), whereas shortening of the atrial ERPs was observed in group 1, compared with the baseline. However, no changes were observed in ventricular ERPs in the three groups. The AF inducibility was higher in group 1 than in groups 2 and 3. Pathological examination showed clear esophageal mucosal breaks in groups 1 and 3. CONCLUSIONS: In this study, we found that the antimuscarinic blockade prevents GERD induced changes to atrial electrophysiology and susceptibility to AF-making it highly likely that autonomic activity is important in mediating this effect.

Neuronal Control of Esophageal Peristalsis and Its Role in Esophageal Disease.

PURPOSE OF REVIEW: Esophageal peristalsis is a highly sophisticated function that involves the coordinated contraction and relaxation of striated and smooth muscles in a cephalocaudal fashion, under the control of central and peripheral neuronal mechanisms and a number of neurotransmitters. Esophageal peristalsis is determined by the balance of the intrinsic excitatory cholinergic, inhibitory nitrergic and post-inhibitory rebound excitatory output to the esophageal musculature. RECENT FINDINGS: Dissociation of the longitudinal and circular muscle contractions characterizes different major esophageal disorders and leads to esophageal symptoms. Provocative testing during esophageal high-resolution manometry is commonly employed to assess esophageal body peristaltic reserve and underpin clinical diagnosis. Herein, we summarize the main factors that determine esophageal peristalsis and examine their role in major and minor esophageal motility disorders and eosinophilic esophagitis.

Identification of neuropeptide y in superior cervical ganglion neurons that project to the oesophagus - A combined immunohistochemical labelling and retrograde tracing study in pigs.

Neuropeptide Y (NPY) is a neuronal active substance taking part in the regulation of gastrointestinal (GI) tract activity. This study used retrograde neuronal tracing and immunofluorescence methods to analyse NPY-positive neurons located in superior cervical ganglion and supplying the cervical oesophagus in the pig. The presence of NPY was observed in 30% of all neurons supplying the part of oesophagus studied. Probably the number of Fast Blue (FB) positive cells depends on the area of the wall injected with FB and the fragment of oesophagus studied. Therefore, the obtained results indicate that the described peptide is an important factor in the extrinsic innervation of this part of the GI tract.

Anatomical predisposing factors of transmural thermal injury after pulmonary vein isolation.

Aims: Transmural thermal injury (TTI), such as oesophageal erosion/ulcer and perioesophageal nerve injury leading to gastric hypomotility, is an important complication associated with pulmonary vein isolation (PVI). However, a predictor of TTI concerning anatomical structures surrounding the oesophagus has not yet been fully elucidated. Therefore, we sought to identify the predisposing factors of TTI after PVI. Methods and results: Consecutive 110 patients, who underwent PVI for atrial fibrillation, received oesophagogastroduodenoscopy 2 days later, were investigated. The relationships between TTI and clinical and anatomical parameters were examined. Based on the computed tomography data, we measured the angle of the left atrial (LA) posterior wall to the descending aorta (Ao) (LA-Ao angle), the branching angle of the left inferior pulmonary vein (LIPV) to the coronal plane (LIPV angle), and the minimum distance between the LA posterior wall and descending Ao enclosing the oesophagus (LA-Ao distance). Transmural thermal injuries occurred in 21 patients (oesophageal erosion in 5 and gastric hypomotility in 16). Age, gender, body mass index, LA diameter, and LA volume index in echocardiography were not associated with TTI. However, the LIPV angle was larger and the LA-Ao distance was shorter in the TTI (+) group compared to the TTI (-) group. With multivariate logistic regression analysis, the LIPV angle [odds ratio (OR): 2.144, P = 0.0031] and LA-Ao distance (OR: 0.392, P = 0.0229) were independent predictors of TTI. Conclusion: The anatomical proximities of the LA posterior wall, LIPV, and descending Ao surrounding the oesophagus are strongly associated with the prevalence of TTI.

A Positive Correlation Between Gastric and Esophageal Dysmotility Suggests Common Causality.

BACKGROUND: Gastric and esophageal dysmotility syndromes are some of the most common motility diagnoses, but little is known about their interrelationship. AIMS: The aim of our study was to determine if a correlation exists between gastric and esophageal dysmotility syndromes. METHODS: We reviewed the records of all patients who underwent both solid gastric emptying scintigraphy (GES) and high-resolution esophageal manometry (HRM) within a 2 year period, with both done between August 2012 and August 2017. All GESs were classified as either rapid, normal, or delayed. All HRMs were classified according to the Chicago Classification 3.0. Correlations were assessed using Fisher's exact test and multiple logistic regression. RESULTS: In total, 482 patients met inclusion criteria. Of patients with a normal, delayed, and rapid GES, 53.1, 64.5, and 77.3% had an abnormal HRM, respectively (p < 0.05 vs. normal GES). Likewise, patients with an abnormal HRM were more likely to have an abnormal GES (54.9 vs. 41.8%, p = 0.005). Multiple logistic regression showed abnormal GES [odds ratio (OR) 2.14], age (OR 1.013), scleroderma (OR 6.29), and dysphagia (OR 2.63) were independent predictors of an abnormal HRM. Likewise, an abnormal HRM (OR 2.11), diabetes (OR 1.85), heart or lung transplantation (OR 2.61), and autonomic dysfunction (OR 2.37) were independent predictors of an abnormal GES. CONCLUSIONS: The correlation between an abnormal GES and HRM argues for common pathogenic mechanisms of these motility disorders, and possibly common future treatment options. Clinicians should have a high index of suspicion for another motility disorder if one is present.