Fatigability of the external anal sphincter muscles using a novel strength training resistance exercise device.

Exercises involving pelvic floor muscles including repetitive voluntary contractions of external anal sphincter (EAS) musculature have been used to improve fecal incontinence. Muscle fatigue is a prerequisite for successful strength training. However, muscle fatigue induced by these exercises has not been systematically studied. We aimed to assess the fatigability of EAS muscles during various exercise methods. Twelve nulliparous (21 ± 2.7 yr) women were studied. We evaluated fatigue during 40 repetitive 3-s contractions and 30-s long squeeze contractions both with and without an intra-anal compressible resistant load. The sequence of exercises was randomized. This load was provided by the continence muscles Resistance Exerciser Device. Anal canal pressures were recorded by high-resolution manometry. Exercise against a resistive load showed significant decrease in anal contractile integral (CI) and maximum squeeze pressure during repetitive short squeeze contractions compared with exercise without a load. Linear regression analysis showed a significant negative correlation between anal CI and successive contraction against load, suggesting "fatigue." Similar findings were observed for maximum squeeze pressure (slope with load = -4.2, P = 0.0003, vs. without load = -0.9, P = 0.3). Long squeeze contraction against a load was also more susceptible to fatigue than without a load (P < 0.0001). In conclusion, repetitive contractions against a compressible load induce fatigue and thus have the potential to strengthen the anal sphincter contractile function than contractions without a load. Fatigue rate in long squeeze contraction exercises with a load is significantly faster than that without a load, also indicating greater effectiveness in inducing muscle fatigue.NEW & NOTEWORTHY Fecal incontinence is a distressing disorder with a mainstay of treatment being pelvic floor muscle exercises. However, none of these exercises has proven occurrence of fatigability, which is an important prerequisite for successful muscle strengthening in rehabilitative exercises. In this study, we proved that we can fatigue the external anal sphincter muscles more efficiently by providing a resistive load during anal repetitive short squeeze contractions and long squeeze contraction exercise.

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.

Older Age Reduces Upper Esophageal Sphincter and Esophageal Body Responses to Simulated Slow and Ultraslow Reflux Events and Post-Reflux Residue.

BACKGROUND & AIMS: It is not clear how age affects airway protective mechanisms. We investigated the effects of aging on upper esophageal sphincter (UES) and esophageal body pressure responses to slow and ultraslow simulated reflux events and post-reflux residue. METHODS: We performed a prospective study of 11 elderly (74 ± 9 years old) and 11 young (28 ± 7 years old) healthy volunteers. Participants were placed in a supine position and evaluated by concurrent high-resolution impedance manometry and an esophageal infusion technique. Potential conditions of gastroesophageal reflux were simulated, via infusion of 0.1 N HCl and saline. UES and esophageal pressure responses were measured during the following: slow infusion (1 mL/s) for 60 seconds, 60 seconds of postinfusion dwell period, ultraslow infusion (0.05 mL/s) for 60 seconds, and 60 seconds of a postinfusion dwell period. All infusions were repeated 3 times. We used the UES high-pressure zone contractile integral (UES-CI) to determine responses of the UES. RESULTS: Young and elderly subjects each had a significant increase in the UES-CI during slow infusions and during entire passive dwell intervals compared with baseline (P < .01, both groups). Ultraslow infusions were associated with a significant increase in UES-CI in only the young group, in the late infusion period, and into the dwell interval (P < .01). During the slow infusions and their associated dwell periods, young subjects had a higher frequency of secondary peristalsis than elderly subjects (P < .05). There was more secondary peristalsis during active infusions than dwell intervals. Secondary peristalsis was scarce during ultraslow infusions in both groups. CONCLUSIONS: UES and esophageal body pressure responses to low-volume ultraslow reflux and associated post-reflux residue are reduced in elderly individuals. This deterioration could have negative effects on airway protection for people in this age group.

Pharyngeal peristaltic pressure variability, operational range, and functional reserve.

The present understanding of pharyngeal motor function remains incomplete. Among the remaining gaps of knowledge in this regard is the magnitude of variability of pharyngeal peristaltic pressure amplitude. Although variability can pose difficulty in interpretation of manometric findings, its magnitude can inform the operational range and reserve of the pharyngeal contractile function. We aimed to define the intra- and intersubject and intersession variability of select pharyngeal manometric parameters and, using this information, determine the number of swallow repetitions for acquiring reliable pharyngeal manometric data. We recorded pharyngeal peristalsis in 10 healthy subjects (age: 50 ± 25 yr, 5 women) by high-resolution manometry during two separate sessions of 20 sequences of 0.5-ml water swallows. Two-way ANOVA showed significant variation in the mean peak peristaltic pressure value across sites (P < 0.0001) as well as within the data at each site (P < 0.0001). Similarly, the pharyngeal contractile integral exhibited significant inter- (P = 0.003) and intrasubject (P < 0.001) variability. The Shapiro-Wilk normality test showed mixed results, in that some sites showed normally distributed data, whereas others did not. A robust Monte Carlo simulation showed that the nominal sample size was different for various tested metrics. For a power of 0.8, commonly accepted as an adequate threshold for acceptable statistical power, the optimal sample size for various peristaltic parameters ranged between 3 and 15. There is significant intra- and intersubject variability in site-specific and integrated parameters of pharyngeal peristalsis. The observed variance indicates a significant operational range and reserve in pharyngeal contractile function while necessitating parameter-specific sample size for reliable results.NEW & NOTEWORTHY Intra- and intersubject variability are significant and different at various sites within the contractile pharynx. In addition, significant swallow-to-swallow and subject-to-subject variability exists in pharyngeal contractile integral. The range of intrasubject variability indicates the existence of broad operational range and reserve. Lastly, our variability studies informed Monte Carlo and power analyses, yielding estimates of sample size that would ensure accurate representation of pressure metric variability.

Effects of laryngeal restriction on pharyngeal peristalsis and biomechanics: Clinical implications.

To date, rehabilitative exercises aimed at strengthening the pharyngeal muscles have not been developed due to the inability to successfully overload and fatigue these muscles during their contraction, a necessary requirement for strength training. The purpose of this study was to test the hypothesis that applying resistance against anterosuperior movement of the hyolaryngeal complex will overload the pharyngeal muscles and by repetitive swallowing will result in their fatigue manifested by a reduction in pharyngeal peristaltic amplitude. Studies were done in two groups. In group 1 studies 15 healthy subjects (age: 42 ± 14 yr, 11 females) were studied to determine whether imposing resistance to swallowing using a handmade device can affect the swallow-induced hyolaryngeal excursion and related upper esophageal sphincter (UES) opening. In group 2, an additional 15 healthy subjects (age 56 ± 25 yr, 7 females) were studied to determine whether imposing resistance to the anterosuperior excursion of the hyolaryngeal complex induces fatigue manifested as reduction in pharyngeal contractile pressure during repeated swallowing. Analysis of the video recordings showed significant decrease in maximum deglutitive superior laryngeal excursion and UES opening diameter (P < 0.01) due to resistive load. Consecutive swallows against the resistive load showed significant decrease in pharyngeal contractile integral (PhCI) values (P < 0.01). Correlation analysis showed a significant negative correlation between PhCI and successive swallows, suggesting "fatigue" (P < 0.001). In conclusion, repeated swallows against a resistive load induced by restricting the anterosuperior excursion of the larynx safely induces fatigue in pharyngeal peristalsis and thus has the potential to strengthen the pharyngeal contractile function.

A human model of restricted upper esophageal sphincter opening and its pharyngeal and UES deglutitive pressure phenomena.

Oropharyngeal dysphagia due to upper esophageal sphincter (UES) dysfunction is commonly encountered in the clinical setting. Selective experimental perturbation of various components of the deglutitive apparatus can provide an opportunity to improve our understanding of the swallowing physiology and pathophysiology. The aim is to characterize the pharyngeal and UES deglutitive pressure phenomena in an experimentally induced restriction of UES opening in humans. We studied 14 volunteers without any dysphagic symptoms (7 men, 66 ± 11 yr) but with various supraesophageal reflux symptoms. To induce UES restriction, we used a handmade device that with adjustment could selectively apply 0, 20, 30, or 40 mmHg pressure perpendicularly to the cricoid cartilage. Deglutitive pharyngeal and UES pressure phenomena were determined during dry and 5- and 10-ml water swallows × 3 for each of the UES perturbations. External cricoid pressure against the UES resulted in a significant increase in hypopharyngeal intrabolus pressure and UES nadir deglutitive relaxation pressure for all tested swallowed volumes (P < 0.05). Application of external cricoid pressure increased the length of the UES high pressure zone from 2.5 ± 0.2 to 3.1 ± 0.2, 3.5 ± 0.1, and 3.7 ± 0.1 cm for 20, 30, and 40 mmHg cricoid pressure, respectively (P < 0.05). External cricoid pressure had no significant effect on pharyngeal peristalsis. On the other hand, irrespective of external cricoid pressure deglutitive velopharyngeal contractile integral progressively increased with increased swallowed volumes (P < 0.05). In conclusion, acute experimental restriction of UES opening by external cricoid pressure manifests the pressure characteristics of increased resistance to UES transsphincteric flow observed clinically without affecting the pharyngeal peristaltic contractile function.

Parkinson's disease is associated with low striated esophagus contractility potentially contributing to the development of dysphagia.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, and more than 80% of PD patients will develop oropharyngeal dysphagia. Despite its striated histology, proximity to airway, and potential negative impact of its dysfunction on bolus transport and airway safety, the contractile function of the striated esophagus in PD patients has not been systematically studied. METHODS: Using our repository of clinical manometry and the Milwaukee ManoBank, we analyzed high-resolution manometry (HRM) studies of 20 PD patients, mean age 69.1 (range 38-87 years); 30 non-PD patients with dysphagia, mean age 64.0 (44-86 years); and 32 healthy volunteers, mean age 65.3 (39-86 years). Patients with abnormal findings based on Chicago Classification 4.0 were identified. Repeat analysis was performed in 20% of the manometric tracings by a different investigator with inter-rater concordance between 0.91 and 0.99. KEY RESULTS: The striated esophageal contractile integral in PD patients was significantly lower than that in non-PD dysphagic patients and healthy controls (p = 0.03 and <0.01, respectively). This significant difference persisted after excluding patients with concurrent Chicago Classification motility disorders (p = 0.02 and 0.01, respectively). In both analyses, the distal esophageal contractile integral did not show any significant difference between groups (p = 0.58 and 0.93, respectively). CONCLUSIONS & INFERENCES: PD is associated with a significant decrease in striated esophagus contractility compared to non-PD and healthy controls. This finding may play a pathophysiologic role in development of dysphagia in this patient population.

Clinical and Pathologic Response to Vedolizumab in a Young Female Patient With Collagenous Gastritis.

Collagenous gastritis is a rare form of gastritis that affects both children and adults. The underlying pathophysiology is not well-understood, and as a result, there are limited options for treatment. We report a case of a young female patient with chronic diffuse abdominal pain, nausea, regurgitation, and early satiety with esophagogastroduodenoscopy showing gastric erythema, atrophic gastric body, and significant gastric nodularity. Biopsies revealed focal erosion and increased subepithelial collagen deposition. She was successfully managed with intravenous vedolizumab infusions after initial therapy with topical budesonide did not result in clinical or endoscopic improvement.

Effect of inter-swallow interval on striated esophagus peristalsis; a comparative study with smooth muscle esophagus.

BACKGROUND: Effect of inter-swallow interval on the contractility of smooth muscle esophagus is well-documented. However, the effects on peristalsis of the striated esophagus have not been systematically studied. A better understanding of striated esophagus motor function in health and disease may enhance the interpretation of manometric studies and inform clinical care. The aim of this study was to assess the effect of inter-swallow interval on striated esophagus compared to findings with that of the smooth muscle esophagus. METHODS: We performed two sets of studies to (1) determine the effect of various inter-swallow interval in 20 healthy volunteers and (2) assess the effect of ultra-short swallow intervals facilitated by straw drinking in 28 volunteers. We analyzed variables using ANOVA with Tukey's pairwise comparison and paired t-test. KEY RESULTS: Unlike smooth muscle esophagus, the striated esophagus contractile integral did not change significantly for swallow intervals ranging from 30 to 5 s. On the contrary, striated esophagus demonstrated absent or reduced peristalsis in response to ultra-short (<2 s) intervals during straw-facilitated multiple rapid swallows. CONCLUSIONS AND INFERENCES: Striated esophagus peristalsis is subject to manometrically observed inhibition during swallows with ultra-short intervals. Inter-swallow intervals as short as 5 s that inhibit smooth muscle esophagus peristalsis do not inhibit striated muscle peristalsis. The mechanisms of these observations are unknown but may relate to central or myenteric nervous system influences or the effects of pharyngeal biomechanics.

Variables influencing manometric parameters of deglutitive and non-deglutitive upper esophageal sphincter: A study of 89 asymptomatic participants.

BACKGROUND: High-resolution manometry overcomes limitations imposed by axial and radial asymmetry as well as swallow and respiration-induced movement of the upper esophageal sphincter (UES), allowing for its reliable use in evaluation of dysphagic and reflux patients. The aim of this study was to determine normative values and their variability across position, sex, age, height, weight, BMI, and volume for clinically relevant deglutitive and non-deglutitive UES parameters. METHODS: We studied 89 asymptomatic volunteers age 19-90 years, (45 female) during 3-10 repetitions of dry, 5 and 10 ml water swallows at 30-s intervals using high-resolution manometry. KEY RESULTS: Upper esophageal sphincter high-pressure zone was longer in men than women and in supine than upright position. UES basal contractile integral and mean basal pressure were higher in supine compared to upright; higher in men than women, inversely correlated with age, correlated positively with height and with weight in the supine position only. UES relaxation duration was longer in upright than in supine position but not affected by age, sex, height, weight, or BMI. It was longer with 5 and 10 ml compared with dry swallows. UES minimum/nadir relaxation and mean relaxation pressures were lower in upright than supine position, increased with increase in age and were higher in men than women. CONCLUSIONS AND INFERENCES: Position, sex, age, height, weight, and volume affect some deglutitive and non-deglutitve UES manometric parameters. BMI does not affect the studied manometric parameters. These effects should be taken into consideration in clinical evaluation of UES.

Identification and characterization of rostral ventromedial medulla neurons synaptically connected to the urinary bladder afferents in female rats with or without neonatal cystitis.

The neurons in the rostral ventromedial medulla (RVM) play a major role in pain modulation. We have previously shown that early-life noxious bladder stimuli in rats resulted in an overall spinal GABAergic disinhibition and a long-lasting bladder/colon sensitization when tested in adulthood. However, the neuromolecular alterations within RVM neurons in the pathophysiology of early life bladder inflammation have not been elucidated. In this study, we have identified and characterized RVM neurons that are synaptically linked to the bladder and colon and examined the effect of neonatal bladder inflammation on molecular expressions of these neurons. A transient bladder inflammation was induced by intravesicular instillation of protamine sulfate and zymosan during postnatal days 14 through 16 (P14-16) followed by pseudorabies virus PRV-152 and PRV-614 injections into the bladder and colon, respectively, on postnatal day P60. Tissues were examined 96 h postinoculation for serotonergic, GABAergic, and enkephalinergic expressions using in situ hybridization and/or immunohistochemistry techniques. The results revealed that > 50% of RVM neurons that are synaptically connected to the bladder (i.e., PRV-152+) were GABAergic, 40% enkephalinergic, and about 14% expressing serotonergic marker tryptophan hydroxylase 2 (TpH2). Neonatal cystitis resulted in a significant increase in converging neurons in RVM receiving dual synaptic inputs from the bladder and colon. In addition, neonatal cystitis significantly downregulated vesicular GABA transporter (VGAT) with a concomitant increase in TpH2 expression in bladder-linked RVM neurons, suggesting an alteration in supraspinal signaling. These alterations of synaptic connectivity and GABAergic/serotonergic expressions in RVM neurons may contribute to bladder pain modulation and cross-organ visceral sensitivity.

Peripheral antinociceptive effects of a bifunctional µ and δ opioid receptor ligand in rat model of inflammatory bladder pain.

There is a need to develop a novel analgesic for pain associated with interstitial cystitis/painful bladder syndrome (IC/PBS). The use of the conventional µ-opioid receptor agonists to manage IC/PBS pain is controversial due to adverse CNS effects. These effects are attenuated in benzylideneoxymorphone (BOM), a low-efficacy µ-opioid receptor agonist/δ-opioid receptor antagonist that attenuates thermal pain and is devoid of reinforcing effects. We hypothesize that BOM will inhibit bladder pain by attenuating responses of urinary bladder distension (UBD)-sensitive afferent fibers. Therefore, the effect of BOM was tested on responses of UBD-sensitive afferent fibers in L6 dorsal root from inflamed and non-inflamed bladder of rats. Immunohistochemical (IHC) examination reveals that following the induction of inflammation there were significant high expressions of µ, δ, and µ-δ heteromer receptors in DRG. BOM dose-dependently (1-10 mg/kg, i.v) attenuated mechanotransduction properties of these afferent fibers from inflamed but not from non-inflamed rats. In behavioral model of bladder pain, BOM significantly attenuated visceromotor responses (VMRs) to UBD only in inflamed group of rats when injected either systemically (10 mg/kg, i.v.) or locally into the bladder (0.1 ml of 10 mg/ml). Furthermore, oxymorphone (OXM), a high-efficacy µ-opioid receptor agonist, attenuated responses of mechanosensitive bladder afferent fibers and VMRs to UBD. Naloxone (10 mg/kg, i.v.) significantly reversed the inhibitory effects of BOM and OXM on responses of bladder afferent fibers and VMRs suggesting µ-opioid receptor-related analgesic effects of these compounds. The results reveal that a low-efficacy, bifunctional opioid-based compound can produce analgesia by attenuating mechanotransduction functions of afferent fibers innervating the urinary bladder.

Differences in fatigability of muscles involved in fecal continence: Potential clinical ramifications.

INTRODUCTION: Fatigue of the anal sphincter complex has been demonstrated using high-resolution anorectal manometry (HRAM). However, the fatigability of individual muscles such as the external anal sphincter (EAS) and puborectalis muscles (PRM) has not been described. Vaginal manometry has been used to study contractile activity of the PRM. By applying both modalities, we attempted to differentiate the fatigability between the PRM and the EAS under different exercise conditions. METHODS: We studied two groups: group 1, 12 healthy women (21 ± 2.7 years) with HRAM and group 2, 10 healthy (20 ± 3 years) women with vaginal manometry. All subjects performed 40 repetitive contractions with and without an intra-anal resistive load. In group 1, areas under the curve (AUC) of the anal canal high-pressure zone (HPZ) including the caudal and rostral halves were compared. In group 2, the maximum and mean pressures of the vaginal HPZ were compared. RESULTS: The AUC decreased significantly only after repetitive contractions against a resistive load (462 ± 129 vs. 390 ± 131 mmHg-cm, p = 0.02), indicating fatigue. The caudal half (EAS) decreased significantly after contractions against a load (288 ± 75 vs. 239 ± 82 mmHg-cm, p = 0.02), while the rostral half (PRM) did not. The vaginal pressures (PRM) also decreased only after repetitive contractions against a load (maximum pressures, 358 ± 171 vs. 239 ± 109 mmHg, p = 0.02). CONCLUSIONS: The EAS and PRM both exhibit fatigue with contractions only against a resistive load. These findings may guide the development of appropriate exercise regimens to target specific muscles involved in fecal continence.

Can Natural Products Suppress Resistant Helicobacter pylori to Fight Against Gastric Diseases in Humans?

More than 50% of the world's population is infected with Helicobacter pylori. H. pylori is the major causative agent of gastric ulcers and gastric cancer. H. pylori eradication using antibiotics either alone or together with a proton pump inhibitor is the primary strategy to decrease the incidence of gastric cancer. Although eradication therapy is effective, there are significant adverse effects and more importantly, resistance to antibiotics occurs, which represents a major therapeutic challenge. Multiple natural products have been shown to suppress H. pylori both in vitro and in animal model systems. However, only a handful of natural products have been evaluated in human clinical trials. The focus of this review is to summarize the results of published human clinical trials to assess the ability of natural products to reduce or eliminate H. pylori infections. Current evidence suggests that these products appear to have great potential to be developed as pharmaceutical candidates for eradication of H. pylori, hopefully both antibiotic-sensitive and antibiotic-resistant strains. Frequent consumption of locally produced foodstuff for controlling H. pylori infection in different countries around the world may well be a feasible long-term solution to fight against this worldwide prevalent pathogen.

Upper esophageal sphincter augmentation reduces pharyngeal reflux in nasogastric tube-fed patients.

OBJECTIVES/HYPOTHESIS: Aspiration of gastric refluxate is one of the most commonly observed complications among long-term nasogastric tube (NGT) fed patients. The upper esophageal sphincter (UES) pressure barrier is the main defense mechanism against pharyngeal reflux of gastric contents. Our objective was to investigate the efficacy and safety of the UES assist device (UES-AD) in preventing gastric reflux through the UES in long-term NGT-fed patients. STUDY DESIGN: Self-Controlled Case series. METHODS: We studied 10 patients (mean age = 90.6 ± 3.4 years, four females) with dysphagia caused by stroke or dementia who were fed for 0.5 to 5 years (median = 3 years) by NGT. External pressures of 20 to 30 mm Hg were applied by using a handmade UES-AD, which was started 2 hours after the beginning of NGT infusion and was alternated between periods of 2 hours on and 2 hours off, for a total of 12 hours. Placement of the impedance sensors within the UES was guided by high-resolution manometry. Trans-UES and intraesophageal reflux events were recorded by using 24-hour combined pH-impedance measurements. RESULTS: No aspiration pneumonia events were noted in the period 1 month before or during the study in any of the cohort. Baseline UES pressure averaged 17.5 ± 9.4 mm Hg and was increased to 38.9 ± 11.9mm Hg after application of the UES-AD. Overall frequency of trans-UES reflux decreased significantly with the UES-AD compared to without (0.8 ± 0.9 vs. 3.3 ± 2.8, P < .05 for the 12-hour study period). There was no effect of the UES-AD on esophageal reflux events (7.4 ± 4.4 vs. 6.4 ± 3.0, P > .05). CONCLUSIONS: UES-AD significantly decreases the number of trans-UES reflux events and can potentially reduce the aspiration risk associated with NGT feeding. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1310-1315, 2018.

Comparative effect of the sites of anterior cervical pressure on the geometry of the upper esophageal sphincter high-pressure zone.

OBJECTIVES/HYPOTHESIS: External cricoid pressure is increasingly used to augment the upper esophageal sphincter (UES). Our objective was to determine the effect of 1) pressures applied to cricoid, supracricoid, and subcricoid regions on the length and amplitude of the UES high-pressure zone (UESHPZ), and 2) the external cricoid pressure on lower esophageal sphincter (LES) tone. STUDY DESIGN: Case-control study. METHODS: We studied 11 patients with supraesophageal reflux (mean age 58 ± 12 years) and 10 healthy volunteers (mean age 47 ± 19 years). We tested 20, 30, and 40 mm Hg pressures to cricoid, 1 cm proximal and 1 cm distal to the cricoid. In an additional 15 healthy volunteers (mean age 46 ± 23 years), we studied the effect of external cricoid pressure on LES tone. UES and LES pressures were determined using high-resolution manometry. RESULTS: There was significant increase of UESHPZ length with application of pressure at all sites. The increase of UESHPZ length was relatively symmetric, more orad, and more caudad when the pressure was applied at the cricoid, supracricoid, and subcricoid levels, respectively. The magnitude of pressure increase was greatest at the middle and orad part of the UESHPZ when the pressure was applied at the cricoid and supracricoid levels, respectively. The corresponding magnitude of increase in the caudad part of the UESHPZ was not observed with pressure at the subcricoid level. There was no change of the LES pressure with application of cricoid pressure. CONCLUSIONS: The effect of external pressure on the UESHPZ is site dependent. Subcricoid pressure has the least effect on UESHPZ. External cricoid pressure at 20 to 40 mm Hg has no effect on the LES pressure. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:2466-2474, 2017.