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1.  Prevention of Esophagopharyngeal Reflux by Augmenting the Upper Esophageal Sphincter Pressure Barrier 
The Laryngoscope  2014;124(10):2268-2274.
Incompetence of the upper esophageal sphincter (UES) is fundamental to the occurrence of esophagopharyngeal reflux (EPR), and development of supraesophageal manifestations of reflux disease (SERD). However, therapeutic approaches to SERD have not been directed to strengthening of the UES barrier function. Our aims were to demonstrate that EPR events can be experimentally induced in SERD patients and not in healthy controls, and ascertain if these events can be prevented by application of a modest external cricoid pressure.
Study Design
Individual case control study.
We studied 14 SERD patients (57±13 years, 8 females) and 12 healthy controls (26±3 years, 7 females) by concurrent intraesophageal slow infusion and pharyngoscopic and manometric technique without and with the application of a sustained predetermined cricoid pressure to induce, detect, and prevent EPR, respectively.
Slow esophageal infusion (1 mL/s) of 60 mL of HCl resulted in a total of 16 objectively confirmed EPR events in none patients and none in healthy controls. All patients developed subjective sensation of regurgitation. Sustained cricoid pressure resulted in a significant UES pressure augmentation in all participants. During application of sustained cricoid pressure, slow intraesophageal infusion resulted in only one EPR event (P<.01).
Slow esophageal liquid infusion unmasks UES incompetence evidenced as the occurrence of EPR. Application of 20 to 30 mm Hg cricoid pressure significantly increases the UES intraluminal pressure and prevents pharyngeal reflux induced by esophageal slow liquid infusion. These techniques can be useful in diagnosis and management of UES incompetence in patients suffering from supraesophageal manifestations of reflux disease.
PMCID: PMC4332774  PMID: 24782387
Regurgitation; cricoid pressure; supraesophageal reflux disease; extraesophageal reflux disease; laryngopharyngeal reflux; gastroesophageal reflux disease
2.  Visceral analgesic effect of 5-HT4 receptor agonist in rats involves the rostroventral medulla (RVM) 
Neuropharmacology  2013;79:345-358.
The 5-HT4 receptor agonist tegaserod (TEG) has been reported to modulate visceral pain. However, the underlying mechanism remains unknown. The objective of the present study was to examine the analgesic mechanism and site of action of TEG. In male rats, visceral pain was assessed by measuring visceromotor response (VMR) to colorectal distension (CRD). Inflammation was induced by intracolonic injection of tri-nitrobenzene sulfonic acid (TNBS). The effect of TEG on the VMR was tested by injecting intraperitoneal (i.p.), intrathecal (i.t.), intracerebroventricular (i.c.v) or in the rostroventral medulla (RVM). The effect of the drug was also tested on responses of CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons. Systemic injection of TEG attenuated VMR in naive and TNBS-treated rats. Similarly, supraspinal, but not spinal, injection of TEG attenuated the VMR. While GR113808, (selective 5-HT4 antagonist) blocked the effect, naloxone (NLX) an opioid receptor antagonist reversed the effect of TEG. Although i.t. NLX did not block the inhibitory effect of TEG in VMR study, i.t. injection of α2-adrenergic receptor antagonist yohimbine blocked the effect of TEG when given systemically. While TEG had no effect on the responses of CRD-sensitive PNA, it inhibited the responses of CRD-sensitive LS neurons in spinal intact condition. This inhibition was blocked by GR113808, NLX and β-funaltrexamine (β-FNA) when injected into the RVM. Results indicate that TEG produces analgesia via activation of supraspinal 5-HT4 receptors which triggers the release of opioids at supraspinal site, which activates descending noradrenergic pathways to the spinal cord to produce analgesia.
PMCID: PMC4321751  PMID: 24334068
5-HT4 receptors; RVM; Visceral pain; Colon; Descending modulation
3.  Intrinsic Functional Connectivity of the Brain Swallowing Network (BSN) During Subliminal Esophageal Acid Stimulation 
Background & Aim
Intrinsic synchronous fluctuations of the fMRI signal are indicative of the underlying “functional connectivity” (FC) and serve as a technique to study dynamics of the neuronal networks of the human brain. Earlier studies have characterized the functional connectivity of a distributed network of brain regions involved in swallowing, called brain swallowing network (BSN). The potential modulatory effect of esophageal afferent signals on the BSN, however, has not been systematically studied.
Fourteen healthy volunteers underwent steady state fMRI across three conditions: 1) transnasal catheter placed in the esophagus without infusion; 2) buffer solution infused at 1ml/min; and 3) acidic solution infused at 1 ml/min. Data were preprocessed according to the standard FC analysis pipeline. We determined the correlation coefficient values of pairs of brain regions involved in swallowing across and calculated average group FC matrices across conditions. Effects of subliminal esophageal acidification and nasopharyngeal intubation were determined.
Subliminal esophageal acid stimulation augmented the overall FC of the right anterior insula and specifically the FC to the left inferior parietal lobule. Conscious stimulation by nasopharyngeal intubation reduced the overall FC of the right posterior insula, particularly the FC to the right prefrontal operculum.
The FC of BSN is amenable to modulation by sensory input. The modulatory effect of sensory pharyngoesophageal stimulation on BSN is mainly mediated through changes in the FC of the insula. The alteration induced by subliminal visceral esophageal acid stimulation is in different insular connections compared to that of conscious somatic pharyngeal stimulation.
PMCID: PMC3864683  PMID: 24251873
cortical swallowing network; default mode network; resting connectivity; negative BOLD; buffer
4.  Effect of Systemic Alcohol and Nicotine on Airway Protective Reflexes 
Injection of water into the pharynx induces contraction of the upper esophageal sphincter (UES), triggers the pharyngo-UES contractile reflex (PUCR), and at a higher volume, triggers an irrepressible swallow, the reflexive pharyngeal swallow (RPS). These aerodigestive reflexes have been proposed to reduce the risks of aspiration. Alcohol ingestion can predispose to aspiration and previous studies have shown that cigarette smoking can adversely affect these reflexes. It is not known whether this is a local effect of smoking on the pharynx or a systemic effect of nicotine. The aim of this study was to elucidate the effect of systemic alcohol and nicotine on PUCR and RPS.
Ten healthy non-smoking subjects (8 men, 2 women; mean age: 32±3 s.d. years) and 10 healthy chronic smokers (7 men, 3 women; 34±8 years) with no history of alcohol abuse were studied. Using previously described techniques, the above reflexes were elicited by rapid and slow water injections into the pharynx, before and after an intravenous injection of 5% alcohol (breath alcohol level of 0.1%), before and after smoking, and before and after a nicotine patch was applied. Blood nicotine levels were measured.
During rapid and slow water injections, alcohol significantly increased the threshold volume (ml) to trigger PUCR and RPS (rapid: PUCR: baseline 0.2±0.05, alcohol 0.4±0.09; P=0.022; RPS: baseline 0.5±0.17, alcohol 0.8±0.19; P=0.01, slow: PUCR: baseline 0.2±0.03, alcohol 0.4±0.08; P=0.012; RPS: baseline 3.0±0.3, alcohol 4.6±0.5; P=0.028). During rapid water injections, acute smoking increased the threshold volume to trigger PUCR and RPS (PUCR: baseline 0.4±0.06, smoking 0.67±0.09; P=0.03; RPS: baseline 0.7±0.03, smoking 1.1±0.1; P=0.001). No similar increases were noted after a nicotine patch was applied.
Acute systemic alcohol exposure inhibits the elicitation PUCR and RPS. Unlike cigarette smoking, systemic nicotine does not alter the elicitation of these reflexes.
PMCID: PMC4160881  PMID: 19550414
5.  Anatomic-manometric correlation of the upper esophageal sphincter: a concurrent US and manometry study 
Gastrointestinal endoscopy  2010;72(3):587-592.
The pharyngoesophageal segment commonly referred to as the upper esophageal sphincter (UES) generates a high-pressure zone (HPZ) between the pharynx and the esophagus. However, the exact anatomical components of the UES-HPZ remain incompletely determined.
To systematically define the US signature of various components of the pharyngoesophageal junction and to determine how these structures contribute to the development of the UES-HPZ.
Prospective, experimental study.
Tertiary Academic Medical Center.
This study involved 18 healthy volunteers.
We studied 5 participants by using a high-frequency US miniprobe (US-MP) and concurrent fluoroscopy and another 13 participants by using the US-MP and concurrent manometry.
Main Outcome Measurements
Relative contribution of various muscles in the UES-HPZ.
Manometrically, the UES-HPZ had a median length of 4.0 cm (range 3.0–4.5 cm). A C-shaped muscle, believed to represent the cricopharyngeus muscle, was observed for a median length of 3.5 cm (range 2.0–4.0 cm). The oval configuration representing the esophageal contribution to the UES was seen in 10 of 13 participants (77%) at the distal HPZ (esophagus to UES transition zone). The flat configuration of the inferior constrictor muscle was noted in 7 of 13 participants (54%) at the proximal HPZ (UES to pharynx transition zone). There were 4 to 5 wall layers versus 3 layers in the distal and proximal HPZ, respectively. The mean (± SD) muscle thickness was relatively constant along the length of the UES-HPZ.
Air artifacts in the UES-HPZ.
The configuration and layers of the UES-HPZ vary along its length. The upper esophagus is a significant contributor to the distal UES-HPZ.
PMCID: PMC4142490  PMID: 20579650
6.  Effect of Aging on Hypopharyngeal Safe Volume and the Aerodigestive Reflexes Protecting the Airways 
The Laryngoscope  2014;124(8):1862-1868.
Studies on young volunteers have shown that aerodigestive reflexes are triggered before the maximum volume of fluid that can safely collect in the hypopharynx before spilling into the larynx is exceeded (hypopharyngeal safe volume [HPSV]). The objective of this study was to determine the influence of aging on HPSV and pharyngoglottal closure reflex (PGCR), pharyngo-UES contractile reflex (PUCR), and reflexive pharyngeal swallow (RPS).
Study Design
Comparison between two groups of different age ranges.
Ten young (25 ±3 standard deviation [SD] years) and 10 elderly (77 ±3 SD years) subjects were studied. PGCR, PUCR, and RPS were elicited by perfusing water into the pharynx rapidly and slowly. HPSV was determined by abolishing RPS with pharyngeal anesthesia.
Frequency–elicitation of PGCR and PUCR were significantly lower in the elderly compared to the young during slow water perfusion (47% vs. 97% and 40% vs. 90%, respectively, P <.001). RPS was absent in five of the 30 (17%) slow injections in the elderly group. In these elderly subjects, HPSV was exceeded and laryngeal penetration of the water was seen. The threshold volume to elicit PGCR, PUCR, and RPS was significantly lower than the HPSV during rapid injections. Except for RPS, these volumes were also significantly lower than HPSV during slow injections.
PGCR, PUCR, and RPS reflexes are triggered at a threshold volume significantly lower than the HPSV in both young and elderly subjects. Lower frequency–elicitation of PGCR, PUCR, and RPS in the elderly can predispose them to the risks of aspiration.
PMCID: PMC4138697  PMID: 24281906
Laryngeal penetrations; aspiration; aging; elderly; aerodigestive reflexes; airway protection
7.  Functional Connectivity of the Cortical Swallowing Network in Humans 
NeuroImage  2013;76:33-44.
Coherent fluctuations of blood oxygenation level dependent (BOLD) signal have been referred as “functional connectivity” (FC). Our aim was to systematically characterize FC of underlying neural network involved in swallowing, and to evaluate its reproducibility and modulation during rest or task performance.
Activated seed regions within known areas of the cortical swallowing network (CSN) were independently identified in 16 healthy volunteers. Subjects swallowed using a paradigm driven protocol, and the data analyzed using an event-related technique. Then, in the same 16 volunteers, resting and active state data were obtained for 540 seconds in three conditions: 1) swallowing task; 2) control visual task; and 3) resting state; all scans were performed twice. Data was preprocessed according to standard FC pipeline. We determined the correlation coefficient values of member regions of the CSN across the three aforementioned conditions and compared between two sessions using linear regression. Average FC matrices across conditions were then compared.
Swallow activated twenty-two positive BOLD and eighteen negative BOLD regions distributed bilaterally within cingulate, insula, sensorimotor cortex, prefrontal and parietal cortices. We found that: 1) Positive BOLD regions were highly connected to each other during all test conditions while negative BOLD regions were tightly connected amongst themselves; 2) Positive and negative BOLD regions were anti-correlated at rest and during task performance; 3) Across all three test conditions, FC among the regions was reproducible (r > 0.96, p<10-5); and 4) The FC of sensorimotor region to other regions of the CSN increased during swallowing scan.
1) Swallow activated cortical substrates maintain a consistent pattern of functional connectivity; 2) FC of sensorimotor region is significantly higher during swallow scan than that observed during a non-swallow visual task or at rest.
PMCID: PMC4130480  PMID: 23416253
resting connectivity; reproducibility; seed based; deglutition
8.  Effect of Maturation of the Magnitude of Mechanosensitive and Chemosensitive Reflexes in the Premature Human Esophagus 
The Journal of pediatrics  2006;149(1):77-82.
To investigate the effect of esophageal mechanosensitive and chemosensitive stimulation on the magnitude and recruitment of peristaltic reflexes and upper esophageal sphincter (UES)-contractile reflex in premature infants.
Study design
Esophageal manometry and provocation testing were performed in the same 18 neonates at 33 and 36 weeks postmenstrual age (PMA). Mechanoreceptor and chemoreceptor stimulation were performed using graded volumes of air, water, and apple juice (pH 3.7), respectively. The frequency and magnitude of the resulting esophago-deglutition response (EDR) or secondary peristalsis (SP), and esophago-UES-contractile reflex (EUCR) were quantified.
Threshold volumes to evoke EDR, SP, or EUCR were similar. The recruitment and magnitude of SP and EUCR increased with volume increments of air and water in either study (P < .05). However, apple juice infusions resulted in increased recruitment of EDR in the 33 weeks group (P < .05), and SP in the 36 weeks group (P < .05). The magnitude of EUCR was also volume responsive (all media, P < .05), and significant differences between media were noted (P < .05). At maximal stimulation (1 mL, all media), sensory-motor characteristics of peristaltic and EUCR reflexes were different (P < .05) between media and groups.
Mechano- and chemosensitive stimuli evoke volume-dependent specific peristaltic and UES reflexes at 33 and 36 weeks PMA. The recruitment and magnitude of these reflexes are dependent on the physicochemical properties of the stimuli in healthy premature infants.
PMCID: PMC4075758  PMID: 16860132
9.  Esophago-Glottal Closure Reflex in Human Infants: A Novel Reflex Elicited With Concurrent Manometry and Ultrasonography 
Our aims were to identify and characterize the glottal response to esophageal mechanostimulation in human infants. We tested the hypotheses that glottal response is related to the type of esophageal peristaltic response, stimulus volume, and respiratory phase.
Ten infants (2.8 kg, SD 0.5) were studied at 39.2 wk (SD 2.4). Esophageal manometry concurrent with ultrasonography of the glottis (USG) was performed. The sensory-motor characteristics of mechanostimulation-induced esophago-glottal closure reflex (EGCR, adduction of glottal folds upon esophageal provocation) were identified. Mid-esophageal infusions of air (N 41) were given and the temporal relationships of glottal response with deglutition, secondary peristalsis (SP), and the respiratory phase were analyzed using multinomial logistic regression models.
The frequency occurrence of EGCR (83%) was compared (P < 0.001) with deglutition (44%), SP (34%), and no esophageal responses (22%). The odds ratios (OR, 95% CI) for the coexistence of EGCR with SP (0.4, 0.06–2.2), deglutition (1.9, 0.1–26), and no response (1.9, 0.4–9.0) were similar. The response time for esophageal reflexes was 3.8 (SD 1.8) s, and for EGCR was 0.4 (SD 0.3) s (P < 0.001). Volume-response relationship was noted (1 mL vs 2 mL, P < 0.05). EGCR was noted in both respiratory phases; however, EGCR response time was faster during expiration (P < 0.05).
The occurrence of EGCR is independent of the peristaltic reflexes or the respiratory phase of infusion. The independent existence of EGCR suggests a hypervigilant state of the glottis to prevent retrograde aspiration during GER events.
PMCID: PMC4028634  PMID: 17617206
10.  Correlation of Glottal Closure Using Concurrent Ultrasonography and Nasolaryngoscopy in Children: A Novel Approach to Evaluate Glottal Status 
Dysphagia  2006;21(1):75-81.
Endoscopic procedures to assess aerodigestive symptoms by evaluating glottal motion are not practical in neonates because of small nares, respiratory difficulties, or additional stress. Our objective was to determine the temporal correlation between concurrent nasolaryngoscopy (NLS) and ultrasonography (USG) evaluation of glottal motion.
Simultaneous USG of the glottis was performed in 10 subjects (5 males, 5 females, age = 4.5 months to 7.1 years) that underwent diagnostic flexible outpatient NLS. The USG transducer was placed on the anterior neck at the level of the vocal cords. The video signals from NLS and USG were integrated and synchronized into real-time cine loops of 1-min duration.
Frame-by-frame evaluation of 10,800 frames identifying glottal opening and closure time was compared between the two modalities by three observers and the timing of glottal closure was marked. Two investigators, blinded to NLS images, identified ultrasonographically determined glottal closure with 99% and 100% accuracy, and the mean probability of missing a closure frame was 0.007 (95% CI = 0.0008–0.024).
Temporal characteristics of glottal motion can be quantified by USG with perfect reliability and safety. This method can be useful in measuring the presence and the duration of laryngeal adduction.
PMCID: PMC4028689  PMID: 16786412
Nasolaryngoscopy; Ultrasonography; Glottis; Infant; Deglutition; Deglutition disorders
11.  Effect of Postnatal Maturation on the Mechanisms of Esophageal Propulsion in Preterm Human Neonates: Primary and Secondary Peristalsis 
The changes in esophageal propulsive characteristics during maturation are not known. Our aim was to define the effects of postnatal maturation on esophageal peristaltic characteristics in preterm human neonates. We tested the hypotheses that: (i) maturation modifies esophageal bolus propulsion characteristics, and (ii) the mechanistic characteristics differ between primary and secondary peristalsis.
Esophageal motility in 10 premature neonates (mean 27.5 weeks gestational age) was evaluated twice at 33.8 weeks (time 1, earlier study) and 39.2 weeks (time 2, later study) mean postmenstrual age. Esophageal manometry waveform characteristics (amplitude and duration, peristaltic velocity, and intrabolus pressure domains) were analyzed during spontaneous primary peristalsis and infusion-induced secondary peristalsis. Repeated-measures and unstructured variance–covariance or compound symmetry matrixes were used for statistical comparison. Values stated as least squares means±s.e.m. or percent.
A total of 200 primary peristalsis and 227 secondary peristalsis events were evaluated. Between time 1 and time 2: (i) proximal esophageal waveform amplitude increased (P < 0.02), with primary peristalsis (38±6 vs. 48±7 mm Hg) and with secondary peristalsis (34±6 vs. 46±5 mm Hg); (ii) distal esophageal waveform amplitude was similar (P = NS), with primary peristalsis (42±4 vs. 43±4 mm Hg) and secondary peristalsis (29±3 vs. 32±4 mm Hg); (iii) proximal esophageal waveform onset to peak duration decreased (P = 0.02) with primary (2.6±0.3 vs. 1.9±0.1 s, P < 0.003) and with secondary peristalsis (2.2±0.2 vs. 1.8±0.1 s); (iv) distal esophageal waveform onset to peak duration decreased (P = 0.01) with primary (2.4±0.3 vs. 1.8±0.1 s) and with secondary peristalsis (1.9±0.2 vs. 1.5±0.1 s); (v) effects of identical stimulus volume on intrabolus pressure were similar (P = NS); however, greater infusion volumes (2 vs. 1 ml) generated higher intrabolus pressure at both time 1 and time 2 (both Ps < 0.05). Between primary and secondary peristalsis (mechanistic variable): (i) no differences were noted at either period, with proximal esophageal waveform amplitudes (P = NS); (ii) differences were noted with distal esophageal waveform amplitudes at each time period (P = 0.0002); (iii) no differences were noted with both esophageal waveforms duration at either period (P = NS); (iv) peristaltic velocity was faster with secondary peristalsis than with primary peristalsis at either period (at earlier study, 7.9±1.4 vs. 2.5±1.4 cm/s and at later study 6.2±1.6 vs. 1.2±1.5 cm/s, both Ps < 0.01).
In preterm neonates, longitudinal maturation modulates the characteristics of primary and secondary peristalsis. Differences in proximal striated muscle and distal smooth muscle activity during peristalsis are evident. Peristaltic velocity is faster with secondary peristalsis. These findings may represent maturation of central and peripheral neuromotor properties of esophageal bolus propulsion in healthy preterm human neonates.
PMCID: PMC3796765  PMID: 19174814
12.  Physiology and Pathophysiology of Glottic Reflexes and Pulmonary Aspiration: From Neonates to Adults 
Pulmonary aspiration is the consequence of abnormal entry of fluid, particulate material, or endogenous secretions into the airway. The two main types of aspiration scenarios include anterograde aspiration, which occurs during swallowing, and retrograde aspiration, which can occur during gastroesophageal reflux (GER) events. The important structures that protect against aspiration include the aerodigestive apparatus: pharynx, upper esophageal sphincter, esophageal body, glottis and vocal cords, and airway. In this article we review the neuroanatomy, physiology, and pathophysiology pertinent to glottic reflexes and airway aspiration across the age spectrum from neonates to adults. We also discuss recent advances in our understanding of glottal reflexes and the relationship of these reflexes to developmental anatomy and physiology, the pathophysiology of aspiration, and aerodigestive interactions.
PMCID: PMC3796769  PMID: 20941656
Pharyngoglottal closure reflex; esophagoglottal closure reflex; laryngeal adductor reflex; upper esophageal sphincter; gastroesophageal reflux
13.  Definition and Implications of Novel Pharyngo-Glottal Reflex in Human Infants Using Concurrent Manometry Ultrasonography 
Glottal relationships during swallowing dominate the etiology of dysphagia. We investigated the pharyngo-glottal relationships during basal and adaptive swallowing.
Temporal changes in glottal closure kinetics (frequency, response latency, and duration) with spontaneous and adaptive pharyngeal swallows were defined in 12 infants using concurrent pharyngoesophageal manometry and ultrasonography of the glottis.
Frequency, response latency, and duration of glottal closure with spontaneous swallows (n = 53) were 100%, 0.27±0.1 s, and 1±0.22 s, respectively. The glottis adducted earlier (P < 0.0001 vs. upper esophageal sphincter relaxation) within the same respiratory phase as swallow (P = 0.03). With pharyngeal provocations (n = 41), glottal adduction (pharyngo-glottal closure reflex (PGCR)) was noted first and then again with pharyngeal reflexive swallow (PRS). The frequency, response latency, and duration of glottal closure with PGCR were 100%, 0.56±0.13 s, and 0.52±0.1 s, respectively. Response latency to PRS was 3.24±0.33 s; the glottis adducted 97% within 0.36±0.08 s in the same respiratory phase (P = 0.03), and remained adducted for 3.08±0.71 s. Glottal adduction was the quickest with spontaneous swallow (P = 0.04 vs. PGCR), and the duration was the longest during PRS (P < 0.005 vs. PGCR or spontaneous swallow).
Glottal adduction during basal or adaptive swallowing reflexes occurs in either respiratory phase, thus ensuring airway protection against pre-deglutitive or deglutitive aspiration. The independent existence and magnitude (duration of adduction) of PGCR suggests a hypervigilant state of the glottis in preventing aspiration during swallowing or during high gastroesophageal reflux events. Investigation of pharyngeal–glottal relationships with the use of noninvasive methods may be more acceptable across the age spectrum.
PMCID: PMC3791891  PMID: 19603008
The Laryngoscope  2012;122(8):1719-1723.
Asymptomatic subjects volunteering for research studies are generally stratified as healthy based on a questionnaire, medical interviewing, and physical examination. The aim of this study was to evaluate the prevalence of upper GI abnormalities in healthy asymptomatic volunteers using unsedated transnasal esophago-gastro-duodenoscopy (T-EGD) with an ultrathin endoscope as an additional screening tool.
This is a prospective study from one academic medical center with extensive experience in T-EGD. Consecutive 150 subjects volunteering for research studies were initially screened by using a gastroesophageal reflux disease (GERD) questionnaire, interviewing, and examination. Based on these, they were stratified as healthy asymptomatic volunteers or with GERD. Unsedated T-EGD was then performed by a faculty who was blinded to the results of the initial assessment.
On initial assessment using GERD questionnaire, medical interviewing, and physical examination, of the total 150 consecutive research volunteers, 83 (33±16, 46 females, 37 males) subjects were healthy asymptomatic volunteers and 67 (36±15, 35 females, 32 males) had symptoms of GERD. On T-EGD, gastrointestinal pathology was found in 15 of 83 (18%) healthy asymptomatic volunteers as compared to 24 of 67 (36%) stratified as having GERD (p <0.01). The esophageal abnormalities found in healthy asymptomatic volunteers were esophagitis (13.3%), Barrett’s esophagus (2.4%), hiatus hernia (2.4%) and gastritis (2.4%).
A small but significant number of asymptomatic subjects have abnormal upper GI findings. Hence, transnasal unsedated endoscopy can be considered as a screening tool to stratify subjects as healthy especially when considering them for research studies.
PMCID: PMC3477703  PMID: 22565357
Transnasal endoscopy; unsedated endoscopy; ultrathin endoscope; gastroesophageal reflux disease; Barretts esophagus
15.  Response of the Upper Esophageal Sphincter to Esophageal Distension is Affected by Posture, Velocity, Volume, and Composition of the Infusate 
Gastroenterology  2012;142(4):734-743.e7.
Background & Aims
Studies of the pressure response of the upper esophageal sphincter (UES) to simulated or spontaneous gastroesophageal reflux have shown conflicting results. These discrepancies could result from uncontrolled influence of variables such as posture, volume, and velocity of distension. We characterized in humans the effects of these variables on UES pressure response to esophageal distension.
We studied 12 healthy volunteers (average 27±5 years old, 6 male) using concurrent esophageal infusion and high-resolution manometry to determine UES, lower esophageal sphincter, and intraesophageal pressure values. Reflux events were simulated by distal esophageal injections of room-temperature air and water (5, 10, 20, and 50 ml) in individuals in 3 positions (upright, supine and semi-supine). Frequencies of various UES responses were compared using χ2 analysis. Multinomial logistical regression analysis was used to identify factors that determine the UES response.
UES contraction and relaxation were the overriding responses to esophageal water and air distension, respectively, in a volume-dependent fashion (P<.001). Water-induced UES contraction and air-induced UES relaxation were the predominant responses among individuals in supine and upright positions, respectively (P<.001). The prevalence of their respective predominant response significantly decreased in the opposite position. Proximal esophageal dp/dt significantly and independently differentiated the UES response to infusion with water or air.
The UES response to esophageal distension is affected by combined effects of posture (spatial orientation of the esophagus), physical properties, and volume of refluxate, as well as the magnitude and rate of increase in intraesophageal pressure. The UES response to esophageal distension can be predicted using a model that incorporates these factors.
PMCID: PMC3327135  PMID: 22248662
esophagus; stomach; airway; GERD
16.  Colonic Butyrate- algesic or analgesic? 
Irritable bowel syndrome (IBS) is a common health issue that is characterized by abdominal pain, abnormal bowel movements and altered visceral perception. The complexity and variability in symptoms pose serious challenges in treating IBS. Current therapy for IBS is primarily focused on reducing the abdominal pain, thereby improving the quality of life to a significant extent. Although the use of fiber rich diet is widely recommended in treating IBS, some studies have questioned its use. Intracolonic butyrate, a short chain fatty acid, is primarily produced by the fermentation of dietary fibers in the colon. In the existing literature there are conflicting reports about the function of butyrate. In rats it is known to induce visceral hypersensitivity without altered pathology, whereas in humans it has been reported to reduce visceral pain. Understanding the molecular mechanisms responsible for this contrasting effect of butyrate is important before recommending fiber rich diet to IBS patients.
PMCID: PMC3191935  PMID: 21981302
Inflammatory bowel syndrome; colonic hypersensitivity; short chain fatty acids; sodium butyrate
17.  Protective Role of Aerodigestive Reflexes Against Aspiration: Study on Subjects With Impaired and Preserved Reflexes 
Gastroenterology  2011;140(7):1927-1933.
Direct evidence to support the airway protective function of aerodigestive reflexes triggered by pharyngeal stimulation was previously demonstrated by abolishing these reflexes by topical pharyngeal anesthesia in normal subjects. Studies have also shown that these reflexes deteriorate in cigarette smokers. Aim of this study was to determine the influence of defective pharyngeal aerodigestive reflexes on airway protection in cigarette smokers.
Pharyngoglottal Closure reflex; PGCR, Pharyngo-UES Contractile reflex; PUCR, and Reflexive Pharyngeal Swallow; RPS were studied in 15 healthy non-smokers (24.2 ± 3.3 SD y, 7 males) and 15 healthy chronic smokers (27.3 ± 8.1, 7 males). To elicit these reflexes and to evaluate aspiration, colored water was perfused into the hypopharynx at the rate of 1 mL/min. Maximum volume of water that can safely dwell in the hypopharynx before spilling into the larynx (Hypopharyngeal Safe Volume; HPSV) and the threshold volume to elicit PGCR, PUCR, and RPS were determined in smokers and results compared with non-smokers.
At baseline, RPS was elicited in all non-smokers (100%) and in only 3 of 15 smokers (20%; P < .001). None of the non-smokers showed evidence of laryngeal spillage of water, whereas 12 of 15 smokers with absent RPS had laryngeal spillage. Pharyngeal anesthesia abolished RPS reflex in all non-smokers resulting in laryngeal spillage. The HPSV was 0.61 ± 0.06 mL and 0.76 ± 0.06 mL in non-smokers and smokers respectively (P = .1).
Deteriorated reflexive pharyngeal swallow in chronic cigarette smokers predispose them to risks of aspiration and similarly, abolishing this reflex in non-smokers also results in laryngeal spillage. These observations directly demonstrate the airway protective function of RPS.
PMCID: PMC3425443  PMID: 21420407
Cigarette Smoking; Airway Protection; Reflux; UES
18.  Neuronal Plasticity in the Cingulate Cortex of Rats following Esophageal Acid Exposure in Early Life 
Gastroenterology  2011;141(2):544-552.
Background & Aims
The cingulate cortex (CC) has been reported to be involved in processing pain of esophageal origin. However, little is known about molecular changes and cortical activation that arise from early-life, esophageal acid reflux. Excitatory neurotransmission via activation of the N-methyl-D-aspartate (NMDA) receptor and its interaction with post-synaptic density protein-95 (PSD-95) at the synapse appears to mediate neuronal development and plasticity. We investigated the effect of early-life esophageal acid exposure on NMDA receptor subunits and PSD-95 expression in the developing CC.
We assessed NMDA receptor subunits and PSD-95 protein expression in rostral CC (rCC) tissues of rats exposed to esophageal acid or saline (control), either during post-natal days 7–14 (P7–P14) and/or acutely, at adult stage (P60), using immunoblot and immunoprecipitation analyses.
Compared with controls, acid exposure from P7 to P14 significantly increased expression of NR1, NR2A, and PSD-95, measured 6 weeks after exposure. However, acute exposure at P60 caused a transient increase in expression of NMDA receptor subunits. These molecular changes were more robust in animals exposed to acid neonatally and rechallenged, acutely, at P60. Esophageal acid exposure induced calcium calmodulin kinase II-mediated phosphorylation of the subunit NR2B at Ser1303.
Esophageal acid exposure during early stages of life has long-term effects, because of phosphorylation of the NMDA receptor and overexpression in the rCC. This molecular alteration in the rCC might mediate sensitization of patients with acid-induced esophageal disorders.
PMCID: PMC3152593  PMID: 21616075
brain; developmental neuroscience; pain processing; CamKII
19.  Neonatal Cystitis-Induced Colonic Hypersensitivity in Adult Rats: A Model of Viscero-Visceral Convergence 
The objective of this study was to determine if neonatal cystitis alters colonic sensitivity later in life and to investigate the role of peripheral mechanisms.
Neonatal rats received intravesical zymosan, normal saline, or anesthesia only for three consecutive days (postnatal days 14th–16th). The estrous cycle phase was determined prior to recording the visceromotor response (VMR) to colorectal distension (CRD) in adult rats. Eosinophils and mast cells were examined from colon and bladder tissue. CRD or urinary bladder distension (UBD)-sensitive pelvic nerve afferents (PNAs) were identified and their responses to distension were examined. The relative expression of N-methyl-D-aspartic acid (NMDA) NR1 subunit in the L6-S1 spinal cord was examined using Western blot.
The VMR to CRD (≥10mmHg) in the neonatal zymosan group was significantly higher than control in both the diestrus, estrus phase and in all phases combined. There was no difference in the total number of eosinophils, mast cells or number of degranulated mast cells between groups. The spontaneous firing of UBD, but not CRD-sensitive PNAs from the zymosan rats was significantly higher than the control. However, the mechanosensitive properties of PNAs to CRD or UBD were no different between groups (p > 0.05). The expression of spinal NR1 subunit was significantly higher in zymosan-treated rats compared to saline treated rats (p <0.05).
Neonatal cystitis results in colonic hypersensitivity in adult rats without changing tissue histology or the mechanosensitive properties of CRD-sensitive PNAs. Neonatal cystitis does results in overexpression of spinal NR1 subunit in adult rats.
PMCID: PMC3117950  PMID: 21592255
cystitis; visceral hyperalgesia; neonatal; viscero-visceral convergence
20.  Differential Activation of Medullary Vagal Nuclei Caused by Stimulation of Different Esophageal Mechanoreceptors 
Brain research  2010;1368:119-133.
Esophageal mechanorecptors, i.e. muscular slowly adapting tension receptors and mucosal rapidly adapting touch receptors, mediate different sets of reflexes. The aim of this study was to determine the medullary vagal nuclei involved in the reflex responses to activation of these receptors. Thirty-three cats were anesthetized with alpha-chloralose and the esophagus was stimulated by slow balloon or rapid air distension. The physiological effects of the stimuli (N=4) were identified by recording responses from the pharyngeal, laryngeal, and hyoid muscles, esophagus, and the lower esophageal sphincter (LES). The effects on the medullary vagal nuclei of the stimuli: slow distension (N=10), rapid distension (N=9), and in control animals (N=10) were identified using the immunohistochemical analysis of c-fos. The experimental groups were stimulated 3 times per minute for 3 hours. After the experiment, the brains were removed and processed for c-fos immunoreactivity or thioinin. We found that slow balloon distension activated the esophago-UES contractile reflex and esophago LES relaxation response, and rapid air injection activated the belch and its component reflexes. Slow balloon distension activated the NTSce, NTSdl, NTSvl, DMNc, DMNr and NAr; and rapid air injection primarily activated AP, NTScd, NTSim, NTSis, NTSdm, NTSvl, NAc and NAr. We concluded that different sets of medullary vagal nuclei mediate different reflexes of the esophagus activated from different sets of mechanoreceptors. The NTScd is the primary NTS subnucleus mediating reflexes from the mucosal rapidly adapting touch receptors, and the NTSce is the primary NTS subnucleus mediating reflexes from the muscular slowly adapting tension receptors. The AP may be involved in mediation of belching.
PMCID: PMC3014375  PMID: 20971087
nucleus tractus solitarius; dorsal motor nucleus; nucleus ambiguus; esophageal mechanoreceptors; pharynx; larynx; belching
21.  Differential Activation of Pontomedullary Nuclei by Acid Perfusion of Different Regions of the Esophagus 
Brain research  2010;1352:94-107.
The objective of this study was to determine the brain stem nuclei and physiological responses activated by esophageal acidification. The effects of perfusion of the cervical (ESOc), or thoracic (ESOt) esophagus with PBS or HCl on c-fos immunoreactivity of the brain stem or on physiological variables, and the effects of vagotomy were examined in anesthetized cats. We found that acidification of the ESOc increased the number of c-fos positive neurons in the area postrema (AP), vestibular nucleus (VN), parabrachial nucleus (PBN), nucleus ambiguus (NA), dorsal motor nucleus (DMN), and all subnuclei of the nucleus tractus solitarius (NTS), but one. Acidification of the ESOt activated neurons in the central (CE), caudal (CD), dorsomedial (DM), dorsolateral (DL), ventromedial (VM) subnuclei of NTS, and the DMN. Vagotomy blocked all c-fos responses to acid perfusion of the whole esophagus (ESOw). Perfusion of the ESOc or ESOt with PBS activated secondary peristalsis (2P), but had no effect on blood pressure, heart rate, or respiratory rate. Perfusion of the ESOc, but not ESOt, with HCL activated pharyngeal swallowing (PS), profuse salivation, or physiological correlates of emesis. Vagotomy blocked all physiological effects of ESOw perfusion. We conclude that acidification of the ESOc and ESOt activate different sets of pontomedullary nuclei and different physiological responses. The NTSce, NTScom, NTSdm, and DMN are associated with activation of 2P, the NTSim and NTSis, are associated with activation of PS, and the AP, VN, and PBN are associated with activation of emesis and perhaps nausea. All responses to esophageal fluid perfusion or acidification are mediated by the vagus nerves.
PMCID: PMC2926140  PMID: 20655885
medulla; pons; esophagus; hydrochloric acid; c-fos; cat
23.  The Feasibility of Establishing Agreement Between Laboratories for Measures of Oropharyngeal Structural Movements 
Kinematic analysis, also commonly referred to as biomechanical analysis, of the swallow is used to measure movement of oropharyngeal structures over time. Two laboratory directors who have used kinematic analysis in their research collaborated to determine the feasibility of establishing agreement between two separate laboratories on measures of structural movements of the swallow. This report describes the process that was followed toward the goal of establishing measurement agreement. Under the direction of the laboratory directors, one research technician from each laboratory participated in a process that included initial meetings, training sessions, and pre- and post-training evaluation of reproducibility.
Because agreement on initial measures of structural movement demonstrated weak correlation on some measures, the research technicians trained together for approximately 6 hours. After training, statistical analyses indicated that (a) most Pearson correlations for measures of structural movements were greater than 0.80 and were highly statistically significant; (b) most percentages of absolute deviation were under 25%; and (c) most concordance coefficients were above .70. These statistics indicate that the two laboratories were able to increase their level of agreement in measuring selected structural movements of the swallow after a brief amount of training.
Factors affecting measurement agreement include image quality, establishment of rules for measuring, and the opportunity for regular discussions among research assistants and investigators from both laboratories.
PMCID: PMC3079209  PMID: 21512610
24.  Altered Mechanosensitive Properties of Vagal Afferent Fibers Innervating the Stomach Following Gastric Surgery in Rats 
Neuroscience  2009;162(4):1299-1306.
Background and Aims
Several types of gastric surgeries have been associated with early satiety, dyspepsia and food intolerances. We aimed to examine alterations in gastric vagal afferents following gastric surgery-fundus ligation.
Six week old, male Sprague-Dawley rats underwent chronic ligation (CL) of the gastric fundus. Sham rats underwent surgery, but without ligation. Another group of rats underwent acute ligation (AL) immediately prior to experiments. Animals were allowed to grow to age 3–4 months. Food intake and weights were recorded post-operatively. Gastric compliance and gastric wall thickness was measured at baseline and during gastric distension (GD). Extracellular recordings were made to examine response characteristics of vagal afferent fibers to GD and to map the stomach receptive field (RF). The morphological structures of afferent terminals in the stomach were examined with retrograde tracings from the nodose ganglion.
The CL group consumed significantly less food and weighed less than control. The mean compliance of CL group was significantly less than control, but higher than the AL. The spontaneous firing and responses to GD of afferent fibers from the CL rats were significantly higher than AL rats. There was a marked expansion of the gastric RF in the CL rats with significant reorganization and regeneration of intramuscular array (IMA) terminals. There was no difference in total wall or muscle thickness among the groups.
CL results in aberrant remodeling of IMAs with expansion of the gastric RF and alters the mechanotransduction properties of vagal afferent fibers. These changes could contribute to altered sensitivity following gastric surgery.
PMCID: PMC2741133  PMID: 19477237
Vagal Afferents; Stomach; Satiety; Fundus ligation; Gastric surgery
25.  A Randomized Study Comparing the Shaker Exercise with Traditional Therapy: A Preliminary Study 
Dysphagia  2009;24(4):403-411.
Seven institutions participated in this small clinical trial that included 19 patients who exhibited oropharyngeal dysphagia on videofluorography (VFG) involving the upper esophageal sphincter (UES) and who had a 3-month history of aspiration. All patients were randomized to either traditional swallowing therapy or the Shaker exercise for 6 weeks. Each patient received a modified barium swallow pre- and post-therapy, including two swallows each of 3 ml and 5 ml liquid barium and 3 ml barium pudding. Each videofluorographic study was sent to a central laboratory and digitized in order to measure hyoid and larynx movement as well as UES opening. Fourteen patients received both pre-and post-therapy VFG studies. There was significantly less aspiration post-therapy in patients in the Shaker group. Residue in the various oral and pharyngeal locations did not differ between the groups. With traditional therapy, there were several significant increases from pre- to post-therapy, including superior laryngeal movement and superior hyoid movement on 3-ml pudding swallows and anterior laryngeal movement on 3-ml liquid boluses, indicating significant improvement in swallowing physiology. After both types of therapy there is a significant increase in UES opening width on 3-ml paste swallows.
PMCID: PMC2895999  PMID: 19472007
Dysphagia; Shaker exercise; Upper esophageal sphincter; Deglutition; Deglutition disorders

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