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1.  Excessive coupling of the salience network with intrinsic neurocognitive brain networks during rectal distension in adolescents with irritable bowel syndrome: a preliminary report 
Background
The neural network mechanisms underlying visceral hypersensitivity in irritable bowel syndrome (IBS) are incompletely understood. It has been proposed that an intrinsic salience network plays an important role in chronic pain and IBS symptoms. Using neuroimaging, we examined brain responses to rectal distension in adolescent IBS patients, focusing on determining the alteration of salience network integrity in IBS and its functional implications in current theoretical frameworks. We hypothesized that (1) brain responses to visceral stimulation in adolescents are similar to those in adults, and (2) IBS is associated with an altered salience network interaction with other neurocognitive networks, particularly the default mode network (DMN) and executive control network (ECN), as predicted by the theoretical models.
Methods
IBS patients and controls received subliminal and liminal rectal distension during imaging. Stimulus-induced brain activations were determined. Salience network integrity was evaluated by functional connectivity of its seed regions activated by rectal distension in the insular and cingulate cortices.
Key Results
Compared with controls, IBS patients demonstrated greater activation to rectal distension in neural structures of the homeostatic afferent and emotional arousal networks, especially the anterior cingulate and insular cortices. Greater brain responses to liminal vs. subliminal distension were observed in both groups. Particularly, IBS is uniquely associated with an excessive coupling of the salience network with the DMN and ECN in their key frontal and parietal node areas.
Conclusions & Inferences
Our study provided consistent evidence supporting the theoretical predictions of altered salience network functioning as a neuropathological mechanism of IBS symptoms.
doi:10.1111/nmo.12695
PMCID: PMC4688218  PMID: 26467966
Irritable bowel syndrome; Salience network; fMRI-guided functional connectivity analysis; Homeostatic afferent processing network; Emotional arousal network
2.  Impaired Upper Esophageal Sphincter Reflexes in Patients with Supra-Esophageal Reflux Disease 
Gastroenterology  2015;149(6):1381-1391.
Background & Aims
Normal responses of the upper esophageal sphincter (UES) and esophageal body to liquid reflux events prevent esophagopharyngeal reflux and its complications, but abnormal responses have not been characterized. We investigated whether patients with supra-esophageal reflux disease (SERD) have impaired UES and esophageal body responses to simulated reflux events.
Methods
We performed a prospective study of 25 patients with SERD (19–82 y old, 13 female) and complaints of regurgitation and supra-esophageal manifestations of reflux. We also included 10 patients with gastroesophageal reflux disease (GERD; 32–60 y old, 7 female) without troublesome regurgitation and supra-esophageal symptoms and 24 healthy asymptomatic individuals (controls; 19–49 y old, 13 female). UES and esophageal body pressure responses, along with luminal distribution of infusate during esophageal rapid and slow infusion of air or liquid, were monitored by concurrent high-resolution manometry and intraluminal impedance.
Results
A significantly smaller proportion of patients with SERD had UES contractile reflexes in response to slow esophageal infusion of acid than controls or patients with GERD. Only patients with SERD had abnormal UES relaxation responses to rapid distension with saline. Diminished esophageal peristaltic contractions resulted in esophageal stasis in patients with GERD or SERD.
Conclusions
Patients with SERD and complaints of regurgitation have impaired UES and esophageal responses to simulated liquid reflux events. These patterns could predispose them to esophagopharyngeal reflux.
doi:10.1053/j.gastro.2015.07.007
PMCID: PMC4628603  PMID: 26188682
extra-esophageal reflux; EUCR; EURR; striated esophagus; cervical; laryngopharyngeal reflux
3.  Mechanisms of cough provocation and cough resolution in neonates with bronchopulmonary dysplasia 
Pediatric research  2015;78(4):462-469.
Background
Cough and deglutition are protective mechanisms that defend against aspiration. We identified mechanisms associated with cough provocation as well as those associated with cough resolution in infants with bronchopulmonary dysplasia (BPD).
Methods
Manometry signatures of cough were recognized in 16 premature infants with BPD undergoing concurrent esophageal manometry, respiratory inductance plethysmography, and nasal air flow measurements. Pretussive and posttussive pharyngo-esophageal motility changes were analyzed. Mechanisms associated with cough and mechanisms that restored respiratory and esophageal normalcy were analyzed.
Results
We analyzed 312 cough events during 88 cough clusters; 97% were associated with recognizable manometric patterns. Initial mechanisms related with coughing included nonpropagating swallow (59%), upper esophageal sphincter (UES) reflex contraction (18%), and lower esophageal sphincter (LES) relaxation (14%). UES and LES dysfunction was present in 69% of nonpropagating swallow-associated cough clusters. Mechanisms restoring post-tussive normalcy included primary peristalsis (84%), secondary peristalsis (8%), and none recognized (8%). UES contraction reflex was associated with cough clusters more frequently in infants on nasal continuous positive airway pressure (NCPAP) (OR = 9.13, 95% CI = 1.88–44.24).
Conclusion
Cough clusters in infants with BPD had identifiable etiologies associated with esophageal events; common initial mechanisms were of upper aerodigestive origin, while common clearing mechanisms were peristaltic reflexes.
doi:10.1038/pr.2015.131
PMCID: PMC4800483  PMID: 26151491
4.  Altered expression of P2X3 in vagal and spinal afferents following esophagitis in rats 
Histochemistry and cell biology  2009;132(6):585-597.
Purinergic P2X3 receptors are predominantly expressed in small diameter primary afferent neurons and activation of these receptors by adenosine triphosphate is reported to play an important role in nociceptive signaling. The objective of this study was to investigate the expression of P2X3 receptors in spinal and vagal sensory neurons and esophageal tissues following esophagitis in rats. Two groups of rats were used including 7 days fundus-ligated (7D-ligated) esophagitis and sham-operated controls. Esophagitis was produced by ligating the fundus and partial obstruction of pylorus that initiated reflux of gastric contents. The sham-operated rats underwent midline incision without surgical manipulation of the stomach. Expressions of P2X3 receptors in thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophageal tissues were evaluated by RT–PCR, western blot and immunohistochemistry. Esophageal neurons were identified by retrograde transport of Fast Blue from the esophagus. There were no significant differences in P2X3 mRNA expressions in DRGs (T1–T3) and NGs between 7D-ligated and sham-operated rats. However, there was an upregulation of P2X3 mRNA in DRGs (T6–T12) and in the esophageal muscle. At protein level, P2X3 exhibited significant upregulation both in DRGs and in NGs of rats having chronic esophagitis. Immunohistochemical analysis exhibited a significant increase in P2X3 and TRPV1 co-expression in DRGs and NGs in 7D-ligated rats compared to sham-operated rats. The present findings suggest that chronic esophagitis results in upregulation of P2X3 and its co-localization with TRPV1 receptor in vagal and spinal afferents. Changes in P2X3 expression in vagal and spinal sensory neurons may contribute to esophageal hypersensitivity following acid reflux-induced esophagitis.
doi:10.1007/s00418-009-0639-4
PMCID: PMC4820021  PMID: 19784665
P2X3 receptor; Dorsal root ganglia; Vagus; Acid reflux; Esophagitis
5.  Intramucosal Distribution of WNT Signaling Components in Human Esophagus 
Goals
To determine expression and localization of Wnt signaling molecules across the esophageal mucosal thickness.
Background
The molecular mechanisms governing the biology and pathobiology of esophageal squamous mucosa in health and disease are not completely understood. Earlier genome-wide expression study of normal-looking esophageal squamous mucosa has shown differential expression of the Wingless-type MMTV integration site family (Wnt) modulators Dickkopf (Dkk) homologs among healthy individuals and patients with reflux esophagitis and Barrett metaplasia suggesting that the Wnt pathway may be involved in esophageal mucosal biology.
Study
Seven full-thickness human donor esophagi were cryosectioned for immunohistochemical analysis, and lamina propria (LP), basal (BC), intermediate (IC), and superficial (SC) cells were also dissected by laser-capture microdissection for real-time polymerase chain reaction.
Results
Wnt1, 2b, and 3a were expressed primarily in BC, Wnt3, and 5b in LP, and Wnt5a in IC. Frizzled 1, low-density lipoprotein receptor-related protein 6, secreted frizzled-related protein 1, T-cell–specific transcription factor 3, and dishevelled 3 were expressed highest in LP decreasing precipitously medially toward SC. Dkk1 predominantly expressed in SC was more than 100-folds greater than other layers (P<0.001). Dkk4 was expressed primarily in SC but Dkk3 was opposite with greatest expression in LP. Immunohistochemical analysis showed Wnt1 and 3a in BC, Wnt5a in IC and SC, Dkk1 predominantly in SC, Dkk4 in SC and IC, and Dkk3 and SFRP1 in LP and BC.
Conclusions
Signaling components are expressed in a differential manner within the different layers of esophageal squamous mucosa suggesting their involvement in mucosal cell biology locally.
PMCID: PMC4811354  PMID: 19309775
wingless-type MMTV integration site family members; Dickkopf homologs; frizzled; secreted frizzled-related protein 1; T-cell–specific transcription factor 3; squamous mucosa
6.  Fatigue Analysis Before and After Shaker Exercise: Physiologic Tool for Exercise Design 
Dysphagia  2008;23(4):385-391.
Recent studies suggest that the Shaker exercise induces fatigue in the upper esophageal sphincter (UES) opening muscles and sternocleidomastoid (SCM), with the SCMs fatiguing earliest. The aim of this study was to measure fatigue induced by the isometric portion of the Shaker exercise by measuring the rate of change in the median frequency (MF rate) of the power spectral density (PSD) function, which is interpreted as proportional to the rate of fatigue, from surface electromyography (EMG) of suprahyoid (SHM), infrahyoid (IHM), and SCM. EMG data compared fatigue-related changes from 20-, 40-, and 60-s isometric hold durations of the Shaker exercise. We found that fatigue-related changes were manifested during the 20-s hold. The findings confirm that the SCM fatigues initially and as fast as or faster than the SHM and IHM. In addition, upon completion of the exercise protocol, the SCM had a decreased MF rate, implying improved fatigue resistance, while the SHM and IHM showed increased MF rates, implying that these muscles increased their fatiguing effort. We conclude that the Shaker exercise initially leads to increased fatigue resistance of the SCM, after which the exercise loads the less fatigue-resistant SHM and IHM, potentiating the therapeutic effect of the Shaker exercise regimen with continued exercise performance.
doi:10.1007/s00455-008-9155-2
PMCID: PMC4811359  PMID: 18369673
Dysphagia; Electromyography; Exercise; Muscle fatigue; Power spectral density; Surface EMG; Therapeutic exercise; Shaker exercise; UES opening; Deglutition; Deglutition disorders
7.  Oropharyngeal dysphagia in older persons – from pathophysiology to adequate intervention: a review and summary of an international expert meeting 
Oropharyngeal dysphagia (OD) is a highly prevalent and growing condition in the older population. Although OD may cause very severe complications, it is often not detected, explored, and treated. Older patients are frequently unaware of their swallowing dysfunction which is one of the reasons why the consequences of OD, ie, aspiration, dehydration, and malnutrition, are regularly not attributed to dysphagia. Older patients are particularly vulnerable to dysphagia because multiple age-related changes increase the risk of dysphagia. Physicians in charge of older patients should be aware that malnutrition, dehydration, and pneumonia are frequently caused by (unrecognized) dysphagia. The diagnosis is particularly difficult in the case of silent aspiration. In addition to numerous screening tools, videofluoroscopy was the traditional gold standard of diagnosing OD. Recently, the fiberoptic endoscopic evaluation of swallowing is increasingly utilized because it has several advantages. Besides making a diagnosis, fiberoptic endoscopic evaluation of swallowing is applied to evaluate the effectiveness of therapeutic maneuvers and texture modification of food and liquids. In addition to swallowing training and nutritional interventions, newer rehabilitation approaches of stimulation techniques are showing promise and may significantly impact future treatment strategies.
doi:10.2147/CIA.S97481
PMCID: PMC4770066  PMID: 26966356
aspiration; dehydration; dysphagia; geriatric; malnutrition; older
8.  Esophageal Acid Stimulation Alters Insular Cortex Functional Connectivity in Gastroesophageal Reflux Disease 
Background
The insula plays a significant role in the interoceptive processing of visceral stimuli. We have previously shown that GERD patients have increased insular cortex activity during esophageal stimulation, suggesting a sensitized esophago-cortical neuraxis. However, information regarding the functional connectivity (FC) of the insula during visceral stimulation is lacking. The primary aim of this study was to investigate the FC of insular subregions during esophageal acid stimulation.
Methods
Functional imaging data was obtained from 12 GERD patients and 14 healthy subjects during four steady state conditions: (1) presence of transnasal esophageal catheter (pre-infusion); (2) neutral solution; (3) acid infusion; (4) presence of transnasal esophageal catheter following infusions (post-infusion). The insula was parcellated into 6 regions of interest (ROI). FC maps between each insular ROI and interoceptive regions were created. Differences in FC between GERD patients and healthy subjects were determined across the 4 study conditions.
Key Results
All GERD patients experienced heartburn during and after esophageal acidification. Significant differences between GERD patients and healthy subjects were seen in: (1) insula-thalamic FC (neutral solution infusion, acid infusion, post-infusion); (2) insula-amygdala FC (acid infusion, post-infusion); (3) insula-hippocampus and insula-cingulate FC (post-infusion).
Conclusions & Inferences
Esophageal stimulation in GERD patients revealed significant insular cortex FC differences with regions involved in viscerosensation and interoception. The results of our study provide further evidence that the insula, located at the transition of afferent physiologic information to human feelings, is essential for both visceral homeostasis and the experience of heartburn in GERD patients.
doi:10.1111/nmo.12464
PMCID: PMC4308507  PMID: 25367277
interoception; heartburn; viscerosensation
9.  Anti inflammatory and anti angiogenic effect of black raspberry extract on human esophageal and intestinal microvascular endothelial cells 
Microvascular research  2014;97:167-180.
Polyphenolic compounds (anthocyanins, flavonoid glycosides) in berries prevent the initiation, promotion, and progression of carcinogenesis in rat’s digestive tract and esophagus, in part, via anti-inflammatory pathways. Angiogenesis has been implicated in the pathogenesis of chronic inflammation and tumorigenesis. In this study, we investigated the anti-inflammatory and anti-angiogenic effects of black raspberry extract (BRE) on two organ specific primary human intestinal microvascular endothelial cells, (HIMEC) and human esophageal microvascular endothelial cells (HEMEC), isolated from surgically resected human intestinal and donor discarded esophagus, respectively.
HEMEC and HIMEC were stimulated with TNF-α/IL-1β with or without BRE. The anti-inflammatory effects of BRE were assessed based upon COX-2, ICAM-1 and VCAM-1 gene and protein expression, PGE2 production, NFκB p65 subunit nuclear translocation as well as endothelial-leukocyte adhesion. The anti-angiogenic effects of BRE were assessed on cell migration, proliferation and tube formation following VEGF stimulation as well as on activation of Akt, MAPK and JNK signaling pathways.
BRE inhibited TNF-α/IL-1β-induced NFκB p65 nuclear translocation, PGE2 production, up-regulation of COX-2, ICAM-1 and VCAM-1 gene and protein expression and leukocyte binding in HEMEC but not in HIMEC. BRE attenuated VEGF-induced cell migration, proliferation and tube formation in both HEMEC and HIMEC. The anti-angiogenic effect of BRE is mediated by inhibition of Akt, MAPK and JNK phosphorylations.
BRE exerted differential anti-inflammatory effects between HEMEC and HIMEC following TNF-α/IL-1β activation whereas demonstrated similar anti-angiogenic effects following VEGF stimulation in both cell lines. These findings may provide more insight into the anti-tumorigenic capacities of BRE in human disease and cancer.
doi:10.1016/j.mvr.2014.10.008
PMCID: PMC4275382  PMID: 25446010
11.  Wnt/β-Catenin Signaling Activation beyond Robust Nuclear β-Catenin Accumulation in Nondysplastic Barrett’s Esophagus: Regulation via Dickkopf-112 
Neoplasia (New York, N.Y.)  2015;17(7):598-611.
INTRODUCTION: Wnt/β-catenin signaling activation has been reported only during the late steps of Barrett’s esophagus (BE) neoplastic progression, but not in BE metaplasia, based on the absence of nuclear β-catenin. However, β-catenin transcriptional activity has been recorded in absence of robust nuclear accumulation. Thus, we aimed to investigate the Wnt/β-catenin signaling in nondysplastic BE. METHODS: Esophageal tissues from healthy and BE patients without dysplasia were analyzed for Wnt target gene expression by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. Esophageal squamous (EPC1-& EPC2-hTERT), BE metaplastic (CP-A), and adenocarcinoma (OE33) cell lines were characterized for Wnt activation by qRT-PCR, Western blot, and luciferase assay. Wnt activity regulation was examined by using recombinant Wnt3a and Dickkopf-1 (Dkk1) as well as Dkk1 short interfering RNA. RESULTS: Wnt target genes (AXIN2, c-MYC, Cyclin D1, Dkk1) and Wnt3a were significantly upregulated in nondysplastic BE compared with squamous mucosa. Elevated levels of dephosphorylated β-catenin were detected in nondysplastic BE. Nuclear active β-catenin and TOPflash activity were increased in CP-A and OE33 cells compared with squamous cells. Wnt3a-mediated β-catenin signaling activation was abolished by Dkk1 in CP-A cells. TOPFlash activity was elevated following Dkk1 silencing in CP-A but not in OE33 cells. Dysplastic and esophageal adenocarcinoma tissues demonstrated further Dkk1 and AXIN2 overexpression. CONCLUSIONS: Despite the absence of robust nuclear accumulation, β-catenin is transcriptionally active in nondysplastic BE. Dkk1 overexpression regulates β-catenin signaling in BE metaplastic but not in adenocarcinoma cells, suggesting that early perturbation of Dkk1-mediated signaling suppression may contribute to BE malignant transformation.
doi:10.1016/j.neo.2015.07.006
PMCID: PMC4547437  PMID: 26297437
12.  Upper and Lower Esophageal Sphincter Kinetics are Modified During Maturation: Effect of Pharyngeal Stimulus in Premature Infants 
Pediatric research  2014;77(0):99-106.
Background
We hypothesized that changes in proximal and distal esophageal sphincter kinetics evoked upon pharyngeal provocation undergo longitudinal maturation.
Methods
Pharyngeal stimulation-induced reflexes were characterized using novel pharyngoesophageal motility methods in 19 healthy premature neonates, studied at 34.7 ± 0.8 wks (time-1), and 39.3 ± 1.1 wks postmenstrual age (time-2). Graded volumes of air (290 infusions) and sterile water (172 infusions) were infused to define sensory-motor characteristics of upstream (pharyngeal reflexive swallow, PRS) and downstream (pharyngo-lower esophageal sphincter relaxation reflex, PLESRR) esophageal reflexes. Data displayed as mean ± SE.
Results
Threshold volumes were similar with air and water for PRS and PLESRR at time-1 and time-2. Multiple PRS responses were noted with water stimulus, and were different between the media (time-1 vs. air, P< 0.0001; time-2 vs. air, P =0.0003). Dose response relationships for water were significant (P<0.01 for PRS and PLESRR time-1 and time-2), but not with air.
Conclusions
Significantly, the recruitment frequency of PRS and PLESRR increases with maturation, liquid is a superior medium for evoking such swallowing reflexes, and stimulus-response relationships for these reflexes are evident. These changes in aerodigestive protective reflexive activity may indicate differences in modulation of excitatory and inhibitory pathways during longitudinal postnatal maturation.
doi:10.1038/pr.2014.147
PMCID: PMC4268006  PMID: 25279989
13.  Analgesic effect of Minocycline in rat model of inflammation-induced visceral pain 
The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5 min of administration, systemic injection of the drug produced a delayed effect (60 min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia.
doi:10.1016/j.ejphar.2014.01.026
PMCID: PMC3984928  PMID: 24485889
microglia; satellite glial cell; minocycline; TNBS; visceral pain
14.  Prevention of Esophagopharyngeal Reflux by Augmenting the Upper Esophageal Sphincter Pressure Barrier 
The Laryngoscope  2014;124(10):2268-2274.
Objectives/Hypothesis
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1002/lary.24735
PMCID: PMC4332774  PMID: 24782387
Regurgitation; cricoid pressure; supraesophageal reflux disease; extraesophageal reflux disease; laryngopharyngeal reflux; gastroesophageal reflux disease
15.  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.
doi:10.1016/j.neuropharm.2013.12.006
PMCID: PMC4321751  PMID: 24334068
5-HT4 receptors; RVM; Visceral pain; Colon; Descending modulation
16.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/nmo.12238
PMCID: PMC3864683  PMID: 24251873
cortical swallowing network; default mode network; resting connectivity; negative BOLD; buffer
17.  Effect of Systemic Alcohol and Nicotine on Airway Protective Reflexes 
OBJECTIVES
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
Acute systemic alcohol exposure inhibits the elicitation PUCR and RPS. Unlike cigarette smoking, systemic nicotine does not alter the elicitation of these reflexes.
doi:10.1038/ajg.2009.330
PMCID: PMC4160881  PMID: 19550414
18.  Anatomic-manometric correlation of the upper esophageal sphincter: a concurrent US and manometry study 
Gastrointestinal endoscopy  2010;72(3):587-592.
Background
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.
Objective
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.
Design
Prospective, experimental study.
Setting
Tertiary Academic Medical Center.
Patients
This study involved 18 healthy volunteers.
Intervention
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.
Results
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.
Limitations
Air artifacts in the UES-HPZ.
Conclusion
The configuration and layers of the UES-HPZ vary along its length. The upper esophagus is a significant contributor to the distal UES-HPZ.
doi:10.1016/j.gie.2010.04.029
PMCID: PMC4142490  PMID: 20579650
19.  Effect of Aging on Hypopharyngeal Safe Volume and the Aerodigestive Reflexes Protecting the Airways 
The Laryngoscope  2014;124(8):1862-1868.
Objectives/Hypothesis
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/lary.24539
PMCID: PMC4138697  PMID: 24281906
Laryngeal penetrations; aspiration; aging; elderly; aerodigestive reflexes; airway protection
20.  Functional Connectivity of the Cortical Swallowing Network in Humans 
NeuroImage  2013;76:33-44.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.neuroimage.2013.01.037
PMCID: PMC4130480  PMID: 23416253
resting connectivity; reproducibility; seed based; deglutition
21.  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.
Objectives
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jpeds.2006.02.041
PMCID: PMC4075758  PMID: 16860132
22.  Esophago-Glottal Closure Reflex in Human Infants: A Novel Reflex Elicited With Concurrent Manometry and Ultrasonography 
BACKGROUND AND AIMS
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.
METHODS
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.
RESULTS
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).
CONCLUSION
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.
doi:10.1111/j.1572-0241.2007.01401.x
PMCID: PMC4028634  PMID: 17617206
23.  Correlation of Glottal Closure Using Concurrent Ultrasonography and Nasolaryngoscopy in Children: A Novel Approach to Evaluate Glottal Status 
Dysphagia  2006;21(1):75-81.
Objectives
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1007/s00455-005-9002-7
PMCID: PMC4028689  PMID: 16786412
Nasolaryngoscopy; Ultrasonography; Glottis; Infant; Deglutition; Deglutition disorders
24.  Effect of Postnatal Maturation on the Mechanisms of Esophageal Propulsion in Preterm Human Neonates: Primary and Secondary Peristalsis 
OBJECTIVES
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.1038/ajg.2008.32
PMCID: PMC3796765  PMID: 19174814
25.  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.
doi:10.1055/s-0030-1265896
PMCID: PMC3796769  PMID: 20941656
Pharyngoglottal closure reflex; esophagoglottal closure reflex; laryngeal adductor reflex; upper esophageal sphincter; gastroesophageal reflux

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