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Sa2022 Subliminal Esophageal Acid Exposure Is Associated With an Increase of Right Insula Functional Connectivity in the Homeostatic Afferent Processing Network
AGA Abstracts
Sa2021
Sa2022
The Stress Hormone Urocortin 1 Induces Gastric Dysfunction by α2Adrenergic Receptor-Mediated Decrease in Ghrelin Signal in Rats Shoki Ro, Mitsuko Ochiai, Eriko Hosomi, Kenjiro Hayashi, Naomi Yamaguchi, Yumi Harada, Naoki Fujitsuka, Koji Yakabi
Subliminal Esophageal Acid Exposure Is Associated With an Increase of Right Insula Functional Connectivity in the Homeostatic Afferent Processing Network Xiaolin Liu, Mark Kern, Arash Babaei, Patrick Sanvanson, Reza Shaker
Background/Aim: Excessive stress in modern society is associated with development of functional dyspepsia, which presents with symptoms of epigastric pain, early satiety and postprandial fullness. The central neural peptides, members of the corticotropin-releasing factor family, play key roles in response to stress. We previously reported that urocortin1 (UCN1) suppressed feeding behavior in fasted rats through an α2-adrenergic receptor (α2AR) activation, which decreases ghrelin secretion (DDW 2014). However, the influence of UCN1 on gastrointestinal (GI) function remains unclear. To elucidate this, we investigated the changes in gastric emptying and GI motility in UCN1-treated rats. Methods: UCN1 (300 pmol/rat) or phosphate-buffered saline (PBS) were intracerebroventricularly (ICV) injected to Sprague-Dawley rats, and gastric emptying and plasma ghrelin levels 2 h after oral administration of test meal were measured. The α2-AR antagonist, yohimbine (5 mg/kg) 15 min before ICV were intraperitoneal(IP) administered to UCN1-treated rats. Furthermore, ghrelin (3 nmol/rat, intravenous (IV)) were administered to UCN1-treated rats. In another set of experiment, the effects of co-administration of rikkunshito (RKT; 1000 mg/kg, which is an endogenous ghrelin enhancer) and with the ghrelin receptor antagonist ([D-Lys3] GHRP-6; 4 μmol/kg IV) was investigated. GI motility was investigated to determine the effects of ghrelin or RKT to UCN1-treated rats using a strain gauge force transducer in free-moving condition. Results: UCN1-treated rats exhibited significantly delayed gastric emptying. Administration of yohimbine improved gastric emptying (UCN1: 22.9±6.5 %, UCN1+yohimbine: 58.5±7.6 %, p<0.05) and significantly increased plasma ghrelin levels (UCN1:47.2±3.6 fmol/mL, UCN1+yohimbine: 81.9±7.8 fmol/mL, p<0.05). Exogenous administration of ghrelin restored delayed gastric empting. Administration of RKT significantly prevented delayed gastric empting and decreased plasma ghrelin levels. The gastric function of RKT was blocked by co-administration of the ghrelin receptor antagonist. ICV injection of UCN1 decreased the amplitude of contraction in the stomach while increasing the amplitude in the duodenum. Motility index of the stomach, but not the duodenum, was significantly reduced by treatment with UCN1 (PBS: 92.1 ± 10.1%, UCN1: 62.8 ± 4.7%), which was improved by the administration of ghrelin or RKT (99.03 ± 7.95%, p<0.05). Conclusions UCN1-induced gastric motility dysfunction with decrease in plasma ghrelin levels was mediated by α2-AR activation. Disturbance in endogenous ghrelin dynamics play an important role in the functional abnormality of the upper GI tract under stressful conditions.
Introduction: Altered brain responses to esophageal acid exposure may underlie symptoms of the gastroesophageal reflux disease, yet the detailed neural processes involved in esophageal viscerosensation remain incompletely understood. Detecting consistent and reliable brain activation to esophageal acid exposure was often perplexed by the unique anatomical and physiological features of the esophagus in slowing down the access of acid to afferent neurons by its epithelial barrier and neutralizing acid before it reaches the afferents by its secreting glands in the submucous tissue. Additional confounding factors may also come from variations of individual swallowing habit. An alternative approach of characterizing esophageal viscerosensation can also be defined in the context of homeostasis regulation of the brain in the face of physiological perturbations. The insula, especially the right anterior division, has been identified as the primary interoceptive cortex supporting visceral awareness and autonomic visceromotor responses that maintain homeostasis. The goal of this study is to determine, using functional magnetic resonance imaging (fMRI), the alteration of insula functional connectivity after subliminal esophageal acid infusion in a small group of healthy volunteers. We hypothesize that the subliminal acid exposure is associated with an increase of the extent of insula functional connectivity particularly in homeostatic processing-related cortical/subcortical regions. Methods: 7 healthy volunteers (4 males; aged 28-78yr.) received a 20-min-long fMRI (3T GE scanner) consisting of a first 5-min PBS, a subsequent 5-min 0.1N HCI, and a final 10-min PBS infusions. The anterior and posterior divisions of the left and right insula were identified as the seed regions. Group functional connectivity map of the final 9 minutes was compared with that of the first 5 minutes based on a model of delayed fMRI brain response to esophageal acid exposure.Results and Discussion: Only the right insula (the anterior and posterior divisions together or separately) showed prominent differences in the spatial extent and location of functional connectivity between the first 5min and final 9-min of the scan (figure). Connectivity maps in both conditions included a similar set of cortical/subcortical structures involved in homeostatic regulation. However, the final 9-min showed more extensive connections in all subareas of the cingulate cortex, the supplementary and primary motor areas, dorsal medial and lateral prefrontal cortices, and subcortical areas in the thalamus, caudate, putamen, parabrachial nucleus, and periaqueductal gray. Our study suggests that right insula functional connectivity, which reflects homeostatic (interoceptive) processing of the brain, may provide a dependable measure of brain network functioning in response to esophageal acid exposure.
Sa2023 Electrical Stimulation of the Abdominal Vagus Nerve Can Be Safely Performed in Patients Undergoing Colorectal Surgery Nathalie Stakenborg, Albert M. Wolthuis, Pedro J. Gomez-Pinilla, Maarten Schrooten, Inne Croux, Iris Appeltans, Kim Van Beek, Gianluca Matteoli, Andre D'Hoore, Guy E. Boeckxstaens
Fig.1 Effects of yohimbine on (A) gastric empting rates and (B) plasma acylated ghrelin levels in ICV UCN1-induced stress model.
BACKGROUND: Vagus nerve stimulation (VNS) is attracting growing interest for its ability to modulate inflammation. We previously showed that a single pre-operative cervical VNS is able to prevent postoperative ileus (POI) via activation of the anti-inflammatory pathway in mice. Therefore, we decided to explore the possibility of peroperative abdominal VNS obviating the need for a cervical procedure. In this study, we first evaluated the feasibility of abdominal VNS in pigs. Secondly, we explored the potency of abdominal VNS to activate the vagus nerve (VN) in patients undergoing colorectal surgery. METHODS: Cervical and abdominal VNS was performed in 8 Landrace pigs (12-14 weeks; 30±3 kg) to select the optimal stimulation parameters and electrode for abdominal VNS. Four electrodes were evaluated: hook and Delta electrode, 2 Delta electrodes spaced 1 cm apart and pacing wires. First, recordings of action potentials (AP) from both VN were evaluated as read-out of VNS. Secondly, the effect of cervical and abdominal VNS (5 and 20 Hz; 0.5, 1 and 2 ms and 2.5 mA) on heart rate was studied. Moreover, the percentage of myelinated fibers (PGP and MBP) was compared between the cervical and abdominal VN. Finally, the effect of abdominal VNS on pancreatic polypeptide (PP) release was measured in patients undergoing colorectal surgery (n=9). Blood samples were taken before and 10 min after VNS. The prestimulation value of PP was set at 100%. RESULTS: Although current-dependent APs were recorded during cervical VNS, we did not detect AP from the abdominal VN. Morphological evaluation revealed significantly less myelinated fibers in the abdominal compared to the cervical VN (10±2% vs 47±6%, P=0.0001), most likely explaining the inability to record AP from the abdominal VN. Hence, heart rate responses were used as read-out to select the optimal electrode. Cervical VNS with pacing wires and the double delta electrode were most effective, leading to a heart rate reduction of 27±6% and 19±4% respectively at 20 Hz, 2 ms, 2.5 mA (Fig. 1). Of note, abdominal VNS did not reduce heart rate, suggesting a safer cardiovascular risk. Hence, pacing wires were used to stimulate the abdominal VN in 9 patients (4573 yrs, 63±9 yrs). Abdominal VNS did not induce heart rate changes, was well tolerated and increased PP (5Hz: 239±100%, 20 Hz: 243±115% of pre-stimulation levels; Fig. 2) compared to sham-stimulation (130±9%). CONCLUSION: Pacing wires most effectively stimulate the cervical VN resulting in a frequency and current dependent heart rate reduction.
Fig.2 Effects of ICV UCN1 and co-administration of RKT on gastrointestinal motility.
AGA Abstracts
S-386
Sa2021
Sa2022
The Stress Hormone Urocortin 1 Induces Gastric Dysfunction by α2Adrenergic Receptor-Mediated Decrease in Ghrelin Signal in Rats Shoki Ro, Mitsuko Ochiai, Eriko Hosomi, Kenjiro Hayashi, Naomi Yamaguchi, Yumi Harada, Naoki Fujitsuka, Koji Yakabi
Subliminal Esophageal Acid Exposure Is Associated With an Increase of Right Insula Functional Connectivity in the Homeostatic Afferent Processing Network Xiaolin Liu, Mark Kern, Arash Babaei, Patrick Sanvanson, Reza Shaker
Background/Aim: Excessive stress in modern society is associated with development of functional dyspepsia, which presents with symptoms of epigastric pain, early satiety and postprandial fullness. The central neural peptides, members of the corticotropin-releasing factor family, play key roles in response to stress. We previously reported that urocortin1 (UCN1) suppressed feeding behavior in fasted rats through an α2-adrenergic receptor (α2AR) activation, which decreases ghrelin secretion (DDW 2014). However, the influence of UCN1 on gastrointestinal (GI) function remains unclear. To elucidate this, we investigated the changes in gastric emptying and GI motility in UCN1-treated rats. Methods: UCN1 (300 pmol/rat) or phosphate-buffered saline (PBS) were intracerebroventricularly (ICV) injected to Sprague-Dawley rats, and gastric emptying and plasma ghrelin levels 2 h after oral administration of test meal were measured. The α2-AR antagonist, yohimbine (5 mg/kg) 15 min before ICV were intraperitoneal(IP) administered to UCN1-treated rats. Furthermore, ghrelin (3 nmol/rat, intravenous (IV)) were administered to UCN1-treated rats. In another set of experiment, the effects of co-administration of rikkunshito (RKT; 1000 mg/kg, which is an endogenous ghrelin enhancer) and with the ghrelin receptor antagonist ([D-Lys3] GHRP-6; 4 μmol/kg IV) was investigated. GI motility was investigated to determine the effects of ghrelin or RKT to UCN1-treated rats using a strain gauge force transducer in free-moving condition. Results: UCN1-treated rats exhibited significantly delayed gastric emptying. Administration of yohimbine improved gastric emptying (UCN1: 22.9±6.5 %, UCN1+yohimbine: 58.5±7.6 %, p<0.05) and significantly increased plasma ghrelin levels (UCN1:47.2±3.6 fmol/mL, UCN1+yohimbine: 81.9±7.8 fmol/mL, p<0.05). Exogenous administration of ghrelin restored delayed gastric empting. Administration of RKT significantly prevented delayed gastric empting and decreased plasma ghrelin levels. The gastric function of RKT was blocked by co-administration of the ghrelin receptor antagonist. ICV injection of UCN1 decreased the amplitude of contraction in the stomach while increasing the amplitude in the duodenum. Motility index of the stomach, but not the duodenum, was significantly reduced by treatment with UCN1 (PBS: 92.1 ± 10.1%, UCN1: 62.8 ± 4.7%), which was improved by the administration of ghrelin or RKT (99.03 ± 7.95%, p<0.05). Conclusions UCN1-induced gastric motility dysfunction with decrease in plasma ghrelin levels was mediated by α2-AR activation. Disturbance in endogenous ghrelin dynamics play an important role in the functional abnormality of the upper GI tract under stressful conditions.
Introduction: Altered brain responses to esophageal acid exposure may underlie symptoms of the gastroesophageal reflux disease, yet the detailed neural processes involved in esophageal viscerosensation remain incompletely understood. Detecting consistent and reliable brain activation to esophageal acid exposure was often perplexed by the unique anatomical and physiological features of the esophagus in slowing down the access of acid to afferent neurons by its epithelial barrier and neutralizing acid before it reaches the afferents by its secreting glands in the submucous tissue. Additional confounding factors may also come from variations of individual swallowing habit. An alternative approach of characterizing esophageal viscerosensation can also be defined in the context of homeostasis regulation of the brain in the face of physiological perturbations. The insula, especially the right anterior division, has been identified as the primary interoceptive cortex supporting visceral awareness and autonomic visceromotor responses that maintain homeostasis. The goal of this study is to determine, using functional magnetic resonance imaging (fMRI), the alteration of insula functional connectivity after subliminal esophageal acid infusion in a small group of healthy volunteers. We hypothesize that the subliminal acid exposure is associated with an increase of the extent of insula functional connectivity particularly in homeostatic processing-related cortical/subcortical regions. Methods: 7 healthy volunteers (4 males; aged 28-78yr.) received a 20-min-long fMRI (3T GE scanner) consisting of a first 5-min PBS, a subsequent 5-min 0.1N HCI, and a final 10-min PBS infusions. The anterior and posterior divisions of the left and right insula were identified as the seed regions. Group functional connectivity map of the final 9 minutes was compared with that of the first 5 minutes based on a model of delayed fMRI brain response to esophageal acid exposure.Results and Discussion: Only the right insula (the anterior and posterior divisions together or separately) showed prominent differences in the spatial extent and location of functional connectivity between the first 5min and final 9-min of the scan (figure). Connectivity maps in both conditions included a similar set of cortical/subcortical structures involved in homeostatic regulation. However, the final 9-min showed more extensive connections in all subareas of the cingulate cortex, the supplementary and primary motor areas, dorsal medial and lateral prefrontal cortices, and subcortical areas in the thalamus, caudate, putamen, parabrachial nucleus, and periaqueductal gray. Our study suggests that right insula functional connectivity, which reflects homeostatic (interoceptive) processing of the brain, may provide a dependable measure of brain network functioning in response to esophageal acid exposure.
Sa2023 Electrical Stimulation of the Abdominal Vagus Nerve Can Be Safely Performed in Patients Undergoing Colorectal Surgery Nathalie Stakenborg, Albert M. Wolthuis, Pedro J. Gomez-Pinilla, Maarten Schrooten, Inne Croux, Iris Appeltans, Kim Van Beek, Gianluca Matteoli, Andre D'Hoore, Guy E. Boeckxstaens
Fig.1 Effects of yohimbine on (A) gastric empting rates and (B) plasma acylated ghrelin levels in ICV UCN1-induced stress model.
BACKGROUND: Vagus nerve stimulation (VNS) is attracting growing interest for its ability to modulate inflammation. We previously showed that a single pre-operative cervical VNS is able to prevent postoperative ileus (POI) via activation of the anti-inflammatory pathway in mice. Therefore, we decided to explore the possibility of peroperative abdominal VNS obviating the need for a cervical procedure. In this study, we first evaluated the feasibility of abdominal VNS in pigs. Secondly, we explored the potency of abdominal VNS to activate the vagus nerve (VN) in patients undergoing colorectal surgery. METHODS: Cervical and abdominal VNS was performed in 8 Landrace pigs (12-14 weeks; 30±3 kg) to select the optimal stimulation parameters and electrode for abdominal VNS. Four electrodes were evaluated: hook and Delta electrode, 2 Delta electrodes spaced 1 cm apart and pacing wires. First, recordings of action potentials (AP) from both VN were evaluated as read-out of VNS. Secondly, the effect of cervical and abdominal VNS (5 and 20 Hz; 0.5, 1 and 2 ms and 2.5 mA) on heart rate was studied. Moreover, the percentage of myelinated fibers (PGP and MBP) was compared between the cervical and abdominal VN. Finally, the effect of abdominal VNS on pancreatic polypeptide (PP) release was measured in patients undergoing colorectal surgery (n=9). Blood samples were taken before and 10 min after VNS. The prestimulation value of PP was set at 100%. RESULTS: Although current-dependent APs were recorded during cervical VNS, we did not detect AP from the abdominal VN. Morphological evaluation revealed significantly less myelinated fibers in the abdominal compared to the cervical VN (10±2% vs 47±6%, P=0.0001), most likely explaining the inability to record AP from the abdominal VN. Hence, heart rate responses were used as read-out to select the optimal electrode. Cervical VNS with pacing wires and the double delta electrode were most effective, leading to a heart rate reduction of 27±6% and 19±4% respectively at 20 Hz, 2 ms, 2.5 mA (Fig. 1). Of note, abdominal VNS did not reduce heart rate, suggesting a safer cardiovascular risk. Hence, pacing wires were used to stimulate the abdominal VN in 9 patients (4573 yrs, 63±9 yrs). Abdominal VNS did not induce heart rate changes, was well tolerated and increased PP (5Hz: 239±100%, 20 Hz: 243±115% of pre-stimulation levels; Fig. 2) compared to sham-stimulation (130±9%). CONCLUSION: Pacing wires most effectively stimulate the cervical VN resulting in a frequency and current dependent heart rate reduction.
Fig.2 Effects of ICV UCN1 and co-administration of RKT on gastrointestinal motility.
AGA Abstracts
S-386