97 Effect of Perception On Cerebral Cortical Functional Connectivity Networks Associated with Rectal...
1
luminally at the gastroesophageal junction through enterosalivary recirculation of dietary nitrate, and during acid reflux, generation of NO is shifted to the distal esophagus. We have demonstrated that high concentrations of luminal NO can impair the gastric mucosal barrier function by disrupting the tight junction (Gut 2008). We hypothesized that NO generated luminally during acid reflux could disrupt the esophageal barrier function and provoke DIS. Aim: To investigate the direct effects of luminal NO on the esophageal barrier function using an ex vivo chamber model. Design and Setting: A chamber model in which the rat esophageal mucosal membrane was mounted between the two halves of a chamber was designed to simulate the microenvironment of the lumen and the adjacent mucosa of the esophagus. On the mucosal side of the chamber, NO was generated by the acidification of physiologic concentrations of sodium nitrite. The epithelial barrier function was evaluated by electro- physiological transmembrane resistance (R) and membrane permeability with 3H-mannitol flux in four groups; Krebs buffer, acid alone (pH 1.5), acid + sodium nitrite 5.0 mM, and acid + sodium nitrite 1.0 mM. Intercellular space diameters were measured on transmission electron microscopy photomicrographs. Results: In all groups except for Krebs buffer, the R decreased rapidly within the initial 15 minutes, followed by gradual decrease thereafter. At 180 minutes, the R decreased by 34% in acid alone group, by 39% in acid + nitrite 1.0 mM group, by 45% in acid + nitrite 5.0 mM group by 55%. Consequently, the administration of acidified nitrite (1.0 mM or 5.0 mM) to the mucosal side significantly decreased the R compared with that of the acid alone (p<0.01). While epithelial permeability with 3H- mannitol slightly increased at 180 minutes in acid alone group, it remarkably increased in acid + nitrite 5.0 mM group. Thus, the administration of acidified nitrite to the mucosal side significantly increased epithelial permeability compared with the acid alone group (p<0.05). DIS was observed in the nitrite groups but not in the acid alone group. Conclusions: The NO generated luminally via acidification of nitrite disrupted the barrier function of the esophageal epithelium and provoked DIS, suggesting that NO generated luminally contributes to DIS observed in GERD patients and plays an important role in the pathophysiology of GERD. 96 The Structure and Function of the Gastro-Esophageal Junction in Health and Reflux Disease Assessed By Magnetic Resonance Imaging and High Resolution Manometry Elad Kaufman, Jelena Curcic, Anupam Pal, Zsofia Forras-Kaufman, Reto Treier, Werner Schwizer, Michael Fried, Peter Boesiger, Mark Fox The gastro-esophageal junction (GEJ) is the key defence against acid reflux. Most reflux events occur during transient lower esophageal sphincter relaxations (TLESRs); however, the frequency and duration of TLESRs in GERD patients and healthy volunteers (HV) is similar.Rather, TLESRs in GERD are more likely to be associated with reflux events.This finding suggests that changes in GEJ structure rather than function may be responsible for increased frequency of reflux events in GERD. Aim: The function and structure of the GEJ was studied using concurrent high resolution manometry (HRM) and magnetic resonance imaging (MRI). Methods:12 HV (5 women,age 25.5) and 8 GERD patients (5 women, age 35.125) with pathological acid exposure but no hiatus hernia on endoscopy and all BMI <25. MR images were obtained before and at regular intervals after ingestion of a large, high-caloric mixed meal labelled with Gd-DOTA paramagnetic contrast.Concurrent pressure measurements were acquired by water-perfused, 22 channel HRM assembly positioned across the GEJ (AMS, Melbourne, AUS) with participants in the right lateral position in a 1.5T MRI (Philips, Best, NL).Anatomic scan: 30x4mm transverse slices, bFFE sequence, FOV= 360x285mm2, matrix=192x190 during 15s breath hold.Dynamic scan with respiratory (diaphragmatic) tracking: 3x8mm oblique coronal slices, 3x380 dynamics, 330ms/dynamic, bFFE sequence, FOV=360x285mm 2 , matrix=192x190, SENSE factor=1.6 over 154s.Gastric and esophageal morphology before and after the meal were reconstructed in 3D and analyzed. MR opaque markers in the HRM catheter allowed pressure data to be correlated with GEJ structure on MRI at rest and during reflux events. Results:Postprandial reflux events were observed during dynamic scans in 9/12 healthy volunteers and all GERD patients.The occurrence of reflux events on MRI correlated with intra-luminal pressure events detected by HRM.Reflux associated TLESRs were preceded by dynamic, upward movement of the GEJ.The number and duration of reflux events in HV was 2(range 0-5) and 11s (range 3- 23s) and in GERD patients 4 (range 2-7) and 24.4s (range 10-129s). 3D analysis of GEJ morphology and intra-luminal distribution of gastric contents revealed differences between HVs and GERD patients that increased with gastric filling. Discussion: Concurrent MRI and HRM provided a comprehensive assessment of GEJ structure and function in HVs and GERD patients. The number and duration of reflux events was increased in GERD patients compared to HVs in the right lateral position. An assessment of the gastro-esophageal structure as well as function is required to improve our understanding of GERD pathophysiology. 97 Effect of Perception On Cerebral Cortical Functional Connectivity Networks Associated with Rectal Sensation Mark Kern, Jonathan Huang, Reza Shaker Previous functional magnetic resonance imaging (fMRI) studies have shown a distributed network of brain activation associated with perceived and unperceived rectal distensions. Information regarding the interaction among network members (cingulate, insula, prefrontal, precuneus and sensory/motor regions) activated by afferent input from the rectum is not well known. Aims: 1) Determine the functional connectivity of brain regions showing fMRI signal changes associated with subliminal and perceived rectal distensions in healthy subjects. 2) Compare regional brain connectivity across unperceived and perceived rectal distension intensities. Methods: We studied 14 healthy right-handed subjects(9F, 18-40 yr) by para- digm-driven, 2-minute fMRI scanning of the left cortical hemisphere during block designs of alternating intervals of randomly timed rest and 15-second intervals of rectal balloon distensions. Three levels of distension were tested, namely, subliminal, barely perceived and 10 mmHg above the perception level. Structural Equation Modeling (SEM) was utilized to generate partial regression coefficients representing the covariance among regional fMRI signal time series activated by rectal distension. Grouped data was used in the SEM calculations to A-17 AGA Abstracts yield maps showing significant (Chi Squared Goodness-of-Fit and parsimonious fit indices) connectivity paths of a general network model based on known anatomical connections among network regions. . Results: For subliminal rectal stimulation, connectivity was shown between the prefrontal region (PF), the sensory/motor (SM), and cingulate, ( C ) network components, as well as connections between the insula (I) and cingulate and precuneus (PrCu) and cingulate. (figure) At liminal and supraliminal levels, additional regions joined network connectivity. These included precuneus and cingulate to sensory/motor (figure). Conclusion: Functional connectivity networks related to registration /processing of afferent rectal signals is dependent on the stimulus intensity and perception. These networks expand as the stimulus intensity reaches perception. 98 Effect of Subliminal Esophageal Acid Stimulation On Cerebral Cortical Activity Associated with Volitional Gastrointestinal and Somatic Motor Tasks Jonathan Huang, Mark Kern, Stephen J. Antonik, Rachel Mepani, Syed Q. Hussaini, Matthew D. Verber, Safwan Jaradeh, Reza Shaker Earlier studies have shown that esophageal acid stimulation enhances swallow-related fMRI cortical activity volume and signal change. It is unknown whether this effect extends to other GI related and somatic motor tasks. Aim: To determine the effect of subliminal esophageal acid stimulation on cerebral cortical fMRI activity associated with maximal external anal sphincter contraction(MEAC) and finger tapping and compare the findings to that of swallowing. Methods: We studied 18 healthy right-handed subjects(10F, 18-35 yr) by paradigm-driven, high spatial resolution fMRI scanning of the left cortical hemisphere during swallowing, MEAC and right index finger tapping. Each volitional activity was done before and after 15 minutes of 0.1M PBS and 0.1N HCl perfusion(1 ml/min). Number of activated voxels was quantified within the prefrontal, precuneus, cingulate gyrus, insula, and sensorimotor cortex, previously demonstrated to comprise the network associated with the studied tasks. Results: Total number of swallow related activated voxels was higher following acid exposure compared to PBS and baseline(* p<0.001, fig). Neither esophageal acid nor PBS exposure had any effect on the number of activated voxels associated with finger tapping. The numbers of activated voxels associated with MEAC following both acid and PBS exposure were similar but higher than baseline(# p<0.001, fig). In a supplementary study(n=5), MEAC related cortical activity increase was found to be directly associated with the infusate volume(Spearman's correlation coefficient 0.075, p=0.002) but not its acidity. This effect lasted approximately 25 minutes. Conclusions: Esophageal afferent stimulation enhances the cerebral cortical fMRI registration of GI related, but not somatic motor tasks. Esophageal chemical stimulation increases swallow related while esophageal mechanical stimulation enhances MEAC related fMRI activity. 99 Increased Allocation of Cognitive Resources for Selective Attention in IBS Patients Eduardo Vianna, Jennifer S. Labus, Steven M. Berman, Brandall Y. Suyenobu, Johanna Jarcho, Kirsten Tillisch, Bruce D. Naliboff, Emeran A. Mayer BACKGROUND: In Irritable Bowel Syndrome and other functional pain disorders, symptom- related worries and associated hypervigilance or hyperattention toward visceral and environ- mental stimuli (gastrointestinal sensations, symptoms or contexts) may play an important role in triggering central pain amplification systems. Attentional processes can be reliably assessed analyzing components of event-related potentials (ERP), such as P300 (positive deflection of ERP signal at 300 ms). AIMS: We have tested the hypothesis that patients with IBS allocate more attentional resources in an attention task. METHODS: Event related potentials (ERP) were recorded from 10 ROME II positive IBS patients (5 female, 5 male) and 10 healthy control subjects (Ctrls; 5 female, 5 male in an auditory oddball paradigm. In this task, subjects were required to detect rare pitch targets in a designated ear (ATTENDED TARGET condition) and ignore rare pitch targets in the non-designated ear (NONATTENDED TARGET condition). RESULTS: In the NONATTENDED TARGET condition, IBS patients did not present differences in P300 component when compared to Ctrls. However, in the ATTENDED TARGET condition, Patients presented an increase in the P300 component compared to Ctrls (p<0.05), and this difference was mainly located in the central and frontal electrodes. DISCUSSION: It is thought that the P300 component reflects inhibition of distracting stimuli, and an increase in allocation of attentional resources for task relevant information. Our data shows that IBS patients show an increase in P300 compared to controls only when attending to a target, and this indicates an increase in allocation of cognitive resources for selective attention. Because the observed P300 wave component has been source localized to DLPFC and rACC/mPFC, these analyses support altered functioning within the attentional networks. This mechanism may play a role in central pain amplification in IBS. 100 Reversibility in Human Swallowing Motor Cortex By Paired Cortical and Peripheral Stimulation to a Unilateral Virtual Lesion: Evidence for Targetting the Contralesional Cortex Emilia Michou, Satish Mistry, Samantha Jefferson, Shaheen Hamdy BACKGROUND/AIMS: Repetitive transcranial magnetic stimulation (rTMS) at 1 Hz has been shown to induce unilateral focal suppression of pharyngeal motor cortex excitability (Mistry et al., JPhysiol., 2007). Moreover, sequential pairing of cortical with peripheral pharyngeal stimuli at 100ms for 10-30 minutes (Paired Associative Stimulation (PAS)) is excitatory to pharyngeal motor cortex (Singh et al., Gastro, in press). Here we investigate whether PAS can reverse the virtual lesion and if the hemispheric site of PAS is important in driving its effects. METHODS: In 10 healthy subjects pharyngeal electromyographic (EMG) responses were recorded using an intraluminal catheter to single pulse TMS of pharyngeal motor cortices in both hemispheres as a measure of cortical excitability. Volunteers underwent AGA Abstracts
Transcript of 97 Effect of Perception On Cerebral Cortical Functional Connectivity Networks Associated with Rectal...
luminally at the gastroesophageal junction through enterosalivary recirculation of dietarynitrate, and during acid reflux, generation of NO is shifted to the distal esophagus. We havedemonstrated that high concentrations of luminal NO can impair the gastric mucosal barrierfunction by disrupting the tight junction (Gut 2008). We hypothesized that NO generatedluminally during acid reflux could disrupt the esophageal barrier function and provoke DIS.Aim: To investigate the direct effects of luminal NO on the esophageal barrier function usingan ex vivo chamber model. Design and Setting: A chamber model in which the rat esophagealmucosal membrane was mounted between the two halves of a chamber was designed tosimulate the microenvironment of the lumen and the adjacent mucosa of the esophagus.On the mucosal side of the chamber, NO was generated by the acidification of physiologicconcentrations of sodium nitrite. The epithelial barrier function was evaluated by electro-physiological transmembrane resistance (R) and membrane permeability with 3H-mannitolflux in four groups; Krebs buffer, acid alone (pH 1.5), acid + sodium nitrite 5.0 mM, andacid + sodium nitrite 1.0 mM. Intercellular space diameters were measured on transmissionelectron microscopy photomicrographs. Results: In all groups except for Krebs buffer, theR decreased rapidly within the initial 15 minutes, followed by gradual decrease thereafter.At 180 minutes, the R decreased by 34% in acid alone group, by 39% in acid + nitrite 1.0mM group, by 45% in acid + nitrite 5.0 mM group by 55%. Consequently, the administrationof acidified nitrite (1.0 mM or 5.0 mM) to the mucosal side significantly decreased the Rcompared with that of the acid alone (p<0.01). While epithelial permeability with 3H-mannitol slightly increased at 180 minutes in acid alone group, it remarkably increased inacid + nitrite 5.0 mM group. Thus, the administration of acidified nitrite to the mucosalside significantly increased epithelial permeability compared with the acid alone group(p<0.05). DIS was observed in the nitrite groups but not in the acid alone group. Conclusions:The NO generated luminally via acidification of nitrite disrupted the barrier function of theesophageal epithelium and provoked DIS, suggesting that NO generated luminally contributesto DIS observed in GERD patients and plays an important role in the pathophysiologyof GERD.
96
The Structure and Function of the Gastro-Esophageal Junction in Health andReflux Disease Assessed By Magnetic Resonance Imaging and High ResolutionManometryElad Kaufman, Jelena Curcic, Anupam Pal, Zsofia Forras-Kaufman, Reto Treier, WernerSchwizer, Michael Fried, Peter Boesiger, Mark Fox
The gastro-esophageal junction (GEJ) is the key defence against acid reflux. Most refluxevents occur during transient lower esophageal sphincter relaxations (TLESRs); however,the frequency and duration of TLESRs in GERD patients and healthy volunteers (HV) issimilar.Rather, TLESRs in GERD are more likely to be associated with reflux events.Thisfinding suggests that changes in GEJ structure rather than function may be responsible forincreased frequency of reflux events in GERD. Aim: The function and structure of the GEJwas studied using concurrent high resolution manometry (HRM) and magnetic resonanceimaging (MRI). Methods:12 HV (5 women,age 25.5) and 8 GERD patients (5 women, age35.125) with pathological acid exposure but no hiatus hernia on endoscopy and all BMI<25. MR images were obtained before and at regular intervals after ingestion of a large,high-caloric mixed meal labelled with Gd-DOTA paramagnetic contrast.Concurrent pressuremeasurements were acquired by water-perfused, 22 channel HRM assembly positioned acrossthe GEJ (AMS, Melbourne, AUS) with participants in the right lateral position in a 1.5TMRI (Philips, Best, NL).Anatomic scan: 30x4mm transverse slices, bFFE sequence, FOV=360x285mm2, matrix=192x190 during 15s breath hold.Dynamic scan with respiratory(diaphragmatic) tracking: 3x8mm oblique coronal slices, 3x380 dynamics, 330ms/dynamic,bFFE sequence, FOV=360x285mm2, matrix=192x190, SENSE factor=1.6 over 154s.Gastricand esophageal morphology before and after the meal were reconstructed in 3D and analyzed.MR opaque markers in the HRM catheter allowed pressure data to be correlated with GEJstructure on MRI at rest and during reflux events. Results:Postprandial reflux events wereobserved during dynamic scans in 9/12 healthy volunteers and all GERD patients.Theoccurrence of reflux events on MRI correlated with intra-luminal pressure events detectedby HRM.Reflux associated TLESRs were preceded by dynamic, upward movement of theGEJ.The number and duration of reflux events in HV was 2(range 0-5) and 11s (range 3-23s) and in GERD patients 4 (range 2-7) and 24.4s (range 10-129s). 3D analysis of GEJmorphology and intra-luminal distribution of gastric contents revealed differences betweenHVs and GERD patients that increased with gastric filling. Discussion: Concurrent MRIand HRM provided a comprehensive assessment of GEJ structure and function in HVs andGERD patients. The number and duration of reflux events was increased in GERD patientscompared to HVs in the right lateral position. An assessment of the gastro-esophageal structureas well as function is required to improve our understanding of GERD pathophysiology.
97
Effect of Perception On Cerebral Cortical Functional Connectivity NetworksAssociated with Rectal SensationMark Kern, Jonathan Huang, Reza Shaker
Previous functional magnetic resonance imaging (fMRI) studies have shown a distributednetwork of brain activation associated with perceived and unperceived rectal distensions.Information regarding the interaction among network members (cingulate, insula, prefrontal,precuneus and sensory/motor regions) activated by afferent input from the rectum is notwell known. Aims: 1) Determine the functional connectivity of brain regions showing fMRIsignal changes associated with subliminal and perceived rectal distensions in healthy subjects.2) Compare regional brain connectivity across unperceived and perceived rectal distensionintensities. Methods: We studied 14 healthy right-handed subjects(9F, 18-40 yr) by para-digm-driven, 2-minute fMRI scanning of the left cortical hemisphere during block designsof alternating intervals of randomly timed rest and 15-second intervals of rectal balloondistensions. Three levels of distension were tested, namely, subliminal, barely perceived and10 mmHg above the perception level. Structural Equation Modeling (SEM) was utilized togenerate partial regression coefficients representing the covariance among regional fMRI signaltime series activated by rectal distension. Grouped data was used in the SEM calculations to
A-17 AGA Abstracts
yield maps showing significant (Chi Squared Goodness-of-Fit and parsimonious fit indices)connectivity paths of a general network model based on known anatomical connectionsamong network regions. . Results: For subliminal rectal stimulation, connectivity was shownbetween the prefrontal region (PF), the sensory/motor (SM), and cingulate, ( C ) networkcomponents, as well as connections between the insula (I) and cingulate and precuneus(PrCu) and cingulate. (figure) At liminal and supraliminal levels, additional regions joinednetwork connectivity. These included precuneus and cingulate to sensory/motor (figure).Conclusion: Functional connectivity networks related to registration /processing of afferentrectal signals is dependent on the stimulus intensity and perception. These networks expandas the stimulus intensity reaches perception.
98
Effect of Subliminal Esophageal Acid Stimulation On Cerebral CorticalActivity Associated with Volitional Gastrointestinal and Somatic Motor TasksJonathan Huang, Mark Kern, Stephen J. Antonik, Rachel Mepani, Syed Q. Hussaini,Matthew D. Verber, Safwan Jaradeh, Reza Shaker
Earlier studies have shown that esophageal acid stimulation enhances swallow-related fMRIcortical activity volume and signal change. It is unknown whether this effect extends toother GI related and somatic motor tasks. Aim: To determine the effect of subliminalesophageal acid stimulation on cerebral cortical fMRI activity associated with maximalexternal anal sphincter contraction(MEAC) and finger tapping and compare the findings tothat of swallowing. Methods: We studied 18 healthy right-handed subjects(10F, 18-35 yr)by paradigm-driven, high spatial resolution fMRI scanning of the left cortical hemisphereduring swallowing, MEAC and right index finger tapping. Each volitional activity was donebefore and after 15 minutes of 0.1M PBS and 0.1N HCl perfusion(1 ml/min). Number ofactivated voxels was quantified within the prefrontal, precuneus, cingulate gyrus, insula,and sensorimotor cortex, previously demonstrated to comprise the network associated withthe studied tasks. Results: Total number of swallow related activated voxels was higherfollowing acid exposure compared to PBS and baseline(* p<0.001, fig). Neither esophagealacid nor PBS exposure had any effect on the number of activated voxels associated withfinger tapping. The numbers of activated voxels associated with MEAC following both acidand PBS exposure were similar but higher than baseline(# p<0.001, fig). In a supplementarystudy(n=5), MEAC related cortical activity increase was found to be directly associated withthe infusate volume(Spearman's correlation coefficient 0.075, p=0.002) but not its acidity.This effect lasted approximately 25 minutes. Conclusions: Esophageal afferent stimulationenhances the cerebral cortical fMRI registration of GI related, but not somatic motor tasks.Esophageal chemical stimulation increases swallow related while esophageal mechanicalstimulation enhances MEAC related fMRI activity.
99
Increased Allocation of Cognitive Resources for Selective Attention in IBSPatientsEduardo Vianna, Jennifer S. Labus, Steven M. Berman, Brandall Y. Suyenobu, JohannaJarcho, Kirsten Tillisch, Bruce D. Naliboff, Emeran A. Mayer
BACKGROUND: In Irritable Bowel Syndrome and other functional pain disorders, symptom-related worries and associated hypervigilance or hyperattention toward visceral and environ-mental stimuli (gastrointestinal sensations, symptoms or contexts) may play an importantrole in triggering central pain amplification systems. Attentional processes can be reliablyassessed analyzing components of event-related potentials (ERP), such as P300 (positivedeflection of ERP signal at 300 ms). AIMS: We have tested the hypothesis that patients withIBS allocate more attentional resources in an attention task. METHODS: Event relatedpotentials (ERP) were recorded from 10 ROME II positive IBS patients (5 female, 5 male)and 10 healthy control subjects (Ctrls; 5 female, 5 male in an auditory oddball paradigm.In this task, subjects were required to detect rare pitch targets in a designated ear (ATTENDEDTARGET condition) and ignore rare pitch targets in the non-designated ear (NONATTENDEDTARGET condition). RESULTS: In the NONATTENDED TARGET condition, IBS patientsdid not present differences in P300 component when compared to Ctrls. However, in theATTENDED TARGET condition, Patients presented an increase in the P300 componentcompared to Ctrls (p<0.05), and this difference was mainly located in the central and frontalelectrodes. DISCUSSION: It is thought that the P300 component reflects inhibition ofdistracting stimuli, and an increase in allocation of attentional resources for task relevantinformation. Our data shows that IBS patients show an increase in P300 compared to controlsonly when attending to a target, and this indicates an increase in allocation of cognitiveresources for selective attention. Because the observed P300 wave component has beensource localized to DLPFC and rACC/mPFC, these analyses support altered functioningwithin the attentional networks. This mechanism may play a role in central pain amplificationin IBS.
100
Reversibility in Human Swallowing Motor Cortex By Paired Cortical andPeripheral Stimulation to a Unilateral Virtual Lesion: Evidence for Targettingthe Contralesional CortexEmilia Michou, Satish Mistry, Samantha Jefferson, Shaheen Hamdy
BACKGROUND/AIMS: Repetitive transcranial magnetic stimulation (rTMS) at 1 Hz has beenshown to induce unilateral focal suppression of pharyngeal motor cortex excitability (Mistryet al., JPhysiol., 2007). Moreover, sequential pairing of cortical with peripheral pharyngealstimuli at 100ms for 10-30 minutes (Paired Associative Stimulation (PAS)) is excitatory topharyngeal motor cortex (Singh et al., Gastro, in press). Here we investigate whether PAScan reverse the virtual lesion and if the hemispheric site of PAS is important in driving itseffects. METHODS: In 10 healthy subjects pharyngeal electromyographic (EMG) responseswere recorded using an intraluminal catheter to single pulse TMS of pharyngeal motorcortices in both hemispheres as a measure of cortical excitability. Volunteers underwent
AG
AA
bst
ract
s
