towards inhibition of IFG and pHPC Conclusion:Nausea during MV versus control wasassociated with typical psychophysiological changes and activated the visual pathways withinhibition of cerebellar areas. In NS subjects nausea related brain activity increased in theprefrontal cortex. The pHPC was inhibited during nausea possibly due to disorientationcaused by sensory conflict during motion video. The IFG appears to monitor levels of nausea.Scopolamine doesn't change visual activation but may modulate pHPC and IFG. Thesepsychophysiological and brain imaging markers can be used to assess efficacy of drugs fornausea prevention and treatmentTable 1 Wilcoxon signed rank tests to compare responses during the nausea video vs controlthat is paired and nonparametric. Results are means and standard error of means.

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A Prospective Assessment of Cognitive Performance in Irritable BowelSyndrome Reveals Persistent Visuospatial Memory DeficitsPaul J. Kennedy, Gerard Clarke, Andrew P. Allen, Ann O'Neill, John A. Groeger, EamonnM. Quigley, Fergus Shanahan, John F. Cryan, Timothy G. Dinan

Background: Irritable bowel syndrome (IBS) is a stress-related functional gastrointestinaldisorder of the brain-gut axis. The cognitive neurobiological model of IBS (Kennedy et al.,2012), proposes that some of the key pathophysiological features, including stress-relatedchanges in hypothalamic pituitary adrenal (HPA)-axis functioning, and the immune-mediateddegradation of tryptophan along the kynurenine pathway, may impact on patients' cognitiveperformance. We recently provided support for this model by showing that patients withIBS exhibit a visuospatial memory deficit associated with alterations in both HPA axis activityand the kynurenine:tryptophan ratio (Kennedy et al., 2012). However, whether visuospatialmemory dysfunction is a stable feature of IBS is currently unknown. AIM: To assess longitudi-nally if patients with IBS consistently exhibit visuospatial memory dysfunction in comparisonto disease controls [Crohns disease (CD)] and healthy controls (HC). Methods: At baseline(visit 1) and 6 months later (visit 2), a cohort of IBS patients (baseline n=39; 6M/33F; meanage: 28 yrs; IQ: 105.5; BMI: 23.7; 6 month follow-up: n= 33), matched CD patients (baselinen= 18;11M/7F; mean age: 32 yrs; IQ: 103.4; BMI: 25.2; 6 month follow-up: n=17), andmatched HC (baseline n=40;11M/29F; mean age 28 yrs; IQ: 108.5; BMI: 23.5; 6 monthfollow-up: n=33), were assessed using a selection of cognitive tests from the CambridgeNeuropsychological Test Automated Battery (CANTAB) and Stroop test. Abdominal painseverity at time of testing was reported by IBS patients on a scale ranging from 0-100.Results: At both visits IBS patients exhibited impaired visuospatial memory performancecompared to HC, evidenced by significantly more errors on the Paired Associates Learning(PAL;visuospatial memory) 6 pattern stage at visit 1 (3.82±.85 vs 1.55±.38, p , .05) whichapproached significance across visit 1 & 2 (3.53±.53 vs 1.92±.53, p=.05), and a significantlygreater number of trials needed to successfully complete the PAL across visit 1 & 2 (1.77±.08vs 1.54±.08, p, .05). Abdominal pain scores in IBS patients did not correlate with anyPAL measures at visit1 & 2 (All p, .05). No significant group differences were identifiedacross visit 1 & 2 on the Intra-Extra Dimensional Set Shift (IED;executive functioning);total errors (p. .05),or Spatial working memory (SWM);total errors (p. .05).Conclusion:Impaired visuospatial memory performance is a persistent and domain-specific feature ofcognitive performance in IBS that is independent of symptom severity. Future researchstrategies in IBS should aim to address how altered cognition, a neglected aspect of thishighly prevalent and debilitating disorder, impacts on patient performance. Moreover, theseresults may inform future treatment strategies in a disorder that currently lacks uniformlyeffective therapies.

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Resting State Brain Changes in Patients With Inflammatory Bowel DiseaseKirsten Tillisch, Cody Ashe-McNalley, Sneha Shaha, Jennifer S. Labus, Jean Stains,Emeran A. Mayer

Background: We have previously demonstrated evidence for visceral hypoalgesia in IBDpatients and for engagement of antinociceptive systems in the brain (1). Recent evidencesuggests that IBD patients also have morphological changes in brain regions concerned withthe processing and modulation of pain. Aims: To identify alterations in the brain's restingstate network function in IBD patients, in particular in regions of an interoceptive processingnetwork, including the insular, somatosensory, and cingulate cortices. Methods: Patientswith either ulcerative colitis (UC) or Crohn's disease (CD) in clinical remission, and healthycontrols (HC) were recruited by advertisement or from the UCLA Digestive Disease Clinics.The use of corticosteroids or centrally acting pain medications was exclusionary. FunctionalMRI data was collected on a Siemen's Trio 3 Tesla scanner. Resting state scans were performedwith the subjects lying quietly with eyes closed for 10 minutes. Data preprocessing wasperformed within SPM8 and fractional amplitude of low frequency fluctuation (fALFF) wasperformed within MATLAB using a frequency band of 0.01-0.08 Hertz. A two sample t-testwas implemented in SPM8 to identify group differences, and small volume corrections wereperformed to specifically analyze the anterior midcingulate cortex, somatosensory cortex,and insula. Results: 22 HC and 26 IBD subjects (19 UC, 7 CD) were included. Mean agein IBD was 28 years and in HC was 33 years. Duration of IBD was 9.7 years (1-35 years).A decreased contribution to resting brain activity was seen in the right insula (dorsal -midposterior) [cluster p=.035, extent=13, t=4.37,MNI coordinates 42,-26,18 ]and somatosensory

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cortex (left Brodmann area 3 [p=.059, extent=11, t=3.81, MNI -38, -18, 56]) in IBD comparedto HC. No differences were noted in the cingulate cortex. Conclusion: Patients with IBDdisplay altered resting brain activity in brain regions associated with visceral and somaticsensation. The finding of decreased amplitude of low frequency brain oscillations in theposterior insula and somatosensory cortex in IBD patients is consistent with prior reportsof decreased brain responses to visceral stimulation and with the clinical findings of unexpect-edly low reporting of abdominal pain in the setting of active inflammation. (1) Mayer EA,et al. Differences in brain responses to visceral pain between patients with irritable bowelsyndrome and ulcerative colitis. Pain. 2005 Jun;115(3):398-409.

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High-Intense Rectal Urgency and Its Representation in the BrainSusanna A. Walter, Mats Lowén, Emeran A. Mayer, Kirsten Tillisch, Maria Engström,Arthur D. Craig

Background: Several brain imaging studies have demonstrated that visceral distensionsactivate the insular cortex but there is limited knowledge about which subregions of theinsula underpin the feeling of rectal urgency. An isobaric rectal balloon distension can besubdivided into the inflation phase when pressure is rising (rise) and a stable phase, whenthe pressure is constant. The rise phase is characterized by a more distinct sensation ofurgency (Akervall et al., 1988). We aimed to study the BOLD response during the rise phaseof a standardized rectal distension in subregions of the insula, in healthy controls. Method:Twenty right-handed female healthy volunteers (mean age 32.2 yrs, range 21-54) wereincluded. Rectal pressure sensory thresholds were determined before functional MagneticResonance Imaging (fMRI) while the subjects were placed in the MR scanner. Blood OxygenLevel Dependent (BOLD) signals were measured during the rise periods (6.6-7.2 sec) of 20rectal distensions (45mmHg). Regions of interest (ROIs) included 10 insula subregions: Left(L) and right (R) anterior ventral, anterior dorsal, posterior ventral, posterior dorsal andmid insula. Results were reported as significant if peak p-value were , 0.05 with familywise error (FWE) correction in the ROIs. Results: The mean values for rectal sensorythresholds for first sensation, first sensation of urgency and maximum tolerable distensionwere 16 mmHg (SD 3.9), 28mmHg (SD 6.2) and 55 mmHg (SD 12.3), respectively. CompletefMRI data were available from 18 subjects. The rise period of the rectal distension generatedsignificant BOLD activation in the right hemisphere in the anterior dorsal, anterior ventral,mid and posterior ventral parts of the insula. On the left side BOLD activity was generatedin mid, posterior ventral and posterior dorsal parts of the insula but not in the anteriorinsula. Akervall S et al, 1988, Manovolumetry: A new method for investigation of anorectalfunction. Gut 29:614-623.

Table 1: Brain regions of interest (ROI) with significant BOLD increases and decreases duringthe rise phase of rectal distensions are shown. Cluster size . 5 are shown. MNI-coordinatesare indicated. Left (L) and Right (R).

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Rikkunshito, Japanese Traditional Medicine, Reduces Urocortin 1-InducedAnorexia and FOS Expression in the Cranial Nerve Nuclei of AutonomicNervesKoji Yakabi, Kiyoshige Takayama, Shoki Ro, Mitsuko Ochiai, Shino Ohno, Yumi Harada,Masamichi Noguchi, Tomohisa Hattori

Background: Rikkunshito(RKT) is a Japanese traditional medicine that is used clinicallyto treat patients with dyspepsia symptoms and anorexia. Recently, we demonstrated thatintracerebroventricular(ICV) urocortin 1 (UCN)-induced anorexia was restored with RKTthrough an increase of ghrelin. However, the details of the mechanism for the action ofRKT still remain to be elucidated. We elucidated that ICV UCN suppressed ghrelin levelsthrough the adrenergic receptor (2012 AGA). The results suggested that peripheral or centralsympathetic nerve might be involved in the inhibition of food intake by ICV UCN. Thereforeit seems possible that RKT may influense the function of autonomic nervous system. Aim:To investigate the involvement of central nervous system in the restoration of anorexia andgastric motility by RKT using the expression of c-fos as a marker of neuronal activation inbrain regulating appetite and visceral function. Methods: Adult male rats with chronicallyimplanted ICV cannula were injected ICV with UCN (300 pmol/rat) or phosphate-bufferedsaline, and 1 h or 2 h later brain was processed for expression of c-fos by in situ hybridizationand Fos by immunohistochemistry respectively. To elucidate effects of RKT on food intakeand plasma ghrelin levels disturbed by UCN, amount of food intake and plasma ghrelinlevels were measured 1 h and 2 h after ICV UCN to fasted rats, RKT (1000 mg/kg) wasorally administered 2 h before ICV UCN. Plasma acyl and desacyl ghrelin levels weredetermined by ELISA. Results: RKT significantly restored the decrease of food intake and

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splasma ghrelin levels at 2 h after ICV UCN. UCN induces c-fos mRNA and Fos proteinexpression in the supraoptic nucleus, paraventricular nucleus of hypothalamus (PVN), locuscoeruleus, solitary tract nucleus (NTS), and ventrolateral nucleus of medulla oblongata(VLM), known to influence sympathetic outflow. Fos expression in NTS was markedlysuppressed by coadministration of RKT (control 84 ± 28, UCN 352 ± 130, UCN + RKT 48± 15; P , 0.05). UCN-induced Fos expression in VLM was also suppressed by RKT (control35 ± 10, UCN 289 ± 94, UCN + RKT 133 ± 27), but not significant (P=0.08). RKT alsosuppressed UCN-induced c-fos expression in PVN. In contrast, the dorsal motor nucleusinvolved in vagal outflow did not show any changes in Fos and fos expression by RKT.Conclusions: These data indicate that a) RKT inhibits the activity of the neuron of NTSsuggesting that RKT inhibits vagal input from the periphery to central nerves. b) As theresult of inhibiton of vagal input, activity of hypothalamic satiety center, PVN is suppressedresulting in the inhibition of the sympathetic outflow from the central nerve to the periphery.RKT may restore disturbed appetite and ghrelin secretion through the restoration of balanceof central autonomic nervous system.

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Altered Activation of Cardiac Sympathetic Discharge and Covariated BrainRegion During Colorectal Distention With Corticotropin-Releasing Hormonein Irritable Bowel SyndromeYukari Tanaka, Joe Morishita, Michiko Kano, Motoyori Kanazawa, Toyohiro Hamaguchi,Manabu Tashiro, Shin Fukudo

Aim Corticotropin-releasing hormone (CRH) is a major mediator of the brain-gut axis. Wepreviously reported that administration of CRH changes activation of the central nervoussystem (CNS) in response to colorectal distention in healthy controls (Gastroenterology 140:S57, 2011) and in IBS patients (Gastroenterology 142: S457-458, 2012). However, evidencehow CRH changes function of the autonomic nervous system (ANS) was lacking. Wehypothesized that exogenous CRH differentially changes ANS activity and CNS-ANS relationduring visceral stimulation in controls and in IBS patients. Methods Subjects were 16 IBSmales aged 22.3 ± 1.8 and 16 healthy males aged 22.8 ± 2.5 as controls. They were randomlyallocated into the CRH injection or saline injection. Using barostat technique, the colorectumwas randomly distended with sham (0 mmHg), mild (20 mmHg), or intense (40 mmHg)stimulus. CRH (2 μg/kg) or saline was then injected and same distention protocol wasrepeated. Positron emission tomography of the brain with radioactive H2

15O was recordedduring each stimulation. Heart rate (HR), high frequency (HF) and low frequency (LF)/HFratio as heart rate variability were analyzed from the electrocardiography. Plasma noradrena-line (NA) were measured at each stimulation. Statistical analysis was done with generalizedestimating equation (GEE). Covariation between changes (delta value: intense − baseline)in regional cerebral blood flow (rCBF) and heart rate variability was analyzed using StatisticalParametric Mapping 8. Results Intense distention induced a significant increase in HR andLF/HF ratio in controls with CRH or saline and in IBS patients with saline. GEE of LF/HFratio in controls showed significant distention effect (p , 0.001), CRH effect (p = 0.022)and CRH x distention interaction (p = 0.019) but IBS patients showed significant distentioneffect alone (p , 0.001). Post-hoc test of LF/HF ratio at intense distention with CRH revealedsignificantly higher than that with saline (p = 0.006). During intense distention, plasma NAlevels significantly correlated with LF/HF ratio with CRH (rho = 0.95, p , 0.01) or saline(rho = 0.91, p = 0.002) in controls but not in IBS patients. In controls, delta LF/HF withsaline significantly covariated with delta rCBF in the left dorsolateral prefrontal cortex anddorsal pons and that with CRH significantly covariated the left insula. In IBS patients, deltaLF/HF with saline significantly covariated with delta rCBF in the left caudate and rightmedial frontal gyrus (BA6) but that with CRH had no significant covariation. ConclusionThese findings suggest more activation of the regional brain of autonomic regulation andcardiac sympathetic discharge at intense colorectal distention with CRH in controls but notin IBS patients.

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Regional Neuroplastic Brain Changes in Patients With Inflammatory BowelDiseases (IBD) and Irritable Bowel Syndrome (IBS)Jui-Yang Hong, Jennifer S. Labus, Zhiguo Jiang, Cody Ashe-McNalley, Jean Stains, BaharEbrat, Kirsten Tillisch, Ivo Dinov, Yonggang Shi, Emeran A. Mayer

Background: Regional alterations in gray matter (GM) have been reported in many chronicpain disorders, including those with peripheral nociceptive drive (including rheumatoidarthritis) and in so called functional disorders where central pain amplifications may playa primary role (including IBS). Aim. Identify differences in GM volume (GMV) and corticalthickness (CT) between age matched patients with IBD, IBS and healthy controls (HCs),determine the influence of sex on these differences, and explore possible correlations ofGMV with clinical parameters. Methods: Structural MRI scans were obtained from 32 IBDin clinical remission (9 Crohns, 23 UC), 31 IBS and 212 HCs. The LONI (UCLA Laboratoryof Neuroimaging) pipeline was utilized for image preprocessing, tissue classification, brainsegmentation and parcellation, and GMV and CT extraction for 14 predefined regions ofinterest,The general linear model (GLM) controlling for age and total GMV and lnear contrastanalysis was used to test for group differences, Partial correlation analyses controlling for totalGMV and age were also perform to further characterize the association between symptoms andregional GMV and CT.9 Significance was interpreted at p ,.05 correcting for family wiseerror rate using a modified Bonferroni procedure. Results: Regardless of sex, IBD comparedto HCs had reduced GMV in bilateral cingulate cortex. In males only, increased regionalGMV was observed for IBD compared to HC in ventrolateral prefrontal cortex (vlPFC) andparahippocampal gyrus. When compared to IBS, IBD showed greater GMV in parahippocam-pal gyrus and cerebellum. For CT, IBD showed reductions in regional CT in the insula(INS), and in several PFC regions: While these reductions involved posterior aspects of theINS in males, the anterior INS was affected in females. Compared to IBS, IBD showed CTreductions in vlPFC. Significantly positive correlations were observed between posterior midcingulate cortex CT and disease duration in IBS (q=0.036, r=0.54) and in IBD (q=0.047,r=.71). In IBD, there was also a significantly positive correlation with abdominal pain ratingsin the posterior INS (q=0.048, r=0.75). Conclusion: Two different measures of GM integrity

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showed distinct regional differences between age-matched samples of IBD, IBS and HCs,which are influenced by the sex of the subjects. In both disease groups, these changes arecorrelated with symptom duration in the pMCC, a key component of the interoceptive brainnetwork. These findings demonstrate differences in GM integrity between HCs and IBD,and suggest differences in the involved brain networks (interoceptive, prefrontal control)between IBD and IBS patients. Grant: U54 RR021813, P41 RR013642, R01 MH71940, U24-RR025736, U24-RR021992, U24-RR021760 and U24-RR026057.

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Novel Esophago-Cortical Responses in Unsedated Human NeonatesDiscovered Upon Concurrent Provocative Manometry and Functional Near-Infrared Spectroscopy (Fnirs)Sudarshan R. Jadcherla, Joanna Floria Pakiraih, Kathryn Hasenstab, Rebecca K. Moore,Nasser H. Kashou

BACKGROUND: Changes in functional near-infrared spectroscopy (fNIRS) signals from thebrain permits non-invasive evaluation of localized cerebral cortical activation by measuringoxy-hemoglobin (HbO) and deoxy-hemoglobin (HbD) concentrations. Hemodynamicresponse is defined as an increase in blood flow leading to an increase in HbO and a relativedecrease in HbD concentrations. Characteristics of fNIRS signals with visceral provocationor swallowing are unknown. AIMS: Our objectives were to establish feasibility to performfNIRS in neonates and to characterize the HbO and HbD concentration changes in thevicinity of fronto-parietal cerebral cortex evoked upon esophageal provocation. METHODS:8 neonates (33.8 ± 2.5 wks gestation) underwent concurrent provocative esophageal manom-etry and NIRS at 46.7 ± 3.7 wks postmenstrual age (4.21 ± 0.57 kg). NIRScout system wasused. A light was emitted via the purpose-built non-invasive NIR-EEG cap placed onto theneonate's head using a minimum of two wavelengths, 760 nm and 850 nm. The cap consistedof 4 sources and 8 detectors placed bilaterally with inter-optode distance of 1.5 cm, andpositioned snugly in the region of fronto-parietal brain bilaterally. Baseline esophagealmotility and NIRS activity were concurrently recorded and both modalities synchronized.Near-infrared Analysis, Visualization and Imaging (NAVI) software was used for data pre-processing. The raw data was low pass filtered with the cut-off frequency of 0.05 Hz toremove the high frequency and noise components, and were further analyzed with MATLABsoftware. Experimental and analytical protocol included spontaneous and provocative swal-lows and its effects on fronto-parietal cortical hemodynamic response. Changes from baselineto the stimulus-reflex response were analyzed. RESULTS: 56 esophageal provocations and8 sham stimuli were analyzable for both esophageal reflex and NIRS response. Peristalticreflex rate was 75%, NIRS response rate was 53.6%, and response to sham stimuli was 0%.Characteristics of hemodynamic response (Table 1) and relationship of peristaltic reflex withNIRS response (Table 2) are described. Hemispheric lateralization was not seen. Increasedchange in HbO concentration between baseline value vs. post-stimulus response were 2.13± 0.31 and 4.16 ± 0.45 μmol/L respectively (p,0.0001). Decreased change in HbD concentra-tion between baseline value vs. post-stimulus response were 0.66 ± 0.62 and -1.05 ± 0.63μmol/L respectively (p,0.0001). CONCLUSIONS: 1) Concurrent provocative esophagealmanometry and fNIRS in neonates is feasible, safe and pragmatic. 2) Activation of fronto-parietal cerebral cortical region is 5.5-fold more frequent with deglutition response. 3)Significant brisk and sustained changes in HbO and HbD are recognized suggesting neuro-physiologic response. *Supported by R01 DK 068158 (Jadcherla)Table 1: Characteristics of hemodynamic response during visceral stimulation

Mean ± SETable 2: Association of esophageal provocation with NIRS response

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Esophageal Acid Induced Brain Functional Connectivity Changes Are VagallyMediatedPatrick P. Sanvanson, Venelin Kounev, Ling Mei, Rupeng Li, James S. Hyde, Bidyut K.Medda, Reza Shaker

Background: Earlier studies have documented activation of a number of cortical regions inresponse to esophageal acid stimulation. These studies have also shown changes in functionalconnectivity of these regions due to acid stimulation. However, the contribution of extrinsicesophageal afferent innervations to these alterations have not been systematically studied.Aim: To investigate the effect of bilateral cervical vagotomy on functional connectivity ofacid responsive cortical regions. Methods: Six Sprague-Dawley rats were studied. Under2.5% isoflurane anesthesia, each rat underwent placement of a femoral arterial line, intrave-nous femoral line, tracheostomy tube, and trans-oral esophageal tube. Continuous infusionof dexmedetomidine (0.1 mg/kg/hr) and vecuronium (2 mg/kg/hr) during MRI acquisitionwas used for sedation. HCl (0.1N, 0.2 ml/min) was infused in the mid-esophagus for 10