837 5-Httlpr Gene Polymorphism Modulates Activity and Connectivity Within An Emotional Arousal Network of Healthy Control Subjects During Visceral Pain Jennifer S. Labus, Emeran A. Mayer, Toyohiro Hamaguchi, Tomoko Mizuno, Michiko Kano, Shin Fukudo Background and Aims: Variants of the function polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) have been implicated in the vulnerability for affective disorders and in IBS pathophysiology. We hypothesized that 5-HTTLPR genotype would moderate: 1) a significant pattern of brain activity discriminating pain from non-pain conditions and 2) the effective connectivity in an emotional arousal network, previously shown to be involved in central pain amplification. Methods: Regional cerebral blood flow (rCBF) of 21 healthy controls (Ctrls; 5 females and 16 males) was assessed using PET (H 2 15 O) during an intense (40 mm Hg) colorectal balloon inflation (INF) or during no INF (0 mm Hg). Polymerase chain reaction was used to determine the genetic polymorphism of the 5-HTTLPR (10 short (s/s) and 11 long (l) (included 9 l/s, 2 l/l). Task partial least squares (PLS) tested for distributed patterns of brain activity discriminating the INF conditions and interacting with genotype. Structural equation modeling (SEM) tested for group differ- ences in the effective connectivity of an emotional arousal network during INF. Results: PLS revealed a significant network of regions (p<.01, 59% cross-covariance matrix variance) differentiating INF from non-INF. Compared to s/s, l carriers showed greater engagement of this network, which comprised regions of activation (including thalamus, insula, sACC, pons) and deactivation (including medial orbital frontal cortex, amygdala, and infragenual ACC) during INF. SEM showed genotype differences in the effective connectivity within the emotional arousal network. That is, s/s showed strong positive connectivity from sACC to amygdala (lack of feedback inhibition of amygdala), while l carriers showed the expected negative connectivity (sACC to AMYG [.46, -.40, χ 2 Δ=7.7]). Conclusions: In healthy Ctrls, s/s genotype is associated with altered connectivity within an emotional arousal network activated by visceral pain. The resultant disinhibition of the amygdala may play a role in central pain amplification, and represent a vulnerability factor for the development of IBS. Support Contributed By: K08 DK 071626 (JSL) NR04881, P50 DK64539, R24 AT002681, DK 64539 838 Contralesional High Frequency Cortical Stimulation Can Reverse a Virtual Lesion in Dominant Swallowing Motor Cortex in Intact Man Shaheen Hamdy, Samantha Jefferson, Satish Mistry, Louise Hancock, John C. Rothwell INTRODUCTION: We have previously shown that transcranial magnetic stimulation (TMS) delivered at 1Hz to pharyngeal motor cortex can unilaterally suppress cortical excitability (virtual lesion) which can transiently alter swallowing behaviour (1). Here we examine if an excitatory intervention (5Hz repetitive TMS (rTMS)) applied to the contralesional hemi- sphere can reverse a virtual lesion as a prelude to applying such neurostimulation in the treatment of dysphagia after stroke. AIMS & METHODS: Healthy volunteers (n=12, 5 male, mean age 39 years) underwent single pulse bi-hemispheric TMS measurements of cortico- pharyngeal excitability via a swallowed intraluminal catheter, before and for 60 minutes after 10 minutes of 1Hz rTMS delivered to unilateral pharyngeal motor cortex. Five Hz rTMS (250 pulses over 90 seconds) or sham was then applied to the contralesional hemisphere randomised to different sessions, 1 week apart. Post-lesional cortical excitability following active intervention vs. sham was compared using ANOVA. RESULTS: As expected, sham rTMS had no effect on the suppression of excitability induced by the virtual lesion, with both lesional and contralesional hemispheres decreasing by a maximum of -35% and -16% respectively. By contrast, active 5Hz rTMS completely abolished the virtual lesion, reversing the direction of excitability both in the lesional and contralesional hemispheres by +35% and +25%, respectively (p=0.035, Figure 1). CONCLUSION: Fast rTMS applied to the contralesional hemisphere completely reverses a unilaterally induced virtual lesion in pharyn- geal motor cortex. These data support the notion that rTMS might be usefully applied in stroke patients, as a therapeutic intervention for dysphagia. REFERENCES: 1. Mistry S., et al. J. Physiol., 2007, in press. Figure 1 839 Chronic Stress Induces Long-Term Smooth Muscle Hypersensitivity By Enhancing the Gene Expression of CA V 1.2 (L-Type) Calcium Channels in Colonic Circular Smooth Muscle Cells Barun K. Choudhury, Xuan-Zheng P. Shi, Sushil K. Sarna Background: Studies to-date have reported the immediate non-transcriptional effects of acute stress on colonic motility dysfunction. Our hypothesis is that chronic, but not acute, stress alters the transcription of genes encoding key signaling proteins of excitation-contrac- tion coupling in colonic circular smooth muscle cells to cause motility dysfunction. Methods: We used a 9-day stress protocol of mixed stressors, water avoidance stress (60 min), forced swimming stress (20 min) and cold-restraint stress (45 min), each applied once daily in a random order. We used one episode of cold-restraint for acute stress. The animals were sacrificed at the end of this period to investigate the effects of chronic stress on the expression of the α 1C subunit of Ca v 1.2 (L-type) Ca 2+ channels, cell contractility, and colonic transit. A-121 AGA Abstracts Each rat served as its own control. Results: At the end of the 9-day chronic stress period, the contractile response to acetylcholine (ACh) in muscle strips and in single dispersed circular smooth muscle cells increased significantly, reaching maximum at 8 hours after the last stressor. By contrast, an acute one-day stress had no significant effect on cell contractility after 8 hours. The plasma concentrations of norepinephrine and corticosterone increased significantly on day 9 (2.5 and 4.5-fold respectively, n=3; p<0.05); but that of corticosterone releasing hormone (CRH) was unaffected (p<0.05; n=3). The daily administration of bretyl- ium tosylate (noradrenergic ganglionic blocker) administered 30 minutes prior to each stress session blocked the chronic stress-induced smooth muscle hypersensitivity, but the non- selective CRH receptor antagonist astressin had no effect. The expression of α 1C protein increased time-dependently on the 9th day of stress, peaking at 8 hours after end of the stress session. The incubation of fresh colonic circular smooth muscle strips with norepinephrine for 24 hours, concentration-dependently increased their contractile response to ACh, and the protein expression of α 1C . The chronic stress also increased the rate of colonic transit at 8 hours after the stress session on the 9th day (geometric center 4.0 ± 0.2 after stress vs. 3.3 ± 0.2 control). The number of pellets per 24 hours increased after 9-day of chronic stress to 52 ± 2, from 35 ± 2, before stress (p<0.5). Conclusions: Chronic, but not acute, stress enhances the gene expression of the α 1C subunit of L-type Ca 2+ channels to enhance cell contractility and colonic transit. These effects last for several hours after the stress is over. The stress-induced release of norepinephrine mediates the gene transcription in colonic smooth muscle cells. 840 Anatomical Connexions Between Brain Areas Activated During Rectal Distension in Healthy Women: A Visceral Pain Network Jean Marc Sabate, Xavier Moisset, Didier Bouhassira, Denis Ducreux, Dominique Glutron, Benoit Coffin Background and Aims: Diffusion Tensor Imaging (DTI) is a promising new imaging method allowing In Vivo mapping of anatomical connections in the living human brain. We combined DTI with functional magnetic resonance imaging (fMRI) to investigate the anatomical relation- ships between areas involved in visceral sensations in humans. Subjects and Methods: Non- painful and moderately painful rectal distensions were performed in 11 healthy women (38.4 ± 3.1 years). fMRI was used to analyse the changes in brain activity during both types of distension. Then, DTI was applied for tracking fibers between the main activated regions. Results: Non-painful distension bilaterally activated the PreFrontal Cortex (PFC), the Anterior Cingulate Cortex (ACC) and the right insula. Painful distension bilaterally activated the primary (S1) and secondary (S2) somatosensory cortices, the motor cortex, the frontal inferior gyrus, the thalamus, the insula, the striatum and the cerebellum. DTI revealed direct connections between insula, and the four areas more frequently activated in this study, i.e. ACC, thalamus, S1, S2 and PFC. Conclusions: The combined use of fMRI and DTI in healthy subjects during rectal distension revealed a neural network of visceral sensory perception involving the insula, thalamus, somatosensory cortices, ACC and PFC. Description of bundles of axons going through activated brain regions during rectal distension Abbreviations: PFC: prefrontal cortex, ACC: anterior cingulate cortex, S1/S2: primary and secondary somatosensory cortices ; FA : fractional anisotropy ; ADC : apparent diffusion coef- ficient. 841 The Natural History of Microscopic Colitis Treated with Corticosteroids Adil A. Abdalla, Yuning Xiong, Edward V. Loftus, Thomas C. Smyrk, Stephen Cha, Patricia P. Kammer, William J. Sandborn, Darrell S. Pardi Background: Microscopic colitis (MC) is a common cause of chronic diarrhea, especially in the elderly. MC appears to be very responsive to corticosteroid therapy; however, symptoms frequently recur once this therapy is stopped. Aims: We sought to examine the clinical course of MC treated with corticosteroids, to compare response rates of prednisone and budesonide, and to compare the response to corticosteroids in two groups: A population- based cohort residing in Olmsted County, Minnesota, and a referral cohort of non-Olmsted County patients. Methods: In this retrospective study, 451 patients with biopsy-proven MC were identified (167 from Olmsted County, 284 from outside the county). Patients treated with corticosteroids were identified by review of the medical records and treatment outcome was examined. Fisher's exact test or logistic regression was used to estimate any response to corticosteroid therapy. Results: We identified 70 patients with biopsy-proven MC who were treated with corticosteroids (median age 63 yrs, 84% female). Of these patients, 42 (60%) had lymphocytic colitis, 19 (27%) had collagenous colitis and 9 (13%) had mixed histology. Prednisone (median dose 25 mg) was used in 46 patients (66%) and budesonide (median dose 9 mg) in 25 (36%). One patient was treated with both drugs sequentially. The percent of patients who received any steroid did not differ based on Olmsted County residence or not (16% vs 15%, respectively; p=0.79). Nine patients were lost to follow-up. Of the remaining 61 patients, 56 (92%) responded to steroids and 5 (8%) were steroid- resistant, with no significant difference in steroid responsiveness between patients residing in Olmsted County and the referral cohort (92% in each). The response rates for prednisone AGA Abstracts