M1282

The BDNF Polymorphism Val66met Predicts Stimulus Driven Plasticity in theHuman Swallowing Motor SystemVanoo Jayasekeran, Neil Pendleton, Glenn P. Holland, Anthony Payton, SamanthaJefferson, Bill Ollier, Michael A. Horan, John Rothwell, Shaheen Hamdy

INTRODUCTION A single nucleotide polymorphism (SNP) of brain derived neurotrophicfactor gene (BDNF) has been shown to influence neurological function. Transcranial magneticstimulation (TMS) studies have suggested that the BDNF SNP producing a valine to methion-ine substitution can modulate plasticity in human motor cortex1,2. This study aimed todetermine if the SNP influences the outcome of two excitatory forms of neurostimulationapplied to the swallowingmotor system. AIMS&METHODSHealthy subjects (n=22, 6males,mean age 59) with predetermined BDNF SNP status (Val/Val or non-Val/Val), underwent bi-hemispheric single pulse TMS measurements of pharyngeal EMG responses recorded froma swallowed intra luminal catheter to assess corticobulbar excitability. Following baselineassessment with TMS, subjects received either pharyngeal electrical stimulation (PES) at5Hz, 75% of sensory threshold, for 10 minutes (n=16, 9 Val/Val and 7 non-Val/Val) or 250pulses of 5 Hz repetitive TMS (rTMS) over the dominant pharyngeal motor cortex (n=22,15 Val/Val and 7 non-Val/Val). Repeated measurements of the cortical excitability wereassessed with TMS up to 60 minutes following the two interventions. Pharyngeal motorcortical excitability for the 2 BDNF SNP genotypes was compared using 2-way ANOVA.RESULTS PES significantly increased the amplitude of pharyngeal motor evoked potentials(MEPs) in the Val/Val group compared to the non-Val/Val group with a strong GENO-TYPE*TIME interaction, (F8,112= 2.4, p=0.018); see Figure 1. By contrast, there was asignificant reduction in latencies of the non-Val/Val group after 5 Hz rTMS (GENO-TYPE*TIME interaction, (F3,60=4.9, p=0.04)). There was no significant difference in MEPlatencies between groups following PES. CONCLUSIONS SNPs of the BDNF gene predictsthe degree of plasticity in the human swallowing motor system to differing forms of neurosti-mulation. Our results suggest that therapeutic response to swallowing interventions inpathology such as dysphagic stroke may be guided by BDNF genotype profiling. REFER-ENCES 1.Kleim J. Nature Neuroscience 2006. 2.Cheeran B et al. Journal of Physiology 2008.

M1283

A Neurostimulation Study of the Human Cerebellum in the Control ofSwallowing Motor PathwaysVanoo Jayasekeran, John Rothwell, Shaheen Hamdy

INTRODUCTION Animal studies (1) have suggested that the cerebellum is important inthe control of swallowing. Human brain imaging studies have reported the activation of thecerebellum in the process of swallowing (2). In this study, we probed the interaction betweencerebellum and pharyngeal motor cortical activity with transcranial magnetic stimulation(TMS) to determine if the cerebellum can be excited to induce pharyngeal activity, and toelucidate if stimulation of the cerebellum can modulate cortical swallowing circuitry inthe motor system. METHODS Healthy volunteers (n=16, mean age=32) underwent TMSmeasurements of pharyngeal EMG recorded from a swallowed intra luminal catheter toassess cortical and cerebellar excitability. Subjects then underwent a paired pulse paradigmwhere active or sham TMS conditioning pulses over the cerebellum were followed bysuprathreshold TMS over the cortical pharyngeal area. Paired pulses were delivered atinterstimulus intervals (ISIs) between 3 - 200 ms allocated randomly, and the corticalresponses were then assessed (compared to baseline and sham) for change in amplitudeusing T-tests.RESULTS Stimulation of the cerebellum over the midline or either hemisphereevoked distinct EMG responses in the pharynx. There was a trend towards cerebellarhemispheric stimulation eliciting greater pharyngeal responses (mean amplitude 55.5 mV± 6.9) than cerebellar midline stimulation (42.8 mV± 5.9); p= 0.08. Following activepreconditioning cerebellar stimulation, the cortically evoked responses were facilitated withmaximal effects at ISIs of 50-200ms; p< 0.05 (Figure 1) an effect not seen with shampreconditioning. CONCLUSIONS This novel study demonstrates that cerebellar stimulationcan evoke direct motor responses within the pharynx, and when excited with TMS, canmodulate cortical swallowing motor pathways. These findings are in keeping with the animalliterature suggesting a facilitatory role for the cerebellum in regulating swallowing and raisesthe possibility that excitatory neurostimulation of the cerebellum may be therapeuticallyuseful in promoting recovery of dysphagia after brain damage. RERERENCES (1) HockmanCH et al. Progress in Neurobiology 1979 (2) Suzuki M. Dysphagia 2003.

S-371 AGA Abstracts

M1284

Altered Brain Network Connectivity Associated With Increased PerceptualResponse to Aversive Gastric Distension and Its Expectation in FunctionalDyspepsia (FD) PatientsLukas Van Oudenhove, Jennifer S. Labus, Patrick Dupont, Joris U. Vandenberghe, RitaVos, Guy Bormans, Koen Van Laere, Koen Demyttenaere, Emeran A. Mayer, Jan F. Tack

Background FD patients show enhanced perception and altered brain responses duringbaseline, expectation and delivery of aversive gastric distension, compared to healthy controls(HCs) (Van Oudenhove DDW 2008). Aim To test the hypothesis that group differences ineffective connectivity of a priori brain circuits underlie the observed differences in perceivedepigastric discomfort. Methods Brain H2

15O-PET data from 25 FD and 11 HCs, scannedduring 3 conditions [baseline (BL), actual gastric distension (DIS) and ‘sham' distension(SHAM)] were used. A multivariate analysis (behavioral partial least squares [bPLS]) wasused to compare brain activity patterns functionally related to perceived epigastric sensations.Structural equation modeling (path analysis) was used to test between-group differences ineffective connectivity within the circuits described above. Results bPLS Two epigastricsensation-related networks were observed. The first network (variance explained 43%,p<.0001) was strongly, negatively correlated with perceptual ratings during BL [r=-.77] andSHAM [r=-.79], but not DIS [r=.08] in HCs (‘non-DIS' network). In contrast, the networkwas moderately correlated with all ratings [r=-0.4] in FD. The second network (varianceexplained 23%, p<.10) was strongly and positively correlated with ratings during DIS [r=.92], but not with BL [r=.02] and only moderately with SHAM [r=-0.41] in HCs (‘DIS'network); in contrast, in FD, correlations with BL, DIS and SHAM were .43, .70 and .51,respectively. Effective connectivity analysis Significant (p<.05) differences in connectivity withinboth networks between HCs and FD were found in both homeostatic-afferent and cognitive-affective pain modulatory pathways (Table 1). Conclusions In HCs, distinct perception-related networks are engaged during DIS and non-DIS conditions. This distinction is partiallylost in FD. These differences in connectivity within homeostatic-afferent and cognitive-affective pain modulatory networks may underlie the perceptual hypersensitivity in FDpatients.Table 1

*: during SHAM; °: during BL; ^: during DIS pACC: perigenual anterior cingulate; aINS:anterior insula; dlPFC: dorsolateral prefrontal cortex

M1285

Alpha 2 Adrenoceptors in Gastrointestinal Vago-Vagal CircuitsKirsteen N. Browning, R. Alberto Travagli

Alpha2 adrenoceptors are known to play an important role in vagally-mediated gastrointesti-nal reflexes, particularly the gastric relaxation induced by esophageal distention. The aimof this study was to examine the location of α2 adrenoceptors within gastric vagal circuitsand the effects of their activation. Whole cell patch clamp recordings were made fromgastric-projecting dorsalmotor nucleus of the vagus (DMV)motoneurons in thin rat brainstemslices. Norepinephrine (NE; 3-300μM) or the α2 adrenoceptor selective agonist, UK14,304,was applied by superfusion for a period of time sufficient for the response to reach plateau(3-5min). In 4 of 44 gastric-projecting DMV neurons tested, NE induced an outward currentthat reached a maximum response of 46±7pA at 300μM. This outward current was mimickedby UK14,304 in 4 of 14 neurons tested (39±15.1pA at 1μM). As described previously, NEdecreased the amplitude of electrically evoked excitatory (glutamatergic) postsynaptic cur-rents (EPSCs) reaching amaximum inhibition of 44±8.9% at 300μM (P<0.05). This inhibitionin EPSC amplitude was blocked by the α2 selective antagonist yohimbine in all 3 neuronstested (44±4% inhibition in control vs 1±1.2% inhibition in the presence of yohimbine;P<0.05) and mimicked by UK14,304 (maximum 38±9.7% inhibition at 1μM; n=10 of 11

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