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Transcranial direct current stimulation (tDCS) priming of 1Hz repetitive transcranial magnetic stimulation (rTMS) modulates experimental pain thresholds

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NeuroscienceLettersxxx (2012) xxx–xxx

ContentslistsavailableatSciVerseScienceDirect

Neuroscience

Letters

j o ur na l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / n e u l e t

Transcranial

direct

current

stimulation

(tDCS)

priming

of

1

Hz

repetitive

transcranial

magnetic

stimulation

(rTMS)

modulates

experimental

pain

thresholds

Tonya

M.

Moloney,

Alice

G.

Witney

TrinityCollegeInstituteofNeuroscienceandTrinityCentreforBioEngineering,DepartmentofPhysiology,2ndFloor,TrinityCollegeBiomedicalSciencesInstitute,152-160Pearse Street,TrinityCollegeDublin,Dublin2,Ireland

h

i

g

h

l

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g

h

t

s

PrimingmotorcortexwithtDCSbefore1HzrTMSstandardizesitseffects.

Thistechniqueisappliedtoexperimentalpainthresholds.

CathodaltDCS–1HzrTMSincreasedheatandcoldpainthresholds.

AnodaltDCS–1HzrTMSdecreasedcoldpainthresholds.

tDCSprimingmayhaveapplicationsinpainreliefintheclinic.

a

r

t

i

c

l

e

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n

f

o

Articlehistory:

Received10October2012 Receivedinrevisedform 21November2012 Accepted22November2012

Keywords: Painmodulation tDCS

rTMS QST

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s

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Transcranialdirectcurrentstimulation(tDCS)andrepetitivetranscranialmagneticstimulation(rTMS) ofprimarymotorcortex(M1)modulatecorticalexcitability.Bothtechniqueshavebeendemonstratedto modulatechronicpainandexperimentalpainthresholds,butwithinconsistenteffects.Preconditioning M1withweaktDCS(1mA)standardizestheeffectsofsubsequentstimulationviarTMSonlevelsofcortical excitability.Hereweexaminewhether1HzrTMS,primedwithtDCS,couldeffectivelystandardizethe modulationofpainthresholds.Thermalpainthresholdsweredeterminedusingquantitativesensory testing(QST)ofthepalmarthenarofbothhandsin12healthymalespreandposttDCS–1HzrTMS overthehandareaoftheleftM1.CathodaltDCSpreconditioningof1HzrTMSsuccessfullyreversedthe normalsuppressiveeffectoflowfrequencyrTMSandeffectivelymodulatedcoldandheatpainthresholds. Conversely,anodaltDCS–1HzrTMSledtoadecreaseincoldpainthresholds.Therefore,thisstudy supportsthatpreconditioningM1usingcathodaltDCSbeforesubsequentstimulationvia1HzrTMS facilitatestheproductionofanalgesia.

© 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Painis a globalhealth problemthat decreasespatient qual-ityoflife. Duetothemultipledifferentcausesofpain,andthe complexity of the pain network, it may be that alone, phar-macologywill neverprovide adequatepainrelief.Non-invasive corticalneurostimulationtechniquesofferanalternativeor supple-menttopharmacologicalinterventionsinpainrelief,andareless costlythanimplantedstimulation[28].Twomajor neurostimula-tiontechniques:transcranialdirectcurrentstimulation(tDCS)and repetitivetranscranialmagneticstimulation(rTMS),particularlyof primarymotorcortex(M1),haverecentlyemergedassuccessfulin

∗Correspondingauthor.Tel.:+353018961019. E-mailaddress:awitney@tcd.ie(A.G.Witney).

themodulationofchronicand experimentalpain[4,16].Recent studiesonthepreconditioningeffectsoftDCSappliedtoM1on subsequentrTMSsuggestthatthismethodmayacttostabilize neu-ralcircuitsandenableneurostimulationprotocolsappropriatefor clinicalapplications.Herethispreconditioningprotocolisusedto assesseffectivenessinmodulatingexperimentalpainthresholds.

1.1. tDCS

tDCSisa neuromodulatorytechnique,whereweakelectrical current(∼1mA)isnon-invasivelyappliedtocorticaltargets.tDCS doesnotfunctiontoinduceactionpotentialsintheneurons,but rathertoinfluencespontaneousneuronalactivityalready occur-ringinthebraininapolaritydependentfashion[15,17,27].Anodal tDCShasbeenfoundtoinduceanincrease incortical excitabil-ityviathedepolarisation ofneuronalmembrane potentialsand

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cathodaltDCShasbeenshowntodecreasecorticalexcitabilityvia thehyperpolarisationofthese[13].ShortlastingeffectsoftDCS oncortical excitability are mediated by the activity of sodium and calcium channels, whereas long term aftereffects depend on both changes in the membrane potential and modulations oftheN-methyl-D-aspartate(NMDA)and gamma-amino-butyric-acid(GABA)receptorefficacy[13].

PreviousstudiesusingtDCStomodulatepainthresholdshave showneffectivenessofbothanodal[1]andcathodal[2] stimula-tioninincreasingpainthresholds[16].ThismaybeduetotDCS beingsomewhatnon-focal,astheelectrodesusedtodeliverthe modulatorycurrentarelarge;differentelectrodemontages;and heterogeneouspatientgroupsinclinicalstudies.fMRIstudieshave revealedthattDCSnotonlyaffectstheunderlyingcortex,butalso provokessustainedandwidespreadchangesinregionalneuronal activity[7].Itremainstobedeterminedhowthesedistantareasare affected,butitisprobablythroughinterconnectionsbetweenthe principallystimulatedareaandthesestructures[9].Thesefindings maketheoptimumpolarityforconsistentpainthresholdreduction difficulttoestablish[16].

1.2. rTMS

rTMSis a non-invasive neurostimulationtechnique that can beusedtomodulatecorticalexcitabilitytosuppressorfacilitate underlyingcorticalactivity.StimulationofM1withlowfrequency rTMS(1Hzorless)isassociatedwithdecreasedcortical excitabil-ity,whereashigherfrequencies(20–50Hz)havebeenassociated withanincreaseinexcitability[14].

rTMSofM1hasprovenefficaciousinthetreatmentofchronic pain [16,19]. Further, high frequency rTMS of M1 in healthy populationsshowthistechniquecanmodulateexperimentalpain thresholds[16,26].ItisthoughtrTMSactstomodulatepathways fromtheinsulaandorbitofrontalcortextotheposteriorthalamus inordertoupregulatethesepainthresholds[12].Theeffectsofhigh frequencyrTMSonpainthresholdshavebeendemonstratedtolast uptoeightdays[11].

1.3. tDCSprimedrTMS

Siebneretal.,demonstratethattDCSmaybeusedto“prime”or “precondition”thebrainbeforesubsequentstimulationviarTMS sothatbaselinecorticalexcitabilitycanbestandardized[25].Low frequency(1Hz)rTMSappliedonitsown,normallyresultsinan inhibitionofcorticalexcitabilityinrelationtothetargetedbrain area.Siebneretal.,foundthatpreconditioningwithcathodaltDCS alteredtheexpectedsuppressiveeffectandledtocortical excita-tion.Similarly,preconditioningwithanodaltDCS[6]resultedin anoverallcorticalinhibitionaftersubsequentstimulationusing 1HzrTMS,againalteringtheexpectedeffects.Thesefindingsare thoughttobeduetocorticalhomeostaticplasticity[3].

InourstudythetechniqueoftDCSprimed1HzrTMSisapplied toexperimentalpainthresholdmodulation.Theaimistoprime M1usinga preconditioninginhibitorysessionofcathodaltDCS, tocause an initialinhibition of corticalactivity, reducing neu-ronalthresholds,therebyfacilitatingtheoverallincreaseincortical excitabilityuponsubsequentstimulationoflowfrequencyrTMS. Thepredictionisthatthisincreasedcorticalexcitationwillinturn, increasepainthresholds.

2. Materialsandmethods

2.1. Participants

Twelvehealthymales(meanage,21.5years,10righthanded); naïve to the experimental aims, participated in the study. No

participants reported any previous or concomitant psychiatric orneurologicaldisease,anyconditionsassociated withacuteor chronicpainorwithsomatosensoryabnormalities.Thestudywas performed in accordance with the Declaration of Helsinki and approvedbytheFacultyofHealthSciencesResearchEthics Com-mittee,TrinityCollegeDublin,Ireland.

2.2. Quantitativesensorytesting(QST)

Todeterminethermaldetectionandpainthresholds,QSTwas performed using a TSA-2001NeuroSensory Analyzerapparatus (Medoc, Ramat Yishai,Israel) that applied thermal stimuli and recorded participants’ responses [6]. Standardized instructions providedwiththeTSA-2001weregiventoeachparticipant.The psychophysical method of limits was used to determine: cold sensationthreshold (CS);warmsensation threshold(WS); cold painthreshold(CP)andheatpainthreshold(HP).A3cm×3cm thermode was attached to the palmar thenar with a Velcro® strap,withthresholds determinedfor thehandboth ipsilateral and contralateral to M1 stimulation. For CS and WS, the ther-modedecreased/increasedintemperature(Mintemp:−0◦C;Max temp:50◦C)atalinearrateof1◦C/sanda returnrateof1◦C/s withanadaptationtemperatureof32◦C.ThethresholdforCS/WS wastested 4timeswithanintervalof 4–6sbetweeneach sep-arate, successive trial. The average value of the 4 trials was expressedindegreescentigrade(◦C)andtakenastheparticipant’s detectionthreshold.In determiningCP/HP thresholds,the ther-modedecreased/increasedintemperature,butatalinearrateof 1.5◦C/s and return rateof 10◦C/s.These thresholdswere mea-suredover3successivetrialswithanintervalof10sbetweeneach trial,beforeaveraging.Thesethresholdmeasurementswerenot counterbalanced;ratherinnocuoussensationperception thresh-oldmeasurements(CS/WS)precededpainperceptionthresholds (CP/HP)inordertoavoidpossiblesensitivitychangescausedby painfulstimulation[5](Fig.1(a)).

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2.3. Electromyogramsanddeterminationofstimulation parameters

Electromyograms(EMGs)wererecordedfromtheright abduc-torpollicisbrevis(APB)muscleusingconductiveadhesiveAg/AgCl electrodes (Tyco Healthcare, Mansfield, UK) in a belly tendon montage. EMGs were recorded through an Octal BioAmp (AD Instruments,Oxford,UK).Theoptimalplacementforsubsequent rTMSstimulationwasdefinedasthesitewheresinglepulseTMS resultedinthelargestmotorevokedpotential(MEP)ina consis-tentfashion.TMSwasappliedusingaMagstimRapid2stimulator (MagstimCompanyLimited,Whitland,Wales,UK)connectedtoa figureofeightcoil(70mm).Thecoilwasangled45◦fromthe mid-lineandheldtangentiallytotheskullduringstimulationasproven successfulinpreviousstudies[18].Therestingmotorthreshold (RMT)wasdefinedastheminimumTMSintensitywhichachieved peak-to-peakMEPamplitudeof≥50␮VintherestingAPBmuscle, in3outof5stimulations.TheRMTmeasuredwasusedtosetthe outputforsubsequentrTMSprotocols.

2.4. PreconditioningtheleftM1usingtranscranialdirectcurrent stimulation(tDCS)

ToprimeM1,tDCS(NewRonika,Italy)wasappliedfor10minat 1.0mAthroughapairofsalinesoaked(0.89%NaCl)synthetic buck-skinelectrodes(25cm2),withtheactiveelectrodeabovetheleft motorcortexandthereferenceelectrodepositioned contralater-allyabovetherightorbit.Theelectrodeswereheldinplacewith useofaMindCap(NewRonika,Italy).Theseparameterswere con-sistentwithpreviousstudies[25].Forshamstimulation,current flowincreasedgraduallyovera5sintervalreachingthedesignated 1mAtomimictheinitialitchingsensationofrealtDCS.The stimu-lationwasthenterminatedafter10s,sothataconditioningeffect oncorticalexcitabilitywasnotinduced[2].

2.5. StimulationofleftM1with1HzrTMS

Thecoilwasplacedtangentiallytothescalpwiththehandle pointingposterolaterallyata45◦anglefromthemidline.Thecoil deliveredatrainof900biphasicpulseswith1sbetweenpulses (15mintotalduration)at90%ofthesubjects’RMT.ShamrTMS wasadministeredwiththecoil tiltedat a45◦ angleawayfrom thesurfaceofthehead,dischargingthesamenumberofstimuli atthesamerateasRealrTMS.AllrTMSprotocolswerecarriedout inaccordancewiththeoutlinedsafetyguidelines[24].

2.6. Experimentalprotocol

Asham-controlled,within-subjectssingle-blindstudywas con-ducted,withfourexperimentalconditions(Fig.1(b))performedin theorderbelow:

(1)ShamtDCS–ShamrTMS. (2)ShamtDCS–RealrTMS. (3)CathodaltDCS–RealrTMS. (4)AnodaltDCS–RealrTMS.

Eachprotocolwasperformedonparticipantsatthesametimeof daytoavoidvariationofpainthresholdsduetocircadianrhythms. Therewasaninterval ofone weekinactivetesting conditions, withthe two control conditions:(1) Sham tDCS– Sham rTMS and(2)ShamtDCS–RealrTMSpresentedfirst,onthesameday. Theinterval wasprovided toavoidinterferencebetweenactive neurostimulationprotocolsthatwould notbe controlledforby counterbalancing.

2.7. Statisticalanalysis

Collecteddatawasfirsttestedfornormalityofdistributionusing thenon-parametricKolmogorov–SmirnovtestwithintheSPSS sta-tistical package (version 19, IBM,New York,US). Once normal distribution wasdetermined, it wasfurther confirmedthrough theanalysisofskewand kurtosis.SeparateonewayANOVAsof thresholdmeanswereconductedforeachcondition,PreandPost stimulation.Athreeway:protocol×hand×time(4×2×2)ANOVA withplannedcomparisonsandBonferonnicorrectionswasthen carriedouttoassessstatisticalsignificancewithinthemodel.For furtheranalysisandstandardizationpurposes,threshold measure-mentswere Ztransformed[2], withinMATLAB(version 2011b, Mathworks,Cambridge,UK)usingtheexpression:

Z=Postneurostimulationscore−Meanofthebaseline

Standard deviationofthebaseline

where “baseline” referstoa mean of allthe pre-testcondition values collapsed over all experimental conditions. Differences betweenZ-scoredQSTdatafromtheright(contralateralto stim-ulation)andleft(ipsilateraltostimulation)palmarthenarofthe handpreandposteachofthe4individualprotocolswere com-paredforeachperceptualmodality(CS,WS,CPandHP)byanother 4×2×2ANOVA.Thresholdvaluesarepresentedasthemeanof eachparticipant’smean±thestandarddeviation.

3. Results

Twelve healthy male participants completed all protocols, designedtoexaminehowpreconditioningM1usingtDCS (cath-odal, anodal and sham) may shape the effects of subsequent stimulation via low-frequency rTMS (1Hz) on innocuous and painfulthermalsensorythresholds.Noneoftheparticipants expe-riencedanyadverseeffectsduringoraftertheneurostimulation sessions.

3.1. Quantitativesensorytesting(QST)analysis

Comparisonsof theQST datawithineachseparatecondition revealedsignificantdifferencesinpain,butnotsensorydetection thresholds,ontherighthand,contralateral tostimulation, asa resultofthetDCSpreconditioningneurostimulationprotocols (pro-tocols3and4).However,thresholdsattheleft,ipsilateralhand werenotaffected,Fig.2.

In Protocol 3,cathodal tDCS priming-1Hz rTMS (Fig.2(C)), therewasanincreaseofpainthresholds.Coldpainthresholds(CP) increasedsignificantlyfromathresholdof11.5±5.2◦Cpre stim-ulationto5.8±3.8◦C poststimulation(F(1,11)=39.63,p<0.001,

2

p=0.783),asdidheatpainthresholdswithmeanof45.9±1.6◦C prestimulationand47.8±1.0◦Cpoststimulation(F(1,11)=23.11,

p<0.01,2

p=0.678).

Contrastingly, Protocol 4, anodal tDCS priming −1Hz rTMS (Fig.2(D))resultedinadecreaseinpainthresholds,withameanCP thresholdof10.5±3.9◦Cpre-stimulationtoameanof13.7±3.7◦C postneurostimulation(F(1,11)=8.93,p<0.05,2

p=0.448) anda meanHPthresholdof46.4±1.5◦Cpre-stimulationto44.8◦±2.1◦C post-stimulation(F(1,11)=12.38,p<0.01,2

p=0.530).Therewere fewobservabledifferencesinsensorydetectionandpainthreshold inthelefthand,ipsilateraltostimulation(Fig.2(E–H)).

To analyse the effect of neurostimulation protocols in the context of the within-subjects design, a 4×2×2 ANOVA was conducted. Main effects were seen for the interaction proto-col×hand×time for both cold pain (F(3,33)=11.061, p<0.001,

2

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Fig.2. Rawsensorythresholds(warmsensation;coldsensation,heatpain,coldpain)arepresentedasdifferencesfrombaselinetemperature(32◦C)acrossdifferent neurostimulationprotocolsonthecontralateral(A–D)andipsilateral(E–H)palmarthenarofthehand(*Denotessignificancep<0.05withtheANOVAprotocol×hand×time).

Withinsubject contrasts identified nodifferences in thresh-olds after control conditions (Protocol 1: Sham tDCS – Sham rTMS or Protocol 2: Sham tDCS – 1Hz rTMS). However, Pro-tocol 3: cathodal tDCS – 1Hz rTMS resulted in a significant increase ofpain thresholds,in regards tocontralateral handto

stimulation(Right).Bothcoldpainthresholds(CP)(F(1,11)=5.57,

p<0.05,2

p=0.336)andheatpainthresholds(HP)(F(1,11)=8.67, p<0.05; 2

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Fig.3.Z-transformedsensorythresholdsacrosstheneurostimulationprotocolsandthecontralateral(right)andipsilateral(left)hands(*Denotessignificance*p<0.05within theANOVAprotocol×hand×time).

Contrastingly,Protocol4:anodaltDCS–1HzrTMSfacilitateda decreaseincoldpainthresholdsonly(F(1,11)=6.38,p<0.05,2

p= 0.367),butwithnoeffectseenonheatpainthresholds.Coldpain thresholds(CP)wereobservedtohavedecreasedsignificantlyin comparisontobaselinecondition.Ineffect,thesubjectperceived anincreasedsensitivitytopainfulthermalstimuli,meaningthey experiencedpainatlessertemperaturesthancomparedtobaseline. Forstandardizationpurposes,QSTdatawasZ-transformed.Data revealedsignificantfindingsforboththecathodalandanodaltDCS – 1Hz rTMS conditions identicaltothose seen in the previous ANOVA(Fig.3).

4. Discussion

ThisstudydemonstratesthatpreconditioningM1usingtDCS prior to1Hz rTMS effectively modulated experimentalthermal painthresholds.Further,thedirectionofpainthreshold modula-tionpost-1HzrTMSwasdependentonthepolarityoftDCSpriming. Forthecathodal(inhibitory)tDCS–1HzrTMSneurostimulation protocol, heat and cold pain thresholdssignificantly increased. Consistentwiththeconceptthatpre-conditioningwithtDCS con-trolsthedirectionoftheeffectofsubsequentrTMS;painthreshold decreaseswereobservedaftertheanodal(excitatory)tDCS–1Hz rTMSneurostimulationprotocol[3,25].

4.1. tDCSprimingtoenhance1HzrTMS

LowfrequencyrTMS(<5Hz)isthoughttofacilitateadepression ofneuronalexcitabilityandisnotefficaciousinthemodulationof painthresholds.Incontrast,highfrequencyrTMS(>5Hz)hasbeen showntoincreaseneuronalexcitabilityandconsequentlyleadtoa

parallelincreaseinpainthresholds[26].AccordingtoaCochrane review,2010,[19]lowfrequencyrTMSalone,wasnotworthyof furtherresearchasapossibleinterventionforchronicpain. How-ever,recentstudieshavedemonstratedthatpreconditioningvia tDCSreversestheexpectedeffectsofsubsequentadministrationof lowfrequencyrTMS[8],onthebasisofstandardizingtheprimary stateofactivityofthetargetedareaofthecortex.Theoretically,this mayimprovetheefficacyoflowfrequencyrTMSforpain modula-tion.OurstudyappliesSiebneretal.’s[25]findingstomodulate experimentalpainthresholds.Thatis,1HzrTMSadministeredto theM1followingaprimingsessionofcathodaltDCS,canreversethe expecteddepressiveeffectonthecortexandalternativelycausea lastingincreaseincorticalexcitability.Therefore,theirconcept pro-videsthebasisforthemodulationofpainthresholdsusingtDCSto facilitatetheefficientuseoflowfrequencyrTMS,whichisnot asso-ciatedwiththeundesirablesideeffectsthataresocloselyrelated tothatofhighfrequencyrTMS.

4.2. Modulationofpainthresholds

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M1asthemostappropriatecorticaltargetfor pain modula-tionalsoremainsatopicrequiringfurtherstudy.Themechanisms underlyingtheanalgesiceffectsafterM1stimulationarenotfully understood and the exact nature of the underlying pathways involved remains hypothetical [10].Functional imaging studies havefoundthat painfulcold and heatstimuli activatemultiple brainareasassociatedwithpainmodulation,including contralat-eralanteriorcingulatecortex(ACC);contralateralprimarymotor andsensorycortices(M1:primarymotorcortex;S1:primary sen-sorycortex); bilateralsecondary sensory cortex (S2: secondary sensorycortex)andmidinsularcortex;periaquaductalgrey mat-ter(PAG);contralateralVPthalamus;medialipsilateralthalamus andthevermisandparavermisofthecerebellum[21].PETstudies latersupportedtheseobservationsasstimulationoftheM1was seentohaveresultedinanincreasedbloodflowtotheinsularand orbitofrontalcortices;theACC;thethalamusandbrainstem[20].

Thereareanumberofproposedmechanismsofpainthreshold modulationviahighfrequencyrTMSthatmayalsoapplytothis tDCSpreconditioningstudy.Firstlytranscranialstimulationofthe M1mayalterintracorticalmotorcircuitry.AccordingtoRaijetal., highfrequencyrTMS(10Hz)wasfoundtore-establish intracor-ticalinhibitioninparallelwithpainrelief[23].Thisinhibitionof M1activitywasrelatedtotheexistenceof20Hzfrequency corti-caloscillationsthatareeliminatedinthepresenceofchronicpain. Inre-establishingthisoscillatoryactivity,itispossiblethat trans-cranialstimulationmayrestoredefectiveinhibitorymechanisms andtherebyresultinthemodulationofpainthresholds. Alterna-tively,ithasbeensuggestedthatofalltheareasactivatedbypainful stimulation,thethalamus;beingthemainrelaycentreforsensory informationtothecortex,mayhaveakeyroleinthemodulation ofpainthresholds.Ithasbeenhypothesizedthatpartofthepain reliefaffordedbystimulationofthemotorcortexcouldpossiblybe throughinfluencingthalamicactivity.HighfrequencyrTMSmay directlyactivatethethalamusviacorticothalamicprojectionsand therebysuppressthetransmissionofsensoryinformationviathe spinothalamicpathway[22].

4.3. Conclusion

InthisstudyaninhibitorysessionofcathodaltDCSwasobserved tohaveeffectivelyprimedM1resultinginaninitialdecreaseof corticalexcitability.Thismaycauseareductioninneuronal thresh-olds,therebyfacilitatingthereversaloftheexpectedsuppressive effectoflowfrequencyrTMS,andalternativelyproducinganoverall increaseincorticalactivity.Thisincreasedcorticalexcitationthen inturn,increasedsensorydetectionandpainthresholdsof ther-malstimuli,andsuccessfullyproducedaformofanalgesia.Overall, preconditioningtDCSbeforerTMSformanewpromisingapproach tothemodulationofpain,andalsootherclinicalapplications[3].

Acknowledgements

ThisworkwassupportedbytheDepartmentofPhysiology, Trin-ityCollege,Dublin.WeparticularlythankProfessorRogerAnwyl, Dr.DanielUlrich,BernardDonneandMartynCahillofTrinity Col-lege,Dublin,inregardstotheiradvicewithexperimentaldesign andcommentsoninitialversionsofthemanuscript.

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