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
i
g
h
t
s
PrimingmotorcortexwithtDCSbefore1HzrTMSstandardizesitseffects.
Thistechniqueisappliedtoexperimentalpainthresholds.
CathodaltDCS–1HzrTMSincreasedheatandcoldpainthresholds.
AnodaltDCS–1HzrTMSdecreasedcoldpainthresholds.
tDCSprimingmayhaveapplicationsinpainreliefintheclinic.
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received10October2012 Receivedinrevisedform 21November2012 Accepted22November2012
Keywords: Painmodulation tDCS
rTMS QST
a
b
s
t
r
a
c
t
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
2 T.M.Moloney,A.G.Witney/NeuroscienceLettersxxx (2012) xxx–xxx
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)).
T.M.Moloney,A.G.Witney/NeuroscienceLettersxxx (2012) xxx–xxx 3
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≥50VintherestingAPBmuscle, 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
4 T.M.Moloney,A.G.Witney/NeuroscienceLettersxxx (2012) xxx–xxx
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
T.M.Moloney,A.G.Witney/NeuroscienceLettersxxx (2012) xxx–xxx 5
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
6 T.M.Moloney,A.G.Witney/NeuroscienceLettersxxx (2012) xxx–xxx
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.
References
[1]A.Antal,D.Terney,S.Kuhnl,W.Paulus,Anodaltranscranialdirectcurrent stimulationofthemotorcortexameliorateschronicpainandreducesshort intracorticalinhibition,JournalofPainandSymptomManagement39(2010) 890–903.
[2] C.G.Bachmann,S.Muschinsky,M.A.Nitsche,R.Rolke,W.Magerl,R.D.Treede, W.Paulus,S.Happe,Transcranialdirectcurrentstimulationofthemotorcortex
inducesdistinctchangesinthermalandmechanicalsensorypercepts,Clinical Neurophysiology121(2010)2083–2089.
[3]G.Cosentino,B.Fierro,P.Paladino,S.Talamanca,S.Vigneri,A.Palermo,G.Giglia, F.Brighina,Transcranialdirectcurrentstimulationpreconditioningmodulates theeffectofhigh-frequencyrepetitivetranscranialmagneticstimulationin humanmotorcortex,EuropeanJournalofNeuroscience35(2011)119–124. [4]F.Fregni,S.Freedman,A.Pascual-Leone,Recentadvancesinthetreatmentof
chronicpainwithnon-invasivebrainstimulationtechniques,LancetNeurology (2007)188–191.
[5] H.Fruhstorfer,U.Lindblom,R.F.Schmidt,Methodofquantitativeestimationof thermalthresholdsinpatients,JournalofNeurology,Neurosurgeryand Psy-chiatry39(1976)1071–1075.
[6]H.Fruhstorfer,U.Lindblom,W.G.Schmidt,Methodforquantitative estima-tionofthermalthresholdsinpatients,JournalofNeurology,Neurosurgeryand Psychiatry39(1976)1071–1075.
[7] Y.H.Kwon,M.H.Ko,S.H.Ahn,Y.H.Kim,J.C.Song,C.H.Lee,Primarymotor cor-texactivationbytranscranialdirectcurrentstimulationinthehumanbrain, NeuroscienceLetters435(2008)56–59.
[8]N.Lang,H.R.Seibner,D.Ernst,M.A.Nitsche,W.Paulus,R.N.Lemon,J.C. Roth-well,Preconditioningwithtranscranialdirectcurrentstimulationsensitizes themotorcortextorapid-ratetranscranialmagneticstimulationandcontrols thedirectionofafter-effects,BiologicalPsychiatry56(2004)634–639. [9]N.Lang,H.R.Seibner,N.S.Ward,HowdoestranscranialDCstimulationofthe
primarymotorcortexalterregionalneuronalactivityinthehumanbrain? EuropeanJournalofNeuroscience22(2005)495–504.
[10]J.P.Lefaucheur,A.Antal,R.Ahdab,D.CiampideAndrade,F.Fregni,E.M.Khedr, M.Nitsche,W.Paulus,Theuseofrepetitivetranscranialmagneticstimulation (rTMS)andtranscranialdirectcurrentstimulation(TDCS)torelievepain,Brain Stimulation1(2008)337–344.
[11]J.P.Lefaucheur,X.Drouot,J.B.Nguyen,Interventionalneurophysiologyforpain control:durationofpainrelieffollowingrepetitivetranscranialmagnetic stim-ulationofthemotorcortex,ClinicalNeurophysiology31(2001)247–252. [12]A.Leung,M.Donohue,R.Xu,R.Lee,J.-P.Lefaucheur,E.M.Khedr,Y.Saitoh,N.
Andre-Obadia,J.Rollnik,M.Wallace,R.Chen,rTMSforsuppressingneuropathic pain:ameta-analysis,JournalofPain10(2009)1205–1216.
[13] D.Liebetanz,M.A.Nitsche,F.Tergau,W.Paulus,Pharmacologicalapproach tothemechanismsoftranscranialDC–stimulation-inducedafter-effectsof humanmotorcortexexcitability,Brain125(2002)2238–2247.
[14]F.Maeda,J.P.Keenan,J.M.Tormos,H.Topka,Interindividualvariabilityofthe modulatoryeffectsofrepetitivetranscranialmagneticstimulationoncortical excitability,ExperimentalBrainResearch133(2000)425–430.
[15]P.C.Miranda,M.Lomarev,M.Hallett,Modelingthecurrentdistributionduring transcranialdirectcurrentstimulation,ClinicalNeurophysiology117(2006) 1623–1629.
[16] V.Mylius,J.J.Borckardt,J.P.Lefaucheur,Noninvasivecorticalmodulationof experimentalpain,Pain153(2012)1350–1363.
[17]M.A.Nitsche,W.Paulus,Excitabilitychangesinducedinthehumanmotor cor-texbyweaktranscranialdirectcurrentstimulation,JournalofPhysiology527 (2000)633–639.
[18]M.A.Nitsche,A.Seeber,K.Frommann,C.C.Klein,C.Rochford,M.S.Nitsche,K. Frick,D.Liebetanz,N.Lang,A.Antal,W.Paulus,F.Tergau,Modulating param-etersofexcitabilityduringandaftertranscranialdirectcurrentstimulationof thehumanmotorcortex,TheJournalofPhysiology568(2005)291–303. [19]N.E. O‘Connell, B.M. Wand, L. Marston, S. Spencer, L.H. De Souza,
Non-invasive brain stimulation techniques for chronic pain, Cochrane DatabaseSystematicReview6(9)(2010)1–126,http://dx.doi.org/10.1002/ 14651858.CD008208.pub2.
[20]R. Peyron,I.Faillenot,P.Mertons,B.Laurent,L.Garcia-Larrea,Motor cor-tex stimulationinneuropathicpain.Correlationsbetweenanalgesiceffect andhemodynamicchangesinthebrain.APETstudy,Neuroimage34(2007) 310–321.
[21]R.Peyron,B.Laurent,L.Garcia-Larrea,Functionalimagingofbrainresponsesto pain.Areviewandmeta-analysis,ClinicalNeurophysiology30(2000)263–288. [22] B.Pleger,F.Jansenn,P.Schwenkreis,B.Volker,C.Maier,M.Tegenthoff, Repet-itivetranscranialmagneticstimulationofthemotorcortexattenuatespain perceptionincomplexregionalpainsyndrometypeI,NeuroscienceLetters 356(2004)87–90.
[23]T.T.Raij,N.Forss,A.Stancak,R.Hari,Modulationofmotor-cortexoscillatory activitybypainfulA␦-andC-fiberstimuli,Neuroimage23(2)(2004)569–573. [24]S.Rossi,M.Hallett,P.M.Rossini,A.Pascual-Leone,T.S.o.T.C.Group,Safety, ethicalconsideration,andapplicationguidelinesfortheuseoftranscranial magnetic stimulation in clinical practice and research, Clinical Neuro-physiology120(2009)2008–2039.
[25]R.H.Siebner,N.Lang,V.Rizzo,M.A.Nitsche,W.Paulus,R.N.Lemon,J.C.Rothwell, Preconditioningoflowfrequencyrepetitivetranscranialmagneticstimulation withtranscranialdirectcurrentstimulation:evidenceforhomeostatic plastic-ityinthehumanmotorcortex,JournalofNeuroscience24(2004)3379–3385. [26]J.Summers,S.Johnson,S.Pridmore,G.Oberoi,Changestocolddetectionand painthresholdsfollowinglowandhighfrequencytranscranialmagnetic stim-ulationofthemotorcortex,NeuroscienceLetters368(2004)197–200. [27]T.Wagner,A.Valero-Cabre,A.Pascual-Leone,Non-invasivehumanbrain
stim-ulation,AnnualReviewofBiomedicalEngineering9(2007)527–565. [28]S.Zaghi,N.Heine,F.Fregni,Brainstimulationforthetreatmentofpain:a