Modelling non-invasive brain stimulation in cognitive neuroscience

(1)

ContentslistsavailableatSciVerseScienceDirect

Neuroscience

and

Biobehavioral

Reviews

jo u rn al h om ep a ge : w w w . e l s e v i e r . c o m / l o c a t e / n e u b i o r e v

Review

Modelling

non-invasive

brain

stimulation

in

cognitive

neuroscience

夽

Carlo

Miniussi

a,b,∗

_,

_Justin

_A.

_Harris

c

_,

_Manuela

_Ruzzoli

d

a_Department_of_Clinical_and_Experimental_Sciences,_National_Neuroscience_Institute,_University_of_Brescia,_Brescia,_Italy b_Cognitive_Neuroscience_Section,_IRCCS_Centro_San_Giovanni_di_Dio_{Fatebenefratelli,}_Brescia,_Italy

c_School_of_Psychology,_The_University_of_Sydney,_Australia

d_Center_for_Brain_and_Cognition,_Departament_de_Tecnologies_de_la_Informació_i_les_{Comunicacions,}_Universitat_Pompeu_Fabra,_Barcelona,_Spain

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received15April2013

Receivedinrevisedform18June2013 Accepted20June2013 Keywords: Behaviour Noise Pedestaleffect rTMS tES Stochasticresonance tACS tDCS TMS tRNS

a

b

s

t

r

a

c

t

Non-invasivebrainstimulation(NIBS)isamethodforthestudyofcognitivefunctionthatisquickly gainingpopularity.Itbypassesthecorrelativeapproachesofotherimagingtechniques,makingitpossible toestablishacausalrelationshipbetweencognitiveprocessesandthefunctioningofspeciﬁcbrainareas. Likelesionstudies,NIBScanprovideinformationaboutwhereaparticularprocessoccurs.However,NIBS offerstheopportunitytostudybrainmechanismsbeyondprocesslocalisation,providinginformation aboutwhenactivityinagivenbrainregionisinvolvedinacognitiveprocess,andevenhowitisinvolved. WhenusingNIBStoexplorecognitiveprocesses,itisimportanttounderstandnotonlyhowNIBSfunctions butalsothefunctioningoftheneuralstructuresthemselves.WeknowthatNIBStechniqueshavethe potentialtotransientlyinﬂuencebehaviourbyalteringneuronalactivity,whichmayhavefacilitatory orinhibitorybehaviouraleffects,andthesealterationscanbeusedtounderstandhowthebrainworks. GiventhatNIBSnecessarilyinvolvestherelativelyindiscriminateactivationoflargenumbersofneurons, itsimpactonaneuralsystemcanbeeasilyunderstoodasmodulationofneuralactivitythatchangesthe relationbetweennoiseandsignal.Inthisreview,wedescribethemutualinteractionsbetweenNIBSand brainactivityandprovideanupdatedandpreciseperspectiveonthetheoreticalframeworksofNIBSand theirimpactoncognitiveneuroscience.Bytransitioningourdiscussionfromoneaspect(NIBS)tothe other(cognition),weaimtoprovideinsightstoguidefutureresearch.

Contents

1. Introduction... 1703

2. Transcranialmagneticstimulation... 1703

2.1. Thevirtuallesionmetaphor... 1703

2.2. Signalreductionversusnoisegeneration... 1704

2.3. Statedependency ... 1705

2.4. Entrainment... 1706

3. Transcranialelectricstimulation... 1707

3.1. Transcranialdirectcurrentstimulation... 1707

3.2. Transcranialalternatingcurrentstimulation... 1708

3.3. Transcranialrandomnoisestimulation... 1708

4. AuniﬁedhypothesisofthefunctionaleffectsofNIBS:noisegenerationinanon-linearsystem... 1709

5. Conclusions... 1710

References... 1710

夽 Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,distributionandreproductionin anymedium,providedtheoriginalauthorandsourcearecredited.

∗ Correspondingauthorat:DepartmentofClinicalandExperimentalSciences,UniversityofBrescia,VialeEuropa11,25123Brescia,Italy.Tel.:+390303501597. E-mailaddress:carlo.miniussi@cognitiveneuroscience.it(C.Miniussi).

(2)

1. Introduction

Non-invasivebrainstimulation(NIBS)methods,whichinclude transcranialmagneticstimulation(TMS)andtranscranialelectric stimulation(tES),areusedincognitiveneurosciencetoinduce tran-sientchangesinbrainactivityandtherebyalterthebehaviourof thesubject.TheapplicationofNIBSaimsatestablishingtherole ofagivencorticalareainanongoingspeciﬁcmotor,perceptualor cognitiveprocess(Hallett,2000;WalshandCowey,2000).

Physically,NIBStechniquesaffectneuronalstatesthrough dif-ferentmechanisms.InTMS,asolenoid(coil)isusedtodelivera strongandtransientmagneticﬁeld,or“pulse”,toinducea tran-sitoryelectriccurrentatthecorticalsurfacebeneaththecoil.The pulsecausestherapidandabove-thresholddepolarisationofcell membranesaffectedbythecurrent(Barkeretal.,1985,1987), fol-lowedbythetransynapticdepolarisationorhyperpolarisationof inter-connectedneurons.Therefore,TMSinduces acurrent that elicitsactionpotentialsinneurons.

By contrast, in tES techniques, the stimulation involvesthe applicationofweakelectricalcurrentsdirectlytothescalpthrough apairofelectrodes(NitscheandPaulus,2000;Priorietal.,1998).As aresult,tESinducesasubthresholdpolarisationofcorticalneurons thatistooweaktogenerateanactionpotential.However,by chang-ingtheintrinsicneuronalexcitability,tEScaninducechangesinthe restingmembranepotentialandthepostsynapticactivityof corti-calneurons.This,inturn,canalterthespontaneousﬁringrateof neuronsandmodulatetheirresponsetoafferentsignals(Bindman etal.,1962,1964,1979;Creutzfeldtetal.,1962),leadingtochanges insynapticefﬁcacy.

TheapplicationofNIBSinvolvesdifferenttypesofprotocols: TMScanbedeliveredasasinglepulse(spTMS)ataprecisetime, aspairsofpulsesseparatedbyavariableinterval,orasaseriesof stimuliinconventionalorpatternedprotocolsofrepetitiveTMS (rTMS)(foracompleteclassiﬁcationseeRossietal.,2009).IntES, differentprotocolsareestablishedbytheelectricalcurrentused andbyitspolarity,whichcanbedirect(anodalorcathodal transcra-nialdirectcurrentstimulation:tDCS),alternatingataﬁxfrequency (transcranialalternatingcurrentstimulation:tACS)oratrandom frequencies(transcranialrandomnoisestimulation:tRNS)(Nitsche etal.,2008;Paulus,2011).

In general,the ﬁnal effects of NIBS on the central nervous systemdependona lengthylistofparameters (e.g.,frequency, temporalcharacteristics,intensity,geometricconﬁgurationofthe coil/electrode,currentdirection),whenitisdeliveredbefore (off-line) or during (on-line) the task as part of the experimental procedure(e.g.,Jacobsonetal.,2011;NitscheandPaulus,2011; Sandrinietal.,2011).Inaddition,thesefactorsinteractwith sev-eralvariablesrelatedtotheanatomy(e.g.,propertiesofthebrain tissue anditslocation,Radman etal.,2007), aswellas physio-logical(e.g.,genderandage,LandiandRossini,2010;Langetal., 2011;Ridding and Ziemann,2010)andcognitive(e.g.,Miniussi etal.,2010;Silvantoetal.,2008;Walshetal.,1998)statesofthe stimulatedarea/subject.

Thisreviewwillfocusonlyontheso-called“on-line” proce-dures.Itwillnotincludeconsiderationof“off-line”protocolswith TMSandtES,inwhichtaskperformanceiscomparedbeforeversus afterstimulation,butisnotassessedduringstimulation.Off-line stimulationinvolvesneuronal activitychangesthat last beyond stimulation(i.e.,short-andlong-termpotentiationordepression, homeostasisofthesystem,metaplasticity)andtoacertainextent aredifferentfromthebasicmechanismsofactionbywhichNIBS directlymodulatesongoingbrainfunctioninon-lineprotocols. Off-lineprotocolswithTMSandtESinduceachangeinthestateof stimulatedareaandthereforetheycanbecomparetotheconceptof statedependency.Inthiscasethechangeinthestateisnotinduced byataskorsubministrationofasubstancebutbyNIBSaftereffects.

WeaimtopresentauniﬁedframeworkforNIBSapproaches.We willlaythegroundworkbyfocusingonthetheoreticaland physi-ologicalmechanismsofactionthathistoricallyhavebeenapplied toTMSandtES,buildingupacoherentviewforexplainingNIBS effectsincognitiveneuroscience.Theunifyingthemeofour per-spectiveistheinductionofneuralnoise,whoseinteractionswith thetask-inducedstateofthestimulatedareawilldeterminethe ﬁnalbehaviouraloutcome.Webelievethatourperspectiveoffers increasedexplanatory powerfor NIBS-induced effects, and will thereforeprovideaddedimpetusforfutureapplications.

2. Transcranialmagneticstimulation

2.1. Thevirtuallesionmetaphor

Theﬁrst ideaconcerningtheeffects of TMSwasthat of the “virtuallesion”approach(Pascual-Leoneetal.,2000;Walshetal., 1998;Walshand Rushworth,1999).By analogywith neuropsy-chologicalstudies,butwithoutmanyoftheconfoundingfactors thattroublepatientstudies(suchascompensationmechanisms, diaschisis, dimensionof thelesion and single-subjectsamples). Theapplication ofTMS couldhinder thefunctioningofa given areaforseveralmilliseconds,andtherebyestablishacausalnexus betweenthestimulatedbrainregionandaparticularfunction.The ideafollowsthestandardlogicofinference.IfcorticalareaAis involvedincognitiveprocessXandisnotinvolvedinprocessY, thealterationoftheactivityofareaAwillresultinaltered per-formanceinX(andnotY);thus,areaAplaysacausalroleinthe performanceofX(andnotY).Inthissense,TMSdescribesa pro-cessinwhich theoryisextractedfromdirect interventionsand overcomesthefundamentallimitsofthecorrelativeapproachesof imagingtechniques[e.g.,functionalmagneticresonance,positron emissiontomography,electroencephalography (EEG)],providing an opportunity to test directly and non-invasively causal rela-tionshipsbetweenthebrainandcognition.Theﬁrstexperiment thatappliedthislogic incognitiveneuroscience wasperformed byAmassianetal.(1989).Theystimulatedtheoccipitalcortexby spTMS,whichwastime-lockedtothepresentationofavisual stim-ulus,whiletheparticipantstriedtodetectthevisualstimulus.The participants’errorrateincreasedwhenTMSwasappliedbetween ∼80and120msfollowingthepresentationofthevisualstimulus. Theauthorsconcludedthattheoccipitalcortex(i.e.,where)makes acriticalcontributiontostimulusrecognitiononlyatthatprecise timewindow(i.e.,when)(Amassianetal.,1989).

Thevirtuallesionapproachreferstothepossibilityofcausally ascertaining wherecognition occursin thebrain. In this sense, TMShasborrowedexperimentalhypothesesfrom neuropsychol-ogy and, after extensive testing, has confirmed most of them (see Miniussi et al., 2012b; Walsh and Pascual-Leone, 2003; Wassermannetal.,2008).Duetoitshightemporalspecificity,TMS hasalsobeenemployedtostudythetimepointatwhicha cogni-tiveeventoccursinthebrain.Forthispurpose,spTMSissuperiorto rTMSbecauseitconfinestheimpactofstimulationtoasmall frac-tionofasecond.Mentalchronometryhasbeenextensivelyapplied toperceptual(e.g.,Amassianetal.,1989; Corthoutetal.,1999; Laycocketal.,2007;Marzietal.,1998;Seyaletal.,1992)or higher-ordercognitiveprocesses(e.g.,Ashbridgeetal.,1997;Chambers etal.,2004;HarrisandMiniussi,2003;Kahnetal.,2005;Mottaghy etal.,2003)andhasbeenusefulindefiningthetemporalactivation ofsinglebrainareasaswellasascertainingtherelativetemporal rolesofdifferentareasinthesamecognitiveprocess,along the continuumofinformationprocessing.

Althoughthe‘virtuallesionassumption’isaveryuseful heuris-ticwheninterpretingthebehaviouraleffectsofNIBS,weneedto developamoresophisticatedexplanatoryframeworkifwewishto

(3)

useNIBStodevelopandtestmorecomplextheoreticalmodels.The virtuallesionapproachattributesanimpairmentofperformanceto alesion,yetthereisnoactualevidencetosupportthisassumption anditwasnotoriginallyintendedinthatmanner.Indeed,inits originaldefinition,theconceptwasexpressedas‘Inthecontext ofatask,theinducedcurrentoperatesas“neuralnoise”;thatis, thepulseaddsrandomactivityinthemidstoforganisedactivity inthecorticalregion.Thisneuralnoiseservestodelayordisrupt performance,anditisinthissensethatTMSoperatesasalesion’ (WalshandRushworth,1999,p.127).Asisfrequentlythecase, tak-ingananalogytooliterallyandtransformingitintoamechanism ofactionisunproductiveinscience.Weshouldconsidertheterm lesiontobeequivalenttoalackofneuralactivityasawholeand, consequently,amissedopportunitytoprocessinformation.By con-trast,theacuteimpactofstimulationcanbepositiveinthesenseof inducedneuralactivityinpoolsofcorticalneuronsunderneaththe coil,evenifthatneuralactivitymightinterferewiththe opportu-nitytoprocessspecificinformationbecauseitcompeteswiththe neuralactivitythatrepresentsthestimulus.Thustheuseful heuris-ticusedtodescribethefinalresultscannotbeusedtointerpretthe functionalmechanismsoftheeffectsinduced;assuchtheeffects thatarehighlightedinTMSstudiescannotbedirectlycompared withthoseoflesionstudies.Furthermore,theuseofTMSasa dis-turbanceapparatushasneverproducedacategoricalfailureinthe subject’sperformancesimilartotheeffectsobservedin neuropsy-chologicalpatients.Thetypeofeffectobtainedisoftenrelatedtoan increaseinthelengthoftimerequiredforinformationprocessing (e.g.,increasedreactiontime),andifareductioninthesubject’s performanceisobserved,itismostlikelyexplainedbythe com-plexityoftheprocessingthatisneededtosolvethetask(Manenti etal.,2008).Inthiscontext,weshouldconsiderTMStobeatool thatinjectsactivitythatcompetesorinteractswithresourcesto solvethetask,thusslowingorhinderingtaskexecution.Moreover, TMShasalsobeenshowntoenhanceperformanceonmany per-ceptualandcognitivetasks(forareviewseeVallarandBolognini, 2011),oftentothesurpriseoftheresearchersinvolved,and lead-ingtocontradictoryexplanationsinthevirtuallesionframework. Indeed,oneofthelimitsof thevirtuallesionhypothesisis that itonlypostulatesanimpairmentofperformance,whileany pos-itiveresultshavebeenaddressedasaparadoxicaleffect.Another shortcomingwiththe“virtuallesion”frameworkisthatits mean-ingisunclear–whatformdoesa“virtual”lesiontakeandhowis itgenerated?TMSmayinterrupttherelevantsignalby terminat-ingneuronalactivityoritmightinduceinterferingactivity(neural noise)inthestimulatedarea;bothwouldmodifyperformancebut throughcompletelydifferentmechanismsofaction(Ruzzolietal., 2010).

Atthispoint,basedontheliterature,wecantradesomeofthe simplicityofthevirtuallesionapproachforincreasedexplanatory powerbyexaminingpossiblealternativehypotheses.Clearly,this stepforwardwillnotinvalidatethestandardlogicofinference(area AplaysacausalroleintheperformanceofprocessXbutnotY).The logicwillbethesame,butitwillallowustodrawtheconclusions fromamoreinformedperspective,abovealltakingintoaccount thatwearestimulatingacomplexadaptivesystem.

2.2. Signalreductionversusnoisegeneration

TMSintroduces activitybydepolarising neurons(Ruohonen, 2003).Forexample,a studythataimedtodirectlymeasurethe effectsinducedbyTMSatthecellularlevel(Moliadzeetal.,2003) demonstratedthat spTMSinduces aneuronal facilitationeffect, enhancingevokedactivityduringtheﬁrst∼500ms,andthereafter decreasingthisactivityforuptoafewseconds.Thedurationof theseeffectswasmodulatedbytheintensityofstimulation,and increasingstimulusintensityledtoanearlypartialsuppressionof

activityapproximately100–150ms,followedbystronger facilita-tion.Howcandepolarisationofneuronscauseinterference?

Neuralcodingisconcernedwiththewayinwhichsensory infor-mationisrepresentedinthebrainbyneurons.Oneofthewaysto codethesignalintensity/strengthisrelatedtoneuronfiring fre-quencyorratecoding,wheresignificanteventsareencodedbythe averageactivityofapoolofneurons(e.g.,Adrian,1928;Bialekand Rieke,1992)(considerthatthisisasimplification,andothertypes oftemporalcodingexistsaswell).Neuronsrespondtotheincreased strengthofastimulusbyincreasingtheirfiringfrequencyandby increasingthenumberof firingneurons(population coding).In behaviouralterms,wecansaythattheactivationofasmallnumber ofneuronsand/oralowfiringrate(i.e.,aweaksignal)willproduce aslowreactiontime(RT)andalowlevelofaccuracyindetecting thestimulustarget.Ifthenumberofneuronsandthefrequency rateincrease,theRTwilllikelybefaster,andtheaccuracymaybe higher.

Nevertheless,thefinal responsegiven bythesystemwillbe basednotsolely onthestrengthofthesignalthatcodes forthe targetbutontheratiobetweenthat signalandotherirrelevant activitythatwecandefineasnoise(seeFig.1aandbnoNIBS condi-tions).Thus,theaccuracyindetectingthetargetwillbebasedonthe relationbetweensignalandnoise(i.e.,thesignal-to-noiseratio).If TMSincreasestheneuralnoise,itwillchangetheratiobetween theactivityofneuronsthatcodeforthetargetandtheactivityof otherneurons(non-specificactivityforthetask),decreasingthe finalperformance.Thiseffectcouldbeinterpretedasthegeneration (increase)ofbackgroundneuralactivity(noise)byTMS,activity thatisunrelatedwithrespecttotherelevantinformation/signal carriedbythestimulatedarea(Fig.1bNIBShighcoherence). Nev-erthelesstheTMS-inducedactivityisnottotallyrandom;thatis,the activityinducedbyTMSmaynotbeindependentofthe stimulus-inducedneuralactivityorwhat werefer toasthe‘stateofthe area’ (seethestate-dependencydescribed below)(Pasley etal., 2009),inwhichcasetheeffectofTMSisnotstatisticallypurenoise (Harrisetal.,2008;Ruzzolietal.,2011)(seeFig.1bNIBS condi-tions).Theprobabilitythataneuronwillbeactivatedbyamagnetic pulsedependsonitsneurophysiologicalstateandonitsspatialand anatomicalcharacteristics,inrelationtotheinducedelectricfield (Amassianetal.,1992;Roth,1994)asillustratedinFig.2. More-over,becausethesignalcanonlybedefinedinconjunctionwitha well-definedstateofthesystem,definingtheassumednatureof thesystemandthetaskdemandhelpstodefinesignals.

Communicationinthenervoussystemalsoreliesonthe tempo-ralcomponentofthefiringrateofaneuralpopulation.Theprecise timingofactionpotentials,andinparticularthetemporal relation-shipofactionpotentialgenerationbetweenneurons,isasignificant elementin neuralcommunication (temporalcoding, Bialekand Rieke,1992).Ina givenareaatagiventime,manysignals con-verge,butonlythosethatwillbeassociatedintime(haveasimilar distribution,seeWuetal.,2002)willgiverisetoeffective commu-nicationmechanisms(BiandPoo,2001).TMS-inducednoisecan interferewithperformancebecauseitcanincreasethenumberof neuronsthatfirewithouttemporalsynchronisation,thus obstruct-ingthesynchronisedconversationbetweenneuronsthatcodefor thegoal.Therefore,neuronresponseswillnotvarylinearlywith thecharacteristicsofthestimulus,andthevarianceofthe inter-nalstimulusdistributionwillincrease,sothatthetemporalcoding ofdischarge bya given populationwillnotbe ensured. Conse-quently,communicationatahigherhierarchicallevelthatrelies onthetimingofthespikingofconverginginformationfrom differ-entareaswillnotbepossible(Guyonneauetal.,2004;Masquelier andThorpe,2007).Thisisjustadifferentwaytoseetheaction ofNIBSonneurons,whiletheeffectsonthesystemswillbethe sameregardlessofthefactthattheinformationiscarriedbyrate ortemporalcoding.

(4)

Threshold Max

A

B

noise

noise noise nois

e

noise target

medium coherence high coherence

Threshold

No NIBS NIBS No NIBS NIBS

Max

Fig.1.(A)Thisfigureillustratestherelationbetweentargetsignalandothernon-targetsignals.Thoseneuronsthatrespondaccordingtothetask-goalaredisplayedastarget signal(yellow),allothersourcesofactivitythatarenotassociatedwiththefinaltask-goalaredefinedasneuronalnoise(purple).Thethresholdrepresentstheminimum intensityofasignaltoreachtheleveltobeincludedinthefinalsubjectivejudgement.Theverticalbarindicatesthesignalstrengthforthejudgement,itsdimensionrepresents thefeaturesofthefinalbehaviouraloutcomeofasysteme.g.,thespeedofreactiontimesordegreeofaccuracy.Thelargerthedifference,thefaster/betterthebehavioural performance.(B)ThenoNIBSplotsillustratetheinteractionbetweentargetsignalandnon-targetactivity(noise)whenanobservertriestoidentifythedirectionofmotion ofamovingstimulus(upperpartofthefigure),dependingonthedifficultyofthetask(lowvs.highmotioncoherence).TheNIBSplotsrepresentpossibleeffectsofNIBSon theneuralpopulationwhoseactivityisbasedonthetaskdemands.Thefinalbehaviouraloutcomewilldependonthefinalneuronalpatterns.Thispatternwillbegivenby theinteractionbetweenthepresentstateandNIBSinducedactivity.NIBS=non-invasivebrainstimulation.(Forinterpretationofthereferencestocolorinthisfigurelegend, thereaderisreferredtothewebversionofthearticle.)

As stated previously, the virtual lesion hypothesis can only predictimpairmentsofperformance;anypositiveresultsare con-sidered paradoxical. But,based on theneural noise generation hypothesis,itiseasytoexplaineitheroutcome.Noiseisthemajor sourceofvariabilitybecauseitisrandomactivitythatis uncor-relatedwithinitselfandwiththegoalofthetaskandwillresult intheimpairmentofperformance.Neverthelessweshould con-siderthatnoisepervadeseverylevelofinformationprocessingin thenervoussystem,fromreceptorsignaltransductiontotheﬁnal behaviouralresponse(Faisaletal.,2008).Moreover,innon-linear systems,suchasthebrain,informationatthethresholdlevelcan bebetterprocessedwithinanoptimumlevelofnoise(comparedto withoutnoise),assuggestedbytheconceptofstochasticresonance. Thiscanbeconsideredapotentialbeneﬁtofnoise(Kitajoetal., 2003,2007;Miniussietal.,2010;Mossetal.,2004;Ruzzolietal., 2010;Schwarzkopfetal.,2011)becausetheinducednoisyactivity maybesynchronisedwiththeongoingrelevantsignal(Ermentrout etal.,2008;Steinetal.,2005).Inthiscontextthepresenceof neu-ronalnoisemightconfertoneuronsmoresensitivitytoagiven rangeofweakinputs(Kitajoetal.,2003,2007),therebyrendering thesignal“stronger”oreven“synchronised”(seeFig.3).TMSmay induceneuronalactivitythataddstotheongoingneuralactivity, whichcanbeconsideredtobepartofthesignalandnotrandom noisedependingontheneuronsthatwillbeactivatedbythetask andthestimulus.

The noise generationhypothesis in NIBS can beunderstood within a slightly different framework based in psychophysics (Solomon, 2009). This perspective was tested experimentally by Abrahamyan et al. (2011), who applied spTMS at different

intensitiesoverV1andconcurrentlymeasuredthethresholdfor detectionofavisualstimulus.Theyfoundthat,atweakintensities belowthephosphenethreshold,TMSsigniﬁcantlyimproved per-formance.Thestudyalsoconﬁrmedthewell-establishedeffectthat highTMSintensities(abovethephosphenethreshold)decreases subjects’visualsensitivity (Amassianet al.,1989).Abrahamyan andcolleaguesarguedthatTMSactsasa“pedestal”(Nachmiasand Sansbury,1974)toincreasetheresponseofthevisualsystem,and thisincrease couldresultinanimprovementora decrementin sensitivitydependingonthescaleofthesensoryandTMS-induced inputs.We returntothis descriptioninmore detaillater,when describingthebiphasicinput-responsefunctionthatcharacterises thebehaviourofneuralsystems.

Experimentalevidencesupportingthenoisegeneration hypoth-esis hasbeenprovided independently by differentTMS studies (Rahnevetal.,2012;Ruzzolietal.,2010;Schwarzkopfetal.,2011; WaterstonandPack,2010),andtheﬁnalresultisthephysiological sumoftheunderlinedcomplexactivityofsubpopulationsof neu-ronsthatcoexistinthestimulatedarea(Rahnevetal.,2012).Thus, abandoningthevirtuallesionapproachinfavourofthedeﬁnition oftheprecisemechanismsofactionmakesitpossibletotestnew hypothesesandtoexpandtheprospectiveapplicationsofTMS. 2.3. Statedependency

Asdescribedabove,wecannotdeducepureTMS-inducedeffects becausetheeffects ofTMSareproportional tothelevelof neu-ronalactivationduringtheapplicationofthepulses(Epsteinand Rothwell,2003).Inthemotorsystem,forexample,theamplitude

(5)

Fig.2. Thefiguredepictsthesituationwheretherandomneuralnoiseinducedby transcranialmagneticstimulation(TMS)willinteractwiththesystemstate. Cir-clesrepresentthehypotheticalstateofneurons.Thefinalpatternwilldependon therelationbetweenactivatedandnon-activatedneuronsandthelocationofthe inducedelectricfield.Thefinalbehaviouraloutcomewilllikelybeanimprovement inperformancein(A)oraworseningofperformancein(B).

Input Time Time Input+noise Time Time

A

B

C

D

Fig.3.Stochasticresonance.Theamountofnoiseintroducedinthesubthreshold sinusoidalsignalcanchangetheﬁnaloutput.Theﬁnalsignalresultsin:(A)Nooutput whennonoiseisintroduce.(B)Verylittleoutputwhenpresentedinthepresenceof weaknoise.(C)Thebestsignalrepresentationwhencombinedwithoptimumlevel ofnoise.(D)Randomandindistinguishablefromnoisealone,whenhighnoiseis introduced(fromWardetal.,2006).

ofthemotor-evokedpotentialcanbeincreasedbythevoluntary contractionofthetargetmuscle(Rothwelletal.,1987)andcortical connectionscanalsobe‘modulated’bythesystemstate(Ferbert etal.,1992).Thisdependenceonstatewasfirstarticulated,inthe TMSfield, bySilvanto (seealsoMoliadzeetal.,2003; Sackand Linden,2003;Silvantoetal.,2008).Accordingtostate-dependency, TMSwillaffectthe“less-activeneuronswithinthestimulatedarea”. Inawell-designedexperiment,Silvantoetal.(2007)adapted sub-jects toa red/greenscreen. Aftercolour adaptation,deliveryof spTMSovertheoccipitalcortexelicitedphosphenesthattookon thesamecolourastheadaptingstimulus.Similarly,adaptationtoa motionstimulusallowedTMStofacilitatethedetectionofmotion intheadapteddirection,whileimpairingthedetectionofmotionin theoppositedirection(Silvantoetal.,2007).State-dependencyhas beentestedandvalidatedunderdifferentexperimentalprotocols (i.e.,primingoradaptation)andfordifferentbrainareas(Cattaneo etal.,2008,2010).Pasleyetal.(2009)attemptedtoprovide physio-logicalsupportforthishypothesis.TheyappliedrTMStothevisual cortexofanaesthetisedcatsandobservedspontaneousand visu-allyevokedneuralactivityintermsofvariability.Theyfoundthat thehigherthepre-TMSlevel ofactivity,thegreater theimpact ofTMSduringspontaneousactivity.Bycontrast,forevoked activ-ity(evokedbyavisualstimulus),thegreaterthebaselineactivity, thelowerthepoweroftheeffectinducedbyTMS(Pasleyetal., 2009).Clearly,statedependencyagaindoesnotprovideanexplicit mechanismofhowTMSaffectscognition;however,state depend-encyisanapproachthatdoesallowneuroscientiststoreconsider theimportanceofthestimulatedareabasedonitsfunctional acti-vationduringaparticulartask.Usingthispracticalapproachwe havetheopportunitytodisentangletheroleof differentneural populationswithinthestimulatedarea.Inthiscontext,wecould considerstatedependencyaformofmetaplasticitythatdescribes theactivity-dependentmodificationofthesystem(Abraham,2008; Bienenstocketal.,1982).

2.4. Entrainment

AmorerecentapplicationofTMSisbasedonwhatisknownas theentrainmenthypothesis(ThutandMiniussi,2009;Thutetal., 2011a,2012),thatis,thepossibilityofinducingaparticular oscil-lationfrequencyinthebrainbymeansofanexternaloscillatory force(e.g.,rTMS,butalsotACS).Thephysiologicalbasisof oscilla-torycorticalactivityliesinthetimingoftheinteractingneurons; whengroupsofneuronssynchronisetheirﬁringactivities,brain rhythmsemerge,networkoscillationsaregenerated,andthebasis forinteractionsbetweenbrainareasmaydevelop(Buzsàki,2006). Differentcognitivestatesareassociatedwithdifferentoscillatory patternsinthebrain(Buzsàki,2006; Canoltyand Knight,2010; Varelaetal.,2001).

Recently,Thutetal. (2011b)directlytested theentrainment hypothesisbymeansofaconcurrentEEG–TMSexperiment.They first determined the individual source of the parietal–occipital alphamodulationandtheindividualalphafrequency (magnetoen-cephalographystudy). TheythenappliedrTMSattheindividual alphapowerwhilerecordingtheEEGactivityatrest.Theresults confirmedthethreepredictionsoftheentrainmenthypothesis:the inductionofaspecificfrequencyafterTMS,theenhancementof oscillationduringTMSstimulationduetosynchronisation,anda phasealignmentoftheinducedfrequencyandtheongoingactivity (Thutetal.,2011b).Ifassociativestimulationisageneral princi-pleforhumanneuralplasticityinwhichthetimingandstrength ofactivationarecriticalfactors,itispossiblethatsynchronisation withinor betweenareasusing anexternal forcetophase/align oscillationscanalsofavourefficientcommunicationand associa-tiveplasticity(oraltercommunication).Inthisrespectassociative, cortico-corticalstimulationhasbeenshowntoenhancecoherence

(6)

ofoscillatoryactivitybetweenthestimulatedareas(Plewniaetal., 2008).Here,anotherformofstochasticresonance,thecoherence resonance(Longtin,1997),canbeintroduced.Incoherence reso-nance,theadditionofacertainamountofnoise inanexcitable system results in the most coherent and proficient oscillatory responses.Thebrain’sresponsetoexternaltiming-embedded stim-ulationcanresultinadecreaseinphasevarianceandanenhanced alignment(clustering)ofthephasecomponentsoftheongoingEEG activity(entraining,phaseresetting)thatcanchangethe signal-to-noise ratioand increase (ordecrease)signal efficacy.In this context, phase resettingor shiftingcansynchronise inputs and favourcommunicationand,eventually,Hebbianplasticity(Hebb, 1949).Thus,rhythmicstimulationmayinduceastatisticallyhigher degreeofcoherenceinspikingneurons,whichfacilitatesthe induc-tionofaspecificcognitiveprocess(orhindersthatprocess).Here, theperspectiveisslightlydifferent(coherenceresonance),butthe underliningmechanismsaresimilartotheonesdescribedsofar (stochasticresonance)andtheadditionalkeyfactoristherepetition ataspecificrhythmofthestimulation.

ThereareindicationsinTMS–EEGresearchthatentrainmentis plausiblebecauseofthecharacteristicsoftheEEGresponsestoa singleTMSpulse.ThespectralcompositionsoftheEEGresponses resemblethespontaneousoscillationsof thestimulatedcortex. Forexample,TMSofthe“resting” visual(Rosanovaetal.,2009) ormotorcortices(Venieroetal.,2011)triggersalpha-waves,the naturalfrequencyattherestingstateofbothtypesofcortices.

Withtheentrainmenthypothesis,thenoisegeneration frame-workmovestoamorecomplexandextendedlevelinwhichnoise issynchronisedwithon-goingactivity.Neverthelessthemodelto explaintheﬁnaloutcomewillnotchange,stimulationwillinteract withthesystemandtheﬁnalresultwilldependonintroducingor modifyingthenoiselevel.

The entrainment hypothesis makes clear predictions with respecttoon-line repetitiveTMSparadigms’frequency engage-mentaswellasthepossibilityofinducingphasealignment,i.e., aresetofongoingbrainoscillationsviaexternalspTMS(Thutetal., 2011a,2012;Venieroetal.,2011).Theentrainmenthypothesisis superiortothelocalisationapproachingainingknowledgeabout howthebrainworks,ratherthanwhereorwhenasingleprocess occurs.Inthissense,TMSislikelythebestavailablemethodtotesta renewedtopicinneuroscience:theroleofbrainoscillations.Infact, itistemptingtospeculatethatoneTMSpulsewillphase-alignthe natural,ongoingoscillationofthetargetcortex.Whenadditional TMS pulses are delivered in synchronywith thephase-aligned oscillation(i.e.,atthesamefrequency),furthersynchronised phase-alignmentwilloccur,whichwillbringtheoscillationofthetarget areainresonancewiththeTMStrain.Hence,weexpect entrain-mentincasesoffrequency-tuningofTMStotheunderlyingbrain oscillations(Venieroetal.,2011).

3. Transcranialelectricstimulation

Aspreviouslyreported,tES (tDCS,tACS,and tRNS)isa non-invasive method of cortical stimulation in which weak direct currentsareusedtopolarisetargetbrainregions.Themostused andbestknownmethodistDCS,asallconsiderationsfortheuseof tDCShavebeenextendedtotheothertESmethods.The hypothe-sesconcerningtheapplicationoftDCSincognitionareverysimilar tothoseofTMS,withtheexceptionthattDCSwasnever consid-eredavirtuallesionmethod.Ithasbeensuggestedthat,depending onthepolarityofthestimulation,tDCScanincreaseordecrease corticalexcitabilityinthestimulatedbrainregionsandfacilitateor inhibitbehaviouraccordingly,therebyenablingtheinvestigation ofthecausalrelationshipsbetweenbrainactivityandbehaviour bymeansofneuralmodulation.AspreviouslymentionedtESdoes

notinduceactionpotentialsbutinsteadmodulatestheneuronal responsethresholdsothatitcanbedefinedassubthreshold stim-ulation.Changesintheneuronalthresholdresultfromchangesin membranepermeability(Liebetanzetal.,2002),whichinfluence theresponseofthetask-relatednetwork.Itispossibleto hypothe-sisethesamemechanismofactionfortESmethodsasforTMS,i.e., theinductionofnoiseinthesystem.However,theneuralactivity inducedbytESwillbehighlyinfluencedbythestateofthe sys-tembecauseitisaneuromodulatorymethod(Paulus,2011)andits effectwilldependontheactivityofthestimulatedarea.Therefore, thefinalresultwilldependstronglyonthetaskcharacteristics,the systemstateandthewayinwhichtESwillinteractwithsucha state.

3.1. Transcranialdirectcurrentstimulation

tDCSinduces membrane depolarisation (anodal stimulation) and hyperpolarisation (cathodal stimulation) (Liebetanz et al., 2002;Nitscheetal.,2003a,b,2004,2005).Fromamethodological perspective,mostofthegeneralconcernsforTMSarevalidfortDCS, withsomeexceptions:tDCSdoesnotinducedepolarisationand thereforewillonlyinducethefiringofneuronsthatarenear thresh-old,whichmeansthatneuronsnotinfluencedbythetaskareless likelytodischarge.Fromacognitiveneurosciencestandpoint,the effectofapplyinganodaltDCSduringtaskexecutionisconsidered toinducefacilitation,whilecathodaltDCSshouldinduceinhibition oftaskperformance.Inthissense,itisbelievedthattDCSprimes thebehaviouralsystembyincreasing/decreasingcortical excitabil-ityandproducingcorrespondingeffectsinthecognitivesystem. Therefore,tDCS-inducedeffectsaremorelikelytobesensitiveto thestateofthenetworkthatisactiveatthatmoment.Thus,the polarisationofneuronsincombinationwithongoingsynapticinput canbecontextualisedinaframeworkofsynapticco-activation.This isevocativeofHebbian-likeplasticitymechanismsasthe combina-tionoftDCSwithtaskexecutionisliketheco-activationofaspecific network.ThespatialandtemporalresolutionofthetDCSeffectsare somewhatreducedcomparedwiththoseofTMS,butthis draw-backmaybeovercomebyconsideringthestateofthesystem,as previouslydescribed.

Whilethemainframeworkofa“facilitatory”anodal stimula-tionanda“worsening”cathodalstimulationiswell-grounded,itis onlyvalidfortheuseoftDCSonthemotorsystem(Nitscheetal., 2008).AnodaltDCSfacilitativebehaviouraleffectshavebeen iden-tiﬁedforseveralfunctions,buttherelationbetweenfacilitationand inhibitionisoftenquitecomplex(Jacobsonetal.,2011).Inmany cognitiveneuroscienceexperiments,thestimulationofnon-motor areashasledtotheobservationthatbehaviouraleffectsareoften notunequivocal,withanodalstimulationusuallyinducing facilita-tionandcathodalstimulationinducingarangeofeffects(Jacobson etal.,2011).Here,thepointisthattheneurophysiological dimen-sioncannotbeusedasasimplemechanisticapproachformapping ontobehaviouraleffects(Miniussietal.,2010).Itcanbesuggested thatanodaltDCSmayinducefacilitationwhenthetaskis well-trainedorfamiliar,butsuchfacilitationisnotpresentduringthe performanceofanoveltask(Dockeryetal.,2009).Forexampleina well-establishedskilledtask,suchasnaming,thenoiseisreduced, sothatthesignalemergesclearlyfromthenoise,andanodal stim-ulationcanfacilitatefasterprocessing.Inthesametask,cathodal tDCSwouldreducethepossibilityofﬁringinresponsetoa stimu-lus,butbecausethesignalisstrongenoughtoelicitaresponse,the probabilitythatcathodalstimulationcaninterferewithtask exe-cutionisquitelow.Inanoveltask,thecontextisdifferent:thereis morebackgroundnoisebecausetheneuralnetworksarenot con-solidated,andmanysignalsclosetothetargetsignalwillbepresent. Inthiscase,anincreaseinnoisebyanodaltDCSwillnothelptask executionasitwillincreasethesignalbutalsothenoise,which

(7)

isclosetothethreshold.Nevertheless,insuchsituations,cathodal tDCScaninducefacilitationbyreducingthegeneralnoiseand help-ingthesignalemerge(Antaletal.,2004;Dockeryetal.,2009).Antal etal.(2004)foundthatcathodaltDCSappliedtotheleftvisual mid-dletemporalarea(MT-V5)improvedperformanceinavisuomotor coordinationtaskwhenalargeamountofvisualnoisewaspresent inthevisualstimulus.Therefore,cathodaltDCSappearstoactasa neuronalfilterthatreducesnoise.Theideaisthesameasthatofthe neurophysiologicalmechanismcalled‘lateralinhibition’–a mech-anismthatcanreducetheneuralactivitydue toanon-relevant signal(noise)togetherwiththatduetotherelevantsignal, sharp-eningtheprofileoftheexcitatoryresponseandimprovingthefinal performance.Therefore,wecannotconsidertDCStobeasimple neuromodulatorymethodinwhichanodal-tDCSincreases excita-tiontoinducebehaviouralfacilitationandcathodaltDCSyieldsthe oppositeeffectviainhibition.Theneuralnoiseinducedbythe stim-ulationwillaffecttheperformancedependingonthestateofthe system,whichismainlydeterminedbythetaskinput.Inthissense, tDCSneuromodulationwillinteractwiththelevelofexcitationof thesystem,drivenbythetasktoshapethefinalresult(Bienenstock etal.,1982).Onceagain,thelevelofnoiseintroducedinthesystem willbethekeyfactorinshapingthefinalresult.

IncontrasttoTMS,tDCSisacontinuousstimulationprocedure. Continuousstimulationcanengageneurophysiological homeosta-sismechanisms,whichservetomaintainneuralactivitywithina normalfunctionalrange(Siebneretal.,2004).Inthiscontext,it couldbesuggestedthatneuronscanadjustthethresholdofthe systembasedontheconstantinput.Thistypeofmechanismcould thereforealtertheﬁnaleffectofthestimulationintermsof excit-atoryorinhibitoryresponsesofthestimulatedarea,particularlyin thecontextofacomplexframework.

3.2. Transcranialalternatingcurrentstimulation

tACSallowsthebraintobestimulatedatspeciﬁcfrequencies: likerTMS,ithasbeensuggestedthattACScanmodulateongoing neuronalactivity(Zaehleetal.,2010)andrelatedbehaviour(Kanai etal.,2008)byinducingspeciﬁcbrainoscillations.Wecan the-oreticallypredictthatthismechanism willproducea frequency ‘entrainment’inthestimulatedcorticalregionorintheconnected areasduringaprolongedstimulation.UsingtACS(asforrTMS), anoscillatorycurrentcanbedeliveredtothecortextoinduceit tooscillateatthatparticularfrequency,whichisarea-dependent (Kanaietal.,2008).AnadvantageoftACSisthattherearefewer safetyconcernsforthismethodthanforrTMS(Rossietal.,2009), andthereforetherearenorestrictionsonthefrequencythatcan beused. Theidea is that, likefor TMS, theso-called ‘rhythmic approach’(Miniussietal.,2012a;ThutandMiniussi,2009)refersto thepossibilityofinvestigatinghowtACSinteractswithoscillatory brainactivityinordertoestablishacausalrelationshipbetween brainoscillationsandcognition.

Several authors applied tACS over the primary motor area withtheaimof specificallyinfluencingbrain oscillations. Stim-ulationwasappliedatdifferentfrequenciesduringmotortasks, anda significantimprovement inperformance wasobservedat thealphafrequencystimulation(Antaletal.,2008;Feurraetal., 2012;Joundietal.,2012;Pogosyanetal.,2009).Ithasbeenalso shownthatchangingthelocalactivitywithtACSmayaffectthe functionalnetworksthatareresponsibleformotorperformance andimprovedtaskexecution(Joundietal.,2012).Invision,Zaehle etal.(2010)demonstrated thattACSwasabletomodulateEEG oscillations,inparticularatalphafrequencywhensubjectswereat rest(notaskwasinvolved).Incontrast,Kanaietal.(2008)reported that occipital stimulation most effectively induced phosphenes whenappliedatthealphafrequency indarkness; whereas,the

betafrequencywasmoreeffectiveinthelight(butseeSchutter andHortensius,2010;Schwiedrzik,2009).

TheeffectoftACSmayrelyontheintrinsic resonanceofthe system.Resonanceisthetendencyofa systemtooscillate with greateramplitudeatspecificfrequenciesthanatothers;these fre-quenciesare relatedtothespecificstructure ofagiven system. Atthesespecificfrequencies,evensmallalternatingcurrentscan producelargeramplituderingingthantheinputbecausethe sys-temstores vibrational energy. Aneasily recognised example is givenbythewind-inducedcollapseoftheTacomaNarrowsBridge (http://www.youtube.com/watch?v=j-zczJXSxnw).Thewind pro-vided a weak external periodic frequency that matched the bridge’snatural structuralfrequency,inducing largeoscillations thatdestroyedthebridge.Thesamemayoccurinthecortex,which produces frequenciesin arange of 0.01upto600Hz. Applying aweakalternatingcurrent atasuitablefrequencyisa coopera-tiveeffectthatcanproducelargeramplituderinging,increasing synchronisation.Resonanceshavenowbeendescribedinvarious centralneurons(Hutcheonand Yarom,2000).Furthermore,ina recentinvitrostudy(Deansetal.,2007),itwasshownthatvery weakextracellular alternatingelectric fields havethe abilityto entrainanoscillatingnetwork(Deansetal.,2007;Radmanetal., 2007;Reatoetal.,2010).Thus,ifagivennetworkiscarriednearthe thresholdlevel(pronetoactivation),asmallpolarisationmaydrive theneuronaldischargethatwillinducephospheneperception.

Ithasbeensuggestedthatthecortexmayactuallyrespondto externalstimulation(i.e.,TMS),producingnaturallocal frequen-cies(Rosanovaet al.,2009; Venieroet al.,2011)depending on theongoingactivity.Giventheneuromodulatorycharacteristicsof tACSandpreviousTMSresults,wemaybeabletomodulate corti-caloscillationswithtACSbutarelikelyunabletosuperimposean “outofcondition/unnatural”frequencyonthesystem.AswithTMS, coherenceresonancecanbethekeymechanismfortheadditionof certainamountsofnoisethatmakesystemoscillatoryresponses more coherentand proﬁcient.In otherwords,tACS produces a smallamountofactivity(noise)thatisclosetothesystem oscil-latoryphase(synchronised),andthissmallamountofactivitywill sumwiththesystem’sresponseincoherenceresonance(Fig.3), increasingthesignal-to-noiseratioandimprovingperformance(or decreasingit).Onceagain,theconceptofstochasticresonancecan beusedinthisframework:aweakperiodicstimulationentrainsthe systemﬂuctuation,enhancingthebiologicalsignal.Althoughvery suggestive,theseconsiderationsareonlyspeculations,andevenif tACSmaybeconsideredanimportantdeviceformanipulating cor-ticaloscillatoryactivity,adequatesupportislacking(Brignanietal., 2013;Schwiedrzik,2009).

3.3. Transcranialrandomnoisestimulation

tRNSinvolvestheapplicationofarandomelectricaloscillation spectrumoverthecortex.Atpresent,tRNScanbeappliedinthree frequencyranges:theentirespectrum(from0.1to640Hz),inthe lowband(0.1–100Hz)orinthehighband(101–640Hz)(Terney etal.,2008).ThistechniqueisnewerthanothertESapplications; therefore,explorationofitspossiblemechanismsofactionin cog-nitionhasbeenlimited.

Terneyetal.(2008)recentlyshowedthattenminutesoftRNS onthemotorcortexathighfrequencybandsisabletopositively modulatecorticalexcitability(i.e.,increasetheamplitudeof motor-evokedpotentials).Behaviouralimprovementinamotorlearning taskalsoresultedfromtheapplicationoftheentirefrequency spec-trum(Terneyetal.,2008).Inarecentstudy,Fertonanietal.(2011) appliedtRNS to the visualsystem and compared the high/low frequencybandstoothertEStechniques(anodal/cathodaltDCS). High-frequencytRNSonthevisualcortexofhealthysubjects dur-inga visualperceptual learning taskwasfoundtosigniﬁcantly

(8)

improve performance more than anodaltDCS, which was pre-viously thought to be thebest methodto positively modulate behaviour.Theauthorssuggestedthat themechanism ofaction oftRNSmightbebasedontherepeatedsubthresholdstimulations thatpreventhomeostasisofthesystem(Fertonanietal.,2011). Thiseffectmightpotentiatetheactivityoftheneuralpopulations involvedinataskand,inturn,facilitatetransmissionbetween neu-rons.

AlsotheeffectsoftRNSmaybeexplainedinthecontextofthe stochasticresonancephenomenon;tRNSisa random-frequency stimulationthatmightinducerandomactivityinthesystem(i.e., noise).Thepresenceofneuronalnoisemightserveasapedestal toboostthesensitivityoftheneuronstoagivenrangeofweak inputs(i.e.,theneuronswiththesamedirectionalityasthesignal), therebyincreasingthesignal-to-noiseratio.Therefore,asdescribed forTMS,tDCSandtACS,theeffectoftRNSonneuronalactivitymay notjustbetherandomadditionofnoisebutmayberelatedtothe functionalactivationinducedbythetask.

Inconclusion,evenifthemechanismofactionoftESis differ-entthanthatofTMS(neuromodulationvs.depolarisation),wecan assumethat,likeTMS,tESinducesneuralactivityinthestimulated area, whichcan theoreticallybe definedasnoise. Nevertheless, whencomparedtoTMS,thenoiseinducedbytESwillneverbe ran-dombutwilldependonstimulationparameters,specifically,the systemstateandinput.ThisisbecausetEScannotinduceadirect over-thresholddepolarisationbutcanmodulatethefiringrateof thestimulatedarea.Suchinducedactivitywillconsequentlyshape behaviouralmeasurements.

4. AuniﬁedhypothesisofthefunctionaleffectsofNIBS: noisegenerationinanon-linearsystem

In TMS, the magnetic pulse causes the rapid and above-thresholddepolarisationofcellmembranesaffectedbythecurrent, leading to the transynaptic depolarisation or hyperpolarisation ofconnectedcorticalneurons.Therefore,TMSactivatesaneural populationthat,dependingonseveralfactors,canbecongruent (facilitate)orincongruent(inhibit)withtaskexecution.tESinduces apolarisationofcorticalneuronsatasubthresholdlevelthatistoo weaktoevokeanactionpotential.However,byinducingapolarity shiftintheintrinsicneuronalexcitability,tEScanalterthe sponta-neousfiringrateofneuronsandmodulatetheresponsetoafferent signals.Inthissense,tES-inducedeffectsareevenmoreboundto thestateofthestimulatedareathatisdeterminedbythetask con-ditions.Inshort,NIBSleadstoastimulation-inducedmodulationof activitythatcanbesubstantiallydefinedasnoiseinduction. Never-theless,suchinducednoisewillnotbejustrandomactivitybutwill dependontheinteractionofmanyparameters,fromthe character-isticsofthestimulationtothetaskperformed.Inotherwords,the noiseinducedbyNIBSwillbeinfluencedbythestateoftheneural populationofthestimulatedarea(Fig.2).

Therelationbetweensignalandnoisecanbeunderstoodwithin asimpleandpreciseframeworkbasedonasigmoidinput-response function.Inbiologicalsystems,thestrengthoftheresponsetoa giveninputisrarelyalinearfunctionofthestrengthoftheinput.In neuroscience,thereisampleevidencethattheresponse(typically thefiringrate)ofindividualneuronstovaryinglevelsofinput inten-sityisdescribedbyasigmoid(S-shaped)function,ofthesortshown inFig.4A(CarandiniandFerster,1997;Sclaretal.,1989).Assuming thestrengthofastimulusisfixed(ats),varyingonlythestrengthof thenoise(n)willchangetheoverallinputstrength(horizontalaxis). Neuronsshowverylittlechangeintheirresponse(verticalaxis)to veryweakinputstrength,butasthestrengthofstimulationpassesa “threshold”theresponsestrengthrapidlyincreases,markedbythe upwardinflexionoftheinput-responsecurve.Thereafter,asinput

Fig.4. (A)Asigmoidinput-responsefunction.Aﬁxedsignal,s,isaddedtodiffering levelsofnoise,n.Thedifferentialresponse,d,tosvariesasafunctionofthesizeofn: whennislow(n1)orhigh(n3),dissmallerthanwhennisatanintermediatelevel (n2).Thefunctionshownhereisbasedonacumulativegammafunction.(B)Theﬁrst derivativeofthefunctioninpanelA,correspondingtotheslopeofthatfunction.It showshow,d,thesensitivityoftheresponsetos,changesacrossallvaluesofn.

strengthincreasesfurther,theneuronalresponsebeginsto “satu-rate”,wherethefunctionbeginstoﬂatten.Thus,theresponsiveness of a neuron to variation in input strength – its discrimination sensitivity – is reﬂected in the slope of the sigmoid input-response function: discrimination sensitivity is low with very weakinput,increasesforinputatanintermediaterangeof inten-sity,andthendecreasesagainasinputapproachesthesaturation point.

Asimilarsigmoid-likefunctionisknowntounderliebehavioural responsestostimulationinmanysensorysystems,althoughinthis casetheshapeoftheinput-responsefunctionisderivedbyreverse inferencefromchangesindiscriminationsensitivity.Forexample, humanparticipantsarerelativelypooratdetectingaveryweak sensorystimulus,andcanonlydiscriminatebetweenthepresence versusabsenceofthestimuluswhenitsstrengthexceedsa thresh-old.However,theyareoftenmuchbetteratdiscriminatingbetween astimulusthatisatthisthresholdversusonethatisjustabovethe threshold.Thisincreaseindiscriminationsensitivity,usually mea-suredasadecreaseindiscriminationthresholds,isknownasthe “pedestaleffect”,andhasbeenshowntooperateatlowsensory

(9)

inputsinvisual,auditoryandtactiledomains(forrecentreviewsee Solomon,2009).Asstimulationintensityincreasesfurther, discrim-inationsensitivitydeclinesaccordingto“Weber’slaw”,inwhichthe sizeofthe“just-noticeabledifference”isafixedratioofthe aver-ageintensityofthestimulibeingdiscriminated.Theoverallpattern ofinitialimprovementandthendeclineindiscrimination sensitiv-ity,describedasa“dipperfunction”whenplottingdiscrimination thresholdagainststimulusintensity,speakstoanunderlying sig-moidfunctionrelatingstimulusstrengthtoperceptualresponse: thefunction is flat for very weakstimuli, becomes steeper for stimuliatlowtointermediateintensities,beforeprogressively flat-teningagainathigherintensities(Fig.4A).

Performanceinanysituationdependsonaccuratedetectionof signalabovenoise.Forexample,ifanobservertriestoidentifythe directionofmotionofamovingstimulus,hisorherabilitywill dependonthestrength ofthecoherentmotionsignalaboveall backgroundmotionsignals.Inneurophysiologicalterms,correctly identifyingdirectionofmotionfromtheresponseofapopulation ofmotion-sensitiveneurons(e.g.,inareaMT)willdependonthe differencebetweenthebaselineresponserateamongallneurons intheentirepopulation,whichconstitutesthelevelofnoise,and theresponseofthosespeciﬁcneuronsthatcodeforthestimulus’ motion(seeFig.1A).Thus,toidentifythesignal,theobservermust comparetheresponsetonoisewiththeresponse tosignalplus noise.Akeypropertyoftheinput-responsefunctiondescribedin theprecedingparagraphisthattheobserveddifferenceinresponse betweentwolevelsofinputwilldependontheabsolute magni-tudesofthoseinputs.Consider,forexample,threedifferentlevels ofnoiseinput,n1,n2,andn3,asdepictedinPanelAofFig.4.To

eachlevelofnoise,astimulusofﬁxedstrength,s,isadded.Even thoughthesizeofsisthesameineachcase,theresponsetos dif-fersdependingonthelevelofnoiseasitistransducedthroughthe sigmoidinput-responsefunction.Intheexampleshown,the dif-ference,d,inresponsetos+nversusnislargerfors+n2thanfor

eithers+n1ors+n3.Theimprovementindetectionofswhennoise

isincreasedfromaverylowlevel,atn1,toanintermediatelevel,

atn2,explainsthestochasticresonanceeffectthatissometimes

observedwhenuncorrelatedinput(noise)isintroducedintoa sys-tem.Thefrequentobservationthatlargeamountsofnoise,suchas atn3,impairperformanceisexplainedbythedecreaseinthe

differ-enceinresponsetos+nversusn.Thecompletefunctionrelating thedetectabilityofstonisshowninPanelBofFig.4.Clearlyas describedbefore,theeffectsofbrainstimulationwillbe propor-tionaltothelevelofneuronalactivationduringtheapplicationof thepulses,theso-calledstatedependencyasrepresentedinFig.5.It shouldbenotedthatashiftinthesigmoidinput-responsefunction canbeinducedalsobyoff-lineNIBSprotocols.

Weproposethattheresponsepropertiesdescribedherepresent averyusefulwaytounderstandtheimpactofNIBSonbrain func-tion and behavioural performance. Given that NIBS necessarily involvestherelativelyindiscriminateactivationoflargenumbers ofneurons,itsimpact ona neuralsystemcan beeasily under-stoodasintroducingoramplifyingnoise(orapossiblereduction ofnoiseinthecase ofcathodaltDCS).Theframeworkproposed hereofferstheopportunitytounderstandhowNIBS,byaltering levelsofnoise,couldusuallyimpair,butsometimesimprove per-formanceonatask,dependingontheamountofnoiseintroduced, theexisting levelofnoise inthesystemorin thetask, andthe sizeofthesignal.Anotherimportantadvantagetothisapproach isthat this single framework canbeapplied readilyacrossthe relevant domains. As described here,it can beapplied equally toconsiderationof responsesof individualneurons,population responsesofneurons,orthebehaviourofasubjectperforminga task.Thusitprovidesatheoreticalbasisfortranslatingexplanatory conceptsandinterpretationofﬁndingsacrossdifferentlevelsofthe system.

Sensitivity

induced

Fig.5. Howasigmoidinput-responsefunctioncanbemodiﬁedbyadaptation. Adap-tationcanalsobeinducedwithanoff-lineNIBSprotocol,changingthestateofthe subjectsandthereforetheﬁnalrelationbetweeninputstrengthandsensitivity(i.e., statedependency).

5. Conclusions

Insum,althoughthetypesandnumberofneurons“triggered” byNIBSaretheoreticallyrandom,theinducedchangeinneuronal activityislikelytobecorrelatedwithongoingtask-relevant activ-ity,yetevenifwearereferringtoanon-deterministicprocess,the noiseintroducedwillnotbeatotallyrandomelement.Because itwillbepartiallydeterminedbytheexperimentalvariables,we couldestimatethelevelofnoisethatwillbeintroducedbythe stimulationandbythetaskandpotentiallydeterminethe interac-tionbetweenthetwolevelsofnoise(stimulationandtask).Clearly, withtranscranial stimulation, we will never be able to induce stimulationwithafocusedandhighlytargetedsignaltoaclearly definedareaofthebraintoestablishauniquebrain-behaviour rela-tionship;therefore,theonlydefinitionthatwecanapplytothe introducedstimulusactivityinthebrainstimulationis‘noise.’The neuraleffectsofNIBSprotocolshavethepotentialtooffer impor-tantinsightsintothemechanismsthatunderliethecapacitiesofthe centralnervoussystemandwillaidtheevaluationof neurocogni-tivetheoriesofthebehaviour-brainrelationship.Theopportunity todirectlyinfluencebrainactivityinacleartheoreticalframework raisesevenmoreexcitingpossibilitiesforfuturebasicandclinical neurosciencestudiesinvolvingNIBS.

References

Abraham,W.C.,2008.Metaplasticity:tuningsynapsesandnetworksforplasticity. NatureReviewsNeuroscience9,387.

Abrahamyan,A.,Clifford,C.W.,Arabzadeh,E.,Harris,J.A.,2011.Improvingvisual sensitivitywithsubthresholdtranscranialmagneticstimulation.Journalof Neu-roscience31,3290–3294.

Adrian,E.D.,1928.TheBasisofSensation.W.W.Norton,NewYork.

Amassian,V.E.,Cracco,R.Q.,Maccabee,P.J.,Cracco,J.B.,Rudell,A.,Eberle,L.,1989. Suppressionofvisualperceptionbymagneticcoilstimulationofhumanoccipital cortex.ElectroencephalographyandClinicalNeurophysiology74,458–462. Amassian,V.E.,Eberle,L.,Maccabee,P.J.,Cracco,R.Q.,1992.Modellingmagnetic

coilexcitationofhumancerebralcortexwithaperipheralnerveimmersedina brain-shapedvolumeconductor:thesigniﬁcanceofﬁberbendinginexcitation. ElectroencephalographyandClinicalNeurophysiology85,291–301. Antal,A.,Boros,K.,Poreisz,C.,Chaieb,L.,Terney,D.,Paulus,W.,2008.

Compara-tivelyweakafter-effectsoftranscranialalternatingcurrentstimulation(tACS) oncorticalexcitabilityinhumans.BrainStimulation1,97–105.

Antal,A.,Nitsche,M.A.,Kruse,W.,Kincses,T.Z.,Hoffmann,K.P.,Paulus,W.,2004. Direct currentstimulation over V5 enhances visuomotor coordinationby

(10)

improvingmotionperceptioninhumans.JournalofCognitiveNeuroscience16, 521–527.

Ashbridge,E.,Walsh,V.,Cowey,A.,1997.Temporalaspectsofvisualsearchstudied bytranscranialmagneticstimulation.Neuropsychologia35,1121–1131. Barker,A.T.,Freeston,I.L.,Jalinous,R.,Jarratt,J.A.,1987.Magneticstimulationofthe

humanbrainandperipheralnervoussystem:anintroductionandtheresultsof aninitialclinicalevaluation.Neurosurgery20,100–109.

Barker,A.T.,Jalinous,R.,Freeston,I.L.,1985.Non-invasivemagneticstimulationof humanmotorcortex.Lancet1,1106–1107.

Bi,G.,Poo,M.,2001.Synapticmodiﬁcationbycorrelatedactivity:Hebb’spostulate revisited.AnnualReviewofNeuroscience24,139–166.

Bialek,W.,Rieke,F.,1992.Reliabilityandinformationtransmissioninspiking neu-rons.TrendsinNeurosciences15,428–434.

Bienenstock,E.L.,Cooper,L.N.,Munro,P.W.,1982.Theoryforthedevelopmentof neuronselectivity:orientationspeciﬁcityandbinocularinteractioninvisual cortex.JournalofNeuroscience2,32–48.

Bindman,L.J.,Lippold,O.C.,Milne,A.R.,1979.Prolongedchangesinexcitabilityof pyramidaltractneuronesinthecat:apost-synapticmechanism.Journalof Physiology286,457–477.

Bindman,L.J.,Lippold,O.C.,Redfearn,J.W.,1962.Long-lastingchangesinthelevel oftheelectricalactivityofthecerebralcortexproducedbypolarizingcurrents. Nature196,584–585.

Bindman,L.J., Lippold,O.C., Redfearn, J.W., 1964. Theaction ofbrief polariz-ingcurrentsonthecerebralcortexoftherat(1)duringcurrentﬂowand (2)intheproductionoflong-lastingafter-effects.JournalofPhysiology172, 369–382.

Brignani,D.,Ruzzoli,M.,Mauri,P.,Miniussi,C.,2013.Istranscranialalternating cur-rentstimulationeffectiveinmodulatingbrainoscillations?PLoSONE8,e56589. Buzsàki,G.,2006.RhythmsoftheBrain.OxfordUniversityPress,Oxford. Canolty,R.T.,Knight,R.T.,2010.Thefunctionalroleofcross-frequencycoupling.

TrendsinCognitiveSciences14,506–515.

Carandini,M.,Ferster,D.,1997.Atonichyperpolarizationunderlyingcontrast adap-tationincatvisualcortex.Science276,949–952.

Cattaneo,L.,Sandrini,M.,Schwarzbach,J.,2010.State-dependentTMSrevealsa hier-archicalrepresentationofobservedactsinthetemporal,parietal,andpremotor cortices.CerebralCortex20,2252–2258.

Cattaneo,Z.,Rota,F.,Vecchi,T.,Silvanto,J.,2008.Usingstate-dependencyof trans-cranialmagneticstimulation(TMS)toinvestigateletterselectivityintheleft posteriorparietalcortex:acomparisonofTMS-primingandTMS-adaptation paradigms.EuropeanJournalofNeuroscience28,1924–1929.

Chambers,C.D.,Payne,J.M.,Stokes,M.G.,Mattingley,J.B.,2004.Fastandslowparietal pathwaysmediatespatialattention.NatureNeuroscience7,217–218. Corthout,E.,Uttl,B.,Walsh,V.,Hallett,M.,Cowey,A.,1999.Timingofactivityinearly

visualcortexasrevealedbytranscranialmagneticstimulation.Neuroreport10, 2631–2634.

Creutzfeldt,O.D.,Fromm,G.H.,Kapp,H.,1962.Inﬂuenceoftranscorticald-ccurrents oncorticalneuronalactivity.ExperimentalNeurology5,436–452.

Deans,J.K.,Powell,A.D.,Jefferys,J.G.,2007.Sensitivityofcoherentoscillationsinrat hippocampustoACelectricﬁelds.JournalofPhysiology583,555–565. Dockery,C.A.,Hueckel-Weng,R.,Birbaumer,N.,Plewnia,C.,2009.Enhancementof

planningabilitybytranscranialdirectcurrentstimulation.Journalof Neuro-science29,7271–7277.

Ermentrout,G.B.,Galan,R.F.,Urban,N.N.,2008.Reliability,synchronyandnoise. TrendsinNeurosciences31,428–434.

Epstein,C.M.,Rothwell,J.C.,2003.TherapeuticusesofrTMS.CambridgeUniversity Press,Cambridge,pp.246–263.

Faisal,A.A.,Selen,L.P.,Wolpert,D.M.,2008.Noiseinthenervoussystem.Nature ReviewsNeuroscience9,292–303.

Ferbert,A.,Caramia,D.,Priori,A.,Bertolasi,L.,Rothwell,J.C.,1992.Corticalprojection to erectorspinaemuscles inman asassessed by focaltranscranial mag-neticstimulation.ElectroencephalographyandClinicalNeurophysiology85, 382–387.

Fertonani,A.,Pirulli,C.,Miniussi,C.,2011.Randomnoisestimulationimproves neu-roplasticityinperceptuallearning.JournalofNeuroscience31,15416–15423. Feurra,M.,Galli,G.,Rossi,S.,2012.Transcranialalternatingcurrentstimulation

affectsdecisionmaking.FrontiersinSystemsNeuroscience6,39.

Guyonneau,R.,Vanrullen,R.,Thorpe,S.J.,2004.Temporalcodesandsparse repre-sentations:akeytounderstandingrapidprocessinginthevisualsystem.Journal ofPhysiology,Paris98,487–497.

Hallett,M.,2000.Transcranialmagneticstimulationandthehumanbrain.Nature 406,147–150.

Harris,I.M.,Miniussi,C.,2003.Parietallobecontributiontomentalrotation demon-stratedwithrTMS.JournalofCognitiveNeuroscience15,315–323.

Harris,J.A.,Clifford,C.W.,Miniussi,C.,2008.Thefunctionaleffectoftranscranial magneticstimulation:signalsuppressionorneuralnoisegeneration.Journalof CognitiveNeuroscience20,734–740.

Hebb,D.O.,1949.TheOrganizationofBehavior;ANeuropsychologicalTheory.Wiley, NewYork.

Hutcheon,B.,Yarom,Y.,2000.Resonance,oscillationandtheintrinsicfrequency preferencesofneurons.TrendsinNeurosciences23,216–222.

Jacobson,L.,Koslowsky,M.,Lavidor,M.,2011.tDCSpolarityeffectsinmotorand cognitivedomains:ameta-analyticalreview.ExperimentalBrainResearch216, 1–10.

Joundi,R.A.,Jenkinson,N.,Brittain,J.S.,Aziz,T.Z.,Brown,P.,2012.Drivingoscillatory activityinthehumancortexenhancesmotorperformance.CurrentBiology22, 403–407.

Kahn,I.,Pascual-Leone,A.,Theoret,H.,Fregni,F.,Clark,D.,Wagner,A.D.,2005. Tran-sientdisruptionofventrolateralprefrontalcortexduringverbalencodingaffects subsequentmemoryperformance.JournalofNeurophysiology94,688–698. Kanai,R.,Chaieb,L.,Antal,A.,Walsh,V.,Paulus,W.,2008.Frequency-dependent

electricalstimulationofthevisualcortex.CurrentBiology18,1839–1843. Kitajo,K.,Doesburg,S.M.,Yamanaka,K.,Nozaki,D.,Ward,L.M.,Yamamoto,Y.,2007.

Noise-inducedlarge-scalephasesynchronizationofhuman-brainactivity asso-ciatedwithbehaviouralstochasticresonance.EPL–EurophysicsLetters,80. Kitajo,K.,Nozaki,D.,Ward,L.M.,Yamamoto,Y.,2003.Behavioralstochastic

reso-nancewithinthehumanbrain.PhysicalReviewLetters90,218103.

Landi,D.,Rossini,P.M.,2010.Cerebralrestorativeplasticityfromnormalageingto braindiseases:aneverendingstory.RestorativeNeurologyandNeuroscience 28,349–366.

Lang,N.,Rothkegel,H.,Reiber,H.,Hasan,A.,Sueske,E.,Tergau,F.,Ehrenreich,H., Wuttke,W.,Paulus,W.,2011.CircadianmodulationofGABA-mediatedcortical inhibition.CerebralCortex21,2299–2306.

Laycock,R.,Crewther,D.P.,Fitzgerald,P.B.,Crewther,S.G.,2007.Evidenceforfast signalsandlaterprocessinginhumanV1/V2andV5/MT+.ATMSstudyofmotion perception.JournalofNeurophysiology98,1253–1262.

Liebetanz,D.,Nitsche,M.A.,Tergau,F.,Paulus,W.,2002.Pharmacologicalapproach to themechanisms of transcranialDC-stimulation-inducedafter-effectsof humanmotorcortexexcitability.Brain125,2238–2247.

Longtin,A.,1997.Autonomousstochasticresonanceinburstingneurons.Physical ReviewE55,868–876.

Manenti,R.,Cappa,S.F.,Rossini,P.M.,Miniussi,C.,2008.Theroleoftheprefrontal cortexinsentencecomprehension:anrTMSstudy.Cortex44,337–344. Marzi,C.A.,Miniussi,C.,Maravita,A.,Bertolasi,L.,Zanette,G.,Rothwell,J.C.,Sanes,

J.N.,1998.Transcranialmagneticstimulationselectivelyimpairs interhemi-spherictransferofvisuo-motorinformationinhumans.ExperimentalBrain Research118,435–438.

Masquelier,T.,Thorpe,S.J.,2007.Unsupervisedlearningofvisualfeaturesthrough spiketimingdependentplasticity.PLOSComputationalBiology3,e31. Miniussi,C.,Brignani,D.,Pellicciari,M.C.,2012a.Combiningtranscranialelectrical

stimulationwithelectroencephalography:amultimodalapproach.ClinicalEEG andNeuroscience43,184–191.

Miniussi,C.,Paulus,W.,Rossini,P.M.,2012b.TranscranialBrainStimulation.CRC Press,BocaRaton,FL.

Miniussi,C.,Ruzzoli,M.,Walsh,V.,2010.Themechanismoftranscranialmagnetic stimulationincognition.Cortex46,128–130.

Moliadze,V.,Zhao,Y.,Eysel,U.,Funke,K.,2003.Effectoftranscranialmagnetic stimulationonsingle-unitactivityinthecatprimaryvisualcortex.Journalof Physiology553,665–679.

Moss,F.,Ward,L.M.,Sannita,W.G.,2004.Stochasticresonanceandsensory informa-tionprocessing:atutorialandreviewofapplication.ClinicalNeurophysiology 115,267–281.

Mottaghy,F.M.,Gangitano,M.,Krause,B.J.,Pascual-Leone,A.,2003.Chronometry ofparietalandprefrontalactivationsinverbalworkingmemoryrevealedby transcranialmagneticstimulation.Neuroimage18,565–575.

Nachmias,J.,Sansbury,R.V.,1974.Gratingcontrast:discriminationmaybebetter thandetection.VisionResearch14,1039–1042.

Nitsche,M.A.,Cohen,L.G.,Wassermann,E.M.,Priori,A.,Lang,N.,Antal,A.,Paulus,W., Hummel,F.,Boggio,P.S.,Fregni,F.,Pascual-Leone,A.,2008.Transcranialdirect currentstimulation:stateoftheart2008.BrainStimulation1,206–223. Nitsche,M.A.,Liebetanz,D.,Lang,N.,Antal,A.,Tergau,F.,Paulus,W.,2003a.Safety

criteriafortranscranialdirectcurrentstimulation(tDCS)inhumans.Clinical Neurophysiology114,2220–2222,authorreply2222–2223.

Nitsche,M.A.,Niehaus,L.,Hoffmann,K.T.,Hengst,S.,Liebetanz,D.,Paulus,W.,Meyer, B.U.,2004.MRIstudyofhumanbrainexposedtoweakdirectcurrentstimulation ofthefrontalcortex.ClinicalNeurophysiology115,2419–2423.

Nitsche,M.A.,Nitsche,M.S.,Klein,C.C.,Tergau,F.,Rothwell,J.C.,Paulus,W.,2003b. LevelofactionofcathodalDCpolarisationinducedinhibitionofthehuman motorcortex.ClinicalNeurophysiology114,600–604.

Nitsche,M.A.,Paulus,W.,2000.Excitabilitychangesinducedinthehumanmotor cortexbyweaktranscranialdirectcurrentstimulation.JournalofPhysiology 527(Pt3),633–639.

Nitsche,M.A.,Paulus,W.,2011.Transcranialdirectcurrentstimulation–update 2011.RestorativeNeurologyandNeuroscience29,463–492.

Nitsche,M.A.,Seeber,A.,Frommann,K.,Klein,C.C.,Rochford,C.,Nitsche,M.S.,Fricke, K.,Liebetanz,D.,Lang,N.,Antal,A.,Paulus,W.,Tergau,F.,2005.Modulating parametersofexcitabilityduringandaftertranscranialdirectcurrent stimula-tionofthehumanmotorcortex.JournalofPhysiology568,291–303. Pascual-Leone,A.,Walsh,V.,Rothwell,J.,2000.Transcranialmagneticstimulation

incognitiveneuroscience—virtuallesion,chronometry,andfunctional connec-tivity.CurrentOpinioninNeurobiology10,232–237.

Pasley,B.N.,Allen,E.A.,Freeman,R.D.,2009.State-dependentvariabilityofneuronal responsestotranscranialmagneticstimulationofthevisualcortex.Neuron62, 291–303.

Paulus,W.,2011.Transcranialelectricalstimulation(tES–tDCS;tRNS,tACS) meth-ods.NeuropsychologicalRehabilitation21,602–617.

Plewnia,C.,Rilk,A.J.,Soekadar,S.R.,Arfeller,C.,Huber,H.S.,Sauseng,P.,Hummel, F.,Gerloff,C.,2008.Enhancementoflong-rangeEEGcoherencebysynchronous bifocaltranscranialmagneticstimulation.EuropeanJournalofNeuroscience27, 1577–1583.

Pogosyan,A.,Gaynor,L.D.,Eusebio,A.,Brown,P.,2009.Boostingcortical activ-ityatBeta-bandfrequenciesslowsmovementinhumans.CurrentBiology19, 1637–1641.

(11)

Priori, A., Berardelli, A., Rona, S., Accornero, N., Manfredi, M., 1998. Polar-ization of the human motor cortex through the scalp. Neuroreport 9, 2257–2260.

Radman,T.,Datta,A.,Peterchev,A.V.,2007.Invitromodulationofendogenous rhythmsbyACelectricﬁelds:syncingwithclinicalbrainstimulation.Journal ofPhysiology584,369–370.

Rahnev,D.A.,Maniscalco,B.,Luber,B.,Lau,H.,Lisanby,S.H.,2012.Directinjectionof noisetothevisualcortexdecreasesaccuracybutincreasesdecisionconﬁdence. JournalofNeurophysiology107,1556–1563.

Reato,D.,Rahman,A.,Bikson,M.,Parra,L.C.,2010.Low-intensityelectrical stimula-tionaffectsnetworkdynamicsbymodulatingpopulationrateandspiketiming. JournalofNeuroscience30,15067–15079.

Ridding,M.C.,Ziemann,U.,2010.Determinantsoftheinductionofcorticalplasticity bynon-invasivebrainstimulationinhealthysubjects.JournalofPhysiology588, 2291–2304.

Rosanova,M.,Casali,A.,Bellina,V.,Resta,F.,Mariotti,M.,Massimini,M.,2009. Nat-uralfrequenciesofhumancorticothalamiccircuits.JournalofNeuroscience29, 7679–7685.

Rossi,S.,Hallett,M.,Rossini,P.M.,Pascual-Leone,A.,SafetyofTMSConsensusGroup, 2009.Safety,ethicalconsiderations,andapplicationguidelinesfortheuseof transcranialmagneticstimulationinclinicalpracticeandresearch.Clinical Neu-rophysiology120,2008–2039.

Roth,B.J.,1994.Mechanismsforelectricalstimulationofexcitabletissue.Critical ReviewsinBiomedicalEngineering22,253–305.

Rothwell,J.C.,Day,B.L.,Thompson,P.D.,Dick,J.P.,Marsden,C.D.,1987.Some experi-encesoftechniquesforstimulationofthehumancerebralmotorcortexthrough thescalp.Neurosurgery20,156–163.

Ruohonen,J.,2003.Backgroundphysicsformagneticstimulation.Supplementsto ClinicalNeurophysiology56,3–12.

Ruzzoli,M.,Abrahamyan,A.,Clifford,C.W.,Marzi,C.A.,Miniussi,C.,Harris,J.A.,2011. TheeffectofTMSonvisualmotionsensitivity:anincreaseinneuralnoiseora decreaseinsignalstrength.JournalofNeurophysiology106,138–143. Ruzzoli,M.,Marzi,C.A.,Miniussi,C.,2010.Theneuralmechanismsoftheeffects

oftranscranialmagneticstimulationonperception.JournalofNeurophysiology 103,2982–2989.

Sack,A.T.,Linden,D.E.,2003.Combiningtranscranialmagneticstimulationand func-tionalimagingincognitivebrainresearch:possibilitiesandlimitations.Brain Research:BrainResearchReviews43,41–56.

Sandrini,M.,Umilta,C.,Rusconi,E.,2011.Theuseoftranscranialmagnetic stim-ulationincognitiveneuroscience:anewsynthesisofmethodologicalissues. NeuroscienceandBiobehavioralReviews35,516–536.

Schutter,D.J.,Hortensius,R.,2010.Retinaloriginofphosphenestotranscranial alter-natingcurrentstimulation.ClinicalNeurophysiology121,1080–1084. Schwarzkopf,D.S.,Silvanto,J.,Rees,G.,2011.Stochasticresonanceeffectsreveal

theneuralmechanismsoftranscranialmagneticstimulation.Journalof Neuro-science31,3143–3147.

Schwiedrzik,C.M.,2009.Retinaorvisualcortex?Thesiteofphospheneinduction bytranscranialalternatingcurrentstimulation.FrontiersinIntegrative Neuro-science3,6.

Sclar,G.,Lennie,P.,DePriest,D.D.,1989.Contrastadaptationinstriatecortexof macaque.VisionResearch29,747–755.

Seyal,M.,Masuoka,L.K.,Browne,J.K.,1992.Suppressionofcutaneousperceptionby magneticpulsestimulationofthehumanbrain.Electroencephalographyand ClinicalNeurophysiology85,397–401.

Siebner,H.R.,Lang,N.,Rizzo,V.,Nitsche,M.A.,Paulus,W.,Lemon,R.N.,Rothwell, J.C.,2004.Preconditioningoflow-frequencyrepetitivetranscranialmagnetic

stimulationwithtranscranialdirectcurrentstimulation:evidencefor homeo-staticplasticityinthehumanmotorcortex.TheJournalofNeuroscience24, 3379–3385.

Silvanto,J.,Muggleton,N.,Walsh,V.,2008.State-dependencyinbrain stimula-tionstudiesofperceptionandcognition.TrendsinCognitive Sciences12, 447–454.

Silvanto,J.,Muggleton,N.G.,Cowey,A.,Walsh,V.,2007.Neuraladaptationreveals state-dependenteffectsoftranscranialmagneticstimulation.EuropeanJournal ofNeuroscience25,1874–1881.

Solomon,J.A.,2009.Thehistoryofdipperfunctions.Attention,Perception,and Psy-chophysics71,435–443.

Stein,R.B.,Gossen,E.R.,Jones,K.E.,2005.Neuronalvariability:noiseorpartofthe signal?NatureReviewsNeuroscience6,389–397.

Terney,D.,Chaieb,L.,Moliadze,V.,Antal,A.,Paulus,W.,2008.Increasinghuman brainexcitabilitybytranscranialhigh-frequencyrandomnoisestimulation. JournalofNeuroscience28,14147–14155.

Thut,G.,Miniussi,C.,2009.NewinsightsintorhythmicbrainactivityfromTMS–EEG studies.TrendsinCognitiveSciences13,182–189.

Thut,G.,Miniussi,C.,Gross,J.,2012.Thefunctionalimportanceofrhythmicactivity inthebrain.CurrentBiology22,R658–R663.

Thut,G.,Schyns,P.G.,Gross,J.,2011a.Entrainmentofperceptuallyrelevantbrain oscillationsbynon-invasiverhythmicstimulationofthehumanbrain.Frontiers inPsychology2,170.

Thut,G.,Veniero,D.,Romei,V.,Miniussi,C.,Schyns,P.,Gross,J.,2011b.Rhythmic TMScauseslocalentrainmentofnaturaloscillatorysignatures.CurrentBiology 21,1176–1185.

Vallar,G.,Bolognini,N.,2011.Behaviouralfacilitation followingbrain stimula-tion:implicationsforneurorehabilitation.NeuropsychologicalRehabilitation 21,618–649.

Varela,F.,Lachaux,J.P.,Rodriguez,E.,Martinerie,J.,2001.Thebrainweb:phase synchronizationandlarge-scaleintegration.NatureReviewsNeuroscience2, 229–239.

Veniero,D.,Brignani,D.,Thut,G.,Miniussi,C.,2011.Alpha-generationasbasic response-signaturetotranscranialmagneticstimulation(TMS)targetingthe humanrestingmotorcortex:aTMS/EEGco-registrationstudy. Psychophysio-logy48,1381–1389.

Walsh,V.,Cowey,A.,2000.Transcranialmagneticstimulationandcognitive neuro-science.NatureReviewsNeuroscience1,73–79.

Walsh,V.,Ellison,A.,Battelli,L.,Cowey,A.,1998.Task-speciﬁcimpairmentsand enhancementsinducedbymagnetic stimulationofhuman visualareaV5. Proceedings:BiologicalSciences265,537–543.

Walsh,V., Pascual-Leone,A.,2003. TranscranialMagneticStimulation:A Neu-rochronometricsofMind.MITPress,Cambridge,MA.

Walsh,V.,Rushworth,M.,1999.Aprimerofmagneticstimulationasatoolfor neuropsychology.Neuropsychologia37,125–135.

Ward,L.M.,Doesburg,S.M.,Kitajo,K.,MacLean,S.E.,Roggeveen,A.B.,2006. Neu-ralsynchronyinstochasticresonance,attention,andconsciousness.Canadian JournalofExperimentalPsychology60,319–326.

Wassermann,E.M.,Epstein,C.,Ziemann,U.,Walsh,V.,Paus,T.,Lisanby,S.,2008. HandbookofTranscranialStimulation.OxfordUniversityPress,Oxford,UK. Waterston,M.L.,Pack,C.C.,2010.Improveddiscriminationofvisualstimulifollowing

repetitivetranscranialmagneticstimulation.PLoSONE5,e10354.

Wu,S.,Amari,S.,Nakahara,H.,2002.Populationcodinganddecodinginaneural ﬁeld:acomputationalstudy.NeuralComputation14,999–1026.

Zaehle,T.,Rach,S.,Herrmann,C.S.,2010.Transcranialalternatingcurrent stimula-tionenhancesindividualalphaactivityinhumanEEG.PLoSONE5,e13766.