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CurrBehavNeurosciRep https://doi.org/10.1007/s40473-017-0134-5 NEUROMODULATION(CSTAGG,SECTIONEDITOR) What Effect Does tDCS Have on the Brain? Basic Physiology of tDCS AsifJamil1&MichaelA.Nitsche1,2 #SpringerInternationalPublishingAG2017 Abstract Keywords Transcranialdirectcurrentstimulation .tDCS . PurposeoftheReview Transcranialdirectcurrentstimulation Neuroplasticity.Physiology.Electricstimulation . (tDCS)caneffectivelymodulateawiderangeofclinicaland Membranepolarization cognitiveoutcomesbymodulatingcorticalexcitability.Here, wesummarizethemainfindingsfrombothanimalandhuman neurophysiologyliterature, which haverevealedmechanistic Introduction evidencefortheacuteandneuroplasticafter-effectsoftDCS. Recent Findings Insights into the magnitude and geometric Agrowingareaofinterestoverthepastdecadeshasbeento orientation oftranscraniallyinduced currentshavebeenpro- understand and alter the physiological mechanisms underly- videdbythecombinationofcomputationalmodelingofcur- ingbasiccognitiveprocesses,aswellasamultitudeofclinical rentflowinanimalslicepreparationsandintracranialrecord- disorders through the use of non-invasive brain stimulation ingsinhumans.Inadditiontoitssynapticeffects,stimulation methods(NIBS).Withthesetechniques,electricormagnetic alsoinducesafter-effectsontheglialandvascularsystems,the currentsaresafelyandcontrollablydeliveredtothecortexto latteralsoobservedinhumansbymagneticresonanceimag- intervene with ongoing cortical physiology and also affect ing.Severalstudieshavealsoobservednon-linearorantago- plasticity-related processes. NIBS have thus far contributed nisticeffectsoftDCSparameters,whichwarrantsfurthersys- totheunderstandingofthe physiologicalroleofmanybrain tematic studies to explore and understand the basic areas and networks and provided the potential to serve as a mechanisms. therapeutictoolforthetreatmentofneurologicalandpsychi- Summary tDCSisavaluableandpromisingtechniqueacross atricdiseasesassociatedwithpathologicalalterationsofplas- the neurophysiological, cognitive neuroscience, and clinical ticityorbrainactivity.Inrecentyears,animportantobjective domainsofresearch.PrimaryandsecondaryeffectsoftDCS hasfocusedonimprovingtheefficacyofthesetoolsbyaiming stillremaintobecompletelyunderstood.Animportantchal- tounderstandthephysiologicalmechanismsofstimulationat lenge for the field is advancing tDCS protocols forward for abasicandfundamentallevel,whichcouldserveasanimpor- optimalinterventionandtreatmentstrategies. tantframeworkforadvancingtechnicalparametersofNIBS. Modern-day NIBS can be divided between those tech- ThisarticleispartoftheTopicalCollectiononNeuromodulation niques which directly induce activity of neurons versus thosewhichmodulatethefiringactivityofneurons.Thefirst * AsifJamil category includes techniques such as transcranial magnetic [email protected] stimulation (TMS), which is based on delivering brief but strong electromagnetic pulses through a coil and primarily affects targeted neuronal populations in the cortex through 1 DepartmentPsychologyandNeurosciences,LeibnizResearch supra-threshold neuronal activation. In contrast, transcranial CentreforWorkingEnvironmentandHumanFactors,Ardeystr.67, 44139Dortmund,Germany electric stimulation (tES), which encompasses both alternat- 2 UniversityMedicalHospitalBergmannsheil, ingcurrentstimulation(tACS)anddirectcurrentstimulation 44789Bochum,Germany (tDCS), do not generate action potentials in the targeted CurrBehavNeurosciRep neuronal populations, but these are primarily effective further refined over the last 17 years, involves using two or through modulation of the resting membrane potential. moreconductiverubberormetalelectrodescoveredinacon- tDCS, in comparison to other techniques, has attracted in- ductive mediumand placed over the scalp.These electrodes creased attention due to (1) its appeal as a well-tolerated, areconnectedtoaconstant-currentstimulatorwhichdeliversa cost-effective,and easilyportabledevice[1]and (2)its abil- stable, weak direct current (1–3 mA in humans) [1]. As we ity to induce physiological effects not only in the targeted discussinthelatersections,theselectionoftDCSparameters cortical area but also across functionally connected net- isnotanarbitraryexercise,butrequirescarefulconsideration works, which can outlast the period of stimulation [2–4]. ofthetargetedregionornetwork,theintendeddurationofthe Aswediscussinthefollowingreview,thecurrentknowl- after-effects,andeventheindividual. edge of the basic effects of tDCS encompasses in vivo, Nevertheless, tDCS is not a wholly novel technique, but in vitro, and in silico studies in animals and humans, which hassteadilyevolvedfromconverginganimalandclinicalfind- range from classic electrophysiology to modern state-of-the- ingsoverthepastseveralcenturies,whereapplicationofelec- artimagingtechniques.Convergingresearchhasbroadlycat- tric currents to the head was observed to result in various egorized the main effects of tDCS as either acute effects, behavioral and therapeutic effects, without realization of a whicharethoseoccurringduringthestimulationperiod,and clear or precise mechanistic basis [11] (see also reviews by after-effects,whichareevidentafterstimulationhasended.In [12]and[13]).Onlyinthelastcenturywasitconfirmed,based thisreview,wediscussanumberoftDCSstudieswhichhave on several physiological experiments in animals, that exter- focusedonthehumanmotorcortexasamodelforobtaining nallyappliedelectricfieldscouldmodulatelocalneuralactiv- reliableand quantitativemetricstomeasure and characterize ity,andthateffectsofpolarizingcurrentsdidnotjustresultin the physiologyofthese effects.Parallel effortstofurther ex- immediate effects but also long-lasting after-effects [14–16]. plore,systematicallyextrapolate,andphysiologicallyorfunc- Moreover,thesefindingssupportedHebb’ssynapticplasticity tionallyvalidatetheserespectiveeffectsinotherbrainregions model of the cortex, which suggests long-term potentiation haveledtotDCSbeingaflexibleandreliableneuromodulator (LTP) and depression (LTD) as the modulatory mechanisms for establishing links of causality between nervous system underlyingthelong-termlearningeffectresultingfromextrin- structure and physiology across a wide range of cognitive sicstimulionneuralfunctions[17].AstDCShasbeenshown andbehavioralfunctionsandalsoforexploringthedynamics to induce both acute and long-lasting effects, we review the anddeterminantsofplasticity-relatedprocessesinthecentral mechanisticevidenceseparately. nervous system. Knowledge about physiological effects of tDCS in non-motor regions is however still limited as com- paredtothemotorcortexmodel,andone-to-onetransferabil- Primary,AcuteEffects ityofmechanismsshouldnotbetakenforgranted,takinginto consideration anatomical and neurochemical differences be- The primary effects of tDCS during stimulation start with tweenareas. polarity-dependent shifts in the resting membrane potential Despite the increasing number and diversity of research ofneurons.Thepolarityofthestimulation(anodalorcathod- and clinical studies using tDCS, a complete and holistic un- al)isconventionallytermedbytherespectivetypeofelectrode derstanding of the underlying mechanisms of tDCS on the placedoverthetargetcorticalareaonthescalp.Insimplistic brain is still missing. As we discuss, recent findings aiming terms,currentflowsfromtheanodetothecathodeandmust tooptimizetDCShaveuncoverednon-linearandantagonistic flow into and out of the cell in order to exert any effect. effects, which further warrants a deeper exploration [5–8]. Characterizing specifically which compartments of the cell Moreover, the effects of tDCS in humans is inter- arepolarizedremainsanimportantquestion;however,effects individually variable, depending on a range of factors such appeartocriticallydependontheneuronalmorphologyrela- ascorticalanatomy,geneticpolymorphisms,orageandgen- tive to the DC electric field [18]. In early interpretations of der. We discuss in the final section how understanding the tDCSeffectsinanimals,itwasobservedthattheneteffectofa interactionbetweenphysiologicaleffects,stimulationparam- surfaceanodeelectrodewasanexcitatoryeffect,likelycaused eters, and inter-individual factors is a crucial objective for bydepolarizationatthesomaandbasaldendrite.Incontrast,a further developing optimized stimulation parameters for use surface-negative current, or cathodal stimulation over the inresearchandclinicalsettings. targeted region, which generated a negative current flow pointing outward from the cortex, resulted in an inhibitory effectduetohyperpolarizationoftheneuron’ssomaandbasal PhysiologyoftDCS dendrite[19].These basic effects ofweakpolarizing current were first observed across several animal studies in the mid ThemoderntechniqueoftDCS,asintroducedintheseminal 50sandearly60sbeforetheadventofTMSinthe90spermit- studies by Priori et al. [9] and Nitsche and Paulus [10] and tedforhumanexperiments. CurrBehavNeurosciRep AnimalModels tomeasurephysiologicaleffectslimitedmoststudiestoinves- tigating only behavioral or phenomenological effects. As Inapioneeringstudy,TerzuoloandBullock[14]observedthat such,severalofthesestudiesvarieddrasticallyinstimulation electric fields of 10 mV/cm were sufficient to modulate the parameters and objective outcome measures. Lippold and spontaneous firingin thecardiac ganglionofthe lobster and Redfearn[28]conducted severaltrialsoftDCS and reported theabdominalstretchreceptorofthecrayfish.Moreover,the that current intensities between 50 and 500 μA resulted in authorsnotedthatthiselectricfieldwas20timesweakerthat polarity-dependent alterations of mood, alertness, quietness, whatwasrequiredto firethesilentneurons.Concordant ob- and apathy. An additional study by this group investigated servationswerealsoreportedinearlyinvivostudiesofthecat chronicallydepressedpatientsandfoundthatanodalcurrents motorandvisualcortexbyCreutzfeldtetal.[20],wherespon- between 20 and 250 μA resulted in improvements during taneousneuronalactivity,inadditiontoEEGevokeddendritic stimulation, some effects lasting for up to 1 or 2 days after- potentialsrecordedfromepi-corticalelectrodes,wasmodulat- wards[29].Afewstudieslookingatmotorcorticalfunctions edinapolarity-dependentmanner.Similarly,Bindmanetal. foundfasterreactiontimes[30,31].Otherstudiesfoundlim- [15]demonstratedthepolarizingeffectofDCstimulationon ited or variable success, possibly due to insufficient current the rat cortex, noting the increase in the mean firing rate of strength,variedelectrodepositioning,andinthecaseofpsy- neurons following surface positive polarization, and a de- chiatric patients, the lack of strict diagnostic criteria [4, 12]. crease following surface-negative polarization. Importantly, Consequently,thetechniquewasslowlyabandonedinpopu- the effect of the polarizing current was not always homoge- larity,probablyinfavorofthethensignificantpharmacolog- nous, as neurons in the deeper cortical layers were often icaladvancements. deactivated by anodal stimulation and activated by cathodal ThedevelopmentofTMSinthe80sandearly90soffereda stimulation[16,20].Therequirementmaydependontheori- new perspective for investigating physiological effects of entationoftheneuronsrelativetotheelectricfield[21]. tDCS[32,33].TheadvantageofTMSwasespeciallyrelevant Modern mechanistic studies using animal preparations have for investigating the physiological effects of tDCS as it delved deeper to understand the geometric and physiological allowedforaquantitativeread-outofmotorcorticalexcitabil- interaction of the induced electric field on other cell types and ityviatheelectromyographicallyrecordedmotor-evokedpo- cell compartments. Here, one important finding has been the tential(MEP),thusovercomingpreviouslimitations.In1998, observationthatDCfieldsmodulatethefunctionalityofallcom- Priori and colleagues [9] reportedthe effects ofDCstimula- partmentsofthecell,includingthesoma,dendrites,axon,pre- tion applied to the human primary motor cortex (M1) and synapticterminal,andaxonhillock[18,19,22],whichintegrate referenced to the chin, with current intensities ranging up to together to determine whether a given neuron fires or not. 0.5mAandstimulationlastingupto7s.MEPselicitedfrom Converging studies combining computational modeling with the hand muscle were recorded before and during tDCS. physiologicalrecordingshavepurportedthe“somaticdoctrine” Although no effects were observed independently for each to characterize how maximum depolarization occurs with an polarity, a decrease in excitability was observed when a electric field parallel to the somatodendritic axis (however, in 0.3mAanodalcurrentwasdeliveredpriortoacathodalcur- humanmodels,tangentialcurrentflowalongthecorticalsurface rent,eachlasting7 s.Possiblereasons for theseantagonistic isalsogenerated,whichcannotbeignoredwhenconsideringthe effects may have been the short stimulation durations or the effects of tDCS [18]). The effect of neuronal polarization does suboptimal electrode positioning to induce sufficient current notonlyholdimportanceforthresholdmodulationbutcanalso flowthroughthecortex[4].In2000,NitscheandPauluscon- initiate changes in action potential rate and timing, which may ducteda systematicstudy which laidthe foundationsfor the amplifyeffects[23,24]. modern-dayversionoftDCS.Here,theelectrodeswereposi- tionedwiththetargetelectrodeoverthemotorcorticalrepre- HumanStudies sentationofthehandknobandthereferenceelectrodeoverthe contralateralorbit(Fig.1c,d).Withcurrentintensitiesofupto Paucity of non-invasive physiological techniques to induce 1mAandlastingfor4s,motorcorticalexcitabilityincreased andmonitoralterationsofbrainactivityandexcitabilitymeant during anodal tDCS and diminished during cathodal tDCS thatearlyinvestigationsintoweakDCstimulationinhumans [10]. In a follow-up study to confirm whether these effects werelimited.Thesestudieswerecompoundedwithtwodiffi- were the result of membrane potential polarization, Nitsche culties:first,asopposedtoanimalstudieswherecurrentcould et al. administered the calcium channel blocker flunarizine bedelivereddirectlytothecortexandmeasuredwithinvasive andthesodiumchannelblockercarbamazepineandobserved electrodes, in humans, the current had to be applied the abolishment of an anodal tDCS increase in excitability transcranially,whichmeantaddedcomplexityinquantitative- when compared to placebo medication [34]. To investigate ly measuring induced effects or effective charge density at GABAergic and glutamatergic synaptic activity, Nitsche targetedregions;second,thelackofsophisticatedtechnology et al. administered the GABA receptor agonist lorazepam A CurrBehavNeurosciRep Fig.1 PhysiologicalbasisoftDCSinanimalandhumanstudies.Early electrodes) and the direction of current flow is presented, which also experimentsonanesthetized rats byBindman et al. [15] demonstrated has a significant meso-lateral component (pointing outwards from the both acute and lasting effects of weak direct currents delivered to the page) (adaptedfromFig.1, [25]).d For the majority of tDCS studies cortex.aIncreaseinspikeactivityduringanodaltDCSanddecreasein on motor cortical excitability, two 35 cm2 electrodes were used, with activityduringcathodaltDCScomparedtobeforestimulation.bEffects the target electrode positioned over the motor cortical representation ofDCstimulationonthesespikingneuronspersistforseveralhoursafter area of the hand knob, and a reference electrode placed over the theendof(a)anodalstimulationand(b)cathodalstimulation.cInthefirst contralateralorbit.eAfter-effectsoftDCSonmotorcorticalexcitability. human experiments byNitsche and Paulus[10],the optimal electrode tDCS of the human motor cortex modulates TMS-elicited MEP montage to induce excitability alterations consisted of one 35 cm2 amplitudes after stimulation for up to 1 h. Anodal tDCS enhances, electrode centered over the motor cortex and another over the whereascathodaltDCSdiminishescorticalexcitability(figuresadapted, contralateral orbit. The magnitude of current density (2 mA, 25 cm2 withpermission,from[26,27]) andtheNMDAreceptorblockerdextromethorphan,butfound Secondary,After-Effects no acute alteration in the anodal tDCS excitability-increase response [34, 35]. Moreover, the role of GABA ergic and The attraction to many modern NIBS techniques is their A glutamatergic interneurons was also investigated via TMS ability to modulate LTP- or LTD-like mechanisms and double-pulsestimulationprotocols,andinlinewiththephar- thereby induce long-lasting effects in the nervous system macologicalevidence,noeffectswereobservedduringeither [37]. For tDCS, this can be accomplished with sustained anodalorcathodaltDCS[36].Together,thesefindingsshow stimulation, in the order of minutes, which results in similaritytoanimalstudies,wherethe weak DCon neurons physiological alterations lasting upwards of several hours duringstimulationprimarilyresultsinpolarizationoftherest- to even more than a day after the end of stimulation [7, ingmembraneandshiftsintheexcitabilityandactivityofthe 26, 27]. Although the precise mechanisms for the long- neuron. term effects are still not completely understood, they are CurrBehavNeurosciRep presumed to be related to synaptic plasticity and funda- neurons affecting other cell functions and cascades remains mentally similar between animals and humans. an open question. Interestingly, a recent calcium imaging studyonmicerevealedthattDCSinduceslong-lastingcalci- AnimalModels um surges in astrocytes [53], which might indicate an addi- tionalmechanismforlocalvasculareffectsaswellasforplas- InBindmanetal.’s[15]investigationofanesthetizedrats,DC ticityeffects,asanincreaseinintracellularcalciumisneces- stimulationfor5minorlongerresultedinprolongedincrease saryforLTPinlocalsynapses[54]. of spontaneous firing activity lasting for hours after anodal Taken together, multiple lines of evidence in the animal stimulation, whereas activity decreased relative to baseline literatureconcludethattDCSinduceslong-lastingphysiolog- after cathodal stimulation (Fig. 1b). These effects were also icaleffectsinthecortex.Theprecisemechanisms,including observed to be dependent on protein synthesis and thus not the relationship between stimulation parameters and physio- likelytobeapurelyelectricalphenomenon[38].Indeed,fur- logical effects, as well as the relationship between neuronal therstudiesonratslicesdemonstratedthatdirectcurrentstim- andnon-neuronaleffectsremaintobefullyunderstood. ulationinducesLTPorLTDinapolarity-dependentmanner, which also depends on NMDA receptors and brain-derived HumanStudies neurotrophic factor (BDNF) [39, 40]. Intracellular calcium alsoincreased following anodalstimulation,aswell asearly Although animal experiments continue to provide a variety of geneexpression,whichalsodependonNMDAreceptors[41, information on physiological mechanisms underlying tDCS- 42].Here,thedurationofstimulationwasalsoshowntobeof inducedneuroplasticity,alargegapstillexistsinthetransferabil- importance, since longer-lasting stimulation bi-directionally ityofthesefindingstohumanmodels,primarilyduetodifficulty regulatedcAMP[43].Arecentstudyonrabbitsdemonstrated in manipulating relevant synaptic components. Nevertheless, thattDCSappliedtothesensorimotorcortexcouldalsomod- studiesusingpharmacologicalmodulationcombinedwithTMS ulate presynaptic mechanisms of synaptic transmission, have provided critical insights on putative mechanisms, which highlightingtherelevanceofadenosinereceptorsinaccount- appeartoinvolvemainlyglutamatergicprocesses. ingforlong-termassociativelearningeffects[44].Theroleof Usingsingle-pulseTMStoelicitMEPs,Nitscheetal.dem- presynapticinputsandongoingspontaneousactivityindriv- onstratedthatanodaltDCSof13minincreasedmotorcortical ing plasticity remains to be fully understood; however, con- excitability for up to 90 min, and 9 min of cathodal tDCS verging evidence points to the importance of local activity decreased up to 60 min (Fig. 1e; [26, 27]). The duration of driving local plasticity [45]. Accordingly, in the study by theseeffectsisintherangeofearlyphaseLTP-andLTD-like Fritsch et al. [39], long-term effects in slice preparations, plasticity [55]. Systematic studies using the combination of which display no major spontaneous activity, were only ac- TMSwithpharmacologicalinterventionswerecarriedoutto complishedwhentDCSwasaccompaniedbylow-frequency investigatethephysiologicalbasisfortheseafter-effects.The electrical stimulation, which was not the case in an in vivo NMDA receptor blocker dextromethorphan abolished the study, in which spontaneous activity in present to a larger after-effects of both anodal and cathodal tDCS [34, 56], degree[46].Similardependencieshavebeenobservedinhu- whereastheNMDAreceptoragonistd-cycloserineprolonged manstudies,wherebackgroundcorticalactivitywasshownto theafter-effectsofanodaltDCS[57],indicatingthedependen- modulateneuroplasticafter-effectsoftDCS[47]. cyoftheglutamatergicsystem.Furtherstudiestosupportthis RelatedtotDCS-inductionofplasticity,especiallywithre- were conducted using double-pulse TMS protocols, which gard to network or remote effects, is the relevant role of the showed reduced intracortical inhibition, but enhanced facili- neurovascularunit[48],whichconsistsofbothneuronaland tation,afteranodaltDCS,andoppositeeffectsaftercathodal non-neuronal cells, such as glial cells, and vascular compo- tDCS[36].Thecalcium-dependencyoftheseeffectswasalso nents,suchasendothelialcellsandbloodvessels.Usinglaser investigated, as evidenced by animal studies showing their Doppler flowmetry (LDF), Wachter et al. [49] observed a involvementwithNMDAreceptors.Here,thecalciumchan- polarity-dependent modulation of tDCS on cerebral blood nel blocker flunarizine abolished the after-effects of anodal flow (CBF) of the rat. Fifteen minutes of anodal tDCS at tDCS [36]. The role of GABA ergic interneurons in modu- A 100 μA increased CBF up to 30 min afterwards, whereas lating tDCS plasticity was also explored. Lorazepam, which 100 μA of cathodal tDCS decreased CBF by 25% for up to enhances active GABA receptors, initially reduced, but then 30 min. Similarly, a functional near-infrared spectroscopy boostedtheexcitabilityenhancementfollowinganodaltDCS, (fNIRS)studyonratsalsoobservedanincreaseinoxygenated buthadnoeffectfollowingcathodaltDCS[35].TMSproto- hemoglobinduringanodaltDCS,whichpersistedfor30min cols examininginter-neuronaleffects found thatbothanodal afterwards[50].Whetherthesephysiologicaleffectsareadi- andcathodaltDCSenhancedI-waves,whicharereducedby rect result of electric fields (e.g., vessel dilation effects from GABAactivity[36].Theinterpretationbehindthisresultbe- DC fields—[51, 52]) or secondary effects from polarized cameclearerafteramagneticresonancespectroscopy(MRS) CurrBehavNeurosciRep studyshowedreductionofGABAfollowinganodalandcath- functional and structural connectivity, have shed important odaltDCS[58].Insum,thesestudiesunderscoretheinvolve- light on mechanisms by which tDCS can induce functional mentofglutamatergicmechanismsindrivingtheafter-effects cortico-cortical, and cortico-thalamic alterations [74, 75]. oftDCS,andthatatDCS-inducedreductionofGABAmight ConsideringthatanimportantaspectoftDCSistomodulate serve as a “gating” mechanism. In addition to investigating learning-relatedmechanisms,thesefindingsofferspecialrel- glutamatergic and GABAergic involvement, effects of other evance to the prospect of integrating the communication of neuromodulators which are relevant for tDCS-induced plas- segregatedcorticalareasatthesystemlevel. ticity, such as dopamine, serotonin, and acetylcholine have Tosummarize,tDCShasprominentneuroplasticafter-effects alsobeenexplored[59–63].Overall,thesestudieshavefound which can be observed in the intact animal and human cortex thattheseneuromodulatorsarenotjustrelevantforestablish- with modern electrophysiological and imaging techniques. In ingneuroplasticitybutcouldalsoalterplasticityinnon-linear additiontolocalandregionaleffectsunderthestimulationelec- andcomplexways,which isofimportantrelevanceforneu- trode,tDCSalsoaffectsfunctionalnetworksatbothcorticaland rologicalorpsychiatricdiseaseswheretheseneuromodulators subcortical levels and can involve the functional activation of areoftenoutofbalance. non-neuronal structures, such as glia, blood vessels, and endo- Several studies have documented neurophysiological after- thelialcells,thusofferingresearchersandcliniciansabroadscope effectsincorticalregionsotherthantheprimarymotorcortex. forpossibleinterventionstrategies. Antaletal.investigatedexcitabilityalterationsinthevisualcor- tex by measuring visual-evoked potentials (VEPs). Anodal tDCSincreasedtheamplitudeoftheN70component,whereas OptimizingtDCSforResearchandClinical cathodaltDCSdecreasedit[64].Inanotherstudy,applicationof Applications tDCS over the visual cortex with an extra-cephalic reference electrode also resulted in polarity-dependent modulation of Despite the heterogeneous, yet increasing, number of tDCS VEPs,bothduringandshortlyafteranodalandcathodaltDCS studies, physiological and functional after-effects following [65]. For the somatosensory cortex, polarity-dependent effects single sessions of tDCS are still relatively short-lasting. wereobservedthroughrecordingsomatosensory-evokedpoten- Criticalfortheefforttoprolong and optimizetDCSefficacy tials(SEPs).AnodaltDCSincreasedSEPamplitudesforatleast are (1) understanding basic effects of tDCS, particularly in 60mininonestudy[66]andcathodaltDCSreducedthosein areas other than the human motor cortex; (2) optimizing the another[67].Intheauditorycortex,anodaltDCSoverthetem- largeparameterspacefortDCSprotocols(e.g.,electrodemon- poralcortexandcathodaltDCSoverthetemporo-parietalcortex tage,currentintensity,andstimulationduration);and(3)un- enhancedauditory-evokedpotentials[68]. derstanding the factors which underlie inter-individual vari- BesidesthelocalandregionaleffectsoftDCS,afewstud- ability, which not only masks real population level effects ies have also observed topographically remote cortical and makinginterpretationofresultsdifficult,butcanalsobelev- subcorticaleffectsoftDCS.Usingpositronemissiontomog- eragedtounderstandmoreabouttDCSeffects.Understanding raphy (PET), it was shown that both anodal and cathodal thesecomponentsmayhelptodevelopbettersuitedstimula- tDCS inducewidespreadincreasesanddecreasesinregional tionprotocols,e.g.,closed-loopsystemsorotherindividually cerebralblood flow(rCBF) [69].As discussed previously, it optimized protocols for highly effective treatment. With re- remainsuncleartowhatextentvasculareffectsarethedirect gardto (2) and (3), we briefly summarize the latest findings resultofcurrentflow,orsecondarilyaffectedthroughsynaptic underlyingtheseefforts(Fig.2). mechanisms. Localized alterations in the hemodynamic re- sponsefollowingtDCShavealsobeenobservedusingarterial tDCSParameters spinlabeling(ASL-fMRI)whereitwasshownthatrCBFin- creased after short repeated durations of anodal tDCS and AlargeportionofthehumanstudiesontDCSconductedthus decreased after cathodaltDCS [70].Thiseffect does not ap- farhavebeenbasedonthe“classic”tDCSprotocol,wherea peartobeconstrainedonlytothemotorcortex,asanodaland current intensity of 1 mA is applied for durations of 9 or cathodaltDCSappliedtotheleftdorsolateralprefrontalcortex 13 min, and an electrode of size 35 cm2 is placed over the (DLPFC) also resulted in polarity-specific alterations in per- targetregionwithareferenceelectrodeoverthecontralateral fusion [71]. Modulations of resting state oscillatory activity, orbit.However,alteringthesestimulationparametershaveled recordedusingEEG,havealsobeenreportedafteranodaland to significant deviations from the canonical after-effects of cathodal tDCS and reiterate the concept of increased or de- tDCS.Forexample,increasingthedurationof1.0mAanodal creasedspontaneousfiringactivityinpyramidalneuronpop- tDCSfrom13to26minresultedinexcitabilitydiminishing, ulations,respectively[72,73].Recentadvancementsinbrain andnotenhancing,after-effects[7],andincreasingthecurrent networkconnectivityanalysesappliedtoneuroimagingdata, intensityof20mincathodaltDCSfrom1mAto2mAcon- such as the use of graph theoretical parameters to assess verted excitability diminution to facilitation [5]. These non- CurrBehavNeurosciRep Fig.2 TowardstDCS optimization.AvenuesfortDCS optimizationcanbebroadly categorizedinto(1)approaches foradvancingtheunderstanding ofthebasicphysiologicaland functionaleffectsofstimulation; (2)systematicandcontrolled studiestoinvestigatetheeffectsof tDCSparameters,suchasdose- responserelationships;and(3) discoveryandinsightsintofactors whichmayresultininter- individualvariability,suchas geneticandanatomical determinants.Understandingthe relationshipbetweenthesethree aspectsiscrucialtoadvancing state-of-the-artprotocolsfor clinicalandresearchapplications lineareffectsarelikelycausedbyacombinationofincreased 2mAcurrentintensitiesresultedinelectricfieldmagnitudes intracellular calcium, which has been shown to convert the of0.4V/minthecortex[83]whereasinanotherstudy,1mA direction of LTD to LTP in animal studies [76, 77], and tDCSinducedanelectricfieldof0.5V/m(i.e.,approximately potassium-channel dependent counter regulation to limit twiceinsize)[84].Insum,thesestudieshighlighttheneedfor LTP plasticity [78]. In order to extend the duration of after- additionalmodelingcombinedwithphysiologicalvalidations effectslongerthan1h,whichisofpracticalbenefitinclinical astheywouldbeofhighbenefittooptimizationefforts. applications,anintervalof20minbetweenconsecutivestim- ulations was found optimal to induce longer-lasting after-ef- Inter-IndividualParameters fects for both anodal (up to 24 h) and cathodal (up to 2 h) tDCS[6,7].Spacedrepetitionprotocolshavealsobeenshown RecentstudieshavesuggestedthattDCSafter-effectscandif- toinducelate-phaseplasticityeffectsinbothanimalslicesand ferentiate based on inter-individual variability between in vivo experiments [7, 79]. An interesting question is the healthy adult participants [8, 85–88]. Factors affecting the extentoftheinteractionbetweencurrentintensities(including inter-individual response variability in tDCS are likely to be greaterthan2mA)andstimulationdurationandrepetition,on similar with factors which affect other NIBS techniques and anodalandcathodaltDCS. includephysiologicalandanatomicalfactorssuchasbaseline Withfurtherregardtooptimizationisthechallengeofop- state or excitability, cortical folding,skull thickness, and ge- timizingthestimulationelectrodemontage.Althoughthemo- netic profile, as well as demographic factors such as gender torcortex–contralateralsupraorbitalridgemontagewasfound andage([89];seealsoreview[90]).Insum,severalofthese tobethemostoptimalformodulatingM1excitability[10],it studies have noted the confounding effect of fluctuations in maynotnecessarilybethemostoptimalforeveryapplication circadianrhythms,motorcorticalexcitabilitybeforeTMS,or or individual. New tools based on finite-element-method shifts in attention (e.g., during eyes-open versus eyes-closed (FEM)modelshavebeendeveloped,whichleverageindivid- conditions)ontDCSafter-effects,whichunderscorestheim- ualMRIimagesinordertodeterminethemostoptimalmon- portance for future studies in designing experiments which tage [80, 81]. These include multi-electrode montages to in- appropriatelycontrolandreportfortheseadditionalfactors. ducemorefocaleffects,suchasthe4×1high-definition(HD- tDCS)montage,whichhasbeenshowntoresultinmorepro- nouncedmotorcorticalexcitabilityafter-effectsincomparison Conclusions totheclassicalmontage[82].However,obtainingcomprehen- sive physiological validations of these montages is a chal- The present review aimed to summarize the current state of lenge,anditremainsunclearwhetherincreasedfocalityisof knowledgeonthemechanismsunderlyingtDCSprimaryef- benefit to neuropsychiatric patients, where often large areas fectsinbothanimalsandhumans,whichinvolvemodulation andnetworksareaffected.Withregardtovalidation,arecent oftherestingmembranepotential,andsecondaryneuroplastic intracranial EEG combined with tDCS study reported that after-effects, which involve both pre- and post-synaptic CurrBehavNeurosciRep modifications. Recent findings have demonstrated direct current stimulation (tDCS). 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Preview What Effect Does tDCS Have on the Brain? Basic Physiology of tDCS

CurrBehavNeurosciRep https://doi.org/10.1007/s40473-017-0134-5 NEUROMODULATION(CSTAGG,SECTIONEDITOR) What Effect Does tDCS Have on the Brain? Basic Physiology of tDCS AsifJamil1&MichaelA.Nitsche1,2 #SpringerInternationalPublishingAG2017 Abstract Keywords Transcranialdirectcurrentstimulation .tDCS . PurposeoftheReview Transcranialdirectcurrentstimulation Neuroplasticity.Physiology.Electricstimulation . (tDCS)caneffectivelymodulateawiderangeofclinicaland Membranepolarization cognitiveoutcomesbymodulatingcorticalexcitability.Here, wesummarizethemainfindingsfrombothanimalandhuman neurophysiologyliterature, which haverevealedmechanistic Introduction evidencefortheacuteandneuroplasticafter-effectsoftDCS. Recent Findings Insights into the magnitude and geometric Agrowingareaofinterestoverthepastdecadeshasbeento orientation oftranscraniallyinduced currentshavebeenpro- understand and alter the physiological mechanisms underly- videdbythecombinationofcomputationalmodelingofcur- ingbasiccognitiveprocesses,aswellasamultitudeofclinical rentflowinanimalslicepreparationsandintracranialrecord- disorders through the use of non-invasive brain stimulation ingsinhumans.Inadditiontoitssynapticeffects,stimulation methods(NIBS).Withthesetechniques,electricormagnetic alsoinducesafter-effectsontheglialandvascularsystems,the currentsaresafelyandcontrollablydeliveredtothecortexto latteralsoobservedinhumansbymagneticresonanceimag- intervene with ongoing cortical physiology and also affect ing.Severalstudieshavealsoobservednon-linearorantago- plasticity-related processes. NIBS have thus far contributed nisticeffectsoftDCSparameters,whichwarrantsfurthersys- totheunderstandingofthe physiologicalroleofmanybrain tematic studies to explore and understand the basic areas and networks and provided the potential to serve as a mechanisms. therapeutictoolforthetreatmentofneurologicalandpsychi- Summary tDCSisavaluableandpromisingtechniqueacross atricdiseasesassociatedwithpathologicalalterationsofplas- the neurophysiological, cognitive neuroscience, and clinical ticityorbrainactivity.Inrecentyears,animportantobjective domainsofresearch.PrimaryandsecondaryeffectsoftDCS hasfocusedonimprovingtheefficacyofthesetoolsbyaiming stillremaintobecompletelyunderstood.Animportantchal- tounderstandthephysiologicalmechanismsofstimulationat lenge for the field is advancing tDCS protocols forward for abasicandfundamentallevel,whichcouldserveasanimpor- optimalinterventionandtreatmentstrategies. tantframeworkforadvancingtechnicalparametersofNIBS. Modern-day NIBS can be divided between those tech- ThisarticleispartoftheTopicalCollectiononNeuromodulation niques which directly induce activity of neurons versus thosewhichmodulatethefiringactivityofneurons.Thefirst * AsifJamil category includes techniques such as transcranial magnetic [email protected] stimulation (TMS), which is based on delivering brief but strong electromagnetic pulses through a coil and primarily affects targeted neuronal populations in the cortex through 1 DepartmentPsychologyandNeurosciences,LeibnizResearch supra-threshold neuronal activation. In contrast, transcranial CentreforWorkingEnvironmentandHumanFactors,Ardeystr.67, 44139Dortmund,Germany electric stimulation (tES), which encompasses both alternat- 2 UniversityMedicalHospitalBergmannsheil, ingcurrentstimulation(tACS)anddirectcurrentstimulation 44789Bochum,Germany (tDCS), do not generate action potentials in the targeted CurrBehavNeurosciRep neuronal populations, but these are primarily effective further refined over the last 17 years, involves using two or through modulation of the resting membrane potential. moreconductiverubberormetalelectrodescoveredinacon- tDCS, in comparison to other techniques, has attracted in- ductive mediumand placed over the scalp.These electrodes creased attention due to (1) its appeal as a well-tolerated, areconnectedtoaconstant-currentstimulatorwhichdeliversa cost-effective,and easilyportabledevice[1]and (2)its abil- stable, weak direct current (1–3 mA in humans) [1]. As we ity to induce physiological effects not only in the targeted discussinthelatersections,theselectionoftDCSparameters cortical area but also across functionally connected net- isnotanarbitraryexercise,butrequirescarefulconsideration works, which can outlast the period of stimulation [2–4]. ofthetargetedregionornetwork,theintendeddurationofthe Aswediscussinthefollowingreview,thecurrentknowl- after-effects,andeventheindividual. edge of the basic effects of tDCS encompasses in vivo, Nevertheless, tDCS is not a wholly novel technique, but in vitro, and in silico studies in animals and humans, which hassteadilyevolvedfromconverginganimalandclinicalfind- range from classic electrophysiology to modern state-of-the- ingsoverthepastseveralcenturies,whereapplicationofelec- artimagingtechniques.Convergingresearchhasbroadlycat- tric currents to the head was observed to result in various egorized the main effects of tDCS as either acute effects, behavioral and therapeutic effects, without realization of a whicharethoseoccurringduringthestimulationperiod,and clear or precise mechanistic basis [11] (see also reviews by after-effects,whichareevidentafterstimulationhasended.In [12]and[13]).Onlyinthelastcenturywasitconfirmed,based thisreview,wediscussanumberoftDCSstudieswhichhave on several physiological experiments in animals, that exter- focusedonthehumanmotorcortexasamodelforobtaining nallyappliedelectricfieldscouldmodulatelocalneuralactiv- reliableand quantitativemetricstomeasure and characterize ity,andthateffectsofpolarizingcurrentsdidnotjustresultin the physiologyofthese effects.Parallel effortstofurther ex- immediate effects but also long-lasting after-effects [14–16]. plore,systematicallyextrapolate,andphysiologicallyorfunc- Moreover,thesefindingssupportedHebb’ssynapticplasticity tionallyvalidatetheserespectiveeffectsinotherbrainregions model of the cortex, which suggests long-term potentiation haveledtotDCSbeingaflexibleandreliableneuromodulator (LTP) and depression (LTD) as the modulatory mechanisms for establishing links of causality between nervous system underlyingthelong-termlearningeffectresultingfromextrin- structure and physiology across a wide range of cognitive sicstimulionneuralfunctions[17].AstDCShasbeenshown andbehavioralfunctionsandalsoforexploringthedynamics to induce both acute and long-lasting effects, we review the anddeterminantsofplasticity-relatedprocessesinthecentral mechanisticevidenceseparately. nervous system. Knowledge about physiological effects of tDCS in non-motor regions is however still limited as com- paredtothemotorcortexmodel,andone-to-onetransferabil- Primary,AcuteEffects ityofmechanismsshouldnotbetakenforgranted,takinginto consideration anatomical and neurochemical differences be- The primary effects of tDCS during stimulation start with tweenareas. polarity-dependent shifts in the resting membrane potential Despite the increasing number and diversity of research ofneurons.Thepolarityofthestimulation(anodalorcathod- and clinical studies using tDCS, a complete and holistic un- al)isconventionallytermedbytherespectivetypeofelectrode derstanding of the underlying mechanisms of tDCS on the placedoverthetargetcorticalareaonthescalp.Insimplistic brain is still missing. As we discuss, recent findings aiming terms,currentflowsfromtheanodetothecathodeandmust tooptimizetDCShaveuncoverednon-linearandantagonistic flow into and out of the cell in order to exert any effect. effects, which further warrants a deeper exploration [5–8]. Characterizing specifically which compartments of the cell Moreover, the effects of tDCS in humans is inter- arepolarizedremainsanimportantquestion;however,effects individually variable, depending on a range of factors such appeartocriticallydependontheneuronalmorphologyrela- ascorticalanatomy,geneticpolymorphisms,orageandgen- tive to the DC electric field [18]. In early interpretations of der. We discuss in the final section how understanding the tDCSeffectsinanimals,itwasobservedthattheneteffectofa interactionbetweenphysiologicaleffects,stimulationparam- surfaceanodeelectrodewasanexcitatoryeffect,likelycaused eters, and inter-individual factors is a crucial objective for bydepolarizationatthesomaandbasaldendrite.Incontrast,a further developing optimized stimulation parameters for use surface-negative current, or cathodal stimulation over the inresearchandclinicalsettings. targeted region, which generated a negative current flow pointing outward from the cortex, resulted in an inhibitory effectduetohyperpolarizationoftheneuron’ssomaandbasal PhysiologyoftDCS dendrite[19].These basic effects ofweakpolarizing current were first observed across several animal studies in the mid ThemoderntechniqueoftDCS,asintroducedintheseminal 50sandearly60sbeforetheadventofTMSinthe90spermit- studies by Priori et al. [9] and Nitsche and Paulus [10] and tedforhumanexperiments. CurrBehavNeurosciRep AnimalModels tomeasurephysiologicaleffectslimitedmoststudiestoinves- tigating only behavioral or phenomenological effects. As Inapioneeringstudy,TerzuoloandBullock[14]observedthat such,severalofthesestudiesvarieddrasticallyinstimulation electric fields of 10 mV/cm were sufficient to modulate the parameters and objective outcome measures. Lippold and spontaneous firingin thecardiac ganglionofthe lobster and Redfearn[28]conducted severaltrialsoftDCS and reported theabdominalstretchreceptorofthecrayfish.Moreover,the that current intensities between 50 and 500 μA resulted in authorsnotedthatthiselectricfieldwas20timesweakerthat polarity-dependent alterations of mood, alertness, quietness, whatwasrequiredto firethesilentneurons.Concordant ob- and apathy. An additional study by this group investigated servationswerealsoreportedinearlyinvivostudiesofthecat chronicallydepressedpatientsandfoundthatanodalcurrents motorandvisualcortexbyCreutzfeldtetal.[20],wherespon- between 20 and 250 μA resulted in improvements during taneousneuronalactivity,inadditiontoEEGevokeddendritic stimulation, some effects lasting for up to 1 or 2 days after- potentialsrecordedfromepi-corticalelectrodes,wasmodulat- wards[29].Afewstudieslookingatmotorcorticalfunctions edinapolarity-dependentmanner.Similarly,Bindmanetal. foundfasterreactiontimes[30,31].Otherstudiesfoundlim- [15]demonstratedthepolarizingeffectofDCstimulationon ited or variable success, possibly due to insufficient current the rat cortex, noting the increase in the mean firing rate of strength,variedelectrodepositioning,andinthecaseofpsy- neurons following surface positive polarization, and a de- chiatric patients, the lack of strict diagnostic criteria [4, 12]. crease following surface-negative polarization. Importantly, Consequently,thetechniquewasslowlyabandonedinpopu- the effect of the polarizing current was not always homoge- larity,probablyinfavorofthethensignificantpharmacolog- nous, as neurons in the deeper cortical layers were often icaladvancements. deactivated by anodal stimulation and activated by cathodal ThedevelopmentofTMSinthe80sandearly90soffereda stimulation[16,20].Therequirementmaydependontheori- new perspective for investigating physiological effects of entationoftheneuronsrelativetotheelectricfield[21]. tDCS[32,33].TheadvantageofTMSwasespeciallyrelevant Modern mechanistic studies using animal preparations have for investigating the physiological effects of tDCS as it delved deeper to understand the geometric and physiological allowedforaquantitativeread-outofmotorcorticalexcitabil- interaction of the induced electric field on other cell types and ityviatheelectromyographicallyrecordedmotor-evokedpo- cell compartments. Here, one important finding has been the tential(MEP),thusovercomingpreviouslimitations.In1998, observationthatDCfieldsmodulatethefunctionalityofallcom- Priori and colleagues [9] reportedthe effects ofDCstimula- partmentsofthecell,includingthesoma,dendrites,axon,pre- tion applied to the human primary motor cortex (M1) and synapticterminal,andaxonhillock[18,19,22],whichintegrate referenced to the chin, with current intensities ranging up to together to determine whether a given neuron fires or not. 0.5mAandstimulationlastingupto7s.MEPselicitedfrom Converging studies combining computational modeling with the hand muscle were recorded before and during tDCS. physiologicalrecordingshavepurportedthe“somaticdoctrine” Although no effects were observed independently for each to characterize how maximum depolarization occurs with an polarity, a decrease in excitability was observed when a electric field parallel to the somatodendritic axis (however, in 0.3mAanodalcurrentwasdeliveredpriortoacathodalcur- humanmodels,tangentialcurrentflowalongthecorticalsurface rent,eachlasting7 s.Possiblereasons for theseantagonistic isalsogenerated,whichcannotbeignoredwhenconsideringthe effects may have been the short stimulation durations or the effects of tDCS [18]). The effect of neuronal polarization does suboptimal electrode positioning to induce sufficient current notonlyholdimportanceforthresholdmodulationbutcanalso flowthroughthecortex[4].In2000,NitscheandPauluscon- initiate changes in action potential rate and timing, which may ducteda systematicstudy which laidthe foundationsfor the amplifyeffects[23,24]. modern-dayversionoftDCS.Here,theelectrodeswereposi- tionedwiththetargetelectrodeoverthemotorcorticalrepre- HumanStudies sentationofthehandknobandthereferenceelectrodeoverthe contralateralorbit(Fig.1c,d).Withcurrentintensitiesofupto Paucity of non-invasive physiological techniques to induce 1mAandlastingfor4s,motorcorticalexcitabilityincreased andmonitoralterationsofbrainactivityandexcitabilitymeant during anodal tDCS and diminished during cathodal tDCS thatearlyinvestigationsintoweakDCstimulationinhumans [10]. In a follow-up study to confirm whether these effects werelimited.Thesestudieswerecompoundedwithtwodiffi- were the result of membrane potential polarization, Nitsche culties:first,asopposedtoanimalstudieswherecurrentcould et al. administered the calcium channel blocker flunarizine bedelivereddirectlytothecortexandmeasuredwithinvasive andthesodiumchannelblockercarbamazepineandobserved electrodes, in humans, the current had to be applied the abolishment of an anodal tDCS increase in excitability transcranially,whichmeantaddedcomplexityinquantitative- when compared to placebo medication [34]. To investigate ly measuring induced effects or effective charge density at GABAergic and glutamatergic synaptic activity, Nitsche targetedregions;second,thelackofsophisticatedtechnology et al. administered the GABA receptor agonist lorazepam A CurrBehavNeurosciRep Fig.1 PhysiologicalbasisoftDCSinanimalandhumanstudies.Early electrodes) and the direction of current flow is presented, which also experimentsonanesthetized rats byBindman et al. [15] demonstrated has a significant meso-lateral component (pointing outwards from the both acute and lasting effects of weak direct currents delivered to the page) (adaptedfromFig.1, [25]).d For the majority of tDCS studies cortex.aIncreaseinspikeactivityduringanodaltDCSanddecreasein on motor cortical excitability, two 35 cm2 electrodes were used, with activityduringcathodaltDCScomparedtobeforestimulation.bEffects the target electrode positioned over the motor cortical representation ofDCstimulationonthesespikingneuronspersistforseveralhoursafter area of the hand knob, and a reference electrode placed over the theendof(a)anodalstimulationand(b)cathodalstimulation.cInthefirst contralateralorbit.eAfter-effectsoftDCSonmotorcorticalexcitability. human experiments byNitsche and Paulus[10],the optimal electrode tDCS of the human motor cortex modulates TMS-elicited MEP montage to induce excitability alterations consisted of one 35 cm2 amplitudes after stimulation for up to 1 h. Anodal tDCS enhances, electrode centered over the motor cortex and another over the whereascathodaltDCSdiminishescorticalexcitability(figuresadapted, contralateral orbit. The magnitude of current density (2 mA, 25 cm2 withpermission,from[26,27]) andtheNMDAreceptorblockerdextromethorphan,butfound Secondary,After-Effects no acute alteration in the anodal tDCS excitability-increase response [34, 35]. Moreover, the role of GABA ergic and The attraction to many modern NIBS techniques is their A glutamatergic interneurons was also investigated via TMS ability to modulate LTP- or LTD-like mechanisms and double-pulsestimulationprotocols,andinlinewiththephar- thereby induce long-lasting effects in the nervous system macologicalevidence,noeffectswereobservedduringeither [37]. For tDCS, this can be accomplished with sustained anodalorcathodaltDCS[36].Together,thesefindingsshow stimulation, in the order of minutes, which results in similaritytoanimalstudies,wherethe weak DCon neurons physiological alterations lasting upwards of several hours duringstimulationprimarilyresultsinpolarizationoftherest- to even more than a day after the end of stimulation [7, ingmembraneandshiftsintheexcitabilityandactivityofthe 26, 27]. Although the precise mechanisms for the long- neuron. term effects are still not completely understood, they are CurrBehavNeurosciRep presumed to be related to synaptic plasticity and funda- neurons affecting other cell functions and cascades remains mentally similar between animals and humans. an open question. Interestingly, a recent calcium imaging studyonmicerevealedthattDCSinduceslong-lastingcalci- AnimalModels um surges in astrocytes [53], which might indicate an addi- tionalmechanismforlocalvasculareffectsaswellasforplas- InBindmanetal.’s[15]investigationofanesthetizedrats,DC ticityeffects,asanincreaseinintracellularcalciumisneces- stimulationfor5minorlongerresultedinprolongedincrease saryforLTPinlocalsynapses[54]. of spontaneous firing activity lasting for hours after anodal Taken together, multiple lines of evidence in the animal stimulation, whereas activity decreased relative to baseline literatureconcludethattDCSinduceslong-lastingphysiolog- after cathodal stimulation (Fig. 1b). These effects were also icaleffectsinthecortex.Theprecisemechanisms,including observed to be dependent on protein synthesis and thus not the relationship between stimulation parameters and physio- likelytobeapurelyelectricalphenomenon[38].Indeed,fur- logical effects, as well as the relationship between neuronal therstudiesonratslicesdemonstratedthatdirectcurrentstim- andnon-neuronaleffectsremaintobefullyunderstood. ulationinducesLTPorLTDinapolarity-dependentmanner, which also depends on NMDA receptors and brain-derived HumanStudies neurotrophic factor (BDNF) [39, 40]. Intracellular calcium alsoincreased following anodalstimulation,aswell asearly Although animal experiments continue to provide a variety of geneexpression,whichalsodependonNMDAreceptors[41, information on physiological mechanisms underlying tDCS- 42].Here,thedurationofstimulationwasalsoshowntobeof inducedneuroplasticity,alargegapstillexistsinthetransferabil- importance, since longer-lasting stimulation bi-directionally ityofthesefindingstohumanmodels,primarilyduetodifficulty regulatedcAMP[43].Arecentstudyonrabbitsdemonstrated in manipulating relevant synaptic components. Nevertheless, thattDCSappliedtothesensorimotorcortexcouldalsomod- studiesusingpharmacologicalmodulationcombinedwithTMS ulate presynaptic mechanisms of synaptic transmission, have provided critical insights on putative mechanisms, which highlightingtherelevanceofadenosinereceptorsinaccount- appeartoinvolvemainlyglutamatergicprocesses. ingforlong-termassociativelearningeffects[44].Theroleof Usingsingle-pulseTMStoelicitMEPs,Nitscheetal.dem- presynapticinputsandongoingspontaneousactivityindriv- onstratedthatanodaltDCSof13minincreasedmotorcortical ing plasticity remains to be fully understood; however, con- excitability for up to 90 min, and 9 min of cathodal tDCS verging evidence points to the importance of local activity decreased up to 60 min (Fig. 1e; [26, 27]). The duration of driving local plasticity [45]. Accordingly, in the study by theseeffectsisintherangeofearlyphaseLTP-andLTD-like Fritsch et al. [39], long-term effects in slice preparations, plasticity [55]. Systematic studies using the combination of which display no major spontaneous activity, were only ac- TMSwithpharmacologicalinterventionswerecarriedoutto complishedwhentDCSwasaccompaniedbylow-frequency investigatethephysiologicalbasisfortheseafter-effects.The electrical stimulation, which was not the case in an in vivo NMDA receptor blocker dextromethorphan abolished the study, in which spontaneous activity in present to a larger after-effects of both anodal and cathodal tDCS [34, 56], degree[46].Similardependencieshavebeenobservedinhu- whereastheNMDAreceptoragonistd-cycloserineprolonged manstudies,wherebackgroundcorticalactivitywasshownto theafter-effectsofanodaltDCS[57],indicatingthedependen- modulateneuroplasticafter-effectsoftDCS[47]. cyoftheglutamatergicsystem.Furtherstudiestosupportthis RelatedtotDCS-inductionofplasticity,especiallywithre- were conducted using double-pulse TMS protocols, which gard to network or remote effects, is the relevant role of the showed reduced intracortical inhibition, but enhanced facili- neurovascularunit[48],whichconsistsofbothneuronaland tation,afteranodaltDCS,andoppositeeffectsaftercathodal non-neuronal cells, such as glial cells, and vascular compo- tDCS[36].Thecalcium-dependencyoftheseeffectswasalso nents,suchasendothelialcellsandbloodvessels.Usinglaser investigated, as evidenced by animal studies showing their Doppler flowmetry (LDF), Wachter et al. [49] observed a involvementwithNMDAreceptors.Here,thecalciumchan- polarity-dependent modulation of tDCS on cerebral blood nel blocker flunarizine abolished the after-effects of anodal flow (CBF) of the rat. Fifteen minutes of anodal tDCS at tDCS [36]. The role of GABA ergic interneurons in modu- A 100 μA increased CBF up to 30 min afterwards, whereas lating tDCS plasticity was also explored. Lorazepam, which 100 μA of cathodal tDCS decreased CBF by 25% for up to enhances active GABA receptors, initially reduced, but then 30 min. Similarly, a functional near-infrared spectroscopy boostedtheexcitabilityenhancementfollowinganodaltDCS, (fNIRS)studyonratsalsoobservedanincreaseinoxygenated buthadnoeffectfollowingcathodaltDCS[35].TMSproto- hemoglobinduringanodaltDCS,whichpersistedfor30min cols examininginter-neuronaleffects found thatbothanodal afterwards[50].Whetherthesephysiologicaleffectsareadi- andcathodaltDCSenhancedI-waves,whicharereducedby rect result of electric fields (e.g., vessel dilation effects from GABAactivity[36].Theinterpretationbehindthisresultbe- DC fields—[51, 52]) or secondary effects from polarized cameclearerafteramagneticresonancespectroscopy(MRS) CurrBehavNeurosciRep studyshowedreductionofGABAfollowinganodalandcath- functional and structural connectivity, have shed important odaltDCS[58].Insum,thesestudiesunderscoretheinvolve- light on mechanisms by which tDCS can induce functional mentofglutamatergicmechanismsindrivingtheafter-effects cortico-cortical, and cortico-thalamic alterations [74, 75]. oftDCS,andthatatDCS-inducedreductionofGABAmight ConsideringthatanimportantaspectoftDCSistomodulate serve as a “gating” mechanism. In addition to investigating learning-relatedmechanisms,thesefindingsofferspecialrel- glutamatergic and GABAergic involvement, effects of other evance to the prospect of integrating the communication of neuromodulators which are relevant for tDCS-induced plas- segregatedcorticalareasatthesystemlevel. ticity, such as dopamine, serotonin, and acetylcholine have Tosummarize,tDCShasprominentneuroplasticafter-effects alsobeenexplored[59–63].Overall,thesestudieshavefound which can be observed in the intact animal and human cortex thattheseneuromodulatorsarenotjustrelevantforestablish- with modern electrophysiological and imaging techniques. In ingneuroplasticitybutcouldalsoalterplasticityinnon-linear additiontolocalandregionaleffectsunderthestimulationelec- andcomplexways,which isofimportantrelevanceforneu- trode,tDCSalsoaffectsfunctionalnetworksatbothcorticaland rologicalorpsychiatricdiseaseswheretheseneuromodulators subcortical levels and can involve the functional activation of areoftenoutofbalance. non-neuronal structures, such as glia, blood vessels, and endo- Several studies have documented neurophysiological after- thelialcells,thusofferingresearchersandcliniciansabroadscope effectsincorticalregionsotherthantheprimarymotorcortex. forpossibleinterventionstrategies. Antaletal.investigatedexcitabilityalterationsinthevisualcor- tex by measuring visual-evoked potentials (VEPs). Anodal tDCSincreasedtheamplitudeoftheN70component,whereas OptimizingtDCSforResearchandClinical cathodaltDCSdecreasedit[64].Inanotherstudy,applicationof Applications tDCS over the visual cortex with an extra-cephalic reference electrode also resulted in polarity-dependent modulation of Despite the heterogeneous, yet increasing, number of tDCS VEPs,bothduringandshortlyafteranodalandcathodaltDCS studies, physiological and functional after-effects following [65]. For the somatosensory cortex, polarity-dependent effects single sessions of tDCS are still relatively short-lasting. wereobservedthroughrecordingsomatosensory-evokedpoten- Criticalfortheefforttoprolong and optimizetDCSefficacy tials(SEPs).AnodaltDCSincreasedSEPamplitudesforatleast are (1) understanding basic effects of tDCS, particularly in 60mininonestudy[66]andcathodaltDCSreducedthosein areas other than the human motor cortex; (2) optimizing the another[67].Intheauditorycortex,anodaltDCSoverthetem- largeparameterspacefortDCSprotocols(e.g.,electrodemon- poralcortexandcathodaltDCSoverthetemporo-parietalcortex tage,currentintensity,andstimulationduration);and(3)un- enhancedauditory-evokedpotentials[68]. derstanding the factors which underlie inter-individual vari- BesidesthelocalandregionaleffectsoftDCS,afewstud- ability, which not only masks real population level effects ies have also observed topographically remote cortical and makinginterpretationofresultsdifficult,butcanalsobelev- subcorticaleffectsoftDCS.Usingpositronemissiontomog- eragedtounderstandmoreabouttDCSeffects.Understanding raphy (PET), it was shown that both anodal and cathodal thesecomponentsmayhelptodevelopbettersuitedstimula- tDCS inducewidespreadincreasesanddecreasesinregional tionprotocols,e.g.,closed-loopsystemsorotherindividually cerebralblood flow(rCBF) [69].As discussed previously, it optimized protocols for highly effective treatment. With re- remainsuncleartowhatextentvasculareffectsarethedirect gardto (2) and (3), we briefly summarize the latest findings resultofcurrentflow,orsecondarilyaffectedthroughsynaptic underlyingtheseefforts(Fig.2). mechanisms. Localized alterations in the hemodynamic re- sponsefollowingtDCShavealsobeenobservedusingarterial tDCSParameters spinlabeling(ASL-fMRI)whereitwasshownthatrCBFin- creased after short repeated durations of anodal tDCS and AlargeportionofthehumanstudiesontDCSconductedthus decreased after cathodaltDCS [70].Thiseffect does not ap- farhavebeenbasedonthe“classic”tDCSprotocol,wherea peartobeconstrainedonlytothemotorcortex,asanodaland current intensity of 1 mA is applied for durations of 9 or cathodaltDCSappliedtotheleftdorsolateralprefrontalcortex 13 min, and an electrode of size 35 cm2 is placed over the (DLPFC) also resulted in polarity-specific alterations in per- targetregionwithareferenceelectrodeoverthecontralateral fusion [71]. Modulations of resting state oscillatory activity, orbit.However,alteringthesestimulationparametershaveled recordedusingEEG,havealsobeenreportedafteranodaland to significant deviations from the canonical after-effects of cathodal tDCS and reiterate the concept of increased or de- tDCS.Forexample,increasingthedurationof1.0mAanodal creasedspontaneousfiringactivityinpyramidalneuronpop- tDCSfrom13to26minresultedinexcitabilitydiminishing, ulations,respectively[72,73].Recentadvancementsinbrain andnotenhancing,after-effects[7],andincreasingthecurrent networkconnectivityanalysesappliedtoneuroimagingdata, intensityof20mincathodaltDCSfrom1mAto2mAcon- such as the use of graph theoretical parameters to assess verted excitability diminution to facilitation [5]. These non- CurrBehavNeurosciRep Fig.2 TowardstDCS optimization.AvenuesfortDCS optimizationcanbebroadly categorizedinto(1)approaches foradvancingtheunderstanding ofthebasicphysiologicaland functionaleffectsofstimulation; (2)systematicandcontrolled studiestoinvestigatetheeffectsof tDCSparameters,suchasdose- responserelationships;and(3) discoveryandinsightsintofactors whichmayresultininter- individualvariability,suchas geneticandanatomical determinants.Understandingthe relationshipbetweenthesethree aspectsiscrucialtoadvancing state-of-the-artprotocolsfor clinicalandresearchapplications lineareffectsarelikelycausedbyacombinationofincreased 2mAcurrentintensitiesresultedinelectricfieldmagnitudes intracellular calcium, which has been shown to convert the of0.4V/minthecortex[83]whereasinanotherstudy,1mA direction of LTD to LTP in animal studies [76, 77], and tDCSinducedanelectricfieldof0.5V/m(i.e.,approximately potassium-channel dependent counter regulation to limit twiceinsize)[84].Insum,thesestudieshighlighttheneedfor LTP plasticity [78]. In order to extend the duration of after- additionalmodelingcombinedwithphysiologicalvalidations effectslongerthan1h,whichisofpracticalbenefitinclinical astheywouldbeofhighbenefittooptimizationefforts. applications,anintervalof20minbetweenconsecutivestim- ulations was found optimal to induce longer-lasting after-ef- Inter-IndividualParameters fects for both anodal (up to 24 h) and cathodal (up to 2 h) tDCS[6,7].Spacedrepetitionprotocolshavealsobeenshown RecentstudieshavesuggestedthattDCSafter-effectscandif- toinducelate-phaseplasticityeffectsinbothanimalslicesand ferentiate based on inter-individual variability between in vivo experiments [7, 79]. An interesting question is the healthy adult participants [8, 85–88]. Factors affecting the extentoftheinteractionbetweencurrentintensities(including inter-individual response variability in tDCS are likely to be greaterthan2mA)andstimulationdurationandrepetition,on similar with factors which affect other NIBS techniques and anodalandcathodaltDCS. includephysiologicalandanatomicalfactorssuchasbaseline Withfurtherregardtooptimizationisthechallengeofop- state or excitability, cortical folding,skull thickness, and ge- timizingthestimulationelectrodemontage.Althoughthemo- netic profile, as well as demographic factors such as gender torcortex–contralateralsupraorbitalridgemontagewasfound andage([89];seealsoreview[90]).Insum,severalofthese tobethemostoptimalformodulatingM1excitability[10],it studies have noted the confounding effect of fluctuations in maynotnecessarilybethemostoptimalforeveryapplication circadianrhythms,motorcorticalexcitabilitybeforeTMS,or or individual. New tools based on finite-element-method shifts in attention (e.g., during eyes-open versus eyes-closed (FEM)modelshavebeendeveloped,whichleverageindivid- conditions)ontDCSafter-effects,whichunderscorestheim- ualMRIimagesinordertodeterminethemostoptimalmon- portance for future studies in designing experiments which tage [80, 81]. These include multi-electrode montages to in- appropriatelycontrolandreportfortheseadditionalfactors. ducemorefocaleffects,suchasthe4×1high-definition(HD- tDCS)montage,whichhasbeenshowntoresultinmorepro- nouncedmotorcorticalexcitabilityafter-effectsincomparison Conclusions totheclassicalmontage[82].However,obtainingcomprehen- sive physiological validations of these montages is a chal- The present review aimed to summarize the current state of lenge,anditremainsunclearwhetherincreasedfocalityisof knowledgeonthemechanismsunderlyingtDCSprimaryef- benefit to neuropsychiatric patients, where often large areas fectsinbothanimalsandhumans,whichinvolvemodulation andnetworksareaffected.Withregardtovalidation,arecent oftherestingmembranepotential,andsecondaryneuroplastic intracranial EEG combined with tDCS study reported that after-effects, which involve both pre- and post-synaptic CurrBehavNeurosciRep modifications. Recent findings have demonstrated direct current stimulation (tDCS). 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