What Effect Does tDCS Have on the Brain? Basic Physiology of tDCS

10 Pages·00.857 MB·English

by  Asif Jamil

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
[e-mail] 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
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Funding Information MAN received support from the EC Horizon
Neurophysiol.2003;114:589–95.
2020Program, FET Grant,686764-LUMINOUS,and grantsfromthe
13. NitscheMA,LiebetanzD,AntalA,LangN,TergauF,PaulusW.
GermanMinistryofResearchandEducation(GCBSgrant01EE1403C,
Chapter27modulationofcorticalexcitabilitybyweakdirectcur-
TRAINSTIMgrant01GQ1424E).
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