The Reason Why rTMS and tDCS Are Efficient in Treatments ...

The hypothesis here is that both non-invasive electromagnetic modalities of brain stimulation, rTMS and tDCS, are efficient in depression ... ThisarticleispartoftheResearchTopic PainandDepression Viewall 11 Articles Articles QingZhao InstituteofPsychology,ChineseAcademyofSciences(CAS),China RaquelC.Martinez HospitalSirioLibanes,Brazil Theeditorandreviewers'affiliationsarethelatestprovidedontheirLoopresearchprofilesandmaynotreflecttheirsituationatthetimeofreview. Opinion Introduction Conclusion AuthorContributions ConflictofInterest Acknowledgments References SuggestaResearchTopic> DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex totalviews ViewArticleImpact SuggestaResearchTopic> SHAREON OpenSupplementalData OPINIONarticle Front.Psychol.,13January2020 |https://doi.org/10.3389/fpsyg.2019.02923 TheReasonWhyrTMSandtDCSAreEfficientinTreatmentsofDepression MilenaČukić1,2* 1DepartmentforGeneralPhysiologyandBiophysics,UniversityofBelgrade,Belgrade,Serbia 2InstitutodeTecnologíadelConocimiento,ComplutenseUniversityofMadrid,Madrid,Spain Introduction Theexactneurophysiologicalmechanismsofrepetitivetranscranialmagneticstimulation(rTMS)andtranscranialdirectcurrentstimulation(tDCS)fortreatingpatientsdiagnosedwithdepressionarestillnotclear.ResultsofpreviousstructuralandfunctionalMRIstudiesshowedanaberatedfunctionalconnectivityinmajordepressivedisorder(MDD)(Vederineetal.,2011;deKwaastenietetal.,2013).Those,aswellasseveralconnectivitystudies(Bluhmetal.,2009;Bermanetal.,2011;Zhangetal.,2011;Kimetal.,2013;Chenetal.,2015)seemtosupportthehypothesisthataberrantfunctionalconnectivitywithinfronto-limbicsystemunderliesthepathophysiologyofdepression.ItshouldbenotedthatantidepressantapplicationofbothrTMSandtDCSisbasedonpreviousfindingsthatthesetwomethodshelpinthecaseofhypoactivityoftheleftdorsolateralprefrontalcortex(DLPFC)(Grimmetal.,2006).Thosestructuralandfunctionaldifferencesprobablyintroduceabnormalphysiologicalcomplexitydemonstratedinelectroencephalographic(EEG)(Ahmadlouetal.,2012;Bachmannetal.,2013;Hosseinifardetal.,2014;DelaTorre-LuqueandBornas,2017;Jaworskaetal.,2018;Lebieckaetal.,2018)aswellasinelectrocardiographic(ECG)signalsindepression(Migliorinnietal.,2012;Rossietal.,2016;Isegeretal.,2019). TDCSislow-intensitymodalityoftranscranialelectricalstimulation(TES)whichinducesverymildsensationsintheskin(StaggandNitsche,2011).MuchlaterdevelopedTMSprimarilyusesastrongmagneticfieldtoinduceanelectricfieldinthecortexpainlessly,initiatingoptimallyfocusedactivationofneuralstructures(Barkeretal.,1985).SomeofitsmodalitiesusedinpsychiatryarerepetitiveTMS(rTMS)andintermittentthetaburstTMS(iTBS).InthepresentabundantliteratureaboutbothrTMSandtDCS,thereisscarceevidenceofwhythesetwotechniquesarecapableofamelioratingdepressivesymptoms.Westilldon'tknowwhatprecisemechanismsbehindthemare.Onlyafractionofpublishedresearch(Amassianetal.,1989;Maccabeeetal.,1990;WassermannandGrafman,2005;Mirandaetal.,2009;IlmoniemiandKičić,2010;Alametal.,2016)describethetheoreticalbackgroundofthosemechanismsfromelectromagnetics/physicspointofview.Themajorityofpublishedstudiesarebasedonmulti-centriccomparisonsofclinicalefficiency(Brunonietal.,2016;Antaletal.,2017;Mutzetal.,2018)andcomputationalmethods-orsimulations(Mirandaetal.,2001,2006;Wagneretal.,2007;Huangetal.,2017).Recently,ateamofleadingresearchersinlowintensityelectricaltranscranialstimulationreviewedclinicaloutcomesfor8,000people(Antaletal.,2017)confirmingitssafetyandeffectiveness,anddefinedtheregulatoryandapplicationguidelinesforfutureresearch. Aterm“non-invasive”(attachedtobothrTMSandtDCS)stemsfromobsoletemedicalpointofviewthatthestimulatingelectrodesdonotenterthecrania(andthestimulationisperformedeitherviasmallelectricalchargesincaseoftDCSorviaFaraday'sinduction).Therealeffectof“non-invasive”electromagneticstimulation(rTMSandtDCS)cannotbemeasureddirectlyduetotheirnon-invasivenature.Opitzstatedinrecentresearch,thattheimportantpointisininterpretabilityofstimulationeffects(Opitzetal.,2015):“ifelectricfieldsaredeliveredinconsistently,buteffectsareobservednevertheless,theresultsaremoredifficulttointerpretbecauseeffectcouldbedrivenbyotherincidentallyaffectedbrainregions.”BothtDCSandTMSareshowntoinitiatethese“unintended”effects:BestmannshowedusingMRIthatTMSofmotorcortexbelowthethresholdpowercanactivatesomeotherdeeperstructures,contrarytopreviousbeliefandLishowedsimilarphenomenainthecaseoftDCS(Bestmannetal.,2003,2004;Lietal.,2018). Thehypothesishereisthatbothnon-invasiveelectromagneticmodalitiesofbrainstimulation,rTMSandtDCS,areefficientindepressiontreatmentsbecauseoftheirprovenabilitytodecreasethephysiologicalcomplexity(Čukićetal.,2013,2019a;Lebieckaetal.,2018;Zuchowiczetal.,2019).ThehallmarkofMDDiselevatedphysiologicalcomplexityofEEGmeasuredbyvariousentropymeasures,fractaldimension,symbolicdynamicapproachmeasures,geometrictechniqueslikerecurrenceplotsandothermeasuresstemmingfromcomplexsystemsdynamicstheory(DelaTorre-LuqueandBornas,2017).Therearealsofindingsthatlinkchangesinheartrhythmcomplexitywithdepression(Migliorinnietal.,2012)andtheoutcomesofrTMStreatment(Roysteretal.,2012;Lebieckaetal.,2018;Isegeretal.,2019). Theevidencesupportingthecloserelationshipbetweentheelectrophysiologicalcomplexity,depressivesymptoms,andrTMSandtDCStreatmentissufficientbutveiled.First,inour2011studyweshowedthatevenasinglepulsetranscranialmagneticstimulation(spTMS)candecreasethecomplexityofelectrophysiologicalsignal(Čukićetal.,2012,2013).Second,Mutanenetal.(2013)usedGlobalRecurrenceanalysisonconcurrentlyrecordedEEGtoshowthatTMSiscapableofinducinga“brain-shift”afterthestimulation.,thatismovingthesystemofbrainnetworkstohigher-energyless-probablestateinhealthycontrols.BasedonthisworkweappliedthesamemethodbutwithtDCS(Čukićetal.,2018b,2019a,b).Čukićetal.(2018b)showedforthefirsttimethegraphicalrepresentationsoftDCS-induced“brain-shift”obtainedbyprincipalcomponentanalysis(PCA)appliedonrawEEGsignalsamples.PCAwasusedinourdataminingprojectstocheckforseparabilityofdataforlaterclassification.Thisstudyre-usedEEGsignalsfrom16healthycontrolsrecordedduringcathodalandanodaltDCSstimulationprotocolsfromPelliciarietal.(2013)(whichisalsoelaboratingonthedifferencebetweencathodalandanodalstimulation).ObtainedPCAplotsareshowingthatmorethanahalfanhourpoststimulationthesystemisstillinhigher-energylower-probablestate“brain-shift”duetothetDCSstimulation.ThefirstthreeprincipalcomponentsofrawEEGsamplesbeforeandaftertDCSstimulationareillustratingthattheybelongtoseparatepartsofthephasespace.OneofparticipantsPCAplotaftercathodalstimulationisshowninFigure1. FIGURE1 Figure1.TheredvoltagesamplesaretakenfromtheEEGrecordingbeforethestimulation,andpinkonesfrom32minafterthetDCSstimulation.ThefirstthreeprincipalcomponentsofrawEEGsamplesbeforeandaftertDCSstimulationareillustratingthattheybelongtoseparatepartsofthephasespace.HereisaPCAplotforpersonnumber8,withcathodal(C)stimulation.ThisfigureispartofresultspublishedinChapter3inbook(ČukićRadenković,2019),butthisparticularPCAplotisnotdisplayedbefore(duetolimitedspaceinpreviouspublication). Severalresearcherswhousedvariousnon-linearmeasuresofcomplexityofEEGconfirmedthatphysiologicalcomplexityiselevatedinMDD(Ahmadlouetal.,2012;Bachmannetal.,2013,2015,2018;Faustetal.,2014;Hosseinifardetal.,2014;Akaretal.,2015;Čukićetal.,2018a,2019a;Lebieckaetal.,2018).Oneofthemostinclusivereviewstudiesonvariousspectral,fractalandothernon-linearmeasuresofrelationshipbetweenphysiologicalcomplexityandMDD,concludedthatEEGsignalsinMDDare“probablymorerandomthanmorecomplex”comparedtothoseofhealthypersons(DelaTorre-LuqueandBornas,2017).Thismightbeduetoimpairedintrinsicfeedbackmechanismsimportantformanyregulatoryfunctions(Goldbergeretal.,2002).Thiskindofabnormalfunctionalconnectivityisreportedinseveralresearchpapersfromseeminglyunrelateddisciplines,likegraphtheoryapplicationinEEGconnectomics(Leeetal.,2011;VanEssenetal.,2012;Castellanosetal.,2013;Kimetal.,2013),andGrangercausalityappliedonfMRIsignals(Hamiltonetal.,2011).ThefMRIandFractionalanisotropy(FA)researchalsofoundthatwithinfronto-lymbicsystemthereisabnormalfunctionalconnectivityinMDD(Vederineetal.,2011;deKwaastenietetal.,2013).DeKwaastenietfoundthatuncinatefasciculus,importantforconnectingprefrontalwithlimbicsystem,isnotfullyfunctionalinMDDpatients(deKwaastenietetal.,2013).Moreover,severalstudiesexaminingconnectivityinMDDfoundadifferentdynamicalfeatures,andseveraldifferentregions(anteriorcingulatecortex,insula,cingulateandhippocampalnetwork)wereconfirmedascandidatesforthesedifferences(Mayberg,1997;Maybergetal.,1997,1999;Bluhmetal.,2009;Bermanetal.,2011;Geetal.,2019).Itischallengingtocomparethesefindingssincetheirmethodologicalapproachesaredifferentinsomanyaspects.Also,Mendezetal.(2012)detectedahigherfocusonlocalconnectionsthanonglobalonesinMDD.Thiscanalsobeseeninpersonswithdepressioninremission:previouslydetectedabnormalfunctionalconnectivitydecreases(Mendezetal.,2012).Lebieckaetal.(2018)showedthatelevatedphysiologicalcomplexitiesdiminishedaftertreatmentinthoseMDDpatientsthatreactedwellonrTMS(asmeasuredbythedecreaseincomplexitycorrespondingtoremissionscoresafterthetreatmentwasmeasured)(seealsoJaworskaetal.,2018).Isegeretal.(2019)alsorevealedtheconnectionbetweensuccessfuliTBSappliedtotheDLPFCandmodulationofautonomicnervoussystem(Isegeretal.,2019). Bestmannetal.(2004)demonstratedthatwithTMSapplicationbelowthemotorthresholdpower,MRIcandetectaresponsefromareasthatwerenotintendedtobestimulated(Bestmannetal.,2004).Lietal.(2018)werethefirstresearchgrouptodemonstratethattDCScanactivatesomestructureswithinDMN.Opitzetal.(2015)concludeintheirworkthateventheconductivityconstants(dielectricconstantsfortissuetypes)usedforcalculatingtheeffectofstimulation,orsimulation,arenotadequatefordescribingthemuchmoredemandingreality.Opitz'steamdetectedbothhigherandloweractualvaluesmeasureddirectly(withthearrayofimplantedelectrodesinpatientsthatwerecandidatesforsurgicalinterventiononepilepticfoci)thanthosepredictedwithstandardsimulationproceduresforTES(Opitzetal.,2015,2018).Theeffectofastimulationcandependonthegeometricalshapeofthesurfaceofsulci,whichcannotbemonitoredduringtheuseofanon-invasiveprocedure,andthatalsocanleadtomajormiss-predictions(Čukić,2006;Čukićetal.,2009;Saturninoetal.,2015;Alekseichuketal.,2018;Opitzetal.,2018). Althoughitcanseemimpossibletocomparethetwonon-invasivebrainstimulationtechniquesthataresodifferentinthesenseoftheirelectromagneticpropertiesandthelevelofpowertheycaninduceinthelivingtissue,wecanstillrecognizethesamefunctionalpattern.InmanyreviewpapersexploringtheefficiencyofbothrTMSandtDCSinclinicalapplications(Brunonietal.,2016;Antaletal.,2017;Mutzetal.,2018),theconclusionsareinline:theyareeffective,andtDCScanbeappliedeveninprimarycare,butalsoasamaintenancetreatmentforalreadysuccessfulrTMS(Mutzetal.,2018).Inastudyexaminingtheeffectofelectroconvulsivetherapy,itisdemonstratedthatmultiscaleentropyischangedafterthetreatment(Okazakietal.,2013),pointingagainatthelinkbetweencomplexitychangesandtheeffectivetreatmentfordepression.Zuchowiczetal.(2019)reportedondetectedsynchronizationofEEGasafeatureofsuccessfulrTMSwhichispointingatreductionofcomplexity,too. Forallelectromagneticstimulationtreatments,theeffectisoftemporarynature.Therationaleisthattheycanatleastamelioratethesymptomsforalimitedtime;afterwhichtheyneedtoberepeated.Thecommonadvantageofnon-invasivebrainstimulationtechniquesovermedicationsisthattherearenoforeseeableharmfulside-effects(Antaletal.,2017). Althoughstudyofphysiologicalcomplexitychangesisstillintherealmofresearchandmainlynotinuseinclinicalsetting,itisexpectedthatsoonclinicianswouldstartusingvaryingelectromagneticmodalitiesofstimulationwithbetterunderstandingofhowtheywork—asmeanstodecreasecomplexitycharacteristicofdepression.Furtherresearchbasedonempiricaldataisnecessarybeforemakingthefinalconclusionthatnon-invasivebrainstimulationtreatmentsmayworkthroughchangingphysiologicalcomplexity. Conclusion Toconclude,afterallabovementionedresultsofvariouslinesofresearchthattriedtobringusclosertounderstandingvariousaberrationsofdepression,bothrTMSandtDCSmightbeefficientbecauseoftheirabilitytodecreasecharacteristicallyelevatedlevelsofphysiologicalcomplexityindepression. AuthorContributions MČconceivedtheideaaboutthearticle,performedaliteratureresearchandwroteentiretext. ConflictofInterest Theauthordeclaresthattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest. Acknowledgments MČthankfultocolleaguesProf.CarloMiniussi,DeboraBrignaniPh.D.,andMariaConccetaPelliciariPh.D.forsharingtheirdatawithmeandforvaluablediscussions,andalsotoProf.DankaSavićforvaluableadviceonimrpovingthetextofthismanuscript.PartofthisworkissupportedbyRISEWISE(H2020-MSCA-RISE-2015-690874). 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Editedby:QingZhao,SecondAffiliatedHospitalofGuangzhouMedicalUniversity,China Reviewedby:RaquelChaconRuizMartinez,HospitalSírio-Libanês,Brazil Copyright©2020Čukić.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).Theuse,distributionorreproductioninotherforumsispermitted,providedtheoriginalauthor(s)andthecopyrightowner(s)arecreditedandthattheoriginalpublicationinthisjournaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionorreproductionispermittedwhichdoesnotcomplywiththeseterms. *Correspondence:MilenaČukić,[email protected];[email protected] COMMENTARY ORIGINALARTICLE Peoplealsolookedat SuggestaResearchTopic>