rTMS: repetitive transcranial magnetic stimulation and ...

Repetitive TMS protocols for depression can mainly be differentiated based on the stimulation location and frequency, but trains, sessions and inter train ... × Login UsernameorEmailAddress* Password* ClickForRegister? LostYourPassword? × Register Email* Password* ClickForlogin? rTMS:repetitivetranscranialmagneticstimulationanddepression HomerTMS:repetitivetranscranialmagneticstimulationanddepression RepetitiveTranscranialMagneticStimulation(rTMS)inDepression:Protocols,MechanismsandNewDevelopments Arns,M.1,2,3,Iseger,T.1,3,Spronk,D.B.1,Brown,T.4&Fitzgerald,P.B.5 1ResearchInstituteBrainclinics,Nijmegen,TheNetherlands 2neuroCareGroup,Munich,Germany 3Dept.ofExperimentalPsychology,UtrechtUniversity,Utrecht,TheNetherlands 4neuroCareGroup,Melbourne,Australia 5EpworthHealthcareandMonashAlfredPsychiatryResearchCentre,Melbourne,Australia Updatedandrevisedversionof:Repetitivetranscranialmagneticstimulationindepression:Protocols,mechanismsandnewdevelopments.InNeuromodulationandneurofeedback:Techniquesandapplications.Elsevier. Abstract Thisbookchapterintroducesandexplainsprotocols,mechanismsandnewdevelopmentsoftranscranialmagneticstimulation(TMS)inthetreatmentofdepression.RepetitiveTMSprotocolsfordepressioncanmainlybedifferentiatedbasedonthestimulationlocationandfrequency,buttrains,sessionsandintertrainintervalsarealsoparametersthatcanbemanipulated.Variousneuroimagingfindingsthatshedlightonpotentialantidepressantmechanismsarediscussed,includingtheroleofthedepressionnetwork,networkconnectivityandoptimizingrTMSusingsuchknowledge.Furthermore,newdevelopmentsinthefieldofengineering,inparticularthedevelopmentoftheH-coil,andnewprotocolsarereviewed.ThechapterfinisheswithadiscussionofthesenewinsightsandpotentialimplementationsthatcouldimproveandenhancetreatmentresponsetorTMS. Introduction TMS(transcranialmagneticstimulation)isanon-invasiveneuromodulationtechnique.Ithasaverydirectinfluenceonbrainphysiology.ThebasicprincipleofTMSistheapplicationofshortmagneticpulsesoverthescalpofasubjectwiththeaimofinducingelectricalcurrentsintheneuronsofthecortex.AtypicalTMSdeviceconsistsofastimulatorthatcangenerateastrongelectricalcurrent,andacoilinwhichthefluctuatingelectricalcurrentgeneratesmagneticpulses.Ifthemagneticpulsesaredeliveredintheproximityofaconductivemedium,e.g.thebrain,asecondarycurrentintheconductivematerial(e.g.neurons)isinduced(Figure1).InthepracticeofTMS,asubjectisseatedinachairandanoperatorpositionsthecoilabovethescalpofthesubject,andtheTMSpulsesareapplied. Rtms25S Figure1:Visualillustrationoftheinductionofelectricalcurrentsinthebrain(greyarrowsinthebrain)throughthemagneticpulsesappliedbymeansofthecoil(grey8-shapedfigure)positionedabovethehead.Thecolorsonthescalpreflecttheelectricalfield,i.e.whereneuralactivationismostfocused.FigureusedwithpermissionfromneuroCareGroup©. AnthonyBarkerandhiscolleaguesattheUniversityofSheffieldwerethefirsttodevelopaTMSdevice,introducinganewneuromodulationtechniqueinneuroscience.Thenewapplication,demonstratedfirstbytheseresearchers,wastheinductionofamotorevokedpotential(e.g.activatingthemusclesabductingthethumb)bymeansofapplyingaTMSpulseovertheprimarymotorcortex(Barker,Jalinous,&Freeston,1985). Initially,TMSwasusedmainlyinstudiesonmotorconductivitythroughinvestigatingthetemporalaspectsandamplitudeoftheevokedmotorresponsesafterstimulatingthemotorcortex.ContinuingprogressonthetechnicalaspectsofTMSdevicessoonmadeitpossibletodelivermultiplepulseswithinashorttimeperiod,i.e.repetitiveTMS(rTMS).WiththedevelopmentofrTMS,researcherswereabletoinducechangesthatoutlastedthestimulationperiod(Pascual-Leoneetal.,1999).ThishasledtoaconsiderableextensionofthepossibleapplicationsofTMS.Currently,rTMSisusedforanincreasingvarietyofapplicationssuchasthestudyofpathophysiologyofdiseases,theinvestigationofthecontributionofcertainbrainregionstoparticularcognitivefunctionsand,mostrelevantforthischapter,thetreatmentofpsychiatricdiseases–mostspecifically,depression. ThepotentialofrepetitiveTMSinthetreatmentofpsychiatricdisorderswassuggestedforthefirsttimerelativelysoonafterthedevelopmentofthefirstTMSdevicein1985.Inastudyonmotorconductivity,changesinmoodinseveralhealthyvolunteerswhoreceivedsinglepulsesoverthemotorcortexweredescribed(Bickford,Guidi,Fortesque,&Swenson,1987).Followingthisinitialobservation,thetechnicalprogressandtheincreasingavailabilityofTMSdeviceshasledtothefurtherinvestigationofrTMSinthetreatmentofdepression.Apartfrombeingthefirstinvestigatedpsychiatricapplication,itisalsothemostwellinvestigatedpsychiatricapplication.Majordepressionhasadisablingeffectondailyactivity,indicatingthateffectivetreatmentiscrucial.Treatmentwithantidepressantmedicationisthemostcommonandfirstlinetreatmentformanyindividuals.However,asignificantpercentageofpatientsaretreatmentresistant(TRD)meaningthattheydonotsufficientlyrespondtoantidepressantmedication(Kelleretal.,2000;Kirschetal.,2008;Rushetal.,2006).Someofthesepatientsproceedtoelectroconvulsivetherapy(ECT).Despiteremarkableclinicalresults(Husainetal.,2004),ECTisacontroversialandunpopulartreatmentoptionduetotherequiredinductionofaseizureandassociatedside-effectssuchasmemorycomplaints(RobertsonandPryor,2006). Followinginitialpositiveresultswithdepression,andduetoitspainlessandnon-invasiveadministration,rTMShasbeenproposedasa‘better’alternativetoECT(Paus&Barrett,2004)orasanalternativeforpatientswhomaynotbewillingtoundergoECT,orforwhomECTmaynotbesuitable.Inordertocompareefficacyofthesetreatments,rTMSandECThavebeenjointlyinvestigatedinseveralstudies(Erantietal.,2007;Rosaetal.,2006).OftheseveralstudiesperformedErantietal.(2007)observedagreatadvantageforECT.However,others(Grunhaus,Schreiber,Dolberg,Polak,&Dannon,2003;Pridmore,Bruno,Turnier-Shea,Reid,&Rybak,2000;Rosaetal.,2006)foundcomparableefficacyratesforECTandrTMSinthetreatmentofdepression.Furthermore,Erantietal.(Erantietal.,2007)includedpatientswithpsychoticdepressionwhereastheotherstudiesonlyinvolvednon-psychoticdepression(Pridmoreetal.,2000),suggestingthatrTMSmaynotbeindicatedforthetreatmentofdepressionwithpsychoticfeatures.Thisnotionwasfurthersupportedbyameta-analysisfromBerlimandcolleagues(Berlim,VandenEynde,&Daskalakis,2013)comparingECTandrTMSstudiesinthetreatmentofdepression.Theyfoundanoveralleffectsizeof1.42favoringECT,whichdroppedtoasmalleffectsizeof0.3whenstudiesthatincludedpsychoticdepressionwereexcluded. TheearlyreportsofrTMSasanantidepressanttreatmentmodalityconsistedofpilotstudieswithsmallnumbersofsubjects.Intheseearlystudiesarbitrarystimulationparametersovervariousandnon-specificbrainregionswereapplied(HoflichG,KasperS,HufnagelA,RuhrmannS,MollerHJ1993).AreportbyGeorgeandcolleagues(Georgeetal.,1995)showedrobustimprovementsindepressivesymptomsintwooutofsixpatients.ThisstudymarkedthestartoftheseriouspursuitofrTMSasapotentialtreatmentoptionfordepressedpatients.Subsequently,areasonablylargenumberofopenlabelaswellasrandomizedsham-controlledstudieswereperformed.MoststudiesfoundamoderatelyfavorabletreatmenteffectforrTMSusingvariousdesigns(Averyetal.,2006;Fitzgeraldetal.,2006,2003;Garcia-Toroetal.,2001;Moggetal.,2008;O’Reardonetal.,2007;Padbergetal.,1999;Rossini,Lucca,Zanardi,Magri,&Smeraldi,2005),whichhasrecentlybeenconfirmedbyseveralmeta-analyses(Schutter2009,2010),twoindependentmulticenterrandomizedcontrolledtrials(Georgeetal.,2010;O’Reardonetal.,2007)aswellasalevelAevidencebasedontherecentlypublishedrTMSguidelines(Lefaucheuretal.,2014). Aftermorethan20yearsofresearch,rTMSisincreasinglyconsideredanacceptableinterventionfortreatmentresistantdepression(TRD).Mostnotably,theabove-mentionedtwoindependentmulticenterrandomizedcontrolledstudies(Georgeetal.,2010;O’Reardonetal.,2007)andrTMSguidelines(Lefaucheuretal.,2014)havebeeninstrumentalinthisprocess.rTMSiscurrentlyapprovedbytheFDAintheUnitedStatesforTRD,bothfor‘regularrTMS’aswellas‘deep-rTMS’(discussedbelow).Inaddition,agrowingnumberofprivateoutpatientaswellashospitalizeddepressionpatientsarebeingtreatedinclinicalsettingsworldwide.RepetitiveTMStreatmentfordepressionisnowbeingreimbursedbyinsurancecompaniesinmoreandmorecountriese.g.theUSandtheNetherlands. Inthischapter,acomprehensiveoverviewofrTMSinthetreatmentofdepressionwillbeprovided.InthefirstsectionvariousrTMSprotocolswillbereviewedintermsofthedifferentstimulationparametersofinterest.Subsequently,potentialneuralmechanismsassociatedwithantidepressantoutcomeswillbereviewed.Finally,newdevelopmentsinthefieldareaddressed. Protocols TheclinicalandphysiologicaleffectsofrTMShavebeenfoundtodependonthefrequency,intensityanddurationofstimulation(e.g.O’Reardonetal.,2007;Averyetal.,2006;Fitzgeraldetal.,2006b;Padbergetal.,2002).ThemostimportantdistinguishingparametersforrTMSprotocolsindepressionarethestimulationfrequencyandthestimulationlocation.Thesewillbediscussedatlengthbyreviewingliteraturethatuseddiversechoicesfortheseparameters.Someotherrelevantparameters(intensity,numberoftrains,intertrainintervalandnumberofsessions)willbebrieflydescribed.InFigure2,someofthecharacteristicsofanrTMSstimulationprotocolareillustrated. RtmsFigure2 Figure2:Examplesof10sofrTMSat1Hz(firsttrace)andat5Hz(secondtrace);1sofrTMSat10Hzandanexampleof20Hzapplication(trainsof2sinterleavedbyapauseof28s).FiguretakenandadaptedfromRossietal.(Rossi,Hallett,Rossini,Pascual-Leone,&TheSafetyofTMSConsensusGroup,2009). ProgressinthedevelopmentoftechnicalaspectsofTMSdevicesandadvancinginsightshaveledtoacontinuingprogressionofexperimentalandinnovativeprotocols.Somemorerecentlydevelopedprotocolsinvestigatedinthetreatmentofdepression,suchasthetaburststimulationanddeepTMSstimulation,arediscussedinthesection‘newdevelopments’. Stimulationfrequency Thestimulationfrequencyreferstothenumberofpulsesdeliveredpersecond,ascanbeprogrammedontheTMSdevice.ExaminationofstimulationfrequenciesinrTMSstudiesindepressionrevealsthat,atfirstglance,twotypesofstudiescanbediscerned:studiesperforminghighfrequency(alsoreferredtoasfast)rTMS(HF-rTMS)andstudiesinwhichlowfrequency(alsoreferredtoasslow)rTMS(LF-rTMS)parametersareapplied.HF-rTMSusuallyincludesfrequencyparametersof5Hzorabove,whilstLF-rTMSincorporatesstimulationfrequenciesof1Hzorbelow.HF-rTMSisusuallyappliedovertheleftdorsolateralprefrontalcortex(DLPFC),whilstLF-rTMSismostlyappliedovertherightdorsolateralprefrontalcortex(see‘stimulationlocation’foramoreelaborateoverview).InadditiontostudiesapplyingsolelyHF-rTMSorLF-rTMS,combinedapproacheshavealsobeenproposedandinvestigated. HighfrequencyrTMS. MostrTMSstudiesindepressionhaveappliedahigh-frequencystimulationprotocol(Averyetal.,2006;O’Reardonetal.,2007).Todate,HF-rTMSprotocolshavemostlyusedstimulationfrequenciesof10Hz(butthishasvariedfrom5to20Hz).Thelargeststudy(O’Reardonetal.,2007)reportedsignificantlybetterclinicalresultsinanactiverTMSgroupincomparisontotheshamgroup,asmeasuredbytheHamiltonRatingScaleforDepression(HAM-D)scaleandtheMontgomeryAsbergDepressionRatingScale(MADRS).Thiswasarandomizedstudyinwhich301medication-freepatientsweretreatedwith10Hzstimulationfrequency.Inanon-industrysponsoredtrialbyGeorgeandcolleagues(2010)theseresultswereindependentlyreplicatedinasampleof190patients.Apartfromtheselargemulti-centerstudies,numeroussinglesitestudiesapplyingstimulationfrequenciesof10Hzhavebeenperformed.Thesehaveshownresponserates(definedasmorethan50%decreaseonthedepressionscale)between30-50%(Averyetal.2006;Garcia-Toroetal.,2001;Moggetal.,2008;O’Reardonetal.,2007;Padbergetal.,1999;Rossinietal.,2005;Georgeetal.,2010).Mostofthesestudieshavebeenperformedintreatmentresistantpatients.InastudybyFitzgeraldandcolleagues(Fitzgeraldetal.,2006),patientswhodidnotrespondtoaprotocolwithfrequenciesof1or2Hz(LF-rTMS)wereassignedtoeithera5Hzor10HzHF-rTMSprotocol.Nosignificantdifferencesinresponsetoa5or10Hzprotocolwereshown.Duetothelimitednumberofstudiesnodefinitiveconclusionscanbedrawn,butresultssuggestthatingeneralHF-rTMS(including5,17or20Hzstimulationfrequencies)dohaveanantidepressanteffect.However,somereportshaveshowndifferentialeffectsofvariousstimulationparameters,includingareportof9HzrTMStendingtobelessbeneficialthan10Hz(Arns2010).Tosummarize,themostoptimalstimulationfrequencyisnotyetknown,but10HzrTMShasbeenmostfrequentlyinvestigatedandisthereforemostcommonlyusedinclinicalsettings. LowfrequencyrTMS. InadditiontotheHF-rTMSstudies,severalLF-rTMSstudieshavebeenperformed(Fitzgeraldetal.,2003;Janueletal.,2006;Kleinetal.,1999).Forexample,inalargesham-controlledstudyKleinetal.(Kleinetal.,1999)showedthat1HzrTMS,inwhich70patientswererandomlyassignedtoshamoractivetreatment,showedsignificantlylargerimprovementindepressionscoresintheactiveascomparedtotheshamgroup.InthelargestcontrolledstudyonLF-rTMSindepression,130patientswereinitiallyassignedtoastimulationprotocolofeither1or2Hz(Fitzgeraldetal.,2006).Ofthe130patientsenrolled,approximately51%couldbeclassifiedasrespondersafter10daysoftreatment.Interestingly,theresponseratesbetweenthe1Hzand2Hzdidnotsignificantlydiffer.AlthoughLF-rTMSisamorerecentlydevelopedprotocolandislesswellstudied,itappearstohavebeneficialeffectscomparabletothoseofHF-rTMS. InordertosystematicallyinvestigateifHForLF-rTMSismorebeneficial,protocolsweredirectlycompared(Fitzgeraldetal.,2003;Fitzgerald,Hoy,Daskalakis,&Kulkarni,2009;Isenbergetal.,2005).Inadouble-blind,randomized,sham-controlledstudy,60treatmentresistantpatientsweredividedintothreegroups;onereceivedHF-rTMStrainstotheleftprefrontalcortexat10Hz,thesecondgroupreceivedfiveLF-rTMStrainsat1Hztotherightprefrontalcortexandthethirdgroupreceivedshamtreatment.TheclinicalresultsshowedthatthegroupstreatedwithHF-rTMSandLF-rTMShadasimilarreductionindepressivesymptomsand,forbothgroups,treatmentresponsewasbetterthanwithintheshamgroup(Fitzgeraldetal.,2003).Inanotherstudywithasimilaraim,27subjectswereassignedtoeitherHF-rTMS(10Hz)orLF-rTMS(1Hz)rTMS.Itwasconcludedthatbothtreatmentmodalitiesappearedtobeequallyefficacious(Fitzgeraldetal.,2009)alsosupportedbyalargeopen-labelstudy(Donse,Padberg,Sack,Rush,&Arns,2018).Schutter(Schutter2010),basedonameta-analysisofallrandomizedcontrolledLF-rTMSstudiesindepression,suggestedthatLF-rTMSmightevenbemorebeneficialthanHF-rTMS.However,directcomparisonsoftheeffectsizesofHFandLF-rTMSdidnotshowastatisticallysignificantdifferenceduetooverlappingconfidenceintervals.MoreresearchwithlargersamplesisrequiredtoconfirmthesefindingsanddemonstrateifLF-rTMSandHF-rTMSaresimilarlyefficacious,orifLF-rTMSismoreefficaciousthanHF-rTMS.Asidefromthecomparisonofclinicaleffects,itappearsthatLF-rTMSisbettertoleratedi.e.patientsreportedlessheadaches.Itmayalsominimizetheriskofinducingadverseeventslikeseizures(Rossietal.,2009). Althoughthevastmajorityofstudieshavefocusedonlowfrequencystimulationappliedtotherightandhighfrequencystimulationappliedtotheleftdorsolateralprefrontalcortex,itistobenotedthatinafewstudiesparametershavevariedfromthesetraditionalsites.Inoneoflargestudyin219depressedpatients,noeffectsoflateralityandfrequencywerefoundwhileallpatientsshowedareductionintheirdepressionsymptoms(Fitzgeraldetal.,2010).Thismayimplicatethatlowfrequencystimulationappliedtotheleftmayalsohaveantidepressanteffects,thusquestioningthetraditionalmodeloflateralityandfrequencyindepression,withrespecttotheDLPFC. CombinedHFandLF-rTMSprotocols. TheseaforementionedstudiesdemonstrateevidencethatactiveHF-rTMSandLF-rTMSaremoreeffectiveinthetreatmentofdepressionascomparedtosham.However,HF-rTMSandLF-rTMSarenotnecessarilyincompatiblewitheachother.Inrecentyears,add-on,bilateral-sequentialandprimingprotocolshavebeenpostulatedandinvestigated. Add-onprotocolsconcernthecombinationofoneprotocolwithanotherprotocole.g.whenpatientsdonotrespondtoLF-rTMSafterseveralsessions,theycanproceedtoHF-rTMStreatment.IntheaforementionedstudybyFitzgeraldetal.(2006)inwhichLF-rTMSwasinvestigated,non-responderstothelowfrequencyprotocolweresubsequentlytreatedwithHF-rTMS.AsubsetoftheseLF-rTMSnon-respondersdidrespondtoHF-rTMS.Hence,itislikelythatdifferentprotocolsactthroughdifferentmechanismsandthatdifferentpatientgroupsarereceptivetodifferentapproaches.Itcouldalsobearguedthatsubjectsintheadd-onprotocolreceivedmoresessions,andpossiblyneededlongertorespondtotreatment.Thus,thefullextentoftheincreaseinresponseratemightnotsolelybeattributedtothechangeinstimulationfrequency. AsecondvariantisthesequentialstimulationprotocolinwhichwithinonesessionbothHF-rTMSandLF-rTMSprotocolsareapplied.OverallnosuperiorityhasbeenfoundofsequentialbilateralrTMS(Fitzgerald,Huntsman,Gunewardene,Kulkarni,&Daskalakis,2006),exceptforBlumbergerandcolleagues(Blumbergeretal.,2012)whofoundaddedvalueofthisapproach,albeittheirunilateralHFrTMSdidnotdifferfromsham.Finally,inarecentstudybyPallantietal.(Pallanti,Bernardi,Rollo,Antonini,&Quercioli,2010)foundthatthata‘simple’unilateralprotocolwasmoreeffectivecomparedtosequentialbilateralrTMS.Nevertheless,itremainsrelevanttofurtherexplorecombinationprotocolsandcomparethemtotraditionalunilateralprotocols,alsolookingatthisoptionasanescalationoptiontoincreasethe‘dose’,i.e.whenpatientsdonotrespondwellenoughin10-15sessionsunilateralrTMS.Sincenumberofstimuliwerekeptthesameat420stimuliforbothunilateralandbilateralprotocols(2010),addingthecontralateralhemisphereandtherebydoublingthenumberofpulses,couldstillhaveaddedvaluebyincreasingnumberofpulses,whichhasinourexperiencebeenfoundtosometimesprovidebenefit(unpublishedobservation). Real-lifeoutcomesanddurability Severallargeopenlabelstudieshaveaddressedthelong-termeffectsofrTMS.Inalargemulticenterstudywith307treatmentresistantMDDpatients(failureofonaverage2.5anti-depressanttreatmentsofadequatedoseandwithoutsatisfactorybenefit),Carpenterandcolleagues(2012)reportedclinician-assessedresponserates(CGI-S)of58.0%andremissionof37.1%.Patient-reportedresponseraterangedfrom56.4to41.5%andremissionraterangedfrom28.7to26.5%.Theauthorsnotethattheseoutcomesdemonstratedresponseandadherenceratessimilartoresearchpopulations.Anotherlargeopenlabelstudyin1132patientsdemonstratedsimilareffectstotheCarpenteretal.(2012)studywith46%responseand31%remissionrates(Fitzgerald,Hoy,Anderson,&Daskalakis,2016).InanextensionoftheCarpenteretal.(2012)study,goodlong-termeffectswereobserved(Dunneretal.,2014).Themajorityofthepatients(62.5%)continuedtomeetresponsecriteriaata12monthfollow-up.SimilarresultswerereportedbyDonseandcolleagues(2018)whoconductedacombinedrTMSandpsychotherapystudywhilealsoinvestigatinglongtermeffectsin196patientswithTRD.CombiningrTMSandpsychotherapyresultedina66%responseanda56%remissionrateattheendoftreatmentwith60%sustainedremissionatasix-monthfollow-upvisit.Theauthorsnotedthat,interestingly,earlysymptomimprovement(atsession10)washighlypredictiveofresponse,andmaythereforebeusedtoguiderTMSpluspsychotherapycontinuation,orescalationtosequentialHFandLFrTMS. Assuch,itseemsthatwithinanaturalisticsetting,rTMScanbeconsideredaneffectivetreatmentsimilartothatfoundinaresearchsetting.Additionally,incombinationwithpsychotherapy,responseandremissionratesmayhavethepotentialtoincreasefurtherandsustaindurableeffects.Ascanbeseeninfigure3,atreatmentresistantpopulationrespondtorTMSalone(monotherapy)similarlytoananti-depressantmedication(monotherapy)inpopulationsreceivingmedicationorpsychotherapyasafirstlinetreatment;and,whencombinedwithpsychotherapy,rTMSpatientsrespondsimilarlytoacombinedmedication/psychotherapyapproach.Thesefindingssuggestaconsiderablepromiseforthishardtotreatpopulationfollowingmanypriorfailedattemptsatdepressivesymptomreduction. Figure3:Responseandremissionratesofvariousantidepressanttreatmentsfromlefttoright,Psychotherapymonotherapy(Cuijpersetal.,2014),Psychotherapyandantidepressants(Kelleretal.,2000),Antidepressantsasfirstline,afterone,twoandthreetreatmentfailuresfromtheSTAR*Dtrial(Rushetal.,2006),rTMSmonotherapy(Carpenteretal.,2012)andrTMScombinedwithpsychotherapy(Donseetal.,2018).NotetherelativeincreaseinresponseandremissionratesforrTMS,especiallyforpatientsthathavehadtwoorthreepriortreatmentfailures,whichisthetypicalpopulationrTMStreatmentfocusseson(TRD). Stimulationlocation Thedorsolateralprefrontalcortex(DLPFC)hasbeentheprimaryareaofinterestforstimulation(seeFigure4).Themotivationbehindchoosingthisbrainareastemsfromvariousimagingstudiesthatindicateddepressionisassociatedwithregionalbraindysfunctionin,amongotherregions,theDLPFC(Cummings1993).Otherresearchershavenotonlyproposedan‘underactivated’L-DLPFC,butsuggestedanimbalancebetweenfrontalregions.Forexample,the‘frontalasymmetryhypothesis’ofdepressionstatesthatindepressionthereisanimbalanceinleftvs.rightfrontalbrainactivation(Henriques&Davidson,1990).Althougharecentmeta-analysesfailedtodemonstrateadifferenceinfrontalalphaasymmetrybetweendepressedandnon-depressedgroupsonthegrouplevel(vanderVinne,Vollebregt,vanPutten,&Arns,2017),theDLPFCisstillthemostcommonlyusedstimulationlocationinrTMSprotocolsfordepression.Inaddition,ofallbrainregionsknowntoberelatedtothepathophysiologyofdepression(e.g.,prefrontal,cingulate,orbitofrontalandparietalcorticalregions)theDLPFCisregardedasmostaccessiblefortreatmentwithrTMS(Wassermann&Lisanby,2001).Onthebasisofsuchprevioustheoriesandfindings,thesupposedly‘activating’/HF-rTMSprotocolsareappliedovertheleftDLPFCandsupposedly‘inhibiting’/LF-rTMSprotocolsareappliedovertherightDLPFC.Thechoiceofthestimulationfrequencyisthuscloselylinkedtothestimulationlocation. DlpfcLeft Figure4:Imageofthelocationofthe(left)DorsolateralPrefrontalCortexinthebrain(FigureusedwithpermissionfromResearchInstituteBrainclinics©) Historically,moststudieslocalizingtheDLPFChavebeenperformedbymeansofthe‘5cmrule’.Thehandareaoftheprimarymotorcortex(M1)(whichelicitsacontralateralmotorresponseofthethumbwhenstimulated),istakenasthedetectablereferencepoint.Fromthere,thecoilismoved5cmanteriorly,inasagittaldirection.PositioningthecoilatthatlocationduringtreatmentisassumedtotargettheDLPFC.Itcanbearguedthatthisliteral“ruleofthumb”hassomeflawsandmayresultininconsistentresultsbetweensessionswithinsubjects,andisusedlessfrequentlythesedays.Recently,theBeam-F3/F4methodhasbeenproposedasanewmethod(Beam,Borckardt,Reeves,&George,2009)whichdoestakeindividualdifferencesinskullsizeintoaccountandisbasedonthe10-20EEGlocationF3orF4.Freesoftwaretoeasilyapplythismethodcanbefoundat:http://www.clinicalresearcher.org/software.htm.Thismethodhasbeenshowntoleadtoanadequatedetermination,withaminimaldiscrepancy,comparedtoMRIneuro–navigatedlocationdetermination(Mir-Moghtadaeietal.,2015). ForMRIneuronavigation,atechniqueinwhichanindividualMRIscanisusedtodeterminetheexactlocationoftheDLPFC,asinglestudyhasfoundanadvantageregardingclinicaleffectivenessinthetreatmentofTRDcomparedtothe5cmrule(Fitzgeraldetal.,2009).However,resultsfromthemulti-centerOPT-TMStrialinwhichanindividualadjustmentcouldbemadebasedonanindividualMRIscan,showednoimprovedclinicaleffectofthisMRI-basedadaptation(Johnsonetal.,2013),andtherearenocomparativestudiesthatcomparedtheeffectivenessofMRI-navigatedrTMSwiththeBeam-F3/F4method. DespitethefactthatthemajorityofthestudiestargettheDLPFC,someauthorshavearguedthatithasneverbeenexperimentallyproventhattheDLPFCisthemosteffectivetargetforrTMStreatmentofdepression.Inaddition,thepathophysiologyofdepressioniscertainlynotlimitedtotheDLPFC(Drevets,Price,&Furey,2008).Therefore,severalotherstimulationtargetshavealsobeeninvestigatedinthetreatmentofdepression.ClinicalefficacyinTRDhasalsobeenreportedafterstimulationoftheDorsomedialPrefrontalcortexorAnteriorCingulateCortexusingadouble-conecoil(Downaretal.,2014;Kreuzeretal.,2015),therightorbitofrontalcortexusingadoubleconecoilFP2/AF8(Fefferetal.,2018)andalimitedeffectinthestimulationoftherightparietalcortex(P4:(Schutter2009)).Althoughthesefindingsneedtobereplicatedinlargerstudies,theyareencouragingregardingsearchingforothercorticaltargetsinthetreatmentofdepressionwithrTMSoutsidetheDLPFC. Stimulationintensity,trains,sessionsandsafety ForrTMStobeeffective,themagneticfieldhastoinducecurrentsintheneuronsofthecortex.Theintensityofthemagneticfieldthatinducesthiscurrentisreferredtoasthestimulationintensity.Thisisusuallyexpressedasapercentageofthemotorthreshold(MT).TheMTisusuallydeterminedpriortoeachsessionbyapplyingtheTMScoiloverthe‘thumb’areaofthemotorcortex.Singlepulsesareappliedbystepwisevariationoftheoutputintensityofthedevice.Theminimaloutputintensitywhichyieldsamotorresponse(movingofthethumb)inatleasthalfoftheappliedtrialsisdeterminedtobetheMT.SoiftheintensityofaTMSprotocolis100%MT,thenitisthesameastheoutputintensityofthedevicewhichwasdeterminedtobeMT.AllotherintensityvaluesarereflectedasapercentageofthisMT,e.g.iftheMTisatanoutputintensityofthedeviceof60%,thenanintensityof110%MTmeansthattheoutputintensityis66%.Althoughthisdeterminationofstimulationintensitymayseemarbitrary,ittakesindividualdifferencesinmotorcortexexcitability(andthereforeexcitabilityofotherbrainregions)intoaccount.ThiscontributestoasaferadministrationofTMSpulsestoanindividual.Indepressionprotocolsreportedtodate,theloweststimulationintensityusedwas80%MT(Georgeetal.,1995)andthemaximalintensityusedwas120%MT(O’Reardonetal.,2007;Rumietal.,2005).Themajorityofthedepressionprotocolstodateusestimulationintensitiesof110%-120%MT. InmostrTMSprotocolsthestimulationisdeliveredinpulsetrains(seeFigure2).Thatis,pulsesaredeliveredintrainsandareseparatedbycertaintimeintervals:theintertraininterval(ITI).Thisisdonefortworeasons.First,theeffectofTMSpulsesiscumulativeinthebrain(Hallett2007;Ridding&Rothwell,2007;Rossi&Rossini,2004),andthissummationcausesanincreaseofthelikelihoodoftheinductionofaseizure.ThispossiblesideeffectofrTMS–theoccurrenceofanepilepticseizure–isminimizedwhenadheringtothepublishedsafetyguidelines(Rossietal.,2009;Wassermann1998)thathavebeencomposedbasedonreportedincidents.Theseguidelinesconcernstimulationparameters(suchasfrequencyofstimulation(Hz),intensityofstimulation(asapercentageofthe‘motorthreshold’(MT),anddurationofastimulationtrain),aswellasotherriskfactorswhichshouldbetakenintoaccount(suchassleepdeprivation,acutewithdrawalofbenzodiazepinesetc.).Sincethepublicationoftheseandprevioussafetyguidelines(Rossietal.,2009;Wassermann,1998),onlyfewreportedincidentsofepilepticseizuresareknown.Currently,theriskofaseizureduetorTMS,accordingtotheliteraturefromresearchonagloballevel,is0.007%(20seizures/300,000sessions)and0.003%(7seizures/250,000sessions,0.1%/patients)inclinicalpractice.Thismeansthattheriskofaseizureiscomparableorlowerthanwithantidepressants(George,Taylor,&Short,2013). Secondly,therepetitivereleaseofstrongelectricalpulsescausesheatingoftheelectronicsoftheTMSdevice.TheITIbetweentrainsallowsthedevicetopartiallycooldown.Duetosafetyreasonsforthesubjectandprotectionofthedevice,alldevicesaremanufacturedtoautomaticallyturnoffassoonasacertainheat-limithasbeenreached.NewerTMSdevicesaredesignedwithbettercoolingsystems(e.g.airorfluidcooledcoils),whichreducethelikelihoodofoverheating.However,theoverheatingofthedeviceisstillpossiblewhenmultiplesessionsareperformedwithinashortperiod,orifahighlydemanding(e.g.highrateofpulsedelivery)protocolisperformed.TraindurationsinHF-rTMSprotocolsareusuallybetween2and10secondswithanITIbetween20-60seconds.InLF-rTMSprotocolsoften,continuousstimulationisused. Instudiesperformedthusfar,thenumberofsessionsappliedhasbeenhighlyvariable,rangingfrom5sessions(Manesetal.,2001;Miniussietal.,2005)touptoorgreaterthan30sessions(Fitzgeraldetal.,2006;O’Reardonetal.,2007).Basedonmorerecentstudies,ageneraltrendtowardsagreaternumberofsessions(>10)areassociatedwithcontinuingimprovementindepressionscores.Schutter(Schutter2009)suggestedthatsimilartoantidepressantmedication,rTMStreatmentmayinvolveadelayedtherapeuticonset.Investigationofthenumberofsessionsoptimallyrequiredisimportantforgaininginformationaboutthetemporalcourseoftheantidepressanteffect. OvertheyearsofrTMSresearchefficacyhasincreasedinlinewithincreaseddosage,whichcanbeexpressedasnumberofpulsesappliedduringatreatmentcourse.Initially,Georgeandcolleagues(1995),appliedatotalofonly5000pulses.Thiswasdoubledin1996byPasqual-Leoneandcolleagues,escalatingto10000pulses.By2007,O’Reardonandcolleagueshadincreasedto90000pulses,whichcontinuedtobewelltolerated(4.5%dropout)andefficacystillrising.Atthispointintime,itseemsadditionalpulseshaveceasedtohaveacumulativeeffectandbythispointapatienthaseitherresponded,orhasnot.Butfurtherinvestigationiswarranted. ThevarietyofprotocolsdiscussedaboveindicatethatrTMSisanactivefieldofresearch.Treatmentoutcomehasbeenshowntovarywithprotocols,butsomeprotocolshaveproventheirefficacy.However,ithasbeenarguedthatitisunlikelythatthecurrentcombinationsofstimulationparameterspotentiateoptimumclinicaleffects.Itislikelythatthereisroomforimprovement,andstudiesdirectlyaddressingthequestionofoptimalstimulationparametersareurgentlyrequired.ThisstatementisfurthersupportedbythefindingthatearlyrTMSdepressionprotocolshaveshownlessfavorableresultscomparedtorelativelynewer,morepromisingprotocols(Gross,Nakamura,Pascual-Leone,&Fregni,2007).Increasingknowledgeaboutthemechanismsunderlyingtreatmentefficacy–thetopicofthenextsection–mayresultinnewprotocolswithclosertooptimaltreatmenteffects. MechanismsofrTMStreatmentindepression LevelsofevidenceforthetreatmentofdepressionviarTMShaveaccumulatedtoapointwhereHF-rTMSonleft-DLPFChasreceivedLevelAstatus(‘definiteefficacy’,Lefaucheuretal.2014).OnlyHF-rTMSofM1contralateraltopainsideforthetreatmentofneuropathicpainhasalsoachievedthisstatus.LevelBstatus(‘probableefficacy’)hasbeenachievedfortreatmentofdepressionusingLF-rTMSonright-DLPFCandis‘probably’additivetoanti-depressantmedication.LevelBevidencehasalsobeenachievedforLF-rTMSofM1contralateraltopainside;antidepressanteffectofHF-rTMSoftheleftDLPFCinPDpatients;LF-rTMSofthecontra-lesionalmotorcortexinchronicmotorstroke;and,HF-rTMSoftheleftDLPFCfornegativesymptomsofschizophrenia(Lefaucheuretal.,2014).Regardlessoftheseevidencelevels,theneuralmechanismsunderlyingbrainmodulationviarTMSremainelusive. Depressionnetwork SincetheriseofneuromodulationtreatmentsfordepressionsuchasrTMSandDeepBrainStimulation(DBS)(Fox,Buckner,White,Greicius,&Pascual-Leone,2012;Listonetal.,2014),newhubsinthedepressionnetworkhavebeenidentified.ThesenewtreatmentsdirectlytargetedDLPFC(Georgeetal.,2010;O’Reardonetal.,2007),thedorsomedialprefrontalcortex(DMPFC)(Downar&Daskalakis,2013;Downaretal.,2014)andthesubgenualcingulatecortex(sgACC)(Maybergetal.,2005)andhaveshownthatdirectstimulationoftheseregionsisassociatedwithclinicalimprovement.RecentinsightsintohowtheseneuromodulationtreatmentsworksuggestnetworkconnectivitychangeswithinaDLPFC-DMPFC-ACCnetworktomediateantidepressantresponse(Foxetal.,2012;Listonetal.,2014),andarealsopossiblyimplicatedinpharmacologicaltreatments.Moreover,newtargetsarestillidentified,suchastheorbitofrontalcortex(Frodletal.,2010). ThesgACCandsectionsoftheDMPFCarecomponentsofthedefaultmodenetworkwhiletheDLPFCispartlyimplicatedinthecentralexecutivenetwork(CEN).AdeficitinswitchingbetweentheDMNandCENiswellknownindepression(Listonetal.,2014;Sridharan,Levitin,&Menon,2008)andisconsideredtobeoneofthemainreasonsbehindcognitivedysfunctionindepression.TheDLPFChasbeendescribedtobehypoactiveindepression(Korgaonkar,Grieve,Etkin,Koslow,&Williams,2012),andanincreaseinfMRIactivityofthisstructureisassociatedwithtreatmentresponse(Fitzgeraldetal.,2006;Koenigs&Grafman,2009).Thishypoactivationcorrelatestotheamountofgreymattervolumereduction(Grieve,Korgaonkar,Koslow,Gordon,&Williams,2013).ContrarytotheDLPFC,thesgACChasbeendescribedtobehyperactiveindepression,alongwithhyperconnectivitytootherpartsoftheDMNobservedwithPETscansandwithfMRI(Listonetal.,2014;Maybergetal.,2005),andadecreaseinactivityofthesgACCisassociatedwithantidepressantresponse(Koenigs&Grafman,2009;Maybergetal.,2005),alsodecreasedgreymattervolumeinMDDhasbeenreportedintheleftanteriorcingulatecortex(Drevetsetal.,1997;Grieveetal.,2013).TheDMPFC,ordorsalnexus,isacoreregiontomultiplenetworks,includingtheDMN,CENandsaliencenetwork(SN),withincreasedfMRIconnectivitytoallthreenetworksindepression(Sheline,Price,Yan,&Mintun,2010).TheDMPFChasbeenobservedtobeabnormallyactivatedduringpositiveandnegativeaffectprocessinginMDD,whichnormalizesaftersuccessfultreatment(Bermpohletal.,2009;Dunlop,Hanlon,&Downar,2015;Maybergetal.,1999). AsrTMSislimitedtocorticalsurfaces,itishypothesizedthatDLPFC-rTMS(andDMPFC-rTMS)mightexertitsantidepressanteffectviatrans-synapticconnectivitytodeeperregions,suchasthesgACC(Foxetal.,2014;Foxetal.,2012;Georgeetal.,1997,1995;Padberg&George,2009).Foxet.al.,(2012)demonstratedanegativecorrelationbetweenthesgACCandtheDLPFCwhichishypothesizedtobeassociatedtotheantidepressantmechanismofrTMS(Foxetal.,2012).Thehigherthenegativecorrelationinactivitybetweenthetwoareaswas,thebetterapatientrespondedtorTMS(2012).Inaddition,DBSinthesgACCwhichsuppressesactivity,resultsinanupregulationoftheactivityintheDLPFC(Maybergetal.,2005).Thus,irrespectiveofthedirectionandcausality,thereisanintricateinterplaybetweenthesgACCandDLPFC,andthisinterplayisrelatedtoMDDsymptom(improvement).Thisinterplayhasalsobeeninvestigatedduringantidepressanttreatment,anditwasshownthatelectroencephalogram(EEG)linear-laggedconnectivitybetweentheDLPFCandthesgACCchangedforrespondersduringtreatment,howeverthiswasonlyobservedinmales(Isegeretal.,2017).Multiplestudieshavedescribedanormalizationoftheexistinghyper-connectivity(Koenigs&Grafman,2009;Listonetal.,2014;Maybergetal.,2005)aftertreatment.However,somestudiesstillreportdifferencesinACCorDLPFCconnectivityaftertreatment,comparedtohealthycontrols.Thereforeitwashypothesizedthatconnectivitytendstonormalizeorresembletheconnectivitypatternofhealthycontrols,butcouldstillbeincomplete(Listonetal.,2014). Thesehubsindepressionarelinkedtothelimbicsystem,suchastheamygdalaandhippocampusbutthereareconvergentfindingsastowhethermetabolicchangesandvolumereductionsassociatedwithdepressionarepresentinthesestructures(Grieveetal.,2013).Wheninvestigatingwhitemattertrajectories,significantreductionswerefoundinregionsassociatedwiththelimbicsystem,butonlyinthemelancholicsubtypeofdepression(Korgaonkaretal.,2010).Moreover,itisbelievedthatthisdepressionnetworkisconnectedtotheheart.ThisisnotsurprisingbecauseMDDhasbeenstronglyassociatedwithahigherriskforcardiovasculardisease(Glassman,2007;Lettetal.,2004;Penninxetal.,2001).Severalstudieshaveshownthatdepressionincreasestheriskforcardiovascularillnessfromtwotofivefold(Horrobin&Bennett,1999).Moreover,autonomicregulationisalreadydisturbedindepressedpatientswithoutheartdisease,manifestedinanoverallhigherHR,andlowerheartHRVincomparisontohealthycontrols(Ehrenthal,Herrmann-Lingen,Fey,&Schauenburg,2010;Lichtetal.,2008;Udupaetal.,2007),andismorepronouncedinpatientswithsevereMDD(Stein,Talcott,&Walsh,2000). Theconnectiontotheheartismediatedbythevagusnerve,the10thcranialnerve.Thevagusnerveispartoftheparasympatheticnervoussystemand,besidesregulatingheartrate,isalsoinvolvedinotherautonomicfunctioningsuchaspupildilation,sweatresponse,salivaproduction,bloodpressure,inflammationandgastrointestinalfunction.Ofthese,gastrointestinalandheartfunctionhavebeenstudiedmostextensivelywithregardstodepression.Heartrateconsistentlydecreaseswhenthevagusnerveisstimulated(Buschmanetal.,2006;Lang&Levy,1989),whichisinlinewiththeparasympatheticactionofthevagusnerve.Conversely,strongpositivecorrelationswerefoundbetweencardiacvagalcontrolandtheBOLDsignalintensityinthesgACCofhealthycontrolsbutnotindepressedsubjects(Laneetal.,2013).Moreover,RRintervals(intervalsbetweenventriculardepolarizations)werepositivelyrelatedwithVMPFCactivityinhealthyparticipantsduringrest(Ziegler,Dahnke,Yeragani,&Bär,2009)andpatientswithACCdamageallshowedabnormalitiesincardiovasculararousalduringcognitivetasks,indicatingabluntedautonomicarousalresponseduringstressfulsituations(Critchleyetal.,2003).FewstudieshavebeenconductedinvestigatingtheeffectofneuromodulationontheVMPFCinrelationtoheartrate,howeveroneolderstudyonmonkeysshowedelectricalstimulationinthepregenualACCassociatedwithcardiacslowing(DUA&MACLEAN,1964).ThesameassociationswithheartratecontrolhavebeenfoundfortheDLPFC.Arecentmeta-analysisdemonstratedthatbothtDCSandrTMSaimedattheDLPFCresultedinreducedheartrate,althoughrTMSwasmoreeffectivethantDCS(Makovac,Thayer,&Ottaviani,2016).Theseeffectswereobservedbothafterleftandrighthemisphericstimulation,althoughsomestudiesdoobservelargerheartratereductionsafterrightDLPFCstimulation. Insummary,thecoreofthedepressionnetworkinvolvestheDLPFCandthesgACC,andtheseregionsareinterconnectedwiththelimbicsystemandtheheart-brainaxis,providingnewinsightsintothepathophysiologyofMDDthatcanbeutilizedtofurtheroptimizetreatmentssuchasrTMS,asisexplainedinmoredetailbelowundertargetengagementregardingNeuro-Cardiac-GuidedTMS(NCGTMS). NewDevelopments Asanewanddynamicfield,rTMSisthetopicofconsiderableresearchandinnovativedevelopmentsarenumerous.Thesedevelopmentsareofadiversenature,includingtechnologicalprogressinequipmentandsoftware,protocolinnovationsandoptimizations,andadvancesintheunderstandingoflong-termeffects.Someexamplesaretheinvestigationofthetaburststimulationapplicability(thedeliveryofburstsof50Hzpulsesusuallyatarateof5Hz)andnewequipmentsuchastheH-coilfordeeperbrainstimulation. Progressinprotocols Inadditiontothe‘traditional’LFandHFfrequencystudies,anewlydevelopedtheta-burststimulation(TBS)protocolhasbeenproposed;referredtoas‘patternedTMS’.Thishasbeenputforwardasatechniquethatcouldhaveimportantimplicationsforthetreatmentofconditionssuchasepilepsy,depressionandParkinson’sDisease(Paulus2005).TBSusuallyinvolvesshortburstsof50HzrTMSappliedatarateof5Hz(hencethenamethetaburststimulation).Infacttherearetwofrequencieswithinonetrainofstimuli;theinterburstfrequencyof50Hz(e.g.3pulsesatarateof50Hz)andthefrequencyofdeliveryofthenumberofburstswithinonesecondwhichisatarateof5persecond(5Hz).TBScanbeappliedaseitheracontinuous(cTBS),orintermittent(iTBS)train(Huang,Edwards,Rounis,Bhatia,&Rothwell,2005).SeeFigure5foranillustrationofbothtypesofTBSprotocols. Figure5:examplesofthetwomostcommonTBSprotocols:continuousTBS(firsttrace)andintermittentTBS(secondtrace).FiguretakenandadaptedfromRossietal.(2009 Untilrecently,therapiddeliveryofpulsesrequiredinaTBSprotocolwasnotpossibleduetotechnicallimitationofolderstimulators.TBShasthereforeonlybeeninvestigatedsince2005.Intheyearsafteritsintroduction,ithasbeenshownthatTBSinduceschangesincorticalexcitabilitythatmaylastlongerthanwithtraditionalTMSprotocols(Huangetal.,2009;Ishikawaetal.,2007).Inregardtotheobservationofthemoresustainedeffect,Chistyakovandcolleagues(2010)suggestedthatTBSmightbemoreeffectivethantraditionalHFandLF-rTMSinthetreatmentofdepression.However,recentworkhasdemonstratedthatTBSprotocolsseemtobeequallyeffectiveinthetreatmentofdepression,butmaybemoreefficientasthesessionlengthisshorter(Bakkeretal.,2014). Technicalprogress InordertofurtherimproveefficacyofrTMSprotocols,anewtypeofcoil‘theH-coil’(Brainsway)wasdeveloped.Thetraditionallyusedcoils(figureofeight/circularcoils)arethoughttopenetrateunderlyingbraintissueonlytoadepthof1.5-2cm(Zangen,Roth,Voller,&Hallett,2005).H-coils,ontheotherhand,arecapableofstimulatingdeeperbrainregionsof4-6cm(2005),albeitothershavearguedthiscoilresultsinmorenon-focal,butnotdeeperstimulation(Fadinietal.,2009). TheH-coilwasthusdevelopedtotargetdeepercorticalregions.In2013theU.S.FoodandDrugAdministration(FDA)approvedtheDeepTMSdevice(usingtheH-coil)forthetreatmentofdepressioninpatientswhohadfailedtorespondtoantidepressantmedicationsintheircurrentepisodeofdepression.ThestudythatresultedinthisFDAapprovalwaspublishedin2015byLevkovitzandcolleagues(Levkovitzetal.,2015)whoconductedadouble-blindrandomizedcontrolledmulticenterstudyevaluatingtheefficacyandsafetyofdTMSinMDD.212MDDoutpatients,aged22–68years,whohadeitherfailedonetofourantidepressanttrialsornottoleratedatleasttwoantidepressanttreatmentsduringthecurrentepisodewererandomlyassignedtoactiveorshamdTMS.TwentysessionsofdTMS(18Hzovertheprefrontalcortex)wereappliedduring4weeksacutely,andthenbi-weeklyfor12weeks.ResponseandremissionrateswerehigherinthedTMSthanintheshamgroup(HDRS–response:38.4vs.21.4%;remission:32.6vs.14.6%).Thesedifferencesbetweenactiveandshamtreatmentwerestableduringthe12-weekmaintenancephase. Forthetimebeing,randomizedhead-to-headcomparisonsofeffectivenessonreductionofdepressivesymptomsbetweentheH-coilandregularfigure-of-eightcoilshavenotbeenpublishedyet.However,theH-coilisaprimeexampleoffurthertechnologicaladvancementswhichmayleadtoincreasedefficacyintime. Optimizingtreatment AbetterunderstandingoftheneurophysiologicalandclinicalfeaturesofdepressedpatientswhorespondtorTMS,togetherwithmoreclarityontheneurobiologicalmechanismsoftheinducedeffectofrTMStreatmentindepressionasdescribedaboveindepressionnetwork,willcontributetothedevelopmentofmoreeffectiveformsofrTMS.Theidentificationofpatients’characteristics(clinical,physiologicalorparametricvariables)isreferredtoaspersonalizedmedicine.Demographicandclinicalfeaturesassociatedwithlessfavorabletreatmentoutcomeareolderage(Brakemeier,Luborzewski,Danker-Hopfe,Kathmann,&Bajbouj,2007;Fregnietal.,2006)andhighertherapyresistance(Brakemeieretal.,2007;Brakemeieretal.,2008;Fregnietal.,2006).However,thishasnotbeenconfirmedbyallstudiesinthisarea(Fitzgeraldetal.,2006). ArecentsystematicreviewonpredictorsforrTMSresponseconcludedthatduetomethodologicalvariabilitygeneralizabilityofresultswaslimited,butsomeindicationswerefoundforbaselinefrontallobebloodflowandpresenceofsomepolymorphisms(5-hydroxytryptamine-1agene,theLLgenotypeoftheserotonintransporterlinkedpolymorphicregion(5-HTTLPR)gene,andVal/Valhomozygotesofthebrain-derivedneurotrophicfactor(BDNF))(Silversteinetal.,2015).WhileEEGmeasureshavebeenrelativelywellstudiedinthepredictionoftreatmentresponsetoantidepressantmedication(Bruderetal.,2008;Cooketal.,1999;Spronk,Arns,Barnett,Cooper,&Gordon,2011),theirpotentialinpredictingresponsetorTMStreatmentisgenerallyconsideredlimitedbutpromising,albeitthereisalargeneedforreplicatedfindings(see(Arns,Drinkenburg,Fitzgerald,&Kenemans,2012;Krepeletal.,2018))asanexampleofnon-replicatedEEGpredictorsin2relativelylargesamples).Thus,currentpredictorsarestillratherlimitedandrequirefurtherreplication(inlargersamples)beforetheiruseinclinicalpracticecanberecommended. Targetengagement TargetengagementcomprisestheuseofadirectfunctionaloutcomemeasureasavalidationfortargetingthecorrectTMSlocation,wherebyitcanbedemonstratedthattherightareaisactivated,eitherdirectlyortrans-synaptically.Inthesamewayasthemotorcortexisidentifiedbythumbmovementasademonstrationofprimarymotorcortexactivation,suchfunctionaloutcomemeasuresarethusfarlackingfortheprefrontalcortexandDLPFC.OneproposedmethodisbyextractingconnectivitypatternstofrontalareasusingthesgACCasaseedregion(Foxetal.,2012;Fox,Liu,&Pascual-Leone,2013).OtherstudieshypothesizethattheDLPFCcouldbemoreaccuratelytargetedwiththeaidofheartrate,socalledNeuro-Cardiac-GuidedTMS(NCG-TMS)(Iseger,Padberg,Kenemans,Gevirtz,&Arns,2017).Asmentionedearlier,thedepressionnetworkandthebrain-heartaxisareinterconnectedandstimulationoftheDLPFCwasshowntoreduceheartrate(Makovacetal.,2016).Theparasympatheticeffectontheheartisshort-lived;stimulationofthevagusnervethereforeusuallyresultsinanimmediateresponseoftheheart,typicallyoccurringwithinthecardiaccycleinwhichthestimulationoccurred,withapeakinheartratedecelerationwithin5seconds(Buschmanetal.,2006).ThereturntoanormalHRisveryquickaftertheactivityofthevagusnerveisreduced(Shaffer,McCraty,&Zerr,2014).Inarecentstudy,itwasshownthatstimulatingdifferentprefrontalscalplocationsledtodifferenteffectsonheartrate,andthatstimulationoftheF4andF3locations(10-20system)resultedinthemostsignificantheartratedecelerations,whereasthiswasnotfoundforcentralsitesoverlyingtheprimarymotorcortex(Isegeretal.,2017).Individualvariationwasalsofound,however(i.e.forsomeindividualsthemostprofoundheartratedecelerationwasfoundforslightlymoreposteriorsitese.g.FC3,FC4relativetoF3andF4),indicatingthattheNCG-TMSmethodcouldbeusedtoindividualizethecorrectstimulationtarget,undertheassumptionthattrans-synapticactivationofthesgACCindeedactivatesthewholeDLPFC-sgACC-VagalnervepathwaythatisinvolvedinMDD.However,ithasyettobeestablishedhowthiscorrelateswithtreatmentoutcomeandifsuchtargetingmethodsresultinincreasedclinicalefficacy. 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