ContinuedfrompreviouspageTrialregistrationDeutschesRegisterKlinisch - PDF document

(Continuedfrompreviouspage)Trialregistration:DeutschesRegisterKlinischerStudien,DRKS00012278.Registeredon23May2017,amendmenton5October2017.Keywords:HRVbiofeedback,Heartratevariability,Biofeedback,Fearofspiders,Spiderphobia,Exposuretherapy,ExpositiontherapyBackgroundSpecificphobiasarecharacterizedbyanexcessiveandirrationalfearofaspecificobjectorsituation,whichiseitheravoidedorenduredwithgreatdistress.About12.5%ofthepopulationmeetthecriteriaforaspecificphobiaatleastonceintheirlifetime[1].Currenttheor-iesonthepathogenesisofanxietydisordersandphobiashavebeenstronglyinfluencedbymodelsofconditioningandassociativelearning[2,3].Inphobicindividuals,exposuretothefear-provokingstimulustriggerstheretrievalofstimulus-relatedfearmemories,which,inturn,leadtothefearresponse[4–6].Onecentralmech-anismofexposuretherapy,thetreatmentofchoiceforspecificphobias,istheextinctionofthesefearresponses.Thisisaccomplishedbyexposingthepatientrepeatedlyandsystematicallytothesestimuliundercontrolledconditions[7–9].Eventhoughexposuretherapyisthefirst-linetreatmentforanxietydisorders,notallpatientsbenefitequallyfromit.Someachieveonlypartialremis-sionorshowareturnoffearafteraninitialtherapeuticsuccess[8–10].Thus,oneofthemainaimsofcurrentresearchonthetreatmentofanxietydisordersistodevelopwaysofincreasingandconsolidatingtheeffectsofexposuretherapy[11,12].Abiofeedbackinterventiontoenhanceheartratevariability(HRV)iscurrentlydiscussedasaparticularpromisingtherapeuticadd-on[13,14].SeveralstudiesshowthatHRVasabiomarkerofautonomousnervoussystem(ANS)functioningislinkedtophysicalandmentalhealth:seriouspsychologicaldisorders,suchasdepression[15]andanxietydisorders[16],areassociatedwithasubstantiallyreducedHRV.Thisreductionisalsolinkedtodecreasedmotivationtoengageinsocialsituations,self-regulationproblems,andlessflexiblereactionstopsychologicalstressors[17].Moreover,inthelongterm,immunedysfunctions,in-flammatoryreactions,cardiovasculardiseasesandhighermortalityareassociatedwithadecreasedHRV[18].However,thusfar,itisnotknownwhichmechanismslinkHRVtohealthandillness.TheheartisinnervatedequallybyboththesympatheticandparasympatheticANSpaths.HRVcanbeconsideredasadynamicindexoftheirinterdependency.However,parasympathetic(vagal)influenceshavethegreaterandfasterimpactonHRV[17].Further,ameta-analysisbasedonneuroimagingstudiessuggeststhatHRVreflectsnotonlytherelationofsympatheticandparasympatheticANSpaths,butalsoanindividual’sabilitytoadapttoenvironmentaldemands[18].Hence,agreaterHRVreflectsanindi-vidual’scapabilitytodealwithdemandsinaflexibleway,whileasmallerHRVcorrespondstoalimitedrepertoryofbehavioralresponses.Irrespectiveofitsprecisemodeofaction(see[19]fordifferenttheories),severalstudiesreportbeneficialeffectsofHRVbiofeedback[13].Theinterventionisgenerallyconceptualizedasabiofeedbackofrespiratorysinusarrhythmia(RSA)thatreflectsthevariationinheartrate(HR)whichaccompaniesbreathing.ParticipantsareinstructedtosynchronizetheirbreathingfrequencywiththeiroscillationsinHR.Thisinterventioniscommonlyand,thereforealsohereafter,calledHRVbiofeedback,althoughtechnicallyitisnotagenuinefeedbackofHRV,butafeedbackofHR[20].DuringstandardHRVbiofeedback,participantsareaskedtoinhalewhiletheirHRincreasesandtoexhalewhileitdecreases.TheyshouldbreatheslowlyinordertoreachtheirindividualresonancefrequencyatwhichtheirRSAisatmaximum.Onaveragethisfrequencyisreachedataboutsixbreathspermin[21].Particularlywell-elaboratedversionsofHRVbiofeedbackcontainseveralvisuallycomplexgraphicalillustra

tionsofHRoscillations,respiratoryrateandRSA(e.g.,[20]).RegardingtheeffectivenessofHRVbiofeedback,arecentmeta-analysisbasedonclinicalandnon-clinicalsamplesreportsbeneficialeffectsofHRVbiofeedbackasastand-aloneinterventiononsymptomsofstressandanxiety[22].HRVbiofeedbacksignificantlyreducesstressandanxietysymptoms(g=.81)andissuperiortovari-ouscontrolconditionssuchaswaitinglistofshambio-feedback(g=.83).Furthermore,severalstudieshaveevaluatedtheeffectsofHRVbiofeedbackasadd-oninter-ventioninclinicalsamples:inposttraumaticstressdis-order,acasestudyandacontrolledtrialhaveshownbeneficialeffectsofHRVbiofeedbackduringexposuretherapy[23,24].Positiveresultsintermsofreducedde-pressionscoresandincreasedHRVhavealsobeenshownforpatientswithdepression[25,26].Further,arecentpilotstudydemonstratedatrendtowardsanincreasedfearreductioninaviophobiapatientswhoreceiveddiaphragmaticbreathingtrainingpriortoexposureinvirtualreality[27].Thetrainingusedafrequencyofsixbreathcyclespermin,whichisequaltotheaveragereson-ancefrequencynormallyusedinHRVbiofeedbackSchäferetal.Trials (2018) 19:184 Page2of11 interventionstomaximizeindividualHRV.Hence,itisplausibletoassumethatthereportedbeneficialeffectsarelinkedtoHRVincreasecausedbyslowdiaphragmaticbreathing.Takentogether,currentevidencesuggeststhatHRVbiofeedbackmaybeausefulstand-aloneinterventionandapromisingadd-ontooltoimprovepsychotherapyout-comes.However,thusfar,thereisalackofrandomizedcontrolledtrials(RCT)supportingtheeffectivenessoftheintervention.Thisiscriticalfortworeasons:firstly,testingtheeffectsofatherapeuticadd-oninacontrolledtrialisnecessaryintermsofadvancingevidence-basedtreatments.Secondly,theeffectsofHRVbiofeedbackneedtobedisen-tangledfrompossibleeffectsofworkingmemory(WM)tasks,asdifferentstudiesdemonstrateapositiveimpactoflow-loadWMtasksonconsolidationandreconsolidationmemoryprocessesrelevantformemorizingtherapeuticinput[28,29].Forexample,theoriesonthemechanismsunderlyingEyeMovementDesensitizationandReproces-sing(EMDR)emphasizetheroleofeyemovementsasalow-loadWM-demandingtask[30,31].PerformingeyemovementsduringimageryexposurereducesWMcapacity,therebydecreasingthevividnessandemotionalityofthetraumaticmemory[32].AimofthecurrenttrialWhileHRVbiofeedbackisnotconceptualizedasaWMtask,itnonethelesscreatesaWMloadthatmightinfluencerelevant(re-)consolidationprocessesduringexposure.Therefore,thecurrenttrialaimstoexaminewhetherHRVbiofeedbackismoreeffectivethanpseudo-biofeedbackthatevokesasimilarWMload.Allexperimentalgroupsreceiveatrainingsessionduringwhichtheylearntwotasks(eitherHRVbiofeedbackandapseudo-biofeedbacktaskortwopseudo-biofeedbacktasks).Bothpseudo-biofeedbacktasksrequirethepartic-ipantstosynchronizearepetitivetappingonatable(A)orarhythmichandmovement(B)withapseudo-physiologicalsignal.Afteroneweekoftrainingathome,allparticipantsreturntothelaboratoryandwatchaseriesofspidervideoclips.Group1(G1,HRV/HRV)istrainedinbothHRVbiofeedbackandinpseudo-biofeed-backtaskA(1),butusesHRVbiofeedbackduringexpos-ure.Group2(G2,HRV/pseudo)receivesthesametrainingasG1,butperformsthepseudo-biofeedbacktaskAduringexposure.Group3(G3,pseudo/pseudo)istrainedintwopseudo-biofeedbacktasks(AandB)andusesthesamepseudo-biofeedbacktaskAasgroup2dur-ingexposure.Group4(G4,pseudo/)istrainedinbothpseudo-biofeedbacktasks(AandB),butperformsnoneofthemduringexposure(foradetailedoverview,seeFig.1).HypothesesBasedonpriorstudiesonHRVbiofeedbackandfindingsontheimpactofWMtasksonexposuretherapy,itishypothesizedthat: Fig.1Experime

ntalflowchartincludingalltrialphasesSchäferetal.Trials (2018) 19:184 Page3of11 1.ParticipantswhoaretrainedinHRVbiofeedback,andwhoutilizeitduringexposure,havethegreatestreductioninfear.2.ParticipantswhoaretrainedinHRVbiofeedback,butwhodonotutilizeitduringexposure,havemorefearreductionthanparticipantswhoarenottrainedinHRVbiofeedback.3.ParticipantswhoutilizeaWMtask(pseudo-biofeedbacktaskA)duringexposureshowgreaterfearreductionthanparticipantswhodonothaveanadditionaltaskduringexposure.Further,wewillanalyzephysiologicalfearmeasure-ments[electrodermalactivity(EDA),electrocardiogram(ECG)andrespiration(RSP)]duringbiofeedbacktrain-ingandexposuresessionsandrelatechangesinthesesignalstochangesinfear.MethodsParticipantsParticipationislimitedtospider-fearfulparticipantsaged18to40years.Participantsareregardedasspider-fearfulindividuals(SFs)whentheyscore14ormoreintheGermanSpiderAnxietyScreening(SAS,[33]),whichisthecommonlyusedcut-offscore[34,35].Moreover,theyhavetoscore50orhigherontheFearofSpidersQuestionnaire(FSQ[36];Germanversion:[33]).Additionally,SFsmustreachaminimumfearscoreof4andanavoidancescoreof3inthesection“SpecificPhobias”ofthestructuredinterviewformentaldisorders(ADIS–section“SpecificPhobias”[39];Germanversion:[40]).Exclusioncriteriaare:presenceofanyothermentaldisorderthanspiderphobia(assessedwiththePatientHealthQuestionnaireD(PHQ-D,[37])andtheBeckDepressionInventory(BDI-II;Germanversion:[38])andanyreportedcardiovas-culardisease(assessedduringthescreeningphase).RecruitingtakesplaceatSaarlandUniversity,inso-cialmediaandthroughthelocalpress.Participantsarecontactedindividuallybytheresearchteamandprovideinformedconsentpriortotheirparticipation.Psychologystudentstakingpartinthestudyreceivecoursecredit.SamplesizeTheintendedsamplessizewascalculatedusingG*Power3.1[39].Anaprioripowercalculation(
=.05,1–=.85)basedontheweightedmeanbetween-groupeffectreportedbyGoessletal.[22]resultedinatotalsamplesizeof80participants.Thus,20participantsperexperimentalgrouparerecruitedtoensuresufficientstatisticalpower.MaterialsandmeasuresInterviewAnxietyDisordersInterviewScheduleforDSM–IVTheAnxietyDisorderInterviewSchedulefortheDiagnosticandStatisticalManualofMentalDisordersIVtextrevised(DSM-IV-TR)(ADIS;[40])isastructuredinterviewwhichreliesonthediagnosticcriteriaoftheDSM-IV-TR.Inthecurrentstudy,thesection“SpecificPhobias”oftheGermanADISversionDIPS(Diagnos-tischesInterviewbeiPsychischenStörungen,[41])isusedtoassesstheparticipants’fearandavoidancebehaviorto-wardsspiders.Subjectiveratings–screeningGermanSpiderAnxietyScreeningTheSAS[33]isafour-itemself-reportquestionnairetoefficientlyscreenSFsinlargersamples.Scoresrangefrom0to24withhighervaluesindicatingastrongerfearofspiders.Inthepresenttrial,thescreeningisperformedbyatrainedmemberoftheresearchteamusingaphoneversionoftheSAS.FearofSpidersQuestionnaire(FSQ)TheFSQ([36];Germanversion:[33])isaself-reportinstrumenttoquantifyfearofspiders.Itconsistsof18itemswhichareratedona7-pointscalerangingfrom“1=notatall”to“7=verymuch”.Thequestionnaireshowsgoodpsychometricproperties[33,36].AnxietySensitivityScale3TheAnxietySensitivityScale(ASI-3;[42];Germanversion:[43])isadministeredtomeasurefearfulcognitionsaboutphysiologicalanxietysymptoms.The16-itemscaleisusedtocontrolforaprioridifferencesbetweenthefourexperimentalgroups.BeckDepressionInventoryIIToassessdepressivesymptomswithinthelasttwoweeks,theGermanver-sionoftheBeckDepressionInventory(BDI-II;Germanversion:[38])isused.Itcontains21itemsrelatedtod

epressionwithscoresrangingfrom0to63.Scoresof17andhigherareconsideredclinicallyrelevant.Participantsscoring17orhigherareexcluded.PatientHealthQuestionnaireDThePatientHealthQuestionnaireD(PHQ-D;[44],Germanversion:[37])isashortandeconomicinstrumentforassessingsymptomsofmentalhealthdisorders.ItsnewestversionreliesontheDSM-IV-TRcriteriaandhasgoodpsychometricproperties[45].Schäferetal.Trials (2018) 19:184 Page4of11 Subjectiveratings–outcomeFearofSpidersQuestionnaireTheFSQ([36];Germanversion:[33])isnotjustusedasascreeningtool,butalsoforoutcomeassessment.DifferencesinFSQscoresfrompretoposttreatmentandtofollow-upareusedastheprimaryoutcomemeasure.Self-efficacyconcerningspidersInaccordancewithShibanetal.[27],threequestionsontheperceivedefficacyinhandlingaspiderareasked(seeAdditionalfile1).STAI-SandSTAI-TTheStateandTraitAnxietyInventory(STAI;[46];Germanversion:[47])isusedtoassesssubjectivebaselineanxiety(traitscale)aswellasshort-termchangesinanxietylevels(statescale).BothSTAIversionsarebriefself-reportquestionnairesconsistingof20itemsrelatedtoperceivednervousness,tensionandworry.Allitemsareratedona4-pointscale.Hence,totalSTAIscoresrangefrom20to80,withhigherscoresindicatinghigheranxietylevels.Bothscalesshowgoodpsychometricproperties[47].SubjectivestressratingsAftereveryfourthvideoclipintheexposuresession,participantsareaskedtoratetheirsubjectivefearandarousallevelson4-pointscalesfrom“1=notatall”to“4=strongly”.BehavioraltestBehavioralApproachTestTotestparticipants’fearandavoidancebehaviortowardsrealspiders,theBehav-ioralApproachTest(BAT;[48])isemployed.TheBAT(asadministeredinapriorstudybyLass-HennemannandMichael[49])consistsofthefollowingprocedure:standinginfrontofaclosedroomthatcontainsahousespider(Tegenariaatrica)measuringabout5cm(legsincluded).Thespiderisplacedinasealedplasticcontaineronatableattheendoftheroom.Next,ifpossible,theparticipantenterstheroom,approachesthecontainer,removesthelid,insertsahandandtriestopickupandholdthespiderforatleast20s.Whentheparticipanthasreachedfor,ortouched,thespider,orwhentheydecidetostopapproaching,theremainingdistanceisnoted.Indetail,13stepsarecoded:0=testroomisnotentered;1=stops5mfromthecontainer,2=stops4mfromthecontainer;3=stops3mfromthecontainer;4=stops2mfromthecontainer,5=stops1mfromthecontainer,6=stopsclosetothetablewiththecontainer,7=touchesthecontainer,8=removesthelid,9=putsahandinthecontainer,10=touchesthespiderwithonefinger,11=holdsthespiderlessthan20s,12=holdsthespiderforatleast20s.Differencesfrompretoposttreatmentareusedasaprimaryoutcomemeasure.PhysiologicalstressmeasurementPhysiologicaldataisrecordedusingtheBiofeedbackSystem(BFS)developedbyFraunhoferIBMT.Thissystemsupportsstate-of-the-artwearablesensorsandwirelesscommunicationtoenhanceusabilityandtheparticipant’scomfort.Theschematicdiagram(seeFig.2)showstheset-upoftheBFS.EDA,ECGandRSPsignalsarerecordedusingtheBITalinobiosignalmeasurementdevice(PLUX–WirelessBiosignalsS.A.,Lisbon,Portugal)withthesamplingfrequencysetto100Hzperchannel,whichissufficientforECGrhythmmonitoring[50].ThreeelectrodesareplacedaccordingtostandardleadIIconfiguration.ForEDAmeasurementtwoelectrodesareattachedtotheproximalpartofthepalmoftheparticipant’snon-dominanthand.Theelectrodesusedarestandardpre-gelledandself-adhesivedisposableAg/AgClelectrodes(KendallH135SG,Medtronic,Minneapolis,MN,USA).TheBITalinoRSPsensorisanadjustable,elastic-fasteningcheststrapwithanintegratedpiezoelectricsensor.HRVbiofeedbackisobtainedbyemployingtheHRmonitorarmbandRhythm+(Sc

oscheIndustries,Inc.,Oxnard,CA,USA)withasamplingfrequencyof1Hz.Thiswristbandisplacedbelowtheelbowoftheparticipant’snon-dominantarm.Allsensordataiswirelesslyroutedtothepersonalcomputer(PC) Fig.2SchematicdiagramoftheBiofeedbackSystemSchäferetal.Trials (2018) 19:184 Page5of11 throughasmartphone(Nexus5,GoogleInc.,MountainView,CA,USA)usingBLE(BluetoothLowEnergy)andWLAN(WirelessLocalAreaNetwork)interfaces.ThePCsoftwareusedfordataacquisitionandvisualizationhasbeendevelopedinC#(VisualStudioEnterprise2015,MicrosoftCorporation,Redmond,WA,USA)asaWindowsFormapplication.Thisapplicationplotsreal-timephysiologicalsignalsandsavesthemintotextfiles.Additionally,thePCsoftwareplotsthevisualizationoftheHRVbiofeedbackandpseudo-biofeedback.SinceallinstructionsarepresentedtotheparticipantsbyusingE-Primesoftware(E-Prime2.0,PsychologySoftwareToolsInc.,Sharpsburg,MD,USA),thePCapplicationincorporatesaninterfaceforreceivingtriggersignalsrelatedtodefinedeventsduringthetrainingandexposuresessions.TasksBiofeedbacktrainingsThebiofeedbacktrainingsessiontakesplaceinthelaboratory.Participantsareseatedinfrontofacomputermonitor,whichdisplaysallinstructions.Thebiofeedbackinformationisdisplayedonasecondmonitor(seeaphotographoftheexperi-mentalset-upasAdditionalfile2).HRVbiofeedbackThetrainingsessionconsistsofaverbalinstructiontosynchronizeone’sbreathingandthedisplayedchangesinHR.Allinstructionsareadaptedfromawell-establishedHRVbiofeedbacktrainingprovidedbyLehreretal.[20].ParticipantsareaskedtoinhalewhenHRisincreasing,andtoexhalewhileitisdecreasing.ThevisualizationofthebiofeedbacksignalissimilartothecommercialStressEraser®device[51].Further,thetrainingincludestwoschematicdiagramsofthesimultaneouslydisplayedHRVbiofeedbackandthecorrectbreathingrhythm(seeasAdditionalfile3).NeithertheschematicnortherealHRdiagramscontainabsoluteHRvaluesinordertopreventtheparticipantsfromfocusingontheirHRlevels.ResonancefrequencyTheBFSobtainsanddisplaysthecurrentbreathingfrequency(breathspermin)basedona“peaksandvalleysdetection”algorithm.Thebreathingfrequencyiscalculatedasthenumberofdetectedpeaksinaperiodof1min.Pseudo-biofeedbackThepseudo-biofeedbacktrainingalsousesverbalinstructionsandaschematicdiagramoftheintendedtrainingresults(seeasAdditionalfile3).IncontrasttotheHRVbiofeedback,participantsareaskedtosynchronizeaspecificmovement(tappingorasmooth,rhythmichandmovement)tothedisplayedsignal.Inordertoillustratetheintendedmovements,shortdemonstrationvideoclipsarepresented.Thepseudo-signalisintroducedas“oxygenvariability”andchangesovertimetomatchthechangesinHRduetothebreathinginstruction.Pseudo-biofeedbacksignalThesignalthatemulatestheoxygenvariabilityisimplementedusingthefollowingequation(Eq.1):ftðÞ¼Asin Tpeakt
þ0:3N;if0t Tpeak2Asin Tpeakt
0:4N;if Tpeak2tTpeak0;ifTpeaktTpeakþTnonpeak8��������:whereTpeakisarandomnumberbetween4and7,Nisarandomnumberbetween0and1,Aistheamplitudethatstartswith6and,after5min,changesto8.Tnon-peakisarandomnumberbetween3and5.EverytimetreachesTpeak+Tnon-peak,tissetto0andnewvaluesfortheperiodsarecalculated.Usingthisequationapseudo-signalisgeneratedwhichlookssimilartotheHRVbiofeedbacksignal.PracticeathomeAttheendofthetrainingsessions,allparticipantsreceiveanMP3filetocontinuetheirtrain-ingathome.Thisfilecontainsanaudioinstructionfora20-minsession,duringwhicheachtypeoftraining(HRVand/orpseudo-biofeedback)ispracticedfor10min.Allinstructionsaskthe

participanttosynchronizetheirbreathingoramovementtoarepeatedlypresented,pleasantaudiosound.IncaseoftheHRVbiofeedback,itsfrequencycorrespondstotheindividualresonancefrequency,whichisdeterminedbytheendoftheinitialtrainingsession.Forbothpseudo-biofeedbacktasksthefrequencyissettoafixedvalue.Toensurethatpartici-pantshavecompletedthetrainingatleastonce,allin-structionversionscontainacodeword,whichparticipantsareaskedtoreportaftertheexposuresession.ExposuresessionFirstly,allparticipantsareintroducedtotheexposureprocedureandrationale,whichismainlybasedontheprinciplesoftheone-sessionexposuretreatmentdevelopedbyÖst[52].Itskeyaspectsarecontrolledexposuretothefear-provokingstimulusandchangesoffearfulcognitions.Everyexposuretrialstartswithaquestiononthecontentofthevideoclip(e.g.,howmanyspidersareshowninthenextclip?)inordertosetacognitivefocusforthefollowingclip.The161-minclips,alltakenfromTVdocumentaries,showde-tailedshotsofspiders.Aftereveryclip,thequestionaskedpriortotheclipispresentedagainandpartici-pantsareaskedtochoosetherightanswerbychoosingbetweenfourpossiblemultiplechoiceanswers.Incaseofacorrectanswer,theparticipantispraised.IncaseofSchäferetal.Trials (2018) 19:184 Page6of11 anincorrectresponse,aninstructionremindingthepar-ticipantstoconcentrateonthevideosinordertoreducetheirfearispresented.Aftereightofthe16clips,thequestionsfocusonpositiveemotionalfeaturesinsteadofcognitiveaspectstochangetheparticipant’sattitudeto-wardsspiders.Participantsareconstantlycomplimentedonidentifyingpositivefacets.SeeFig.3foradetailedil-lustrationoftheexposureprocedure.ProcedureanddesignThetrialtakesplaceattheDepartmentofClinicalPsychologyandPsychotherapyatSaarlandUniversity.Itincludessevenphases:initialscreeninganddiag-nosticphase,randomization,(pseudo)-biofeedbacktraining,practiceathome,exposuretospidervideoclips,post-assessmentandfollow-upassessments.ForadetailedtemporaloverviewseetheStandardProtocolItems:RecommendationsforInterventionalTrials(SPIRIT)Figure(Fig.4).TheSPIRITChecklistisprovidedasAdditionalfile4.ScreeninganddiagnosticphaseParticipantswhovolunteeredtotakepartinthetrialarecontactedbyphoneforashortscreeningusingtheSAS[33].Participantsscoring14orhigherareinvitedtocompleteanonlinequestionnaireadministeredviaSoSciSurvey[53],whichconsistsoftheSTAI-T,theFSQ,thePHQ-D,theASI-3,theBDI-IIandthreequestionsontheperceivedself-efficacyinhandlingspiders.Ifpartici-pantsreachaFSQscoreof50orhigher,theyareaskedtoattendanassessmentattheDepartmentofClinicalPsychologyandPsychotherapy.Thisfirstassessmenttakesabout45minandcontainstheADISsection“SpecificPhobias”andtheBAT.Bothareadministeredbyatrainedmemberoftheresearchteam.Participantswithanavoidancescoreofatleastthreeandafearscoreofatleastfourareinvitedtotakepartinthebiofeedbacktraining.RandomizationTherandomizationprocessusingageneratedlistiscon-ductedbyamemberoftheresearchteamwhoisnotin-volvedinthedatacollectionprocess.Participantsareallocatedtooneofthefouraforementionedexperimen-talgroups(n=20pergroup):(1)group1(G1,HRV/HRV);(2)group2(G2,HRV/pseudo);(3)group3(G3,pseudo/pseudo);and(4)group4(G4,pseudo/).BiofeedbacktrainingThebiofeedbacktrainingsessionstartswitharestingphaseof5mintoassessbaselineHRV.Afterwards,par-ticipantscompletetheSTAI-S.Then,dependingontheexperimentalgroup,thetrainingsessionstarts.Allpar-ticipantsreceivetwotypesoftraining,eachlasting30min.Theorderofbothtrainingpartsisrandomizedwithineverygroup.Aftereachtypeoftraining,partici-pantscompletetheSTAI-Sagaintoevaluatethe

ircurrentanxietylevel.PracticeathomeAttheendofthetrainingsession,allparticipantsreceiveanaudiofileforhometraining.Theversionofthepro-videdfiledependsontheparticipants’individualreson-ancefrequency(G1andG2)ortakestheformofastandardaudiofileforbothpseudo-biofeedbacktasks(G3andG4).Participantsareaskedtocontinuethetrainingfor6days(20minaday).ExposuresessionTheexposuresessionisconductedoneweekaftertheinitialtrainingsessioninthesamelaboratoryusingthe Fig.3SchematicillustrationoftheexposuresessionSchäferetal.Trials (2018) 19:184 Page7of11 sametechnicaldevices.Allexposuresessionstakeplaceintheafternoon(between2p.m.and6p.m.)tocontrolfordiurnalcortisollevels,whichcaninfluenceexposureeffects[49].Atfirst,allparticipantscompletetheSTAI-S.Thenparticipantsgoontoconductexposure.G1re-ceivesHRVbiofeedbackduringexposure,whereasG2andG3arepresentedwithpseudo-biofeedback(taskA).G4hasnoadditionaltaskduringexposure.PostassessmentSubsequenttotheexposuresession,thepostassessmenttakesplace:participantscompletetheSTAI-S,theFSQandtheASI-3.Again,theyanswerthreequestionsontheirperceivedself-efficacyindealingwithaspiderandthepost-exposureBATisperformed.Follow-upassessmentsOneweekandonemonthaftertheexposuresession,participantsarecontactedbytheresearchteamandaskedtocompleteanonlineversionoftheFSQandtoanswerthequestionsonself-efficacyinhandlingaspider.DatacollectionandstatisticalanalysesQuestionnairedataisregisteredusingSoSciSurvey[53]andexportedasa.csvfile.TheBATresultsarenotedinanExcelsheetbyamemberoftheresearchteam.Further,behavioraldataconcerningthetrainingandexposuresessionsiscollectedusingtheE-PrimesoftwareandphysiologicaldataisstoredasatextfileusingtheBFS.Allstatisticalanalyseswillbecon-ductedbyamemberoftheresearchteam,whowasnotinvolvedinthedatacollectionprocess,usingIBMSPSSversion24[54].Thealphalevelwillbesettop0.05.Themainhypotheseswillbetestedusingamixedanalysisofvariance(ANOVA)withgroupasthebetween-subjectsfactorandtime(preassessment,postassessment,follow-uponeweek,followupfourweeks)asthewithin-subjectsfactor.Allanalyseswillbereportedwithpartial2astheeffectsize. Fig.4StandardProtocolItems:RecommendationsforInterventionalTrials(SPIRIT)FigureofthecurrenttrialSchäferetal.Trials (2018) 19:184 Page8of11 DiscussionTheresultsofthecurrenttrialshouldprovideevidenceontheeffectivenessofHRVbiofeedbackasatooltoenhanceexposure-therapyoutcome.Incontrasttoexist-ingstudies,thecurrentstudycarefullycomparestheeffectsofaHRVbiofeedbackinterventionwiththoseofalow-loadWM-demandingtaskduringexposure.Moreover,thestudyrelatesexposure-evokedchangestoalterationsinphysiologicalsignalsduringexposureandtothesignalsrecordedduringthepriortrainingsession.IfHRVbiofeedbackisfoundtobebeneficial,monitoredphysiologicalchangesmightprovideimport-antinformationonthemechanismsunderlyingtheseeffects.Finally,theassociationbetweenphysiologicalfearcorrelatesandsubjectivelyperceivedfearandarousalisexaminedatfourpointsduringexposure.Thisishighlyrelevantaspriorstudiesonthisrelation-shiphaveshowninconsistentfindings[55,56].However,ithastobenotedthatthecurrenttrialusesasubclinicalsample.Incaseofpromisingfindings,fur-therstudiesneedtoexamineifHRVbiofeedbackinter-ventionsalsoimprovetheeffectivenessofstate-of-the-artpsychotherapyinclinicalsamples.Overall,thecurrentRCTisafirststepofadetailedevaluationprocessaimingtoimproveexposuretherapybyusingHRVbiofeedbacktechniques.TrialstatusAtthetimeofinitialmanuscriptsubmission,recruitmentwasalreadyinprogress(sinceJune2017)butnotyetcomple

te(prospectivecompletioninMay2018).Themanuscriptreportsprotocolversion2(5/10/2017).AdditionalfilesAdditionalfile1:Questionsonself-efficacyinhandlingaspider.(PDF25kb)Additionalfile2:Photographoftheexperimentalset-up.(PDF13386kb)Additionalfile3:Schematicdiagramofheartratevariability(HRV)biofeedbackandpseudo-biofeedbacktasks.(PDF387kb)Additionalfile4:SPIRITChecklist.(DOC122kb)AbbreviationsADIS:AnxietyDisorderInterviewScheduleforDSM-IV;ANS:Autonomousnervoussystem;ASI-3:AnxietySensitivityIndex3;BAT:BehavioralApproachTest;BDI-II:BeckDepressionInventoryII;BLE:BluetoothLowEnergy;DSM-IV-TR:DiagnosticandStatisticalManualofMentalDisordersIVtextrevised;ECG:Electrocardiogram;FSQ:FearofSpidersQuestionnaire;HR:Heartrate;HRV:Heartratevariability;PC:PersonalComputer;PHQ-D:PatientHealthQuestionnaire9-Germanversion;RCT:Randomizedcontrolledtrial;RSP:Respiration;SAS:GermanSpiderAnxietyScreening;SF:Spider-fearfulindividual;STAI-S/-T:StateTraitAnxietyInventoryStateorTrait;WLAN:WirelessLocalAreaNetwork;WM:WorkingmemoryAcknowledgementsWearegratefultotheGermanFederalMinistryofEducationandResearch(BundesministeriumfürBildungundForschung)forfundingthisstudywithanappliedresearchgrant.Wethankanyindividualtakingpartinourstudyforcontributingtoourresearch.Moreover,wethankallMaster’sstudentsandstudentassistantswhosupportedthetrial.FundingFundingforthistrialwaskindlyprovidedbytheGermanFederalMinistryofEducationandResearchthroughanappliedresearchgrant(contractnumbers13GW0158Band13GW0158C)withintheprogram“Medicaltechnologysolutionsforthedigitalhealthcare”(German:“MedizintechnischeLösungenfürdiedigitaleGesundheitsversorgung”).Membersoftheproject“DigiPhobie–DigitalTherapyfortheTreatmentofSpecificPhobiaatHome”(German:“DigiPhobie–DigitaleTherapiezurhäuslichenBehandlungvonspezifischenPhobien”)aretheDepartmentofClinicalPsychologyandPsychotherapy,FraunhoferInstituteforBiomedicalEngineering,SaarlandUniversityMedicalCenter,andPromotionSoftwareGmbH.Thefoundershadnoroleinthedevelopmentandthedesignofthetrial.Ithadalsonoinfluenceinthepreparationorapprovalofthemanuscript.AvailabilityofdataandmaterialsDatasetscontaininginformationonparticipantlevelwillbedepositedinpubliclyavailablerepositories(whereavailableandappropriate)inmachine-readableformat.Authors’contributionsSKSdraftedthemanuscriptandcontributedtotrialdesign.FRIsupervisedthedevelopmentoftheBFSandselectedwearablesensors.KALHimplementedthePCsoftwareoftheBFSaspartofherMaster’sthesis.FNimplementedthesmartphone-baseddatatransmissionbetweenwearablesensorsandPCaswellasthetriggerinterfaceforE-Prime.SKcontributedtothedesignoftheBFSandthedataanalysismethodology.MSsupportedthemanuscriptwriting.JLHandTMcontributedtotrialdesignandsupervisedthemanuscriptwriting.Allauthorsreadandapprovedthefinalmanuscript.EthicsapprovalandconsenttoparticipateEthicalapprovalhasbeengrantedbytheEthicalCommitteeoftheFacultyofHumanScienceofSaarlandUniversity(reference:17–03).Participantsprovideinformedconsentiftheyareinterestedinparticipating.Participants’declarationofconsentcanberevokedatanytimeofthetrial.Modificationsofthetrialarecommunicatedtoallrelevantpartners.ThesponsorofthestudyisProf.TanjaMichael,SaarlandUniversity(t.michael@mx.uni-saarland.de).ConsentforpublicationConsentforpublicationisobtainedfromallparticipantsaspartoftheinformedconsentprocess.CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.SaarlandUniversityandFraunhoferInstituteforBiomedicalEngineeringsupporttheundertakingofthisstudy,butdidnothavea

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