Feel the Time. Time Perception as a Function of Interoceptive ...

Time perception is a fundamental element of human awareness. Our consciousness, our ability to perceive the world around us and, ultimately, ... Articles IrinaStrigo UniversityofCalifornia,SanFrancisco,UnitedStates J.MichaelHerrmann UniversityofEdinburgh,UnitedKingdom MarcWittmann InstituteforFrontierAreasofPsychologyandMentalHealth(IGPP),Germany Theeditorandreviewers'affiliationsarethelatestprovidedontheirLoopresearchprofilesandmaynotreflecttheirsituationatthetimeofreview. Abstract Introduction MaterialsandMethods Results Discussion AuthorContributions ConflictofInterestStatement Acknowledgments Footnotes References SuggestaResearchTopic> DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex totalviews ViewArticleImpact SuggestaResearchTopic> SHAREON OpenSupplementalData ORIGINALRESEARCHarticle Front.Hum.Neurosci.,06March2018 |https://doi.org/10.3389/fnhum.2018.00074 FeeltheTime.TimePerceptionasaFunctionofInteroceptiveProcessing DanieleDiLernia1*,SilviaSerino1,2,GiovanniPezzulo3,ElisaPedroli2,PietroCipresso1,2andGiuseppeRiva1,2 1DepartmentofPsychology,UniversitàCattolicadelSacroCuore,Milan,Italy 2AppliedTechnologyforNeuro-PsychologyLab,IRCCSIstitutoAuxologicoItaliano,Milan,Italy 3InstituteofCognitiveSciencesandTechnologies,NationalResearchCouncil,Rome,Italy Thenatureoftimeisrootedinourbody.Constellationsofimpulsesarisingfromthefleshconstantlycreateourinteroceptiveperceptionand,inturn,theunfoldingoftheseperceptionsdefineshumanawarenessoftime.ThisstudyexploredtheconnectionbetweentimeperceptionandinteroceptionandproposestheInteroceptiveBuffersaturation(IBs)index.IBsevaluatessubjects’abilitytoprocesssalientstimulifromthebodybymeasuringsubjectivedistortionsofinteroceptivetimeperception,i.e.,theestimateddurationoftactileinteroceptivestimulations.Thirtyfemalehealthysubjectswererecruitedthroughconsecutivesamplingandassessedforcommonvariablesrelatedtointeroceptivealterations:depressivesymptoms(BeckDepressionInventory,BDI-II),eatingdisorders(EDI-3)risk,andanxietylevels(StateTraitAnxietyInventory,STAI).Interoceptivecardiacaccuracy(IAc)wasassessedaswell.Subjectsperformedverbaltimeestimationofinteroceptivestimuli(IBs)deliveredusingaspecificallydesignedinteroceptivetactilestimulator,aswellasverbaltimeestimationofvisualandauditorystimuli.ResultsshowedthatIBsindexpositivelycorrelatedwithIAc,andnegativelywithEDI-3DriveforThinness(DT)risksubscale.Moreover,IBsindexwaspositivelypredictedbyIAc,andnegativelypredictedbyDTandsomaticfactorsofdepression.Ourresultssuggestthatunderestimationsininteroceptivetimeperceptionareconnectedtodifferentpsychologicalconditionscharacterizedbyadiminishedprocessingofhighsaliencestimulifromthebody.Conversely,overestimationsofthedurationofinteroceptivestimuliappeartobefunctionofsubjects’abilitytocorrectlyperceivetheirownbodilyinformation.EvidencesupportedIBsindex,fosteringtheconceptofinteroceptivetreatmentsforclinicalpurposes. Introduction Timeperceptionisafundamentalelementofhumanawareness.Ourconsciousness,ourabilitytoperceivetheworldaroundusand,ultimately,ourverysenseofselfareshapeduponourperceptionoftimeinloopconnectingmemoriesofthepast,presentsensationsandexpectationsaboutthefuture.Yet,thewayweperceivetimeiswidelydebated. ScalarExpectancyTheory(Gibbonetal.,1984)isoneofthemostacceptedframeworksoftimeperception(Church,1984;Treismanetal.,1990).AcoretenetofSETisaninternalclockwithapacemaker-accumulatorcomponent.Pulsesemittedbythepacemakerarestoredintheaccumulator,andtheamountofunitsstoredinafinitespaninfluencessamplefrequencyandourtimeperception.Ahighpulseratewillstoremoreunitsintheaccumulator,thereforeleadingtooverestimationinsubjectiveperception,whereasalowpulseratewillproduceoppositeeffects.RecentdevelopmentsofSETincludedmemoryanddecisionmakingcomponentsalongwiththepacemaker-accumulatorunit,providingamoreefficientneurocognitiveframeworkfortimeawareness(Gibbonetal.,1984;Luietal.,2011).Moreover,theAttentionalGateModel(ZakayandBlock,1996)introducedattentionasmediatorofthemodeswitchbetweenthepacemakerandtheaccumulator.Specifically,attentioncancontrolthemodeswitch(WeardenandPenton-Voak,1995;Droit-VoletandMeck,2007;Weardenetal.,2010;Ogdenetal.,2015a)insuchawaythat,iftheswitchisopen,someemittedpulsescanbelostthereforecontractingourperceptionoftime(BurleandCasini,2001;Wittmann,2009;Ogden,2013). Thepacemaker-accumulatorframeworkhasbeenconnectedtoanembodiedmodeloftimeperception(WittmannandvanWassenhove,2009;Wittmannetal.,2010)byseveralauthors.Inthisperspective,bodilystatesandemotionsrepresentcentralelementswhereashighphysiologicalarousal(GilandDroit-Volet,2012;Grecuccietal.,2014;Ogdenetal.,2015a;YooandLee,2015;Mionietal.,2016)canincreasethepulsefrequencyofthepacemaker,creatingoverestimationofsubjectivetimeperception(Wittmann,2009).Numerousotherauthorsalsosuggestedthatarousalandbodilysignalsaredeeplyconnectedwithsubjectivetimeawareness(Droit-VoletandGil,2009;GilandDroit-Volet,2012;Pollatosetal.,2014;Ogdenetal.,2015a,b),leadingtotheconclusionthatperceptionoftimeisintimatelyrootedinourbody. Anembodiedperspectiveoftimeisalsosupportedbyvariouscomputationalneuroscientificmodelsthathighlighttheimportanceofthebodyandofbodilymovements.EvidencefromTomassiniandMorrone(2016)suggestedthatsubjectiveperceptionoftimeisconnectedtothemotorcortexwhereassensory-motorconflictsintegrationcontributestosubjectivedistortionoftimeacrossdifferentmodalities.Inasimilarway,Orgsetal.(2013)linkedtheperceptionoftimetotheprocessingofhumanmovementsthatsubsidesvisualandmotorcorticalareas.Moreover,complementaryevidenceidentifiedadirectlinkbetweentemporalevaluationandvisuo-motorrepresentationofmotoractions,highlightingtheconnectionbetweentimeperceptionandbodymovements(Gavazzietal.,2013)alsoonrepresentativelevel.Perceptionoftimeappearsthereforeasafundamentalrequirementofseveralfunctionsrelatedtothebody.Tothisaccount,BuonomanoandLaje(2010)proposedtheconceptof“populationclocks”thatenvisionsperceptionoftimeasanemergingtraitofrecurrentlyconnectedneuralnetworksthatencodetime,andspecificallymotortime,intheactivitypatternsofapopulationofneurons(Buonomano,2014).Alongwithpreviousdiscussedevidence,theseconvergingdatasupportthereforeanembodiedperspectiveoftimeperceptioninhumans(KranjecandChatterjee,2010;Wittmann,2014)whichintegratesseveralsources,fromemotionstobodymovements,tocreateourawarenessoftime. FurthersupporttotheembodiedperspectiveoftimecomesfromCraig’srecentworkonthe“interoceptivematrix”anditsrelationstohumantimeawareness.Theinteroceptivematrixlocatedintheanteriorinsularcortex(AIC)receivesafferentinputsfromsmalldiametersensoryfibersthroughthelaminaIspinothalamocorticalpathway,whichcarriesfundamentalinformationfromallthetissuesofthebody(Craig,2002,2003,2009;Guetal.,2013;GuandFitzGerald,2014)creatinginteroceptiveperceptions.RecentstudiesshowedselectiveactivationoftheAICintimeperception(Raoetal.,2001;Coull,2004;LewisandMiall,2006;Liveseyetal.,2007)specificallywithintherangeofsub-secondstoseconds,confirmingAICasoneofthecoreconstituentsofhumanawarenessoftime. Acentralcomponentoftheinteroceptivematrixistheinteroceptivebuffer(Craig,2009)thatprocessesandcomparesinteroceptiveinformationwithpreviousandpaststatesofthebody,inordertopredictfutureconditionsoftheorganism(Friston,2009,2010;Fristonetal.,2011;Seth,2013;Ondobakaetal.,2017).Theseinteroceptivepredictionsservetooptimizethefunctioningoftheorganism,thuspromotingpredictionregulation—acontrol-theoreticprocessthathasbeencharacterizedintermsofallostasis(Sterling,2012)or,moreformally,asapredictionerror(orfree-energy)minimization(Sethetal.,2011;Seth,2013;Suzukietal.,2013). Craig(2009)proposedthattheinteroceptivebuffermayplayakeyroleintimeperceptionaswell.Thisisbecausethebufferhasafinitedimensionanditcanbeeasilyfilledupwithinteroceptiveinputs,alteringourperceptionoftime.Specifically,highrateofsalientstimulicansaturatethefinitedimensionofthebuffer,speedingupthesamplingfrequency,effectivelyslowing(Tseetal.,2004;CampbellandBryant,2007;vanWassenhoveetal.,2008;WittmannandPaulus,2008;Droit-Voletetal.,2011)theperceptionoftime,whichwillappearto“standstilltothesubjectiveobserver”(Craig,2009).Contrary,whentheinteroceptivebufferisnotfilledup“largeintervalsoftimeintheobjectiveworldcanappeartopassquickly”(Craig,2009). Nonetheless,somestudiesrevealedaparadoxintimeperception,whenhighratesofhighsaliencestimulicanproduceoppositeeffects(Droit-VoletandMeck,2007;Droit-VoletandGil,2009).Thesefindingsmaybeexplainedbyafunctionalprocessinglateralizationofdifferentinteroceptivevalences.Specifically,AICappearedtobeasymmetricallyactivatedindefiniteconditions,whereasparasympatheticinputsarepreferentiallyprocessedbythemidandleftinsula,whilesympatheticactivityisusuallyprocessedbytherightAIC(Craig,2009).AccordingtoCraig’semotionalasymmetryperspective,whenweexperienceadominantsympatheticarousal,stimuliprocessedintherightAICspeedupthesampleratefrequency,accumulatingpulsesintheinternalclock,leadingthereforetooverestimationofsubjectivetimeperception.Conversely,whenweareengagedinaparasympathetic(e.g.,affiliative)activation,stimuliarepreferentiallyprocessedbytheleftAIC,leadingtoasubjectiveunderestimationoftimeduetoalackofsympatheticactivity(Craig,2009). Thepresentstudystartedfromthehypothesisthattimeperceptionisintimatelyrelatedtothefunctioningoftheinteroceptivebuffer(Craig,2009).However,whilepreviousstudiesexploredhowbodilystatescanaltersubjectivetimeperception,ourstudyfocusedontheoppositepossibility:thatis,thepossibilitytoassessthedegreeofbodilyinputprocessingthroughdistortionsofinteroceptivetimeperception.ThekeyideaofInteroceptiveBuffersaturation(IBs)indexistoassessparasympatheticinteroceptivestimuli,whicharepreferentiallyprocessedbytheleftinsula(Gordonetal.,2013)fordistortionsinsubjectivetimeestimationduetothesympatheticworkloadofthecoactiverightinsula.Parasympatheticinteroceptivestimuliarereproduciblethroughaspecifickindoftouchcalledaffectivetouch(Olaussonetal.,2002,2016).ThiskindoftouchencompassesactivationofC-Tafferentsconnectedtotheinteroceptivesystem.Tothisgoal,IBsdesignusesacustomdeveloped“interoceptivestimulator”abletosendinteroceptivetactileinputs,consequentlymeasuringdistortioninsubjectivetimeestimationofthesestimuli.Theestimateddegreeoftimedistortioncanthereforeprovideinsightonsubject’sbodilyinformationprocessingduetotherelativeinterferenceofotherinteroceptiveinputsinthesubjectivetimeestimation. Tothebestofourknowledge,interoceptivebufferhasneverbeenoperationalizedneitherexperimentallyexplored,thereforeourresultscanprovidepowerfultheoreticalandclinicalinsightsregardingtherelationshipbetweenbodilystatesandinteroceptiveprocessing. Fromapracticalpointofview,therationalebehindtheIBsindexistoreverseengineertheconnectionbetweentheinteroceptivematrixandthesubjectiveperceptionoftime,feedinginteroceptivestimulithroughtheC-TafferentsinthesecondarytouchsystemconnectedtothelaminaIspinothalamocorticalpathway.UsingtheIBsmethodology,subjectiveoverestimationsoftimewouldsuggestadominanceofsympatheticarousal,whilesubjectiveunderestimationsoftimewouldsuggesttheoppositecondition. AccordingtotheemotionalasymmetryframeworkC-T(affective)touch(Olaussonetal.,2002;Ackerleyetal.,2014a,b;LiljencrantzandOlausson,2014)comprisesaparasympatheticactivationprimarilyprocessedbytheleftAIC(Gordonetal.,2013)thatmightleadtoanunderestimationoftimeperceptioninhealthysubjects(Craig,2009).Nonetheless,contextualinterferencescausedbysympatheticstimuli—suchashigharousingnegativeones—processedbytherightAICshouldinterferewiththisendogenoustimebasecreatingdistortionsinperceptiontowardsanoverestimationoftime. Numerousstudiessuggestedanasymmetriceffectofsympatheticandparasympatheticinputontimeperception.Indeed,timeperceptionofparasympatheticinteroceptiverelatedstimuliappearedunderestimatedinnormalconditionswithoutsympatheticdominantactivation(Ogdenetal.,2015b);conversely,inducedsympatheticstimuliareabletodirectlyaltertheinternaltimebaseline,paradoxicallyleadingtoamoreaccurateperception(Mellaetal.,2011)endorsingthenotionofanemotionaladvantageforhomeostaticregulation(Ogdenetal.,2015a)asalsoconfirmedbyotherauthors(Angrillietal.,1997;BuettiandLleras,2012;Droit-Voletetal.,2013;Pezzuloetal.,2018). Comprehendingandstudyingtheinteroceptivebufferhasparamountvalue.Correctaccesstointeroceptiveinformationiskeytoallostasisandadaptiveregulationoftheorganism,whereasdifferentconditionssuchasanorexianervosa(Pollatosetal.,2008)depression(Dunnetal.,2007)andchronicpain(DiLerniaetal.,2016b)appearedconnectedtoalterationsininteroceptiveprocessing.Althoughseveralotherindexesarecurrentlyavailabletoassessdifferentinteroceptivefactors(Garfinkeletal.,2015),IBsindexmayprovideanadvancedinstrumentwiththeabilitynotonlytoidentifyspecificalterationsbutalsothenatureandthedirectionoftheprocessesinvolvedinthesealterations.Commoninteroceptivedeficitscanbethereforeconnectedtolowbuffersaturationlevelsindicatingadiminishedprocessingofstimuliarisingfromthebody(i.e.,anorexianervosa,depression)butalsowithhighsaturationlevelsofnegativearousalstimuli(i.e.,chronicpain,anxiety)thatcanimpairtheperceptionofotherinputs.Furthermore,IBsmightalsodetectalteredprocessingbeforethepresenceofactualdeficits,providinganearlyindicatorofclinicalconditionsnotyetmanifested. TotestIBsmethodology,thestudyutilizedastreamofinteroceptiveparasympatheticstimulisentthroughtheC-TafferentsinthesecondarytouchsystemconnectedtothelaminaIspinothalamocorticalpathway,consequentiallymeasuringforsubjects’distortionsintimeperception.Stimuliweredeliveredusinganinteroceptivestimulatorspecificallydevelopedforthetask.Consideringaforementionedbodyofevidence,wehypothesizedthathealthysubjectswillunderestimatethedurationofparasympatheticC-Tinteroceptivestimuli.Furthermore,wehypothesizedthatIBsindex(i.e.,thedegreeofdurationestimationofinteroceptivestimulation)willpositivelycorrelatewithinteroceptiveaccuracy(IAc)asaproxyofinsula’sactivity(Pollatosetal.,2007a).Moreover,wehypothesizedthatseveralpsycho-physiologicalconditionsthatareknowntointerferewithAICactivitywillinfluenceIBsaswell,leadingtodistortionsintimeperceptionaccordinglytosubjects’sympatheticandparasympatheticbalance.Specifically,wehypothesizedthatdepressivesymptoms(Dunnetal.,2007,2010;Pollatosetal.,2009;PaulusandStein,2010;Wiebkingetal.,2015)andeatingdisordertendencies(Pollatosetal.,2008),willinterfereinanegativedirection,whileanxietysymptoms(WhymanandMoos,1967;Pollatosetal.,2009,2014;Dunnetal.,2010;PaulusandStein,2010;YooandLee,2015)andothersympatheticstimuli(Ogdenetal.,2015a)inapositiveone. Wetestedthesehypothesesonhealthysubjectsassessingforcommonvariablesconnectedtointeroceptivealterations.WeassessedforriskofanorexianervosathroughEDI-3(Garneretal.,1983)DriveforThinnesssubscale(Eshkevarietal.,2012),anddepressivesymptomsthroughBeckDepressionInventory(BDI-II;Becketal.,1961).Furthermore,weassessedanxietyfactorsthroughStateTraitAnxietyInventory(STAI;Spielbergeretal.,1970)andendogenousinteroceptivecardiacaccuracy(IAc)aswell(Schandry,1981). MaterialsandMethods Participants Aspartofalargerenlistingprocedureintheuniversitycampus,30femalesubjectswererecruitedthroughconsecutivesampling.Age(mean=25.87years,SD=6.616)andBMI(mean=20.827,SD=2.24)werecomparabletootherhealthysamplesusedininteroceptivestudies(Garfinkeletal.,2015).Samplewascomposedonlybyfemalesubjectstoavoidsomatosensorydifferencesinperceptionduetogenderrelatedfactors(Fillingimetal.,2009)assuggestedbyOgdenetal.(2015b).Furthermore,asolelyfemalesampleensurednodifferencesrelatedtoscalessensitivity,especiallyregardingeatingdisorderriskassessedbyEDI-3(Garneretal.,1983;Clausenetal.,2011;Eshkevarietal.,2012). Exclusioncriteriawerethepresenceofcurrentpsychologicalorphysicaldiagnoses,alterationsintactileperception(paraesthesia),allodyniaandheartrelatedconditions.Subjectswereaskedtoavoidpharmacologicalmedicationsinthe12hbeforetheexperimentandnicotineandcaffeineinthe2hbeforetheexperiment. ThisstudywascarriedoutinaccordancewiththerecommendationsoftheEthicsCommitteeofCatholicUniversityofSacredHeartofMilanwithwritteninformedconsentfromallsubjects.AllsubjectsgavewritteninformedconsentinaccordancewiththeDeclarationofHelsinki(2008).TheprotocolwasapprovedbytheEthicsCommitteeofCatholicUniversityofSacredHeartofMilan. Procedure Onarrival,subjectsreceivedinformationabouttheexperimentandproceededtogivewrittenconsent.Followingabriefanamnesticinterviewandaseriesofpsychologicalquestionnaires,subjectswereconnectedtoaportableECGdevicewithAg/AgClelectrodestoperformtheIActask.Attheendofthetask,electrodeswereremovedandsubjectsperformedIBs,audioandvideotasks.IBs,audioandvideotaskswerepresentedinrandomizedorder. PsychologicalAssessment Aftertheirarrivalsubjectstookparttoabriefanamnesticinterviewwithapsychologistspecializedinpsychopathologicalandpersonalityassessment.Afteranamnesticdatacollectiontheyperformedabatteryofquestionnaires.DepressivesymptomswereassessedthroughtheBDI-II(Becketal.,1961).BDI-IIisa21itemsself-reportquestionnairewithstrongliteraturesupport.AnxietysymptomswereassessedthroughthewellvalidatedSTAI(Spielbergeretal.,1970).STAIisa40-itemscalethatprovidedmeasureofstate(STAI-S)andtrait(STAI-T)anxiety.RisksforeatingdisorderswereassessedthroughEDI-3(Garneretal.,1983)risksubscales(Eshkevarietal.,2012).EDI-3risksubscalesassessedthreedifferentaspectofeatingdisordersrisk:DriveforThinness(DT),Bulimia(B)andBodyDissatisfaction(BD).Globalriskindex(EDRC)iscomposedsummingthescoresofthesethreesubscales. InteroceptiveAccuracy AnIAcscorewasestablishedwiththeSchandryheartbeattask(Schandry,1981)throughaportableECGunitsamplingat250Hz(Villarrubiaetal.,2014a,b;Stojanovićetal.,2015;Ševcíketal.,2015;HugengandKurniawan,2016)withAg/AgClelectrodes.Timeintervalswere25,35,45and100s.Accuracyindexwascalculatedwiththefollowingformula:1/4∑(1−(|recordedheartbeats−countedheartbeats|)/recordedheartbeats). WefocusedoncardiacinteroceptionnotonlybecauseSchandrytaskisconsideredthestandardmeasureforIAc,butalsobecauseCraig(2009)suggestedthattimeperceptionmightbefundamentallybaseduponcardiorespiratoryfunction. InteroceptiveStimulation TheInteroceptiveBuffersaturation(IBs)taskappliedinteroceptiveparasympatheticstimuliandaskedtheparticipantstoestimatethedurationofthesestimuli.Whilethereareseveraldifferentkindsofinteroceptivestimuli,forthegoalofthisstudyweusedlighttouchasprimaryparasympatheticinput(Ackerleyetal.,2014b).NeuroanatomicalevidenceidentifiedspecificCtactile(C-T)afferents,whichreportdirectlytotheAIC(Gordonetal.,2013)thatareexquisitelysensitivetolighttouch(Vallboetal.,1999;Ackerleyetal.,2014b).UnmyelinatedC-Tfibersselectivelyrespondtoslowtactilebrushingstimulibetween1cm/sand10cm/s(Crucianellietal.,2013;McGloneetal.,2014).Therefore,weusedaninstrumentexplicitlydevelopedtodistributepreciseC-Tstimuli(Figure1)andspecificallyprogrammedfortheIBstask. FIGURE1 Figure1.InteroceptiveStimulator. UnmyelinatedC-fibertactileafferentsareaspecifictypeoffibersthatcanbefoundinnotglabrousskin,constitutingasecondarytouchsystemthatprojectsintheAIC(Olaussonetal.,2002).Theyhavebeenspecificallyidentifiedinthefacialskin(Nordin,1990)andintheforearm(Vallboetal.,1995,1999;Wessbergetal.,2003).Theyarereceptivetolowforceandlowvelocitystrokesstimuli(Ackerleyetal.,2014a,b).TheyexhibitaparticularfiringbehaviorwithandinvertedUrelationshipwithstrokevelocity(Lökenetal.,2009),atendencytofatigue(Iggo,1960;Wessbergetal.,2003)andanafter-dischargepatternthatmaypresentsecondarycharacteristicsuchasdelayedacceleration(Vallboetal.,1995,1999). Forsuchreason,theinteroceptivestimulatorhasbeendesignedtoprovidecontinuousinteroceptivestimuliontheforearm,accountingforallC-Tafferentsfactors.C-Tafferentsshowedtheirmaximalmeanfiringfrequencyatslowstrokingvelocityof3cm/s(Ackerleyetal.,2014a),thustheinteroceptivestimulatorwassettomovethebrushtipattheexactspeedof3cm/s(±0.5cm/s).Thebrushtiphadanovalshapeareaof≈35mm2,tomatchthereceptivefieldofahumanC-Tafferent(Wessbergetal.,2003;LiljencrantzandOlausson,2014).Thebrushusedaconstantforce<2.5mNthatisreportedasC-Tthresholdbydifferentauthors(Nordin,1990;Vallboetal.,1999;Macefield,2009),measuredaccordingtoVallboetal.(1999).Furthermore,thebrushdesignhasbeenspecificallydevelopedtoavoidfatigueandinexcitability(Iggo,1960;Wessbergetal.,2003).Asamatteroffact,C-Tafferentsdecreasetheirfiringratetozeroafter5sofcontinuousstimulation(LiljencrantzandOlausson,2014).Therefore,thebrushtipmovedinacircularpattern(10cmoftotallength)atspecificvelocityof3cm/splusalinearvelocityof0.5cm/s.Consideringcircularpattern,receptivefieldarea,brushtipdimensions(8.6×4.1mm)andstrokesvelocity,asingleclusterofC-Tafferentsreceivedstimulationonlyfor≈0.3s(0.28s)withinasinglerevolution,widelybelowthe5slimit.Therestspanbetweenfieldstimuliallowedpossibleafter-dischargestobeexpressedwithintheactivetestduration.Furthermore,6srestingphasebetweensingletrialsand1minrestingphasebetweenstimulationblocksensuredanacceptablerecoveryoftheC-Tafferentfields.Delayedaccelerationdidnothaveaparticularrelevanceforourdesign,consideringthatisnotassociatedwithsubjectivesensations(Vallboetal.,1995,1999). InteroceptiveBufferSaturation(IBs)Index TheIBstaskisbasedontheTactileEstimationTask(TET)forspatialrecognition,buttheprotocolisadaptedtotemporalestimation(Krameretal.,2011),thusprovidingasimpleandnon-invasiveproceduretoassessthedegreeofestimationofdurationoftheinteroceptivestimulus.Thetaskconsistsindeliveringinteroceptivebrushstrokestosubject’sleftvolarforearm,andsuccessivelyaskingforverbaltimeestimation(VET)ofthetimepassed.ThechoiceofVET1isduetoitseffectivenessinprobingtimeperceptionrelatedtovisual,auditory(GilandDroit-Volet,2011)andtactiledimensions(Ogdenetal.,2015b)assessingforalterationsinpulserateswithinthepacemaker-accumulator(Mionietal.,2016).Previousstudiesfocuseduponinducingdistortionsintheinnerflowoftime,troughexternalinductivestimuli.Conversely,IBsindexwillusethenaturalflowoftimeinsidetheinteroceptivematrixtoprobethesaturationofinteroceptivebuffer. Previousstudiesregardinginteroceptivetouchutilizedstimulationatdifferentvelocity(>20cm/s)ordifferenttargetsites(i.e.,palmsofthehands)ascontrolprocedures.ThesecontroltasksrelyuponA-fibersstimulationandthesefibersareselectivelyactivatedbyhighvelocities/highpressurestimuliorselectivelypresentinthepalmofthehands(Ackerleyetal.,2014a,b;LiljencrantzandOlausson,2014;McGloneetal.,2014).Nonetheless,thesekindofcontrolconditionswerenotsuitableforthepresentstudydesignduetothefactthatperceiveddurationdependsonperceivedspeed(Tomassinietal.,2011),excludingthepossibilitytousefaststimuli(speed>20cm/s)ascontrolforinteroceptivetouch(Crucianellietal.,2013;Ackerleyetal.,2014a).Additionally,slowbrushstimulionthepalmofthehandsshowedhedonic(parasympathetic)velocity-independentvalence(Ackerleyetal.,2014b),whichcouldcompromiseIBstaskdesign.Moreover,differentclinicalsubjectsexhibiteddeficitsintactileperceptionconnectedtoA-fibers(Keizeretal.,2011,2012;Stantonetal.,2013;Catleyetal.,2014),thusA-fibersstimulationcannotbereliablyusedascontrolprocedureinperspectiveofIBsindex.Therefore,commonaudioandvisualtimeestimationtaskswereperformedascontrolproceduresuponseparatesensorymodalities. Subjectswereseatedinachairinacomfortableroomwhiletheclinicianexplainedtheexperiment.Theywereinstructedtogivea“subjectivetimeestimationofthestimulation”.Theywereinstructednottocountthetimepassing,topayattentiontothefeelingofthestimulationandtoclosetheireyesfortheentiredurationoftheprocedure.Toavoidcounting,cliniciansuggestedfocusingonthephysicalsensationofthestimulation.Subjectswereinstructedthatstimulicouldlastbetween“1and30sapproximately”,toavoidlevellingunderestimationeffect(Ogdenetal.,2015b).Subjectslaidtheirleftarmonthetableinfrontoftheclinician,bareskin(Tsakirisetal.,2011;Ackerleyetal.,2014b).Theclinicianbegantheexperimentstartingthetrainingblockonthestimulatorprogramdeliveringthreebrushstimuliof7,21,and15s,allowingthesubjecttofamiliarizewiththeprocedure.Nofeedbackswereprovidedforeffectivedurationsorforperformances.Aftereachstimulus,apauseof6sallowedcliniciantoaskthesubject,“Howmanysecondsdoyoufeelthestimuluslasted?”Afterthetrainingprocedure,clinicianstartedtheexperimentaltaskwithrandomizedtimedurations.IBsindextaskdeliveredstimulifrom8sto18s,atfixedintervals(8,10,12,14,16,18).Theexperimentaltaskprovidedsixrandomizedpredeterminedstimuliperblock,forthreerandomizedblocks.Partialaccuracyindexforeachtimeintervalwascalculatedwiththefollowingformula:1/3∑((timeestimation−realtime)/realtime).Totalindexwascalculatedasmeanofpartialindexes. AudioandVideoTimeEstimation Audioandvideoestimationtaskswerecommontasksfrequentlyusedandwelldescribedintheliterature.FollowingKrameretal.(2011),audiotaskpresentedaseriesofaudioamplitude-steadycomplextones.VideotaskreplicatedproceduresfromWeardenetal.(1998)substitutingtoneswitha4×4cmlightbluesquarepresentedonaniPad.Stimulidurationswere100,200,500,1000and3000msreplicatedsixtimeseachandpresentedinrandomorder.Audiotaskhadatrainingprocedureof1000,300and1500ms.Videotaskhadatrainingprocedureof1500,1000and500ms.Subjectswerenotinformedaboutdurationsorperformances(Weardenetal.,1998;Grondin,2010;Krameretal.,2011)buttheywereinformedthatstimulicouldlastbetween50msand4000ms(Ogdenetal.,2015b).Aftereachstimulussubjectswrotetheestimateddurationinmillisecondsonadatacollectiongrid.Accuracyindexeswerecalculatedwiththefollowingformula:1/6∑((timeestimation−realtime)/realtime).Totalindexwascalculatedasmeanofpartialindexes. StatisticalAnalyses ToverifyunderestimationofinteroceptiveC-Tstimuli,aseriesofonesamplet-testwereusedtodetermineifmeantimeestimationforeverysingleintervaldifferedsignificantlyfromrealtimevalues.Thesameprocedurehasalsobeenappliedtoaudioandvideomeanestimations. ArepeatedmeasuresANOVAwasrunforIBspartialindexesbetweenfirst,secondandlaststimulationblocktoverifythatIBstaskdidnothaveanyeffectonthebuffer. ArepeatedmeasuresANOVAwasrunforIBs,audioandvideoaccuracyindexestoidentifysignificantdifferencesbetweenaccuracyverbalestimationscoresindifferentsensorymodalities.Bonferroniposthocwasruntoidentifydifferencebetweengroups. Duetoknownlimitations(Dunnetal.,2010)inherentassessmentscalesused,differentfactorstructureshavebeenimplementedtobetterexplorerelationshipbetweenvariables.Specifically,analysesimplementedatwo-factorsstructureforBDI-IItoexploresomaticandcognitivedepressionfactors(Steeretal.,1999;Storchetal.,2004),andafour-factorsstructureforSTAItoexplorethepresenceandtheabsenceofanxietyelements,bothinstateandtraitdimensions(VigneauandCormier,2008).Furthermore,scatterplotgraphsandliteratureregardinginteractionbetweeninteroceptionanddepression(Dunnetal.,2007,2010;Pollatosetal.,2009)suggestedaquadraticnegativerelationshipbetweenBDI-IIsomaticfactorandIBs. Correlationanalyseswererunforvariablesofmaininterest.Moreover,amultipleregressionanalysiswasconductedwithIBsindexasdependentvariableandIAc,EDIDTsubscaleandBDI-IIsomaticsymptomsaspredictors. Followingliteraturesuggestions(Pollatosetal.,2009;Dunnetal.,2010),asecondmultipleregressionanalysiswasconductedwithIBsindexasdependentvariableandIAc,EDIDTsubscale,BDI-IIsomaticsymptomsandinteractionbetweenthesomaticcomponentofBDI-IIandthepositivefactorofSTAI-Saspredictors.Allvariableswerecenteredbeforeenteringtheregressionanalysis.ThepositivefactorofSTAI-SandthesomaticfactorofBDI-IIwerealsoz-standardizedbeforecalculatingtheinteractionterm.Allthelowleveltermswereleftintheregression,aspermethodologicalrecommendations(Aikenetal.,1991).Residualplotswerecheckedalongwithnormalityforobservedstandardizedandunstandardizedresiduals.ThesameregressionanalyseswerealsoconductedwithaudioandvideoaccuracyindexesinsubstitutionofIBsindex. Results SamplePsychologicalCharacteristics TotalsampleofN=30showedhighlevelsoftraitanxiety(mean=42.90,SD=9.732)andmoderatetohighlevelofstateanxiety(mean=35.80SD=7.406).Resultswerecomparabletootherpreviousstudies(Aktekinetal.,2001;Pollatosetal.,2007b,2009). Depressivesymptomswerehigher(mean=7.60,SD=5.157)thanprevioussamplesininteroceptivestudies(Pollatosetal.,2009)withsubjectsinrangeofmildclinicaldepression(Steeretal.,1999;Storchetal.,2004)allowingustomeaningfullyexplorerelationshipwiththisvariable. Nonetheless,depressivesymptomslevelswerecomparabletonormativedataforsimilarpopulations(Storchetal.,2004).EDI-3subscalesassessedmoderaterisksofEDspecificallyrelatedtoBD(mean=12.77,SD=7.938;BD)andDriveforThinness(mean=7.47,SD=6.564;DT).Severalsignificantcorrelationswerefoundbetweenpsychometricvariables.ResultsaresummarizedinTables1,2.ScatterplotdistributionsareprovidedinFigure2. TABLE1 Table1.Samplecharacteristicsandpsychologicalassessment. TABLE2 Table2.Correlationanalysesfornormallydistributedvariablesofmaininterest. FIGURE2 Figure2.Scatterplotdistributions.IBs,interoceptivebuffersaturationindex;IAc,interoceptivecardiacaccuracy;EDI_DT,EDIdriveforthinnessrisksubscale;Audio,Audioaccuracyindex;Video,videoaccuracyindex;BDI,BeckDepressioninventory;STAI_T,STAItraitanxiety;STAI_S,STAIstateanxiety. InteroceptiveAccuracy Interoceptivecardiacaccuracy(Schandry,1981)isameasureofheart-ratedetectionability,andthissensitivityhasbeencorrelatedwithactivationintheanteriorinsula(Pollatosetal.,2007a)andprovidedastandardmeasureofinteroceptiveawareness(Garfinkeletal.,2015).IAcmeanscorewas0.473(SD=0.231)andmedianwas0.50.IAcsignificantlypositivelycorrelatedwithIBsindex(r=0.504,p=0.005).ResultsaresummarizedinTable2. InteroceptiveBufferSaturationIndex Ashypothesized,healthysubjectssignificantlyunderestimateddurationsofinteroceptivestimuli.Meanscoreswerenormallydistributed.Aseriesofonesamplet-testshowedsignificantlyunderestimationofmeantimeperceptionofinteroceptivestimuliforalltimespans:8s(t(29)=−7.396,p<0.001,d=−1.35),10s(t(29)=−5.628,p<0.001,d=−1.02),12s(t(29)=−8.162,p<0.001,d=−1.49),14s(t(29)=−7.004,p<0.001,d=−1.27),16s(t(29)=−6.955,p<0.001,d=−1.27),18s(t(29)=−7.111,p<0.001,d=−1.298).ResultsaresummarizedinFigure3. FIGURE3 Figure3.Meantimeestimationsofinteroceptivetactilestimuliacrossdifferenttimespans.InteroceptiveBuffersaturation(IBs)VET,meanverbalinteroceptivetimeestimation.*p<0.05,**p<0.01,***p<0.001. Ashypothesized,IBstaskdidnothaveanymanipulativeeffectonthebuffer,confirmingtheeffectivenessofthetaskasassessmentinstrument.ArepeatedmeasuresANOVAshowednostatisticallysignificantdifferencesonpartialIBsindexesbetweenfirst,secondandlaststimulationblock(F(2,58)=0.142,p=0.868,ηp2=0.005).ResultsindicatedthatIBstaskdidnotaltersubjects’endogenousbaseline2. Ashypothesized,Pearson’scorrelationanalysesshowedasignificantlypositivelinearrelationshipbetweenIBsandIAc(r=0.504,p=0.005)andsignificantlynegativelinearrelationshipbetweenIBsandEDIDriveforThinness(r=−0.375,p=0.041).ResultsaresummarizedinTable2. Scatterplotandliterature(Dunnetal.,2007,2010)suggestedaquadraticrelationshipbetweendepressionandinteroceptiveprocessing.Ashypothesized,IBscorrelationwithaquadratictermofBDI-IIsomaticfactorapproachsignificanceforanegativerelationship(r=−0.358,p=0.052). AmultipleregressionanalysiswasconductedwithIBsindexasdependentvariableandIAc,EDIDriveforThinnessandquadratictransformationofBDI-IIsomaticfactoraspredictors.Sampledimensionassuredanadequatepower(Harrell,2015)fortheanalysis.Ashypothesized,variablessignificantlypredictedIBs(R2=0.443,F(3,26)=6.880,p<0.001).BetastandardizedcoefficientsindicatedthatIAcsignificantlypositivelypredictedIBs(β=0.420,p=0.009)whileEDIDriveforThinness(β=−0.306,p≤0.05)andsomaticdepressivefactorofBDI-II(β=−0.324,p≤0.05)3significantlynegativelypredictedsaturationlevelsintheinteroceptivebuffer. Toexplorerelationshipbetweenanxietyandinteroceptivebufferlevels,asecondmultipleregressionanalysiswasconductedwithIBsindexasdependentvariableandIAc,EDIDriveforThinness,BDI-IIsomaticquadratictransformationandinteractionbetweenthesomaticcomponentofBDI-IIandthepositiveSTAI-Sfactoraspredictors(Pollatosetal.,2009;Dunnetal.,2010;PaulusandStein,2010).VariablessignificantlypredictedIBs(R2=0.529,adjustedR2=0.406,F(6,23)=4.306,p<0.005).IAcpositivelypredictedsaturationlevelsinthebuffer(β=0.465,p=0.005)whileEDIDriveforThinness(β=−0.345,p=0.028)andBDI-IIsomaticfactor(β=−0.394,p=0.018)significantlynegativelypredictedIBs.InteractiontermbetweensomaticBDI-IIfactorandpositiveSTAI-Sfactorapproachedsignificance(β=0.318,p=0.083).Samplesizewasslightlyunderpoweredforthisregressionmodel,nonethelessmethodologicalrecommendationsindicatedthatmultipleregressionisquiterobusttosmallsampleifadjustedR2isconsideredinsubstitutionofR2(AustinandSteyerberg,2015). AudioandVideoTimeEstimation Onesamplet-testswereperformedbetweenaudioandvideotimeestimationsandrealtimespans.Wilcoxontestswereperformedfornot-normallydistributedvariables.Audioestimationsdidnotshowanystatisticallysignificantdifferencefor100,200,1000and3000mstimespans(p>0.05)comparedtorealtimespans.Subjectssignificantlyoverestimated500msaudiostimuli(t(29)=3.958,p<0.001,d=0.722).Videoestimationsdidnotshowanystatisticallysignificantdifferencefor100,500,1000mstimespans(p>0.05)comparedtorealtimespans.Subjectssignificantlyoverestimated200msvideostimuli(t(29)=2.242,p=0.033,d=0.409)andsignificantlyunderestimated3000msvideostimuli(t(29)=−3.032,p=0.005,d=−0.553).ResultsaresummarizedinFigure4.Onesamplet-testsforpairedsamplewereperformedbetweennormallydistributedaudioandvideotimeestimations.Wilcoxontestswereperformedfornot-normallydistributedvalues.Subjectsjudgedaudiostimulisignificantlylongerthanvideostimuliintimespans500,1000and3000ms(p=0.005).At-testforpairedsamplewasperformedbetweenaudioandvideoaccuracyindexeswithoutanystatisticallysignificantdifference(p=0.232).Audioandvideoaccuracyindexessignificantlypositivelycorrelated(r=0.588,p=0.001).ResultsaresummarizedinTable2.Regressionanalysesforaudio(p=0.490)andvideo(p=0.478)accuracyindexeswereperformedwithIAc,EDI_DTandBDI-IIsomaticfactor.Bothmodelsfailedtoreachstatisticalsignificance4. FIGURE4 Figure4.Meantimeestimationofaudioandvideostimuliacrossdifferenttimespans.AudioVET,meanverbalaudiotimeestimation;VideoVET,meanverbalvideotimeestimation.*p<0.05,**p<0.01,***p<0.001. RelationshipBetweenMeasures ArepeatedmeasuresANOVAwithaGreenhouse-GeissercorrectionwasperformedbetweenIBs,audioandvideoaccuracyindexes(factoraccuracy).Resultsreportedastatisticallysignificantdifferencebetweenaccuracyindexes(F(1.806,52.371)=16.037,p<0.001,ηp2=0.356).PosthoctestsusingBonferronicorrectionrevealedthatIBsaccuracyindexwassignificantlyunderestimatedcomparedtobothaudio(p<0.001)andvideo(p=0.003)accuracyindexes.Nostatisticallysignificantdifferenceswerefoundbetweenaudioandvideoaccuracyindexes(p=0.697)althoughaudiostimuli(mean=0.241,SD=0.080)werejudgedlongerthanvideoones(mean=0.126,SD=0.116). Severalstatisticallysignificantcorrelationswerefoundbetweenpsychometricvariables.ResultsaresummarizedinTable2. Discussion Thestudyexploredtheconnectionbetweentimeperceptionandinteroceptiveprocessing,proposingtheIBsindexasanovelconstructabletoprovideinformationaboutco-activeprocessingwithintheinteroceptivematrix(AIC;Craig,2002,2003,2009).TheIBsindexrelieduponaverbalestimationtaskofinteroceptivestimulisentthroughthesecondarytouchsystemconnectedtothelaminaIspinothalamocorticalpathway.Bidirectionaldistortionsinthesubjectivetimeperceptionofthesestimuliprovideinformationaboutsympatheticandparasympatheticactivityinthecortex.Theinteroceptivebufferisakeycomponentoftheinteroceptivematrixanditconstantlyprocessesandcomparesinformationarisingfromthebody,creatingbodilymeta-representationsshapedupontheasymmetricalrelationshipbetweentherightandtheleftinsula.Understandingsaturationlevelswithinthebuffercanprovidemeaningfulinsightaboutthisrelationship,whereashighlevelsofsaturationmayindicatelargeamountofsympatheticstimuliprocessedintherightinsula,whileoppositeresultsmayindicatethattheinteroceptivesystemisactuallyprocessingalowamountofhighsaliencesympatheticstimulifromthebody. Recentevidenceidentifieddeficitsintheinsulaconnectedwithradicallydifferentpsychopathologicalconditions.Chronicpain(Schaeferetal.,2012;Weissetal.,2014;Duscheketal.,2015),depression(Dunnetal.,2007,2010;Pollatosetal.,2009;Sprengelmeyeretal.,2011;SlizandHayley,2012;Stratmannetal.,2014),eatingdisorders(Pollatosetal.,2008;Fischeretal.,2016)andseveralotherconditions(Rossoetal.,2010;WylieandTregellas,2010;Hattonetal.,2012;Naqvietal.,2014)comprisedalterationswithintheinteroceptivenetwork.Nonetheless,itisnotclearlyunderstoodhowradicallydifferentconditionscanimpairtheinsulanetworkinasimilarway. Inourpreviouswork(DiLerniaetal.,2016a),wesuggestedthatIBsmayprovideabettermeasureofinteroceptiveprocessingcomparedtootheravailableindexes,becauseitpermitstodisentanglethedifferentialeffectsofinteroceptivealterationswithinthematrix.Conceptualizingthesealterationsintermsofbuffersaturationlevelssuggeststhathighlevelsofnegativearousingstimulimayimpairinteroceptiveprocessingthroughwidespreadinterferences(i.e.,interoceptivenoise),whereaslowstimuliprocessingmayreducebodyawareness(i.e.,interoceptivesilence),withbothconditionsleadingtodeficitsininteroceptiveperception. Thedesignofthestudydidnotincludenon-interoceptivecontrolstimuli,asexplainedinthe“MaterialsandMethods”section.Thiswasduetothenatureofthetaskweadopted,inwhichdifferentstimulationspeeds—whicharenecessarytoperformnoninteroceptivestimulation—wouldhaveyieldedincomparableresultsinatimeestimationtask.AsecondequallyimportantimplicationthatdefinedIBsdesignisalsothatinteroceptivetactilestimuliareneverexclusivelyrelatedtoC-Tfibers.NeurophysiologicalevidenceindicatedthateveryC-Trelatedstimulusalwayscomprisesaconcomitantactivationofmyelinatedtactilefibersprocessedbythesomatosensorycortex(Roudautetal.,2012).AlthoughamechanicalstimulationsuchastheonedeliveredbytheinteroceptivestimulatorcanbetunedtoproducemassivepeakactivationsinC-Ttactileafferents,everyinteroceptivetactilestimulusalwayspartiallyactivatesothermyelinatedfibers(Crucianellietal.,2013;Ackerleyetal.,2014a,b).Thereforeanon-interoceptivecontroltaskwouldhaveyieldedincomparable,albeitinformative,resultsfromIBsperspective.Thiswas,amongothers,oneoftheprominentreasonsaccordingtowhichwehavechosendifferentsensorymodalities(audioandvideo)ascontrolprocedures;alsoinagreementwithprotocolstostudyemotionsandtimeperceptionthatusuallycomparedresultsacrossdifferentunrelatedperceptivesystems.Nonetheless,consideringIBsdesign,onlycorrelationsbetweentheindexwiththeSchandry’staskandthequestionnairescanbeusedforaninterpretationregardinginteroceptiveprocesses. Ashypothesized,resultsconfirmedthathealthysubjectssignificantlyunderestimatedthedurationofparasympatheticinteroceptiveC-Tstimuli,comparedtoactualtimespans.ResultsconfirmedpreviousfindingsaboutC-Tprocessing(Leonardetal.,2014;Ogdenetal.,2015b),supportingthemethodologyusedinthepresentstudyandtheeffectivenessofthedevicedeveloped.Comparingourresultswithpreviousstudiesaboutsympatheticstimuli(Droit-Voletetal.,2011;Ogdenetal.,2015a)alsoendorsedCraig’semotionaltimeasymmetryframeworkandconsequentlytherationalebehindtheIBsindex.SignificantunderestimationofC-Tstimulisuggestedthathealthysubjectswithoutdominantsympatheticactivationtendtohaveareducedstimuliprocessingintherightinsulabuffer,matchingalowpulseratewithintheinteroceptiveinternalclockthereforeexperiencingacontractionintimeperceptionduetoalackofsalienceinbodilyarousal. Ashypothesized,IBsindexpositivelycorrelatedandwaspositivelypredictedbyinteroceptivecardiacaccuracy(IAc).ThisresultprovidedstrongsupportregardingthevalidityofIBsindexduetotheontologicalconnectionbetweenthebufferandthedegreeofactivationoftheinsula(Pollatosetal.,2007a).Nonetheless,correlationwassufficientlydistincttosuggestthatIBsindexandinteroceptivecardiacaccuracyaretwodifferent,albeitintertwined,constructs. IBsindexnegativelycorrelatedandwasnegativelypredictedbyEDI-3DriveforThinnesssubscale,suggestinganinterestinginsightregardingtheconnectionofthebufferwithbodyperception.IAcissignificantlyreducedinclinicalsubjectswithanorexianervosa(Pollatosetal.,2008);nonetheless,thenatureofthesedeficitsisnotreallyunderstoodeventhoughtheycanbeequallyfoundinradicallydifferentconditions(DiLerniaetal.,2016b).Inoursample,wefoundnosignificantcorrelationbetweenIAcandDriveforThinness,asexpectedforhealthyfemalesthatdidhaveneitherinteroceptivedeficitsnoranorexianervosa.Conversely,wefoundanegativecorrelationbetweenIBsandDriveforThinnessrisk,suggestingthatpredispositionforanorexianervosacanbeconnectedtolowsaturationlevelswithininteroceptivebuffer.Consideringourresults,lowsaturationlevelsinthebuffer(IBs)canbedescribedasahypo-saturationconditionwhereastheinteroceptivematrixprocessesloweramountsofhighsalience(i.e.,hunger,thirstetc.)stimulifromthebody.Thisimpairedprocessingactivitycanthereforeleadtopervasivealterationsinbodyperceptionand,ultimately,totheinteroceptivedeficitsandbodilydistortionsidentifiedinanorexianervosa(Pollatosetal.,2008).RecentfMRIevidenceshowedconsistentalterationsintheinsulanetworkbothonfunctional(Gaudioetal.,2015;Kerretal.,2016)andstructurallevel(Gaudioetal.,2017)indicatingimpairedprocessingofhighsaliencebodilystimuliinanorexianervosa(Wierengaetal.,2015),thereforesupportingourresults.Moreover,anorexicsubjectsshowednoimpairmentinatimedurationtaskconnectedtonon-interoceptiveneutraltactilestimuli(Spitonietal.,2015)fosteringtheconclusionthatIBsresultsarestrictlyconnectedtoprocessingwithininsulanetworkanditsrelationshipwithbodyperception. DepressionandanxietysymptomsdidnotshowadirectlinearcorrelationneitherwithIBsnorIAcaccuracyindexes,partiallydivergingfrompreviousliteratureresults(Pollatosetal.,2009).Thisdifferencecouldbedueeithertolimitedsampledimensioninourstudyortothelackofsensitivityofthetwoassessmentscalesweused,whichwouldbeinkeepingwithotherpreviousresults(Dunnetal.,2010).OurresultsindicateapooreffectivenessofBDI-IIandSTAIquestionnairestoassessinteroceptivedimensionsofdepressionandanxiety.Dunnetal.(2010)suggestedthatBDI-IIandSTAIquestionnairesmayhaveconfoundingoverlappingconstructs,moredirectlyconnectedtoglobalseveritymeasuresandthereforetheymightberelativelyinappropriatetomeasureinteroceptivecomponents.Ourfindings,relatedtoasmallalbeitrepresentativesample,confirmedthisperspectivealsothroughasignificantcorrelationbetweenthescales. Toeffectivelyassessbodilycomponentsofdepressionandanxiety,wethereforeimplementedseveralwellvalidatedfactorstructures.BDI-IIwasdividedintotwo-factorsconnectedtosomaticandcognitivecomponentsofdepression(Steeretal.,1999;Storchetal.,2004).STAIwasdividedintofour-factorsthatdescribedpositiveandnegativeitemsofanxiety,bothinstateandtraitconditions(VigneauandCormier,2008). Consequently,wefocusedonthesomaticfactorofBDI-IIandamoreaccurateanalysisidentifiedanot-linearnegativerelationship(Dunnetal.,2007)betweendepressivesomaticsymptomsandIBslevels.Ourresultssuggestedthatdepressionnegativelyinterferedwithsaturationlevelsinthebufferpromotingahypo-saturationconditioninwhichdepressivesomaticcomponentsappearedtoberelatedtoadiminishedprocessingofhighvalencearousingstimuliintherightinsula.Theseresultsarealsosupportedbypreviousneurophysiologicalevidencethatindicatedahypo-response(Wiebkingetal.,2015)alongwithreductioningraymattervolumeoftheinsula(Sprengelmeyeretal.,2011;Stratmannetal.,2014)inmajordepressivedisorders. Inourstudy,anxietymeasuredthroughSTAIquestionnairefailedtoprovidestatisticallysignificantresults.Thiscouldbeduetothesmallsamplesizebutmoreprobablytothegeneralconstructwithinthescalethatisprimarilyorientedtoglobalseveritymeasuresratherthananxietypositivearousalsymptoms(Dunnetal.,2010).Followingliteraturerecommendations(Pollatosetal.,2009;Dunnetal.,2010;PaulusandStein,2010),wenonethelessexploredtheinteractionbetweensomaticdepressivefactorandpositivestateanxietyfactor.Theinteractionapproachedapositivestatisticalsignificancesuggestingsomefurtherconsiderationsthat,nonetheless,mustbeconsideredwithcaution.Specifically,comorbiditybetweensomaticdepressiveandanxietysymptomsappearedtohaveamoderatelypositiveinfluenceuponsaturationlevelsinthebuffer,suggestingabiologicalprevalenceofsympatheticarousalpreferentiallyprocessedintherightinsula.Severalauthorsbackedthisperspectivethatreliedupontheroleofhigharousalstimuliintheoptimalfunctioningoftheorganism(Jänig,2008;Wiechetal.,2010;Uddin,2015)supportingthenotionofanemotionaladvantageinperceptionprocessingforhomeostaticregulatorypurposes,whichfosterenhancedattentiontobodilysignals(Ogdenetal.,2015a;YooandLee,2015). Interestingly,healthysubjectsdidnotsystematicallyunderestimatedurationsofaudioandvideostimuli.Moreover,asignificantdifferencebetweenIBs,audioandvideoaccuracyindexessuggestedsecondaryimplicationsregardingtimeperceptiontheories.Specifically,ourfindingsindicateddifferentpacemaker-accumulatorunits,connectedtodifferentsensorymodalities.Audioandvideoindexesshowedapositivesignificantcorrelationbetweeneachother,butfailedtosignificantlycorrelatetointeroceptivetimeperceptionindicatingseparatedtimeprocessingpathways.Moreover,regressionanalysisalsofailedtobesignificantfortheaudioandvideoaccuracyindexes,suggestingthataudioandvideotimeestimationprobablyreferredtodifferentprocessingcircuits,partiallydistinctfromtheinteroceptivesystem.Theseresultsaresupportedbyrecentliterature(Mionietal.,2016)accordingtowhichtimeperceptionindepressionshowedinconclusiveresults(ThonesandOberfeld,2015)alongwithnot-inductivetimestudiesinanxietythatalsoprovidedmixedresults(Lueck,2007;Brown,2016). Apossibleexplanationforthesignificantdifferencebetweenaudio,videoandIBsaccuracyindexescanberelatedtothedifferenttimespansused,suggestingthattimeestimationintherangeofmillisecondsisnotsusceptibletothesamepsycho-physiologicalcomponentsthatcontributetoIBsindex.Nonetheless,differentstudiesusedtimespanswithinmillisecondsrangetoidentifyaparasympathetic(Ogdenetal.,2015b)andsympathetic(Droit-VoletandMeck,2007;GilandDroit-Volet,2011,2012;Droit-Voletetal.,2013;Ogdenetal.,2015a;ThonesandOberfeld,2015;YooandLee,2015;Mionietal.,2016)influenceupontheinternalclock.Moreover,timespansintherangefromsecondstosubsecondshaveoftenbeenconsideredconnectedtothesametimeperceptionmechanisms(Church,1984)whereasevidencefromliteraturefoundnodifferenceintimeintervalsasafactor(Macaretal.,2002).Furthermore,evidencefromcomputationalneurosciencesuggestedthattimeestimationsfrommillisecondtosecondsrelyuponthesameencodingprocessingpatterns(KarmarkarandBuonomano,2007).KarmarkarandBuonomano(2007)alsosuggestedthatshorttimeintervals—astheloweronesintheaudioandvideoestimationtasks—arealsoprobablyconnectedtoanonlineartimemetricencodedinlocalneuralnetworksandthereforetheyshouldbeevenmoresensibletothepsychophysiologicalvariablesthatcontributetoIBsindex.Inasimilarmanner,Craigsuggestedthattheinteroceptivenetworkmight“provideabasisforthehumancapacitytoperceiveandestimatetimeintervalsintherangeofsecondstosubseconds”(Craig,2009)alsosupportingthepossibilitytocoherentlyexploredifferenttimespans.Thisevidencesuggestedthattimespansinmillisecondsrangeshouldbesensibletoalterationsinbodilyprocessing,thusexcludingthedurationofthestimuliasafactorandallowingthedesignofthestudytoselectthemostappropriateandthemostsensibletimeintervalsforeachsensorymodality. Consideringourresults,itisthereforepossiblethattimeperceptionisprocesseddifferentlydependingonthesensorymodalityinvestigatedandthattimeinformationcollectedbyseveraldifferentinternalclocksaresub-sequentiallymergedinaglobaltimeperceptionawareness,composedbydifferentelementsaccordingtotheircontextualsalience.Thishypothesisremainstobetestedinfuturestudies. InteroceptiveBuffer,ActiveInferenceandPredictiveCoding Fromamoreformal,predictivecoding(orinteroceptiveinference)perspective,buffersaturationcanbeunderstoodintermsofwell-knownmechanismsofprecision(orgain)controlduring(Bayesian)inference.Oneessentialroleofinteroceptiveinferenceisintegratingvariousinteroceptivesignalstoformanestimateofthestateofthebody(e.g.,heartrateaswellasgastricandrespiratorysignalstoassessmomentaryfatigueorfear),basedonwhichtheorganismcantakeadaptiveaction(Pezzulo,2014;Pezzuloetal.,2015).Importantly,whileformingthisestimate,thereliabilityofalltheinteroceptivesignals(aswellasofpriorinformation)mustbeevaluated,too;signalsthathavehighersalienceorprecision(orloweruncertainty)areweightedmoreandhavehigherimpactontheinference,whereaslower-precisionsignalshavelesserimpactandinsomecasescanbealsodisattendedorignored—thusimplementingaformofprecision(orgain)controloverinteroceptiveprocessing.Withinthisframework,signalsthatarehighlysalientorhavehighbehavioralsignificance(e.g.,threats)wouldbeplausiblyaffordedahighgain,hencedominatingtheinferenceandreducingtheimpactofothersignals(aka,saturatingthebuffer).Thisisingeneralanadaptivemechanism,whichwouldaffordprioritytothemostimportantsignals;butinsomecases,itcanbecomemaladaptive.Forexample,expectingtheenvironmenttobetoovolatilemightleadtoover-samplingit(like,e.g.,inanxiety)andtoasystematicoverestimationoftheprecisionofsensoryandinteroceptivesignals.Conversely,otherpathologicalconditions(e.g.,anorexia)maybelinkedtointeroceptiveprecisiondown-regulation,andthustoasystematicallydiminishedprocessingofstimuliarisingfromthebody(aka,silencingoneofthechannelsofthebufferratherthansaturatingit).Thisframeworkwouldshedlightonthedifferentwaysinteroceptiveinferencecanbecomeaberrant,due(forexample)tothefallaciousup-ordown-regulationoftheprecisionofinteroceptive(orother)signals—andhowthisinturnwouldproducemaladaptivebehaviorthatisspecificofdifferentclinicalconditions(Fristonetal.,2014). ClinicalImplicationofInteroceptiveBufferSaturation IBsindexcanprovideinsightregardinginteroceptivealterationsinapparentlydifferentconditions,nonethelessthisknowledgemayserveotherpurposesbesidessimpleassessment.Specifically,pathologicalconditionswithanhyper-saturatedstatusmightpresentalterationsinbodilysignalsconnectedtoanoverflowofsympathetic-relatedstimuliinthebuffer(i.e.,interoceptivenoise)loweringtheaccesstootherinteroceptiveinformation(DiLerniaetal.,2016a).Conversely,hypo-saturatedconditionsmaybeconnectedtoageneralimpairmentofwholestimuliprocessingthatlimitedinputs(i.e.,interoceptivesilence)fromactuallyreachingAIC. Ifconfirmed,thisperspectivemayhaveimportantimplicationsbeyondassessment,foreseeingtheconceptof“interoceptivetreatments”.Asamatteroffact,clinicalconditions(i.e.,anxietyorchronicpain)characterizedbyanoverflowofsympatheticrelatedinteroceptivestimuli(i.e.,hyper-saturation)maybenefitfromaninteroceptiveparasympatheticstimulationwithlowvariancetopromoteco-activationoftheleftinsula,reducingprocessingintherightAICwiththeultimategoalofcontrastingsymptomsseverity.Conversely,ifaclinicalconditionwillshowhypo-saturationduetoablockthatimpairsinteroceptiveinformationtoactuallyreachtheinsula(i.e.,depressionoranorexianervosa),interoceptivetreatmentsbaseduponinteroceptivestimuliwithhighvariancecouldprovideawaytofosterhighsalienceprocessingintherightAIC,restoringacorrectaccesstobodilyinformation.Ifconfirmed,albeithighlytheoretical,theseperspectivescanprovideinnovativeinsightsintreatmentfields,forseveraldifferentpsychopathologicalconditions. Limitations Severallimitationsimpairedstudydesignandresults.Samplesizewasreduced,nonethelessconsecutivesamplingprovidedhighlyinformativedata,andliteratureconfirmedanadequatestatisticalpower(AustinandSteyerberg,2015;Harrell,2015)relatedtonumberofsubjectsandstatisticalanalysesperformed. Asolelyfemalesampleensuredcomparableresultsonsomatosensoryrelatedtests(Fillingimetal.,2009)andpsychologicalassessment(Garneretal.,1983;Clausenetal.,2011;Eshkevarietal.,2012)neverthelessthedesignofthestudydidnotexploreIBsinmalepopulation. Thestudyutilizedaudioandvideostimuliascontrolproceduresduetothefactthatsomaticnon-interoceptiveconditions(i.e.,differentvelocitiesordifferentbodylocations)werenotsuitablewithinIBsdesign.Thischoiceallowedustoexploretimeperceptionupondifferentsensorymodalities.However,theabsenceofsomaticcontrolstimulididnotallowustoexplorepossibledifferencesinsomaticnon-interoceptiveprocessing.Moreover,interoceptivestimulationalwayspresentsconcomitantactivationofAβreceptors(Ackerleyetal.,2014a,b;Ogdenetal.,2015b)thereforenon-interoceptivestimuliwithaparasympatheticcomponentmaycorrelatewithIBsindex.Theseproblemsmightbeaddressedbyusingreliablesomaticcontrols,suchasvibrationalstimulithatspecificallytarget(LiljencrantzandOlausson,2014)Paciniancorpusclesatafrequencybetween150Hzand–300Hz(Roudautetal.,2012).Nonetheless,thiskindofstimulationrequiresaspecificallydesignedprototypenotavailableduringthisstudy. BDI-IIandSTAIquestionnairespresentedseverallimitationsregardingconstructmeasures,overlappingtheoreticalrelevance,andeffectivenesstomeasureinteroceptivecomponents(Dunnetal.,2010).Inourstudy,theselimitationswerepartiallyaddressedthroughseveralfactorstructuresnonethelessadifferentmodelofanxietyanddepressioncouldprovidebetterassessmentofinteroceptivedimensions.Specifically,thetripartitemodelofmooddisorders(ClarkandWatson,1991)mightprovideamoreeffectiveframeworkforinteroceptiverelatedcomponents.ThismodelreliesupontheMoodandAnxietySymptomQuestionnaire(MASQ-S;Watsonetal.,1995;KeoghandReidy,2000)toassessseveraldimensionsconnectedtosymptomsofnonspecificgeneraldistress,symptomsspecifictodepressionandsymptomsspecifictoanxiety.Specifically,MASQ-SsubscalesAnxiousArousal(17items)andAnhedonicDepression(22items)mightprovidebetterresultscomparedtoglobalseveritymeasuresreportedbyBDI-IIandSTAI.Unfortunately,Italianvalidationoftheinstrumentwasnotavailableatthetimeofthisstudy. Lastly,literaturesuggestedthatbeliefandexpectationscanlimitSchandrytaskvaliditytoassessforinteroceptivecardiacawareness(Ringetal.,2015).Nonetheless,heartbeatperceptiontask(Schandry,1981)remainedthemostvalidateandmostreliableinstrumentforIAcassessment(Pollatosetal.,2007a;CritchleyandGarfinkel,2015;Garfinkeletal.,2015). ConclusionandFutureDirections Ourresultsprovidedapowerfultheoreticalinsightregardingtherelationshipbetweentimeperception,interoceptiveprocessingandpsycho-physiologicalconditions.DistortionsininteroceptivetimeperceptionrecordedbyIBsindexappearedtobefunctionofdifferentsympatheticandparasympatheticco-activationprocesseswithininsulacortex. Nonetheless,differentquestionsremaintobeexplored,promotingfutureresearchdirections.Specifically,itwillbefundamentaltotestIBsindexproposalondifferentpathologicalconditionsconnectedtoinsuladeficits,suchaschronicpain,anorexianervosaanddepressionalsocomparingresultstohealthysubjects’performances. Furthermore,IBsresultsmaysupporttheconceptof“interoceptivetreatments”asclinicalapplicationsforanewnon-pharmacologicaloptiontotreatavarietyofdisorderscharacterizedbyinteroceptivenetworkalterations.Thesekindsoftreatments,tailoreduponspecificdysregulationsoftheinsulacortex,mightprovidepowerfulinstrumentstoreducesymptomsseverityinthoseconditionsthatareresistanttopharmacologicalmedications,withoutanysideeffectorinteractionwithconcomitanttherapies(DiLerniaetal.,2016a;Rivaetal.,2016,2017).Interoceptivetreatmentsmaythereforeprovethemselvesaneffectiveoptiontopromoteabalancedfunctioningoftheorganismbothinclinicalandhealthypopulation,openingabrandnewfieldofmedicineandneuroscience. AuthorContributions DDL:conceptualization,investigation,writing—originaldraft,hardwareandsoftwaredevelopment.DDLandSS:methodology.SS,GP,EP,PCandGR:writing—review,editingandsupervision. ConflictofInterestStatement Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest. Acknowledgments SSandGRwerefundedbytheMIURPRINresearchproject“Unlockingthememoryofthebody:VirtualRealityinAnorexiaNervosa”(201597WTTM). Footnotes ^Ontheotherhand,wedismissedtimeproductionandreproductiontasksbecausethatareusuallydependentuponattentionandworkingmemoryprocesses“ratherthanvariationininternalclock”(Mionietal.,2016). ^IBsisproposedasanassessinginstrument;thereforewecheckedifthestimulationhadanykindofeffectuponsubject’stemporalperception.Weverifiedthisbyconfrontingmeanestimationsofthefirststimulationblockwithmeanestimationsonthelaststimulationblock.Aneffectoftheinteroceptivestimulationwouldhaveproducedvariationsintemporalestimationacrossblocks.Sincewedidnotobservesignificativedifferencesintimeestimationbetweenfirstandlaststimuli,acrossalltheprotocol,weconcludedthatthestimulationitselfdidnothaveanyimpactonsubject’sendogenoustimeperception. ^BDI-IIsomaticfactorquadratictransformation(β=−0.324,p=0.037)|ModelwithuntransformedtermR2=0.461,F(4,25)=5.337,p<0.003,IAcβ=0.420,p=0.01,EDI_DTβ=−0.308,p=0.05,BDI-IIsomaticuntransformedtermβ=−0.136,p=0.369,BDI-IIsomaticquadratictransformedtermβ=−0.303,p=0.053.ResidualsK-S>0.200,S-W=0.928. ^Modelwithuntransformedterm:Audioaccuracyindexp=0.611,Videoaccuracyindexp=0.288. 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Editedby:IrinaStrigo,UniversityofCalifornia,SanFrancisco,UnitedStates Reviewedby:MarcWittmann,InstitutfürGrenzgebietederPsychologieundPsychohygiene,GermanyJ.MichaelHerrmann,UniversityofEdinburgh,UnitedKingdom Copyright©2018DiLernia,Serino,Pezzulo,Pedroli,CipressoandRiva.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).Theuse,distributionorreproductioninotherforumsispermitted,providedtheoriginalauthor(s)andthecopyrightownerarecreditedandthattheoriginalpublicationinthisjournaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionorreproductionispermittedwhichdoesnotcomplywiththeseterms. *Correspondence:DanieleDiLernia,[email protected] COMMENTARY ORIGINALARTICLE Peoplealsolookedat SuggestaResearchTopic>