responses steady-state Characterization implant of cochlear artifacts in electrically evokedauditory Biomedical Signal Processing and Control

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BiomedicalSignalProcessingandControl31(2017)127–138

ContentslistsavailableatScienceDirect

Biomedical

Signal

Processing

and

Control

j ou rn a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / b s p c

Characterization

of

cochlear

implant

artifacts

in

electrically

evoked

auditory

steady-state

responses

Hanne

Deprez

a,b,∗

_,

_Robin

_Gransier

a

_,

_Michael

_Hofmann

a

_,

_Astrid

_van

_Wieringen

a

_,

Jan

Wouters

a

_,

_Marc

_Moonen

b

a_KU_Leuven,_Experimental_ORL,_Dept._{Neurosciences,}_Herestraat_49,₃₀₀₀_Leuven,_Belgium

b_KU_Leuven,_STADIUS,_Dept._Electrical_Engineering_(ESAT),_Kasteelpark_Arenberg_10,₃₀₀₀_Leuven,_Belgium

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received18March2016

Receivedinrevisedform23June2016 Accepted26July2016

Keywords:

Cochlearimplant(CI) CIstimulationartifacts

Electricallyevokedauditorysteady-state responses(EASSR)

Linearinterpolation Monopolarmodestimulation

a

b

s

t

r

a

c

t

Objective:Electricallyevokedauditorysteady-stateresponses(EASSRs)areneuralpotentialsmeasured

intheelectroencephalogram(EEG)inresponsetoperiodicpulsetrainspresented,forexample,through

acochlearimplant(CI).EASSRscouldpotentiallybeusedforobjectiveCIﬁtting.However,EEG

sig-nalsarecontaminatedwithelectricalCIartifacts.Inthispaper,wecharacterizedtheCIartifactsfor

monopolarmodestimulationandevaluatedatwhichpulserate,linearinterpolationoverthesignalpart

contaminatedwithCIartifactissuccessful.

Methods:CIartifactswerecharacterizedbymeansoftheiramplitudegrowthfunctionsandduration.

Results:CIartifactdurationswerebetween0.7and1.7ms,atcontralateralrecordingelectrodes.At

ipsi-lateralrecordingelectrodes,CIartifactdurationsarerangefrom0.7tolargerthan2ms.

Conclusion:Atcontralateralrecordingelectrodes,theartifactwasshorterthantheinterpulseinterval

acrosssubjectsfor500pps,whichwasnotalwaysthecasefor900pps.

Signiﬁcance:CIartifact-freeEASSRsarecrucialforreliableCIﬁttingandneuroscienceresearch.TheCI

artifacthasbeencharacterizedandlinearinterpolationallowstoremoveitatcontralateralrecording

electrodesforstimulationat500pps.

license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Acochlearimplant(CI)isanelectronicdevicethatcanrestore hearingin severelyhearingimpairedsubjects.ACIsystem con-sistsofthreemainparts:anexternalspeechprocessor,theimplant, andanelectrode arrayinsertedinthecochlea.Thespeech pro-cessorconvertstheincomingsoundtoanelectricalstimulation pattern,whichistransmittedtotheimplantviaaradiofrequency (RF)link.Theelectrodesstimulatetheauditorynervewithbiphasic charge-balancedpulses[1].Twostimulationmodesareoftenused,

Abbreviations: AGF,amplitudegrowth function;C,maximum comfortable stimulationlevel;CI,cochlearimplant;d,interpolationduration;D,STIMartifact duration;EABR,electricallyevokedauditorybrainstemresponse;(E)ASSRs, (electri-callyevoked)auditorysteady-stateresponses;ECAP,electricallyevokedcompound actionpotential;I,interceptoftheCIartifactAGF;ICA,independentcomponent analysis;PCA,principalcomponentanalysis;POD,programmingdevice;RF,radio frequency;RFartifact,RFcommunicationlinkartifact;STIMartifact,electrical stim-ulationartifact;T,thresholdstimulationlevel;,slopeoftheCIartifactAGF.

∗ Correspondingauthorat:KULeuven,STADIUS,Dept.ofElectricalEngineering (ESAT),KasteelparkArenberg10bus2446,3001Leuven,Belgium.

E-mailaddress:hanne.deprez@esat.kuleuven.be(H.Deprez).

dependingonthereturnelectrode:bipolarmodeforstimulation betweenintra-cochlearelectrodesandmonopolarmodefor stim-ulationbetweenintra-andextra-cochlearelectrode(s).Inclinical settings, pulses are oftendelivered at highrates in monopolar mode,whichrequireslessbatterypowerthanstimulationin bipo-larmode.Furthermore,thresholdlevelsvarylessoverstimulation electrodes with stimulation in monopolar compared to bipolar mode,resultingineasierCIﬁtting.

Sinceearlyimplantationisprovencrucialforspeechand lan-guagedevelopment (e.g.[2]), anincreasingnumber of severely hearingimpairedinfantsreceiveaCIwithintheﬁrstyearoflife. PriortoCIactivation,thethreshold(T)andmaximumcomfortable (C)stimulationlevelsaredeterminedbasedonbehavioral(verbal) feedback.Thisisparticularlychallengingininfantsand subjects whocannotgivereliablebehavioralfeedback.Insuchcases, objec-tiveCIﬁttingbasedonelectrophysiologicalmeasurementscould beused.

Objective CI ﬁtting based on electrophysiological measure-ments is currently under investigation. Transient responses to low-rate stimuli measured at the electrode-nerve interface (ECAPs)andatthebrainstemlevel(EABRs)havebeeninvestigated as objective measures for threshold estimation. However, the http://dx.doi.org/10.1016/j.bspc.2016.07.013

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Fig.1.ExampleofaCIartifactforS8,withaCIattherightside,measuredwith37HzAM900ppspulsetrainsatasubthresholdstimulationamplitude.Left:timeand frequencydomainsignalsatrecordingelectrodesTP8(ipsilateral)andTP7(contralateral),referencedtoCz.Right:spatialdistributionofspectralpoweratthemodulation

frequency,referencedtoCz.TheunitsofthetopographyplotaredBnV=20log10nV,where1␮Vcorrespondsto60dBnVand0.1␮Vcorrespondsto40dBnV.Noneural

responseisexpectedtobepresent,assubthresholdstimulationlevelswereused.

thresholdvaluesobtainedwiththesemethodsthatuselow-rate stimuliareonlymoderatelycorrelatedwithbehavioralthresholds tohigh-ratepulsetrains[3–6].

ObjectiveCIﬁttingbasedonelectricallyevokedauditory steady-stateresponses(EASSRs)isalsobeingresearched.EASSRsareneural steady-stateresponsestoelectricalstimuliwithaperiodicity,such asa modulated pulsetrain. Theyare theelectrical analogue of auditorysteady-stateresponses(ASSRs),whichareevoked acous-tically,andcanberecordedwithheadmountedscalpelectrodes. ASSRsaretheresultofneuralphase-lockingtoanauditory stim-ulusand theresponse isbelieved toresultfromdifferentbrain regions,dependingontherepetitionormodulationfrequencyof thestimulus(furthercalledresponsefrequency)[7,8].(E)ASSRscan bedetectedinthefrequencydomainattheresponsefrequencyby meansofastatisticaltest,e.g.anF-testoraHotellingT2_test_[9,8]. EASSRsarecorruptedbyelectricalstimulationartifacts,which canbecausedbyboththeelectricalstimulationpulsesandtheRF communicationlinkbetweentheexternalspeechprocessorand theimplant.The former canhave a periodiccomponent atthe responsefrequencywhichmaydistorttheneuralresponse[12]. Fig.1showstheEEGsignalrecordedontwochannelsintimeand frequencydomain,forsubthresholdstimulation.BothEEGsignals haveacomponentatthemodulationfrequency,whichiscausedby theelectricalstimulationsincenoneuralresponseisbelievedtobe present.Thespatialdistributionofthespectralcomponentatthe modulationfrequencyisshowninthetopographyplot,indicating thattheelectricalstimulationartifactispresentonallrecording electrodes.Theamountofdistortionishighlysubject-dependent, andisaffectedbythestimulationparametersandtherecording electrode positions. Stimulation in monopolar mode results in largerCIartifactsthaninbipolarmode[10,11].

ItwasrecentlydemonstratedthatEASSRsinresponseto high-ratestimuliresultinelectrophysiologicalthresholdsthatcorrelate wellwithbehavioral thresholdsforstimulationinbipolarmode [12].Thenextstepistoevaluatethresholdestimationbasedon EASSRsforclinicallyusedparameters,inparticularforstimulation inmonopolarmode.

StimulationartifactscontaminatingtheEEGareaproblemin variousdomainswhereelectricalormagneticstimulationisused, includingdeepbrainstimulation,transcranialmagneticand cur-rentstimulation,somatosensoryandcochlearimplantstimulation. Changestothemeasurementset-up,suchasmaximum separa-tionofstimulationandrecordingelectrodeleads,propergrounding ofamplifierandsubject,andcarefulskinpreparationcanhelpto reduceartifactamplitudes[10,13].However,noneofthese meas-urescancompletelypreventthepresenceofexcessivestimulation artifactsintheEEG.Optimalreference electrodeplacement has beeninvestigatedfortransientresponsestocochlearimplant stim-ulation[14],butoptimalselectionofreferenceelectrodehasnotyet beenassessedforartifactremovalinEASSRmeasurements. Stimu-lusdesigncanalsohelptoavoidstimulationartifacts:responsesto alternatingpolaritypulseshavebeenaveragedinordertoreduce thestimulationartifact[15,16],orshortstimulihave beenused suchthatthestimulationartifacthasdecayedbeforetheresponse occurs[16].Adjustmentstothestimuliarenotdesirableinourcase, becauseweaimtomeasureEASSRstoclinicallyusedstimuli. There-fore,stimulationisrestrictedtocathodic-first,biphasicpulses,with fixedpulsewidthandinterphasegap,presentedathighratesand inmonopolarmode.

ArtifacteliminationmethodsremoveEEGchannelsorepochs thatarecontaminatedwithartifact.Thisisdoneforexamplewith ocularartifactsintheEEG.However,allepochsareaffectedby stim-ulationartifactsinEASSRmeasurementsbecauseofthecontinuous stimulation.Furthermore,mostrecordingchannelsareaffectedby stimulationartifact. Therefore, artifact eliminationmethods are notappropriateforartifactremovalinEASSRmeasurements,since almostalldatawouldberejected.

Severalmethods havebeenproposedforstimulationartifact minimization.Singlechanneltechniquesincludefrequency[17], time–frequency[18–20],oradaptivefiltering[21–26].Template subtraction [27–30] has also been investigated. In the case of EASSR,frequency domain filteringis inappropriatebecausethe stimulationartifacthasacomponentattheresponsefrequency. For adaptive filtering and template subtraction, assumptions

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H.Deprezetal./BiomedicalSignalProcessingandControl31(2017)127–138 129

Fig.2.SimulatedCIartifactspectrumforunmodulatedpulsetrainspresentedatarepetitionfrequencyof40pps(left)andforhigh-rate(900pps)40HzAMpulsetrains (right),inthecaseofsymmetric(top)andasymmetricCIartifacts(bottom).

concerningthestimulationartifactshapeorﬁlteringprocessneed tobemade.

Interpolation methods [31,32,10,12] have also been used. Fortime-restrictedstimulationartifacts,aninterpolationcanbe appliedbetweenapre-artifactandpost-artifactsample,effectively removingthestimulationartifact.Thismethodisonlysuccessfulif theinterpulseintervalislargerthanthestimulationartifact dura-tion,andithasbeenvalidatedforEASSRmeasurementsinbipolar stimulationmode.

Multichannel techniques such as beamforming [33], prin-cipal (PCA) [16] and independent component analysis (ICA) [14,16,34–41]wereinvestigatedinvariousdomains.CIstimulation artifactshavesuccessfullybeenremovedfromtheEEGfor tran-sientresponsesusingmultichannelmethods,butthesemethods havenotyetbeeninvestigatedforsteady-stateresponses. Clini-cally,multichannelEEGsystemsareexpensiveandrequiremore subjectpreparationtime.

TheaimofthisstudyistocharacterizetheCIartifactfor mod-ulatedhigh-ratepulsetrainsstimulatedinmonopolarmodeand investigatethefeasibilityofstimulationartifactremovalwithlinear interpolation.Modulatedpulsetrainsareamodelforthe electri-calpulsesequencesafterprocessingofspeechbytheCIprocessor. LinearinterpolationwaschosenastheCIartifactremovalmethod, becauseitsefﬁciencyhasbeendemonstratedforbipolar stimula-tion,anditcanbeappliedtosinglechanneldata.TheCIartifact characterizationwillhelptoexplorethefeasibilityofotherabove mentionedCIartifactremovalmethods.Theinﬂuenceofreference electrodepositionontheCIartifactcharacteristicsandthe operat-inglimitsoftheinterpolationmethodwillbeinvestigated.

2. Materialsandmethods

TheCIartifactconsistsoftwomainpartsfromtheRF commu-nicationlink(theRFartifact)andfromtheelectricalstimulation (theSTIMartifact).TheCIartifactistime-lockedtotheelectrical

stimulationpulseandcancontainafrequencycomponentatthe modulationfrequency[10,12],ascanbeseeninFig.1forrecorded dataandFig.2forsimulatedcases.Thismayresultindistorted EASSRpropertiessuchasamplitudeandphaseandfalsepositive EASSRdetections.

InCochlearNucleus®_implants,_the_stimulation_amplitude_of_the pulsesisnonlinearlyencodedintheRFtransmissionandis there-foreconstantforstimulationpulseswithdifferentamplitudes[28], whereastheSTIMartifactamplitudeisrelatedtothestimulation pulseamplitude.Forstimulationwithunmodulatedpulsetrains, boththeRFandtheSTIMartifactarepresentattheresponse fre-quency(namelytherepetitionfrequencyofthestimulationpulses). For stimulationwithhigh-rate modulatedpulsetrains,onlythe STIMartifactispresentattheresponsefrequency(namelythe mod-ulationfrequencyofthestimulationpulses).Furthermoreifthe STIMartifactissymmetric,noSTIMartifactwillbepresentatthe responsefrequency,ascanbeseeninFig.2.Inthefollowing,we onlyconsiderstimulationwithhigh-ratemodulatedpulsetrains. Inthis case,onlytheSTIMartifactcomponentsareproblematic forEASSRmeasurementsastheymayhaveacontributionatthe modulationfrequency.

ThescalingoftheCIartifactswithincreasingstimulation ampli-tudeisquantiﬁedbymeansoftheslopeoftheCIartifactamplitude growthfunction(AGF).Iftheslopeiszero,theCIartifactsdonot scalewithchangingstimulationamplitude,whichindicatesthat theywillnotbepresentatthemodulationfrequency.IfCI arti-factsarepresentatthemodulationfrequency,theycanpossiblybe removedwithalinearinterpolation.However,thisonlyworksif theCIartifactisshorterthantheinterpulseinterval.Therefore,the STIMartifactdurationisalsoquantiﬁed.

EASSRsweremeasuredin11subjectswithaCochlearNucleus® CI with stimulation below the subject’s behavioral threshold level.Detailsaboutsubjects,stimulation,andrecordingsetupare describedinSections2.1,2.2and2.3,respectively.CIartifactAGF interceptsandslopesandSTIMartifactdurationsweredetermined

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Table1

ListofsubjectswithCochlearNucleus®_implant_details._S:_subject_identiﬁer;_Sex:_M:

male,F:female;Age:ageinyears;Exp:CIexperienceinyears;Sideofimplantation: R:right,L:left;PR:pulseratetested.

S Sex Age Exp Implanttype Side PR

500pps 900pps S1 F 55 16 CI24R L x S2 M 64 11 CI24R L x x S3 M 19 17 CI24M L x S4 F 85 5.7 CI24R L x x S5 M 74 1.2 CI24RE R x S6 M 52 1.7 CI24RE R x S7 M 64 16 CI24R L x x S8 M 52 1.9 CI24RE R x x S9 F 44 0.5 CI422 R x x S10 F 77 1.9 CI24Re L x S11 F 63 2.5 CI24RE R x

forallsubjectsasdescribedinSection2.4.Allsignalprocessingand

statisticalanalysesweredoneinMATLABR2013a. 2.1. Subjects

Intotal,11adultsubjectsparticipatedintheexperiments.They allhad aCochlearNucleus® _CI._Details_can_be_found_in_Table_1. Allsubjectstook partvoluntarily and signed an informed con-sentform.Theexperimentswereapprovedbythemedicalethics committeeoftheUniversityHospitalsLeuven(approvalnumber B32220072126).

2.2. Stimulationsetup

Anin-housedevelopedstimulationsoftwareplatform gener-ated the electrical stimulation pulse sequences with speciﬁed stimulationparameters,suchaspulserate,modulationfrequency, stimulationelectrode,etc.[10].Theelectricalpulsesequenceswere senttoaprogrammingdevice(POD)connectedtoaL34research speechprocessorprovidedbyCochlearLtd.,therebybypassingthe subject’sclinicalspeechprocessor.

CochlearNucleus® _implants_have _two_return _electrodes out-sidethecochlea,i.e.thecasingandtheballelectrode.Allsubjects werestimulatedinmonopolarmodeMP1+2,i.e.betweenan intra-cochlear electrode and thetwo extracochlear return electrodes whichareelectricallycoupled[42].Anintracochlearelectrodein themiddleofthearraywasused:electrode11wasusedforall subjectsexceptS1,forwhomelectrode13wasused.Thestimuli consistedofamplitude-modulated(AM)pulsetrainswith modula-tionfrequenciesinthe40Hz-range,whichisoftenusedfortesting adultsbecauselargeresponsesareexpectedhere.Clinicallyused symmetricbiphasicpulseswithapulsewidthof25␮sandan inter-phasegapof8␮swereusedforstimulation.

Thresholdandcomfortlevelsweredeterminedforstimulation withunmodulated(Tu andCu)andAMpulsetrains(TmandCm). TheTlevelisthestimulationamplitude(inCochlearclinicalcurrent units(cu),aunitofelectricalcurrent)thatelicitsajustperceivable auditoryperception.TheClevelis thestimulationamplitudeat perceivedmaximumcomfortableloudness.For AMpulsetrains, thedeterminedTmandCmrefertothemaximumamplitudeofthe AMpulsetrainsthatresultinajustperceivableauditorysensation andamaximallycomfortablesound,respectively.

Twostimulationpulseratesweretested:500ppswhichisatthe lowerendofclinicallyusedstimulation,and900ppswhichisthe defaultpulserateusedinCochlearNucleus®_implants._The_stimuli weremodulatedwithfrequenciesinthe40Hzrange.Subjectswere stimulatedatsubthresholdstimulationpulsetrainintensities,with modulationdepthequalto(Cm−Tu)/(Cm+Tu),during5min.

2.3. Recordingsetup

Tostudytheeffectofreferenceelectrodeposition,a64-channel active-electrodeBioSemiActiveTwoDCEEGrecordingsystemwas used.Thesystemhasa24bitresolutionoveradynamicrangeof 524mVPPandasamplingrateof8192Hzwasused.Therecording setuphasabuilt-inanalog5thordersinclow-passﬁlterwitha cutofffrequencyof1638Hz.Recordingelectrodeswereplacedon thesubject’sheadaccordingtothepositionsoftheinternational 10–20system[43].Atriggersignalwassenttotherecordingsystem forsynchronizationatthebeginning ofeachrecordingepochof 1.024s.AfterEEGsignalrecordingduring5min,thesignalswere rereferencedofﬂinetothreecommonlyusedreferenceschemes: averagereference,vertexreferenceCz,andforeheadreferenceFpz. The recordings were made in a soundproof and electrically shieldedroom.Subjectswereseatedina comfortablechairand wereaskedtomoveaslittleaspossible.Asilentbutsubtitledmovie oftheirchoicewasplayed,toguaranteethesameattentionalstate acrosssubjectsandmeasurements.

2.4. CIartifactcharacterization 2.4.1. CIartifactamplitudegrowth

TheCIartifactAGFA(As)showshowtheCIartifactamplitudeA changeswithincreasingstimulationpulseamplitudeAs.

TheCIartifactamplitudeApwasdeterminedforevery stimu-lationpulse.Letxp(t,c)betheEEGsignalfollowingpulsep(with stimulationamplitudeAs(p)␮A)attimetandchannelc.Inthe fol-lowing,wewillmakeabstractionofthechannelcasthemethod canbeappliedtoeverychannelseparately.Ap(in␮V)wasdeﬁned asthesumofthepulse’smaximalandminimalamplitude. Ap=

max

t xp(t)+mint xp(t)

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For symmetrical artifacts, with equal negative and positive amplitudes,Apwillbezero.Forasymmetricalartifacts,Apwilldiffer fromzero.

For each stimulation pulse pstimulated at amplitude As(p), themaximalandminimalEEGamplitudesweredeterminedand summed,resultinginAp.Next,thesevalueswereaveragedforall pulsespresentedatthesamestimulationamplitude,suchthatone CIartifactamplitudeAisdeterminedforeach stimulationpulse amplitudeAs.Inaﬁrstapproximation,theCIartifactAGFA(As)can bemodeledasalinearfunctionofAs:A(As)=mAs+Iwithintercept Iandslopem=◦,asshowninFig.3.Thebestlinearﬁtwas deter-minedforeverychannelwithaleastsquaresprocedure,resulting invaluesfortheinterceptIandslope.

TheinterceptIrepresentsasymmetricCIartifactcomponents thatareconstantacrossstimulationpulseintensities;these arti-factcomponentsaremainlycausedbytheRFartifact.Theslope representsasymmetricCIartifactcomponentsthatchangewith increasingstimulationpulseamplitude,namelytheSTIMartifact. IftheCIartifactissymmetric,bothandIwillbezero.Ifiszero andIisnon-zero,theCIartifactismainlycausedbyRF transmis-sion.IfbothandIarenon-zero,theCIartifactconsistsofRFand STIMartifact.OnlytheSTIMartifactcomponentsareproblematic forEASSRmeasurementsasthesearetheonlycomponentsthat haveacontributionatthemodulationfrequency.

Aslopeof1◦correspondstoanincreaseof0.017␮V/␮A.Inthis study,thestimulationamplituderangeaveragedoversubjectsis about100␮A.Therefore, the amplitudedifferencebetweenthe largestandsmallestpulseamplitudefor=1◦is1.7␮Vforan aver-agesubject.Thisisalargevalue,comparedtotheneuralresponse whichhasamplitudesbetween20and500nVforaveragesubjects inthe40Hzrange[12].

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Fig.3. CIartifactAGFsforS1andS8,measuredwith37HzAM900ppspulsetrainsatasubthresholdstimulationamplitude,betweenanipsilateraloccipitalelectrode(O2)

andforeheadreferenceelectrode(Fpz).

CIartifactAGFswereconstructedforallsubjects.Examplesof suchAGFsareshowninFig.3.Pulseratesof500and900ppswere used,althoughnotallsubjectsweretestedwithstimulationatboth pulserates,asshowninTable1.TheDCbiaswasremovedfromthe recordedEEGsignalswithasecond-order2Hzhigh-passﬁlterand theEEGsignalswererereferencedtoeitheraveragereference,Cz, orFpz.ThevaluesoftheinterceptIandslopeoftheCIartifact AGFweredeterminedforeveryrecordingchannelandfordifferent recordingelectrodeconﬁgurations.

2.4.2. STIMartifactduration

Artifactswereremovedbylinearinterpolationbetweena pre-stimulusandpost-stimulussample.Thetimebetweenthepre-and post-stimulussampleis calledtheinterpolationdurationd.The maximumpossibleinterpolationdurationisdeﬁnedasthe inter-pulseinterval,whichistheinverseofthepulserate,andequals 2msand1.1msforstimulationat500and900pps,respectively. Inthiscase,onesampleperpulseperiod,thepre-stimulus sam-ple,isretained.Alinear interpolationwasappliedbetweenthe pre-stimulussampleat−100␮sandpost-stimulussamples vary-ingbetween+500and+1900␮s,instepsof100␮sfor500pps.For 900pps,post-stimulussamplesvaryingbetween+500and+900␮s, wereused,instepsof100␮s.Thesamplingrateisnotanexact mul-tipleofthepulserate.Therefore,thestartofastimulationpulseis notexactlyalignedtoasample.Thestartandendsamplesofthe interpolationarecalculatedforeachpulseseparately,byrounding thestartandendtimeoftheinterpolationtothenearestsample. Lookingoverthewholerecording,theaveragetimebetweenthe startoftheinterpolationintervalandthestartofastimulationpulse isequaltothepre-stimulusinterpolationduration.Equivalently, theaveragetimebetweenthestartofastimulationpulseandthe endoftheinterpolationintervalisequaltothepost-stimulus inter-polationduration.Post-stimulussamplesbefore+500_␮swerenot used,astheCIartifactpeaklastsforabout500␮s,ascanbeseenin Fig.4.

After linear interpolation, the signals were ﬁltered with a second-order2Hzhigh-passﬁlter,rereferencedtoeitheraverage reference,CzorFpz,andsplitinto1.024sepochs.The300 result-ingepochs,correspondingtoa5minrecordinglength,werethen averagedtoreducethenoiseleveln.Then,theresultingspectral amplitudesAmatthemodulationfrequencyinfunctionofthe inter-polationdurationdweredetermined,asillustratedinFig.4.

WhentheinterpolationdurationisshorterthantheSTIM arti-fact,Am(d)maystillcontainsomeSTIMartifact.However,Am(d) decreaseswithincreasinginterpolationduration,asalargerpart oftheSTIMartifactisthencanceled.Whentheinterpolation dura-tionislongerthantheSTIMartifactduration,Am(d)stabilizesat theneuralresponseamplitude,namelytherealEASSRamplitude. Am(d)stabilizestothenoiselevel,inourcase,asnoneuralresponse isexpectedtobepresentforsubthresholdstimulation.

AnAm(d)AGFexampleisshowninFig.4.ThedifferencesinAm forincreasinginterpolationdurationdwerecomparedtothenoise levelafteraveragingn.TheSTIMartifactdurationDwasdeﬁnedas theshortestinterpolationdurationforwhichthisdifferencedidnot exceedthesubjectdependentnoiseleveln,whichisapproximately 50nV:

D=d:[Am(d)−Am(d−1)]<n (2)

IfAm(d)didnotsaturate,meaningthatthedifferenceinAm(d)was notsmallerthanthenoiselevelforanyinterpolationdurationd,the STIMartifactdurationDwassetequaltothemaximalinterpolation duration.

2.4.3. Statisticalanalyses

TheinterceptIandslopeoftheCIartifactAGFandtheSTIM artifact duration Dwere determinedas described above for all recording electrodes and for three reference electrode conﬁgu-rations inall subjects.Leftandright recordingelectrodes were switchedforsubjectswithaCIattherighthandside,toputthe resultsinthesameﬁgureforsubjectswithaCIattheleftandright

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0.5 0.7 0.9 1.1 1.31.5 1.7 1.9 0 0.05 0.1 0.15 0.2 0.25 Spectral amplitude at f m A m (uV) 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9 0 0.05 0.1 0.15 0.2 0.25 −600 −500 −400 −300 −200 −100 0 Amplitude (uV) Ipsilateral −50 0 50 100 Contralateral

Post−stimulus interpolation duration d (ms)

Fig.4.CIartifactpulse(top)andAm(d)AGFwithincreasinginterpolationdurationdforsubjectS2(bottom).StimulationbelowTlevelat500pps,foripsi-andcontralateral

recordingelectrodes.TheSTIMartifactdurationsareindicatedindash-dottedlines.ReferenceelectrodeCz.

handside.Theresultingsignalswereaveragedacrossallsubjectsto obtaintheaverageCIartifactproﬁleshowninFig.5.Thismaygive ablurredview,asCIartifactsmaybelocalizedslightlydifferently inallsubjects.

Inthefollowing,onlyrecordingelectrodeslocatedinthe pos-teriorpartofthehead(Tx,C(P)x,P(O)x,Ox,Ix)wereconsidered.For eachsubject,themedianvalueof,IandDovertherecording elec-trodeswasdetermined.Astatisticalanalysisinvestigatingtheeffect ofreferenceelectrode,hemisphere,andpulserateon,IandDwas

carriedout.Alleffectsarereportedatasigniﬁcancelevelof5%. ThedatawerenotnormallydistributedaccordingtoaJarque–Bera test,andthereforeonlynonparametrictestswereused.AFriedman analysiswasusedtoinvestigatetheeffectofreferenceelectrodeon theCIartifactAGFslopeandSTIMartifactdurationforeachpulse rateandforeachhemisphere.Theeffectofhemispherewas inves-tigatedusingWilkinsonsignedranktests(averagingtheresultsfor referenceelectrodesCzandFpz).TheinﬂuenceofpulserateonCI artifactAGFslopeandSTIMartifactdurationwascheckedforeach

Fig.5. MeanslopeandinterceptIoftheCIartifactAGFandmeanSTIMartifactduration,averagedoverallsubjectswithrecordingswithstimulationat500pps.Average reference(leftcolumn)andreferenceelectrodeCz(rightcolumn).

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H.Deprezetal./BiomedicalSignalProcessingandControl31(2017)127–138 133 −10 0 10 20 30 40 50 60 Ipsilateral

CI artifact AGF slope θ (degrees)

0 200 400 600 800 1000

CI artifact AGF intercept I (uV)

S2 S4 S6 S7 S8 S9 S10 S11 0 2 4 6 8 10 Contralateral S2 S4 S6 S7 S8 S9 S10 S11 0 200 400 600 800 1000 Subject

Fig.6.CIartifactAGFslopeandinterceptIforipsi-andcontralateralposteriorrecordingelectrodesforeachsubjectwithrecordingswithstimulationat500pps.Reference electrodeCz.Theboxplotshowsthemedianand25th(q1)and75thpercentiles(q3).Outliers(+)arealldatapointsthatfalloutsidetherange [q1±1.5(q3−q1)] .

hemisphere(averagingtheresultsforreferenceelectrodesCzand Fpz),usingWilkinsonranksumtests.

3. Results

3.1. CIartifactAGFslopeandintercept

CIartifactAGFslopesandinterceptsareshowninFigs.6and7. TheCIartifactissymmetricifbothandIarezeroandthisisonly thecaseforsubjectS1(Fig.7).

MostsubjectshadaCIartifactAGFsimilartothatofsubjectS8 inFig.3.TheCIartifactslopeisdifferentfromzero,whichmeans thattheSTIMartifactcontributestotheCIartifact.

3.2. STIMartifactduration

Fig.8 showsSTIM artifactdurationsDfor each subject sep-arately, on all ipsilateral and contralateral posterior recording electrodes respectively. For stimulation at 500pps, the median STIM artifact duration at the ipsilateral posterior electrodes is 1.6ms,althoughtheSTIMartifactdurationisclosetoorlongerthan 2msatsomeelectrodesinsomesubjects(Fig.8).Forstimulation at900pps,thedeterminedSTIMartifactdurationisequalto1.1ms inalmostallsubjectsatipsilateralrecordingelectrodes.Disthus largerthanthemaximumpossibleinterpolationduration.

Atcontralateralrecordingelectrodes,themedianSTIMartifact durationis1and0.9msat500and900pps,respectively.For stim-ulationat900pps,Discloseorequalto1.1msinsomesubjects (Fig.8).

3.3. Inﬂuenceofreferenceelectrodeandhemisphere

TheslopeandinterceptIoftheCIartifactAGFandtheSTIM artifact duration D are largest in theproximity of the implant (Fig.5).,IandDarelargerinthecontralateralhemispherefor averagereferencethanforreferenceelectrodeCz.

For stimulation at 500pps, a significant influence of ref-erence electrode on CI artifact AGF slopes was found in the ipsilateral(2₍₂₎₌_7.8,_p₌_0.021)_and_the_{contralateral}_hemisphere (2₍₂₎₌_6.8, _p₌_0.034), _see _Fig. _9. _In _the _ipsilateral_hemisphere, largerCIartifactAGFslopeswerefoundfortheFpzreference elec-trodemontage. In thecontralateralhemisphere,more variation inCIartifactAGFslopeisobservedwhenreferenceelectrodeCz isusedcomparedtowhenreferenceelectrodeFpzischosen.For stimulationat900pps,asignificantinfluenceofreferenceelectrode onCIartifactAGFslopeswasfoundintheipsilateralhemisphere (2₍₂₎₌_9,_p₌_0.011)_and_in_the_{contralateral}_hemisphere₍2₍₂₎₌_7, p=0.030).

Forstimulationat500pps,asignificantinfluenceofreference electrodeonCIartifactAGFinterceptwasfoundinthe contralat-eral (2₍₂₎₌_7, _p₌_0.030), _but _not _in _the _ipsilateral _hemisphere (2₍₂₎₌_1.0,_p₌_0.607),_see_Fig._10._In_the_{contralateral}_hemisphere, smallerCIartifactAGFinterceptswerefoundfortheFpzreference. For stimulationat 900pps, nosignificantinfluenceofreference electrodeonCIartifactAGFinterceptswasfoundintheipsilateral hemisphere(2₍₂₎₌_1.75,_p₌_0.417)_or_in_the_{contralateral} hemi-sphere(2₍₂₎₌_0.75,_p₌_0.687).

Forstimulationat500pps,thereferenceelectrodewasfoundto haveasignificantinfluenceonSTIMartifactdurationonipsilateral (2₍₂₎₌_6.1, _p₌_0.048) _and _{contralateral} _electrodes ₍2₍₂₎₌_14.6, p<0.001).Inthecontralateralhemisphere,shorterSTIMartifact durationswerefoundfortheFpzreference.Intheipsilateral hemi-sphere,the STIMartifact duration is largerthan themaximum possibleinterpolationdurationforstimulationat900pps. There-fore the influence of reference electrode on the STIM artifact durationwasonlycheckedinthecontralateralhemisphere.The ref-erenceelectrodewasfoundtohaveasignificantinfluenceonSTIM artifact durations in the contralateral hemisphere (2₍₂₎₌_13.0, p=0.002).ShorterSTIMartifactdurationswereagainfoundforthe Fpzreference.

For stimulation at 500pps there was a signiﬁcant effect of hemisphere on CI artifact AGF slope, offset and STIM artifact duration (p=0.008, p=0.008, and p=0.008, respectively). Prior

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−10 0 10 20 30 40 50 60 Ipsilateral

CI artifact AGF slope θ (degrees)

0 200 400 600 800 1000

CI artifact AGF intercept I (uV)

S1 S2 S3 S4 S5 S7 S8 S9 0 2 4 6 8 10 Contralateral S1 S2 S3 S4 S5 S7 S8 S9 0 200 400 600 800 1000 Subject

Fig.7.CIartifactAGFslopeandinterceptIforipsi-andcontralateralposteriorrecordingelectrodesforeachsubjectwithrecordingswithstimulationat900pps.Reference electrodeCz.

tothestatisticalanalysisresultsfor referenceelectrodesCz and Fpz were averaged. For these reference electrodes, the CI arti-fact AGF slope is smaller and STIM artifact duration is shorter in the contralateral hemisphere. For stimulation at 900pps, a signiﬁcanteffectofhemispherewasfoundontheCIartifactAGF slope and intercept (p=0.016 and p=0.016, respectively),with smallerCIartifactAGFslopesandinterceptsinthecontralateral hemisphere. The effect of hemisphere on STIM artifact dura-tioncould not beinvestigated, as theSTIM artifact duration is

longerthanthemaximalinterpolationdurationintheipsilateral hemisphere.

3.4. Inﬂuenceofpulserate

NosignificantinfluenceofpulserateonCIartifactAGFslope wasfound,forneitherofthehemispheres(p=0.798andp=0.721 foripsi-andcontralateralhemisphere,respectively).Nosignificant influenceofpulserateonCIartifactAGFinterceptwasfound,for

0.6 0.8 1 1.2 1.4 1.6 1.8 2 500 pps Ipsilateral 900 pps S2 S4 S6 S7 S8 S9 S10 S11 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Contralateral S1 S2 S3 S4 S5 S7 S8 S9 Subject

STIM artifact duration D (ms)

Fig.8.STIMartifactdurationforipsi-andcontralateralposteriorrecordingelectrodesforeachsubjectwithrecordingswithstimulationat500and900pps.Reference electrodeCz.Dottedlinesindicatetheminimumandmaximumpossibleinterpolationdurationat500and900pps.

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Fig.9. CIartifactAGFslopeperpulserate(500and900pps),hemisphere(ipsi-andcontralateral)andreferenceelectrode(averagereference,CzandFpz).Thesymbols*,

**,and***indicatethatp-valuesaresmallerthan0.05,0.01,and0.001,respectively. neitherofthehemispheres(p=0.235andp=0.328foripsi-and contralateralhemisphere,respectively).Nosigniﬁcantinﬂuenceof pulserateonSTIMartifactdurationwasfoundinthe contralat-eralhemisphere(p=0.343).STIMartifactdurationsforbothpulse ratescouldnotbecomparedintheipsilateralhemisphere,asthe STIMartifactdurationexceededthemaximumpossible interpola-tiondurationat900pps.

4. Discussion

Inthisstudy,theCIartifactwascharacterizedbasedonthree properties,namely, theCI artifactAGF slope and intercept and theSTIM artifact duration. The CI artifact AGF slope and STIM

artifactdurationdescribehowtheCIartifactscaleswithstimulation amplitudeandhowlongittakestheSTIMartifacttohavedecayed completely,respectively.SignificantlylargerCIartifactAGFslopes andinterceptsandSTIMartifactdurationsarefoundatipsilateral recordingelectrodesthanatcontralateralones.Forelectrodes pos-itionedatthecontralateralside,thereferenceelectrodelocation canhaveaninfluenceontheCIartifactAGFslopeandintercept(for stimulationat500pps)andSTIMartifactduration.Nosignificant influenceofpulserateonanypropertyhasbeenfound.Basedon theSTIMartifactdurations(Fig.8),itshouldbepossibletoremove STIMartifactsatcontralateralelectrodeswithalinear interpola-tionforstimulationat500pps.Forstimulationat900pps,more advancedmethodsareneeded.

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Fig.11.STIMartifactdurationperpulserate(500and900pps),hemisphere(ipsi-andcontralateral)andreferenceelectrode(averagereference,CzandFpz).Dashedand

dottedlinesindicatethemaximumpossibleinterpolationdurationat500and900pps,respectively.Thedash-dottedlineindicatestheminimuminterpolationdurationused fortheanalysis.

Itisnotrecommendedtouseaveragereferencesubtractionwith CIstimulation.Whenthesubtractedreferencecontainsmore arti-factthanthechannel fromwhichit issubtracted,theresulting signalinthatchannelcouldcontainmoreCIartifactafter refer-encesubtractionthanbefore.LargeCIartifactsignalspresentat someelectrodeswillbiasthemeansignaloverchannels,resulting inlargeCIartifactsatallchannelsafterreferencesubtraction.

ThereferenceelectrodehasnotonlyaninﬂuenceontheCI arti-factcharacteristics,but alsoonthedetectedEASSR.Thesource oftheEASSRsisorientedalongadipole.Inordertorecord reli-ableEASSRswithmaximalamplitudes,theanalysisandreference electrodesshouldbeplacedonoppositesidesalongand perpen-diculartotheaxisofthisdipole.ThelocationoftheEASSRsource inthebrainvarieswithvaryingmodulationfrequencies.EASSRs tomodulationfrequenciesinthe40Hzrange(20–60Hz)originate fromsub-corticalsources[7].Whetheritispossibletoadequately recordEASSRswithaspeciﬁccombinationofanalysisandreference electrodesthus dependsontheselected modulationfrequency. EASSRswerealsorecordedatsuprathresholdstimulationlevelsfor thesamesubjects,andforthemodulationfrequencieswetested inthe40Hzrange,itwasstillpossibletorecordreliableEASSRs whenreferenceelectrodeFpzwasselected(datanotpresented). ReferenceelectrodeFpzisalsooftenusedinclinicalABRandASSR measurementsininfants[44].Itshouldbenotedthat referenc-ingthedatatoFpz canleadtoincreasednoise levels,resulting in reduced EASSR detectionsor requiring longer measurement times.

OnlyonesubjecthadsymmetricCIartifacts,thatdidnotscale withincreasingstimulationamplitude.CIartifactshada contribu-tionatthemodulationfrequencyforallothersubjects.

TheamplitudeAmatthemodulationfrequency,consistingof contributions from the STIM artifact and the neural response, reduceswithincreasinginterpolationduration.TheAmdifference forsubsequentinterpolationdurationswascomparedtothenoise levelafteraveraging.TheSTIMartifactdurationisthe interpola-tiondurationforwhichthisdifferencebecomessmallerthanthe noiselevel.BecausewelookatthesaturationofAm,andnotat itsabsolutelevel,this methodcanalsobeappliedtorecordings

withstimulationatsuprathresholdlevels.Furthermore,thetimeT overwhichtheEEGsignalswereaveragedplaysanimportantrole here,sincethenoiselevelisdependentonthis.Thenoiselevelis reducedwithafactor√2eachtimetheaveragingtimeisdoubled. TheSTIMartifactdurationthusdetermineswhethertheSTIM arti-factcanberemovedbylinearinterpolationforrecordingtimeT.For longerrecordingtimes,thecontributionoftheSTIMartifactmay notbebelowthenoiselevelandtheSTIMartifactispossiblynot completelyremovedbyapplyinglinearinterpolation.

Forstimulationat500pps, theSTIMartifactcanberemoved atcontralateralrecordingelectrodeswithalinearinterpolation.In thecontralateralhemisphere,thevariabilityof(forstimulation at 500pps) and Dwassmallerfor more frontalreference elec-trodes,seeFigs.9and11.Therefore,forrecordingelectrodesinthe contralateralhemisphere,thechancethattheSTIMartifact dura-tionislongerthanthemaximumpossibleinterpolationdurationis reducedbychoosingamorefrontalreferenceelectrode.

Linearinterpolationisnotsufficienttoexamineresponsesat ipsilateralrecordingelectrodesorforstimulationpulserateshigher than500pps.Otherstimulationartifactremovalmethodsshould therefore be examined. Further modeling of CI artifacts could allowtemplatesubtractionoradaptivefilterdesignforCIartifact removal.Multichannelmethodscouldpossiblybeused,withthe disadvantage–forCIfittingpurposes–thattheserequireamore expensivesetupandmoresubjectpreparationtime.

OnlysubjectswithCochlearNucleus®_implants_participated_in thisstudy.However,thestimulationartifactscausedbyimplants fromothermanufacturersshouldbeexamined,usingthemethods presentedhere.Differencescanbeexpected,asother manufactur-ersusedifferentclinicalparameters.

Inthisstudy,a64-channelrecordingset-upwasused,which allowedtoinvestigatetheinﬂuenceofreferenceelectrode posi-tionontheCIartifactcharacteristics.Setupswithlesschannelscan usuallybeoperatedathighersampleratesandhavelowpass ﬁl-terswithhighercut-offfrequencies,whichcouldresultinshorter STIMartifactdurations.Themethodpresentedinthisstudycanstill beusedtodeterminetheSTIMartifactdurationandtherequired interpolationduration.

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H.Deprezetal./BiomedicalSignalProcessingandControl31(2017)127–138 137 Inthisstudy,subjectswereonlytestedatsubthreshold

stim-ulation amplitudes. STIM artifact durations may be larger for suprathresholdstimulationamplitudes.Largerstimulation ampli-tudesmayresultinlargerCI artifactamplitudes.Assumingthat the decay constant doesnot change,it takes longer for larger CIartifact amplitudestodecaybelow thenoise level.However, 11subjectsweretested,wherethestimulationamplitudesused werejustbelowthesubject’sbehavioralTlevels.TherangeofT levelsobservedinthesesubjectsisquitediverse,resultingin max-imumstimulationpulseamplitudesusedbetween108and190cu, andbetween86 and167cuforstimulationat500and900pps, respectively.Wewouldarguethattheresultsfromthisstudyare representative,sinceawidevarietyofstimulationlevelswasused. Hereonlyonestimulationelectrodeinthemiddleofthearray wasused.Thestimulationelectrodeisnotexpectedtohavemuch inﬂuenceontheCIartifactcharacteristics.Futureresearchshould focus on the inﬂuence of stimulation electrode position on CI artifactcharacteristics,whichcanbeevaluatedwiththetools pre-sentedinthisstudy.

5. Conclusion

Inmostsubjects,theCIartifactwasatleastpartlycausedby theSTIMartifact.BasedonthedatapresentedinFigs.5and9–11, itisnotrecommendedtouseaveragereferenceforEASSR mea-surements.CIartifactAGFslopesandinterceptsandSTIMartifact durationsarelargerinthecontralateralhemispherefortheaverage referenceconfigurationthanCzorFpzreference.Inthe contralat-eralhemisphere,thereferenceelectrodehasasignificantinfluence ontheCIartifactAGFslopeandinterceptforstimulationat500pps andontheSTIMartifactduration.Inthecontralateralhemisphere, smallervariabilitiesinCIartifactAGFslopes(at500pps)andSTIM artifactdurationswereobservedwhenmorefrontalreference elec-trodeswereused.STIMartifactdurationswerebetween0.7and 1.7msand0.7and2ms,atcontralateralandipsilateralrecording electrodes,respectively.Thisshouldmakeitpossibletoremove theCIartifactatthecontralateralrecordingelectrodeswitha lin-earinterpolationinmostsubjects,forstimulationat500pps.For stimulationat900ppsorforstimulationat500ppsatipsilateral recordingelectrodes,moreadvancedCIartifactattenuation meth-odsareneeded.

Acknowledgments

Theauthorswouldliketothankallsubjectswhoparticipated inthestudy.Furthermore,aspecialthanksgoesouttoRobertLuke andTomFrancartfortheirvaluablefeedbackthroughoutthestudy. ThisresearchworkwascarriedoutintheframeofResearchProject FWOnr.G.066213‘Objectivemappingofcochlearimplants’,IWT Project(IWT,110722)‘Signalprocessingandautomaticﬁttingfor nextgenerationcochlearimplants’andKULeuvenResearchCouncil CoEPFV/10/002(OPTEC).Thesecondauthorissupportedwitha Ph.D.grantbytheHermesfonds(141243).Noneoftheauthorshave potentialconﬂictsofinteresttobedisclosed.

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