Brainstem auditory evoked potentials in children with autism spectrum disorder 夽,夽夽

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www.jped.com.br

ORIGINAL ARTICLE

Brainstem auditory evoked potentials in children with autism spectrum disorder ^夽,夽夽

Mariana Keiko Kamita

^∗

, Liliane Aparecida Fagundes Silva , Fernanda Cristina Leite Magliaro , Rebeca Yuko Couto Kawai , Fernanda Dreux Miranda Fernandes , Carla Gentile Matas

UniversidadedeSãoPaulo(USP),FaculdadedeMedicina(FM),DepartamentodeTerapiaFísica,FonoaudiologiaeTerapia Ocupacional,SãoPaulo,SP,Brazil

Received8August2018;accepted13December2018 Availableonline22February2019

KEYWORDS Autisticdisorder;

Electrophysiology;

Auditoryevoked potentials

Abstract

Objectives: Thisstudyaimedtoanalyzetheneuralencodingofverbalandnonverbalstimuliin individualswithautismspectrumdisorderusingbrainstemauditoryevokedpotentials.

Methodology: Thirtyindividualsbetween 7and12yearsofageandofbothgenderspartici- patedinthisstudy.Fifteenwerediagnosedwithautismspectrumdisorder,and15hadtypical development.Allsubjectshadnormalhearingandnootherimpairments.Anelectrophysiolog- icalhearingassessmentwasperformedusingbrainstemauditoryevokedpotentialswithclick andspeechstimuli.

Results: Inthebrainstemauditoryevokedpotentialswithclickstimuli,themeanwaveIlatency waslongerfortherightearinbothgroups,andinterpeakintervalsIII---Vweregreaterforthe individualswithautismspectrumdisorder.Forbrainstemauditoryevokedpotentialswithspeech stimuli,waveVlatencywasshorterinindividualswithautismspectrumdisorder.

Conclusion: These data suggestthat individualswith autismspectrum disordermay havea dysfunction ofthecentral auditory nervous systemfor nonverbal stimuliand faster neural encodingoftheinitialpartoftheverbalstimulus,suggestinghypersensitivitytocomplexsounds suchasspeech.

4.0/).

夽 Pleasecitethisarticleas:KamitaMK,SilvaLA,MagliaroFC,KawaiRY,FernandesFD,MatasCG.Brainstemauditoryevokedpotentialsin childrenwithautismspectrumdisorder.JPediatr(RioJ).2020;96:386---92.

夽夽StudyconductedattheUniversidadedeSãoPaulo,FaculdadedeMedicina,DepartamentodeFisioterapia,FonoaudiologiaeTerapia Ocupacional,SãoPaulo,SP,Brazil.

∗Correspondingauthor.

E-mail:marikeikokamita@gmail.com(M.K.Kamita).

https://doi.org/10.1016/j.jped.2018.12.010

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PALAVRAS-CHAVE Transtornoautista;

Eletroﬁsiologia;

Potenciaisevocados auditivos

Potenciaisevocadosauditivosdetroncoencefálicoemcrianc¸ascomtranstornodo espectrodoautismo

Resumo

Objetivos: Esteestudovisouanalisaracodiﬁcac¸ãoneuraldeestímulosverbaisenãoverbaisem indivíduoscomtranstornodoespectrodoautismocomousodepotenciaisevocadosauditivos detroncoencefálico.

Metodologia: Participaram30indivíduosentresetee12anosedeambosossexos;15foram diagnosticados comtranstorno do espectrodo autismoe 15apresentaram desenvolvimento típico.Todososindivíduosapresentaramaudiçãonormalenenhumaoutraalteração.Foifeita uma avaliaçãoeletrofisiológica daaudição como usodos potenciais evocados auditivosde troncoencefálicocomestímulosdecliqueefala.

Resultados: Nospotenciaisevocadosauditivosdetroncoencefálicocomestímulosdeclique,a médiadovalordelatênciadaondaIfoimaiorparaoouvidodireitonosdoisgruposeosintervalos interpicosIII-Vforammaioresparaosindivíduoscomtranstornodoespectrodoautismo.Para ospotenciaisevocadosauditivosdetroncoencefálicocomestímulosdefala,alatênciadaonda Vfoimenornosindivíduoscomtranstornodoespectrodoautismo.

Conclusão: Nossosdadossugerem queosindivíduoscomtranstorno doespectrodo autismo podem teruma disfunção dosistemanervosoauditivo centralparaestímulos nãoverbaise codificaçãoneuralmaisrápidadaparteinicialdosestímulosverbais,oquesugerehipersensi- bilidadeasonscomplexos,comoafala.

0/).

Introduction

Autism spectrum disorder (ASD) is a central disorder characterized by the inability to establish interpersonal relationshipsandtoreactnormallytosituationsearlyinlife, withanemphasisonsocialwithdrawal.¹

According to the Diagnostic and Statistical Manual of MentalDisorders,²individualswithASDmayexhibitbehav- ioralpatternsthatincluderestrictedinterestsandrepetitive andstereotypedbehaviors.Furthermore,changesinrecip- rocalsocial interactionsand modesofcommunication are observed.Additionally,itisknownthatindividualswithASD mayhave perceptual, cognitive,andmemorydisordersof attentionthatcanbemistakenforauditorydeﬁciencies.²

Moreover,individualswithASDmaybehyper-orhyposen- sitivetosensorystimuliandcanbeverysensitivetosounds;

they maybe troubled by loud sounds (hyperacusis)or be unabletohearandrespondtoloudsoundsornoises(hypoa- cusis).Suchsensitivitiesarealsoobservedinrelationtolight andtactilesensation.³Consequently,itisimportanttoper- formacompleteaudiological assessmentthatinvestigates boththeperipheralandthecentralauditorypathways.⁴

Althoughtheyareveryuseful inroutinehearingassess- ments,conventionalorconditionedtonalaudiometry,which areusedtoassesshearingacuity,andthebattery oftests used to assess central auditory processing have limited clinicalapplicabilityforindividualswithASDbecausethey requireactiveresponsesfromthepatient.Individualswith ASDarenotalwaysabletorespondaccuratelytothestimuli presentedand/orperformthenecessarytasks.

Consequently, it is importantto include electrophysio- logicaltestsintheassessmentofindividualswithASD.Such testsmaybeabletoboth predictthehearingthresholdof

theseindividualsandtoidentifypossiblechangesinthecen- tralauditory pathways, thus aiding in diagnosis and early intervention.

Ofthetestsusedfortheelectrophysiologicalassessment of hearing, brainstem auditory evoked potentials (BAEPs) areable toreﬂect synchronized electrical activity of the brainstem’sneuralelementsinresponsetoacousticstimu- lation,andthisneuronalactivitycanbeobservedintheﬁrst millisecondsafterthepresentationofthesoundstimulus.^5,6 Twotypesofacousticstimulicanbeusedtoelicitelectro- physiologicalresponses:verbalandnonverbal.Thesestimuli havedifferentcharacteristicsandelicitdifferentresponses;

verbal stimuli are composed of a more complex tempo- ral structure, and the response to these stimuli requires synchronic neuronal activation.⁷ The perception of these acousticcharacteristics is related to neural encoding, an essentialfunctionof thecentral auditorynervoussystem, whichmustsimultaneouslyprocessmultiplecuestodecode alinguisticmessage.⁸

Severalstudieshaveevaluatedtheroleoftheauditory pathwayatthelevelofthebrainsteminindividualswithASD using BAEPs.^4,9---17 In general, the literature demonstrates thatthispopulationmaypresentalterationsin BAEPs;the most common ﬁndings are increased latency of waves III and V^4,9,10 and an increase in the interpeak intervals for I---IIIandI---V,suggestingdamagetothebrainstemsofthese patients.^4,10,12,13However,thesestudieshaveevaluatedthis populationusing onlyone typeof acousticstimuli:clicks.

The resultshave differed, however,and more studies are neededinthisareatostrengthenthehypotheses.

As the assessment of sound information processing is of interest to scientiﬁc research in this population, the presentstudyisinnovativeinitsassessmentofBAEPswith

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bothverbalandnonverbalstimuliinindividuals withASD.

Thisresearchisofgreatimportancebecauseitcanreﬂect the changesin soundconduction via the central auditory pathways,allowingabetterunderstandingofacousticinfor- mation processing. The present study used two different typesofstimuli;itmakesanimportantcontributiontothe literaturebecauseonlyoneprevious studycomparedboth stimulustypes.Althoughitisnotapioneeringstudyonthe subject, most previous studies of BAEPs in ASD usedonly nonverbalstimuli.

ConsideringthatindividualswithASDarehypo-orhyper- sensitive to sounds, the hypothesis of this study is this population will present abnormalities in BAEPs with both speech and click stimuli. Thus, this study aimed to ana- lyzetheneuralencodingofverbalandnonverbalstimuliin individualswithASDusingBAEPs.

Materials and methods

This was a prospective, cross-sectional clinical study approvedbytheResearchEthicsCommitteeundernumber 227/15.Allsubjectswhoparticipatedinthesurveyandtheir parentsreceivedexplanationsandsignedinformedconsent forms.

Sample

The studyincluded 30individuals agedbetween 7 and12 yearsandofbothgenders.Thesamplewasdividedintotwo groups:

• ASD group: A total of 26 families of individuals diag- nosedwithASDwereinitiallycontacted. Ofthese,only 15individualsparticipatedandwereabletocompleteall assessments(twofemalesand13males,withameanage of 9.07±1.75years). Alltheindividuals withASDwere diagnosedbypsychiatristsandneurologistsaccording to the DSM-IV criteria. The Autism Behavior Checklist was usedtoguaranteethehomogeneityofthegroup,andthe participatingindividualsscoredbetween75and85.The WisconsinCardSortingTestwasusedtoassesscognitive development; the results were analyzed by an experi- encedpsychologistandindicatedperformancearoundthe lowlimitsofnormaldevelopment.Alltheindividualswith ASD communicated verbally with major deﬁcits in the functional use of language.The absence of any neuro- logicaldisorder(suchasseizuresand/orsyndromes)was aninclusioncriterion.

• Typicaldevelopmentgroup(TD):Thisgroupcomprised15 normal,healthyindividualswhowerematchedbyageand gender totheASDgroup.Theydidnotpresent anypsy- chiatricdisorders,neurologicalantecedents,orauditory and/orspeechorlanguagecomplaints,andweresponta- neouslyandvoluntarilyrecruited.

Inadditiontotheabovementionedinclusioncriteria,only childrenwithnormalhearingwereconsidered.To ruleout possible hearing loss, an initial anamnesis wasconducted withtheparentor guardiantoinvestigatetheindividual’s medicalhistory,andmeatoscopywasperformedtoruleout possibleobstructionoftheexternalearcanal.

Subsequently,thefollowingprocedureswereperformed, andthefollowingnormalitycriteriawereapplied:

• Acoustic immittance measurement: Tympanometry was performedusinganAT235(Interacoustics^®,AT235,Den- mark) with ipsilateraland contralateral acoustic reﬂex analysisatfrequenciesof0.5,1,2,and4kHz.Theinclu- sioncriterion wasthe presence of a type Acurve with acousticreﬂexes.

• Pure tone audiometry: A audiometer (Grason-Stadler^®, GSI6,USA)wasused.Thiswasperformedatfrequencies of0.5, 1, 2,and 4kHz, andin some cases, playcondi- tioningwasused.The accepted normalitycriterionwas anaudibilitythresholdofupto20dBHLforallmeasured frequencies.

• Speechaudiometry:Aaudiometer(Grason-Stadler^®,GSI 6,USA)wasused.Thespeechrecognitionthreshold(SRT) andthespeechrecognitionpercentageindex(SRPI)were assessed using the word lists suggested by Santos and Russo.¹⁸ThenormalitycriteriawereanSRTofupto10dB HLabovethemeanpuretonethresholdforthefrequen- cies of 0.5, 1, and 2kHz;for the SRPI, more than 88%

correctresponsesatanintensityof30dBabovetheSRT wasconsideredacceptable.

All tests were conducted in a soundproof booth, and thesoundstimuliwerepresentedthroughsupra-auralhead- phones.

Procedures

Electrophysiological hearing assessments were performed usingtheSmart EPUSBJunior(Intelligent HearingSystem 5020,USA)inanacousticallytreatedroomwiththesubject sittingcomfortablyinarecliningchair.

Theparticipant’sskinwascleansedwithabrasivepaste, andtheelectrodeswereplacedusingelectrolyticpasteand microporous tapeaccording totheIES 10-20 international standard.¹⁹ The impedancevaluesof the electrodes were maintained below 5k. BAEPswere measured using click andspeechstimulitransmittedviainsertearphones.

BAEPswithaclickstimuluswereperformedwithrarefied polarityat 80dBHLandwere presentedat arateof 27.7 stimulipersecondforatotalof2048stimuli.Therecording windowwas24ms.Twotestswereperformedoneachear sothatreproducibilityofthetraceand,consequently,the presenceoftheresponsecouldbeverified.Afterthetraces werecollected,theabsolutelatenciesofwavesI,III,andV, andinterpeakintervalsI---III,III---V,andI---Vwereidentified andanalyzed.

BAEPswithspeechstimuliwereperformedusingthesyl- lable/da/,whichwasdeliveredtotherightearonlyatan intensityof80dBHL,arateof11.1stimulipersecondanda recordingwindowof60ms.Twosweepsof3000stimuliwere performedforatotalof6000stimuli.Aftercollection,the tracesweresummed;inthetraceresultingfromthissum, theabsolutelatenciesofwavesV,A,C,D,E,F,andOand theV-Aamplitudewereidentiﬁedandanalyzed.

After the data were collected, they were submitted to descriptive and inferential statistical analyses. For the BAEPs with a click stimulus, the descriptive analysis

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was performed using summary measures for the absolute latenciesofwavesI,III,andVinmilliseconds(ms)andfor interpeakintervalsI---III,III---V,andI---Vinmicrovoltsbyear (rightandleft)andbygroup(TDandASD).Intheinferential analysis,eachlatencyandinterpeakintervalwasanalyzed usinganadjustednormalmixedmodelinwhichthepatient effect wasconsidered random and group and ear effects were considered ﬁxed.²⁰ For each model, the diagnostic analysis showed that the adjusted model performed well.²¹

Asigniﬁcancelevelof0.05wasadoptedforeachhypoth- esistest.First,thehypothesisthattherewasnointeraction effectbetweengroupandearwastested.Whenthishypoth- esiswasnotrejected(p-value>0.05),thehypothesesthat therewerenogrouporeareffectsweretested.

FortheBAEPswithspeechstimulus,theequalityofthe twogroups’ means for allvariables wastested using Stu- dent’s t-test for twoindependent sampleswith the same variance.²² Homoscedasticity and normality assumptions wereveriﬁedandwereshowntobesatisﬁed.

Results

TheBAEPresultswereanalyzedusingdescriptivemeasures for theabsolutelatency ofwaves I,III,andVin theright andleftearsofbothgroups(Fig.1).

For each of the absolute latencies of waves I, III, and V,anadjustedmodelthattookintoaccountthegroupand earvariableswasapplied.Theinteractionsbetweenthese variablesforeachwave(p-valuesof0.783,0.606,and0.179 forwavesI,IIIandV,respectively)werecomparedforeach groupirrespectiveofearandforboth earsirrespectiveof group.

Therewasevidenceofaneareffect;themeanabsolute latencyofwaveIintherightearwasgreaterthanthatof theleftear(p-value=0.037)irrespectiveofgroup;themean absolutelatenciesofwavesIIIandVdidnotdifferbetween ears(p-valuesof0.326and0.613,respectively).

Therewasnoevidenceofagroupeffect;themeanabso- lutelatenciesofwavesI,III,andVdidnotdifferbetween groups(p-valuesof0.666, 0.682,and 0.211,respectively) foreithertherightorleftear.

ForinterpeakintervalsI---III, III---V,andIV,a descriptive analysiswasperformedontherightandleftearsfor both groups(Fig.2).

Similartothemethodusedforthelatencies,theinferen- tialanalysisofinterpeakintervalsI---III,III---V,andI---Vused anadjustedmodelthattookintoaccountthegroupandear variables.Astherewasnointeractionamongthesevariables (p-valuesof0.634,0.107,and0.099forinterpeakintervals I---III,III---V,andI---V,respectively),theearswerecompared irrespectiveofgroup,andthegroupswerecomparedirre- spectiveofear.

Theresultsshowedevidenceofagroupeffect.Themean of interpeak interval III---V in the ASD group was greater than that of the TD group (p-value=0.046). The means ofinterpeakintervalsI---III andI---Vdidnotdifferbetween thetwogroups(p-valuesof0.368and0.332,respectively).

InterpeakintervalsI---III,III---V,andI---Vdidnotdifferbetween theears(p-valuesof0.261,0.918,and0.069,respectively).

FortheBAEPswithspeechstimulus,descriptivemeasures wereperformedfortheabsolutelatenciesofwavesV,A,C, D,E,F,andO,andtheV-Aamplitudeinbothgroups(Fig.3).

Signiﬁcant differenceswereobservedbetweenthe two groups only for the absolute latency of wave V (p- value=0.011), and the mean of the TD group waslonger thanthatoftheASDgroup.

Discussion

BAEPsareobjectivemeasuresthatdonotrequiretheindi- vidual’s active response. Consequently, one of the main clinicalapplicationsofBAEPsistheassessmentof popula- tionsthataredifﬁculttoassessusingbehavioralmethods, suchasindividualswithneurologicalandpsychiatricdisor- ders,includingchildrenwithASD.^4,6

2.3 4.3

4.2 4.1 4 3.9 3.8 3.7 3.6 3.5 3.4

3.3 5.3

5.4 5.5 5.6 5.7 5.8 5.9 6 6.1 6.2

Mean 6.3 Mean

Mean

Median Median

Median 2.2

2.1 2 1.9 1.8 1.7 1.6 1.5 1.4 1.3

ASD Right

Latency (ms)

Right Right

Left Left Left

V III

I

ASD ASD ASD ASD ASD

TD TD TD TD TD TD

Figure1 DescriptivemeasuresofwavelatenciesI,III,andV(ms)ofBAEPswithclickstimulus,bygroupandear.ASD,autism spectrumdisorders;TD,typicaldevelopment;ms,milliseconds.

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1.6 3.7 1.7

1.7 1.8

1.8

1.9 1.9

2 2

2.1 2.1

2.2

2.3

2.4 2.4

2.5 2.5

2.6

3.8 3.9 4 4.1 4.2 4.3 4.4 4.5 4.6

Median Median Median

Mean Mean Mean

ASD ASD ASD ASD ASD ASD

Right Right Right

Interpeak (µV)

Left Left Left

I-V

I-III III-V

TD TD TD TD TD TD

Figure2 DescriptivemeasuresofinterpeaksI---III,III---V,andI---V(ms)ofBAEPswithclickstimulus,bygroupandear.ASD,autism spectrumdisorders;TD,typicaldevelopment;␮V,microvolts.

Mean Median

5.5 6.5 7.5 8.5 9.5

37.5 36.5 35.5 34.5 33.5 32.5

31.5 36

38 40 42 44 46 48

59 57 55 53 51 49

47 0.2

0.3 0.4 0.5 0.6 0.7 0.8 0.9

P=0.801 P=0.357

P=0.250 P=0.234

ASD ASD ASD ASD

ASD ASD

E F O

C D

A V

10.5 13.5

12.5 11.5 10.5 9.5 8.5

7.5 16.5 21

22 23 24 25 26 27 28

17.5 18.5 19.5

p=0.090 20.5 p=0.634 p=0.953

p=0.011

V-A

Latency (ms)Latency (ms) Amplitude (μV)

TD TD TD TD

TD TD

Figure3 DescriptivemeasuresofwavelatenciesV,A,C,D,E,F,andOandtheV-AamplitudeofBAEPswithspeechstimulus,by groupandear.ASD,autismspectrumdisorders;TD,typicaldevelopment;ms,milliseconds;␮V,microvolts.

Thisstudyaimedtoanalyzetheneuralencodingofver- balandnonverbalstimuliofindividualswithASDusingthe BAEPs. To that end, BAEPs were elicited using click and speech stimuli in a group of children with ASD, and the resultswerecomparedwiththoseofTDchildren.

RegardingtheBAEPselicitedbyclickstimuli,nodiffer- ences were observed between the absolute wave latency valuesofindividualswithASDandTDchildren.Regardingthe interpeakintervals,therewasagroupeffectforinterpeak intervalIII---V,forwhichtheASDgroupshowedgreatervalues thantheTDgroup.

The scientific literature is inconsistent regarding BAEP findings. Some studies confirm the lack of changes in the absolute wave latencies of BAEPs^12,15---17; however, other authorshavefoundanincreaseintheabsolutelatenciesof wavesIIIandIV,⁹anincreaseinthelatenciesofwavesIand V,¹⁰ andincreasedlatenciesofwaveVintheright earand waveIintheleftearinindividualswithASD.²³

The dysfunctions observed along the auditory pathway inindividualswithASDhavealsobeen highlightedinother studies that observed changes in the interpeak intervals.

One study that assessed children with ASD also found

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changes only in theIII---V interpeak intervalin these chil- drencomparedwithchildrenwithTD.¹²Otherstudieshave alsoobservedincreasesinthisinterpeakinterval,alongwith otherchanges.10,12,13,23

Additionalstudieshavefoundchangesinterpeakintervals otherthanthoseobservedinthisstudy,suchinterpeakinter- valIII---IV,⁹interpeakintervalsI---IIIandI---V,¹⁵ andinterpeak intervalI---III.²⁴ Incontrast,other studieshavereportedno statisticallysigniﬁcantchangesinBAEPswithclickstimuliin individualswithASD.^16,17

Consideringtheﬁndingsdescribedintheliterature,itcan bedeterminedthatindividualswithASDmayhaveadistinct patternof soundtransmissionthroughoutthenervoussys- tem;additionally,somestudies describealterationsin the lower and/or upper brainstem; despite this, an extended onsetofwaveVhasbeendemonstratedtobethemostfre- quentalterationamongindividualswithASD.Althoughthe resultsof thepresentstudy shownormalabsolutelatency for wave V,the increase in the III---V interpeakintervalis alsosuggestiveofapossiblechangeintheupperbrainstem regionintheseindividuals.

The changesin thelatency values,interpeakintervals, andwaveamplitudesofBAEPsareknowntoreﬂectchanges inthemyelinationi,axondiameter,andsynapticefﬁcacyof theauditorypathwaysatthebrainstemlevel.^25,26Thus,the resultsofthisstudysuggestthatchildrenwithASDexhibit abnormalcorticalstructuresatthebrainstem level,which impairstheconduction ofneuroelectricalimpulsesofnon- verbalstimulibetweenthecochlearnucleiandthelateral lemniscus.

Regarding the BAEPs elicited by speech stimuli, a sta- tisticallysigniﬁcantdifferencewasfoundbetweenthetwo groupsintheabsolutelatencyofwaveV,whichwasshorter intheASDgroupthanintheTDgroup.However,theabsolute latenciesofwavesA,C,D,E,F,andO,andtheV-Aampli- tudeshowednostatisticallysigniﬁcantdifferencesbetween thegroups.

Speech stimuli are complex and consist of numerous acousticcharacteristics.⁸ To capturethese signals,encoding must occur at the beginning of the stimulus in the brainstem.⁷

Some individuals with ASD may be hypersensitive to sounds and other sensory stimuli, which may make them more sensitive tothe acousticcharacteristics of a sound.

This hypersensitivity could explain the decrease in the latencyofwaveVin theASDgroup,whichsuggestsfaster neuralencodingoftheinitialportion(onset)ofthespeech stimulus. This possible hyperresponsiveness to processing theimmediatestartoftheacousticstimulusdoesnotseem tobesustainedthroughtheendofthestimulus(offset),as thisdifferencewasnotobservedfortheothercomponents (wavesA,C,D,E,F,andO).³

The ﬁndingsof this study differfrom thoseof another study inwhich absolute latenciesof waves V,A, C,and F oftheBAEPswerelongerintheASDgroupthaninthe TD group.²⁷

A study usingclickand speechstimuli inchildren with ASDfoundthatthechildrenwithASDhadnormalBAEPsin responsetoclickstimuli;however,whenspeechstimuliwere used, approximately20% of the children with ASD exhib- itedaberrantencodingcomparedtocontrols.The authors suggested that speech stimuli were more sensitive than

click stimuli for detecting subtle difﬁculties in language processing.²⁸

This variation was not considered in all of the com- parative studies above, which may have resulted in a veryheterogeneousresearchsample.Currently,individuals withASDcanbesubdividedintolow-andhigh-functioning groups.²⁵ This variation was not considered in all of the comparativestudies above,which mayhave resulted in a veryheterogeneousresearchsample.Furthermore,thedis- crepanciesintheresultscouldbeduetodifferencesinthe mechanismsof auditory pathwaydysfunctionin along the spectrumof this disorderor todifferencesin the mecha- nismsusedtoprocessstimuli(clickversusspeech).^29,30

Thepresentstudydrewparticipantsfromasinglecenter andwasperformedwithasmallsample;thus,thegeneral- izationof itsﬁndingsis limited.Therefore,futurestudies shouldperformelectrophysiological examinationsofhear- inginagreaternumberofindividualswithASDandshould use these potentials to investigate neuronal plasticity in advanceoftherapeuticintervention.

Funding

ThisresearchwasfundedbySãoPauloResearchFoundation (Fundac¸ãodeAmparoàPesquisadoEstadodeSãoPaulo--- FAPESP2015/13239-7).

Conﬂicts of interest

Theauthorsdeclarenoconﬂictsofinterest.

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