Persistent primary reflexes affect motor acts: Potential implications for autism spectrum disorder

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Contents lists available atScienceDirect

Research

in

Developmental

Disabilities

Persistent

primary

reﬂexes

affect

motor

acts:

Potential

implications

for

autism

spectrum

disorder

Alice

Chinello

a

_,

_Valentina

_Di

_Gangi

b

_,

_Eloisa

_Valenza

b,∗

a_{Physiotherapist}_at_ULSS₁₆_–_Unità_Locale_Socio_Sanitaria,_Padova,_Italy

b_Department_of_{Developmental}_Psychology_and_{Socialization,}_University_of_Padua,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received11October2015

Receivedinrevisedform19July2016 Accepted22July2016 Availableonlinexxx Keywords: Primitivereﬂexes Motoracts Communicativegestures BroaderAutismPhenotype

a

b

s

t

r

a

c

t

Intypicalmotordevelopmentprogressinuseofgoal-directedactionsand communica-tivegesturesdependsontheinhibitionofseveralprimitivereflexes,especiallythosethat involvethehandormouth.Thisstudyexploredtherelationshipbetweenthepersistence ofprimitivereflexesthatinvolvethehandormouthandthemotorrepertoireinasample of12-to17-month-oldinfants.Moreover,sincechildrenwithAutismSpectrum Disor-ders(ASD)oftenhavedifficultyinperformingskilledmovementsandshowpoorgesture repertoire,andsinceASDrepresentstheupperextremeofaconstellationoftraitsthat maybecontinuouslydistributedinthegeneralpopulation,weinvestigatedthe relation-shipbetweenthepersistenceofprimitivereflexesinthesamesampleofinfantsandthe subclinicalautistictraitsmeasuredintheirparents.Resultsrevealedthatthepersistence oftheprimitivereflexescorrelatedwithmotorrepertoireirrespectiveofinfant’sage,andit wasgreateramonginfantswhoseparentshadmoresubclinicalautistictraits.Ourfindings suggestthatthepersistenceofprimitivereflexesmightalterthedevelopmentaltrajectory offuturemotorabilityandthereforetheirevaluationmightbeanearlyindicatorofatypical development.

1. Introduction

Currentlyresearchersareincreasinglyrecognizingtheeffectthatmotorskillshaveonotherareasofdevelopment,such associalcognitionandlanguage(Leonard&Hill,2014).Theemergenceofnewmotorskillschangesinfants’experiencewith objectsandpeopleinwaysthatarerelevantforbothgeneralcommunicativedevelopmentandtheacquisitionoflanguage

(Iverson,2010).Forinstance,itwasfoundthatmotorskillsat18monthsweregoodpredictorsofcommunicationskillsat

3years,supportingthehypothesisthatearlyvarianceinmotorabilitiesisusefulinunderstandinglaterdevelopmentof languageandcommunication(Wang,Lekhal,Aarø,&Schjolberg,2012).

InadditiontotheprimarydiagnosticcriteriaforAutismspectrumdisorder(ASD)reportedintheDiagnosticandStatistical ManualofMentalDisorders(DSM-5,5thedition,AmericanPsychiatricAssociation,2013),childrenwithautismoftenhave difﬁcultyinperformingskilledmovementsandshowpoorgesturerepertoire(Gernsbacher,Sauer,Geye,Schweigert,&

Goldsmith,2008;McDufﬁeetal.,2007;Ozonoffetal.,2008;Stone,Ousley,Yoder,Hogan,&Hepburn,1997;Watson,Crais,

Baranek,Dykstra,&Wilson,2013).UsingretrospectivereportsofmanualmotorskillsinchildrenwithanASDdiagnosis,

∗ Correspondingauthorat:DipartimentodiPsicologiadelloSviluppoedellaSocializzazione,UniversitàdegliStudidiPadova,viaVenezia8,35131 Padova,Italy.

E-mailaddress:[email protected](E.Valenza).

http://dx.doi.org/10.1016/j.ridd.2016.07.010

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Gernsbacherandcolleagues(2008)foundthatchildrenclassifiedashavinghighlyfluentspeechinanassessmentbya speech-languageprofessionalwerereportedtohavemuchbettermanualmotorskillsinearlylifethanthosewithmoderatelyfluent orminimallyfluentspeech.Reportsoftheearlymanualmotorskillsofaproportionofthechildrenwerecorroboratedby homevideoanalysisbyresearchersblindtotheresultsofthecaregiverinterview.

Moreover,agrowingbodyofevidencesuggeststhatadultsandchildrenwithASDshowabnormalitiesofposturalcontrol

(Fournier,Hass,Naik,Lodha,&Cauraugh,2010;Bhat,Landa,&Galloway,2011;Schmitz,Martineau,Barthélémy,&Assaiante,

2003).Forexample,studiesusingforceplatformtechnologytomeasureposturalswayhaveconsistentlyreportedthat individualswithASDexhibitgreaterposturalswayduringquietstancethantypicallydevelopingindividuals.

Basedontheseﬁndings,ithasbeensuggestedthatmotordelaysduringtheﬁrstyearsoflifepredictthemainimpairments thatarecharacteristicofASD(Bhatetal.,2011;Kaur,Srinivasan,&Bhat,2015).Thishypothesishasbeentestedininfant siblingsofchildrendiagnosedwithASD,whohaveaheightenedriskofdevelopingASD.Alongitudinalstudyofmotor developmentin3-to6-month-oldhighrisk(HR)infants(Bhat,Galloway,&Landa,2012)reportedthat70%ofHRinfants withearlymotordelayssubsequentlyexhibitedcommunicationdelays.

Similarly,LeBartonandIverson(2013)reportedthatﬁnemotorskillsin12-month-oldHRinfantspredictedexpressive languageat36months.DuringfreeexplorationofobjectsHRinfantsshowreducedmouthingandgrasping,andatsixandnine monthsoldHRinfantalsoshowexcessivelooking(Iverson,Capirci,&Caselli,1994;Iverson&Fagan,2004;Iverson&Thelen

1999;Koterba,Leezenbaum,&Iverson,2014).Theseﬁndingsweresupportedbyarecentlongitudinalstudyofdifferent

formsofobjectexploration(includingoral,visualandmanualbehaviours)ininfantsexploringthreeobjectsofvarying size.Thedatarevealedobject-baseddifferencesinexplorationpatternsbetweenHRandlowrisk(LR)infants(Libertus&

Landa,2014).Together,theseﬁndingssuggestthatinfantsatHRforASDshowatypicalmotordevelopmentpatternsthat

seemtopredictsocialandlinguisticoutcomes.Studiesofposturalcontrolalsosuggestthatapatternofposturaldelaysand abnormalitiesemergesrelativelyearly-wellbeforetheendoftheﬁrstyear-ininfantswhowilllaterreceiveadiagnosisof

ASD(Esposito,Venuti,Maestro,&Muratori,2009;Nickel,Thatcher,Keller,Wozniak,&Iverson,2013;Ozonoffetal.,2008;

Teitelbaum,Teitelbaum,Nye,Fryman,&Maurer,1998).

Itwassuggestedthatalmostallofthemovementdisturbancesinautismcanbeinterpretedasinfantilereﬂexes“gone astray”;i.e.,somereﬂexesarenotinhibitedattheappropriateageindevelopment,whereasothersfailtoappearwhenthey should(Teitelbaumetal.,2004).

Indeed,progressinmotordevelopmentisrelatedtoareﬂexiveprocess,inwhichtheinfantgraduallymaturesbythe inhibitionofmoreprimitivemotorforms(Teitelbaumetal.,2004).

Primary(orprimitive)reflexesaremusclereactionsthatoccurautomaticallyinresponsetoaspecificstimulus;they emergeduringfoetaldevelopmentandarecriticalforthesurvivalofthenewborninfant(Castielloetal.,2010;Zoiaetal., 2007).Primaryreflexesarereadilyelicitedduringthefirstsixmonthsafterbirth(Allen&Capute,1989;Caputeetal.,1984;

Dubowitz,Dubowitz,&Mercuri,1999;Jordan-Black,2005;Khan,Garcia-Sosa,Hageman,Msall,&Kelley,2014;McPhillips&

Jordan-Black,2007;Yang,2004;Zafeiriou,2004),however,asthenervoussystemmatures,theyareprogressivelyinhibited

andgraduallysupersededbyposturalreﬂexes(Fong,Tsang,&Ng,2012;Geuze,2003;Wilkinson,1994).

Ifprimaryreﬂexesareretainedbeyondthenormaldevelopmentalperiodtheyhavethepotentialtodisruptmaturation processesandreducethebrain’sabilitytoprocesssensoryinformationeffectively(GoddardBlythe,2000,2011;Parfrey,

Gibbons,Drinkwater,&Behm,2014).Inotherwords,thepersistenceofprimaryreﬂexesbeyondthenormaltimespan(12

months)interfereswithsubsequentdevelopmentandisindicativeofneurologicalimpairment(Holt,1994).

Severepersistenceofprimaryreﬂexespredominantlyindicatesintractablephysicalproblemssuchascerebralpalsy

(Pavão,NevesdosSantos,Woollacott,&CicutoFerreiraRocha,2013),whereasmilderpersistenceisassociatedwithless

severedisorders includinglearning difﬁculties(McPhillips, Hepper,&Mulher, 2000; McPhillips& Jordan-Black,2007;

McPhillips&Sheehy,2004).Insummary,theinhibitionofprimitivereﬂexesenablesthedevelopmentofmotorskillsthat

allowtheinfanttoactonandinteractwiththeenvironmentinincreasinglycomplexways.

Inlightoftherelativelyrapidpaceatwhichtypicallydevelopinginfantsbecomecapableofgoal-directedactionsand communicativeacts(theyusuallyachieveboth duringthefirst18 monthsoflife)itissurprisingthatnostudieshave investigatedtheeffectsofthepersistenceofprimitivereflexesonmotoractsandcommunicativegesturesininfancy.This studyattemptedtoaddressthisgapbyexploringtherelationshipbetweenthepersistenceofprimitivereflexesthatinvolve thehandormouthandthemotorrepertoireinasampleof12-to17-month-oldinfantsdrawnfromthegeneralpopulation. Wetestedthreeprimaryreflexes—grasping1_,_rooting2_and_sucking3_._We_expected_to_find_a_higher_rate_of_persistence_of theseprimitivereflexesinyoungerthaninolderinfants.Wealsoexpectedthatthepersistenceoftheprimitivereflexes wouldreduceinfants’performanceintestsofinteractionswithobjects(i.e.,actions)andwithpeople(i.e.,communicative gestures)irrespectiveoftheirage.

1 _The_palmar_grasp_reflex_is_elicited_inserting_the_index_finger_into_the_palm_of_the_infant_from_the_ulnar_side_and_applying_a_light_pressure_to_the_palm. Theresponseofthereflexcomprisesflexionofallfingersaroundthefinger.

2 _The_rooting_reflex_is_elicited_stroking_with_a_finger_the_infant’s_cheek_or_mouth._Infant_turns_the_head_by_moving_it_in_steady_decreasing_arcs_until_the fingerisfound.Afterbecomingusedtorespondinginthisway,theinfantwillmovedirectlytothefingerwithoutsearching.

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Wewerealsointerestedininvestigating,inthesamegeneralpopulation-basedsample,therelationshipbetweenthe persistenceofprimitivereﬂexesandthesubclinicalautistictraitsmeasuredintheirparentswhocompletedapaperversion oftheAutismSpectrumQuotientquestionnaire(AQ;Baron-Cohen,Wheelwright,Skinner,Martin,&Clubley,2001).Itis wellknownthatASDrepresentstheupperextremeofanexusoftraitsthatarecontinuouslydistributedinthegeneral population(e.g.,Baron-Cohenetal.,2001;Constantino&Todd,2003;Dawsonetal.,2002).Peoplewithadiagnosisofautism manifestautistictraitsattheextremeendofthisdistribution,whereasunaffectedfamilymembersofautisticindividuals maydisplaysubclinicalautistic-liketraits.Therefore,neurocognitivedysfunctionsassociatedwithautismcanbefoundnot onlyinaffectedindividualsbutalsointheirgeneticrelatives,manyofwhomhavesocialandcommunicationimpairments similartothoseinASD,butinmilderform(e.g.,Baron-Cohen,1995;Belmonte,Gomot,&Baron-Cohen,2010;Dawson

etal.,2005;Sucksmith,Roth,&Hoekstra,2011).Boltonandcolleaguesweretheﬁrstthatreferredtotheoccurrenceof

thesecharacteristicsasevidenceofabroaderautismphenotype(BAP—Boltonetal.,1994).TheAQisasensitivemeasureof autistictraitsinthegeneralpopulation,implyingthattraitsreachingaclinicallevelinautismalsoexisttoalesserdegreein nonclinicalcounterparts(Baron-Cohenetal.,2001;Ruzichetal.,2015).Previousstudieshavealsoconfirmedaconsistent genderdifferenceinthemeanAQscore:typicalmalesscoresignificantlyhigherthantypicalfemales,whilepeopleofboth sexeswithanautismspectrumconditionscoreattheextremehighendofthescale,inlinewiththeextrememalebrain (EMB)theoryofautism(Baron-Cohen,2002;Baron-Cohenetal.,2014).Theextrememalebraintheorypositsthatthere aretypicalmaleandfemalecognitiveprofiles(‘braintypes’)inthegeneralpopulation,intwodomains:empathizing(the driveandabilitytoidentifyaperson’sthoughtsandfeelings,andtorespondtothesewithanappropriateemotion)and systemizing(thedriveandabilitytoanalyzeorbuildsystems).Typicalfemales,onaverage,exhibitmoreempathizingand lesssystemizingcomparedtotypicalmales,andpeoplewithautismshowanextremeofthis‘maleprofile’.

Weexpectedthatinfantswhoseparentsdisplayedhigherlevelsofautistictraits(althoughstillbelowtheclinical thresh-old)wouldalsoshowmorepersistentprimitivereﬂexes.Moreover,giventhat,inthenonclinicalpopulationsubclinical autistictraitsaremorecommoninmales(Baron-Cohen,2003;Baron-Cohenetal.,2001;Constantino&Todd2003;Ruzich etal.,2015),weexpectedtoobservemoreASDsubclinicaltraitsinfathersthaninmothers,andthereforethatinfantreﬂex scoreweremainlyrelatedtopaternalAQscore.

2. Method 2.1. Participants

Theresearchinvolved34infants(15boysand19girls)agedfrom12to17months(averageage:461days)whowere recruitedfromalistoffamilieswhohadexpressedinterestintakingpartininfantdevelopmentstudies.Allinfantswerefrom full-term,uncomplicatedpregnanciesandwerefreeofknownorsuspectedabnormalities;theywereallfrommiddle-class families.Mostoftheparticipants(22)weretestedinnurseriesinacityinnorthernItaly;theremaining12infantswere testedintheirhomes.Fifty-sixparentsoutofthe68completedtheAQquestionnaire.Theresearchprotocolwasapproved bythePadovaUniversityethicscommittee(protocoln.1645)andthestudywasconductedinaccordancewiththeprinciples oftheDeclarationofHelsinki.Parentsgavewritteninformedconsentfortheirinfants’participationpriortothestartofdata collection.

2.2. Materials

Thepersistenceofgrasping,rootingandsuckingreflexeswasassessedusingGoddard’sscale(GoddardBlythe,2002).A soft,disposablebrushwasusedtostimulatethehandsandmouthofeachinfant.Toelicitthegraspingreflexthebrushwas movedfromtheradialtotheulnarsideofthemetacarpalheadandfromthemetacarpalheadoftheforefingertothetwist ofthecreaseontheradialside.Thebrushwasmoveddownwardsfromtheouterbaseofthenosetobeyondthecornerof themouthtoelicittherootingreflex,andmovedaroundinthecentralareaabovetheupperliptoelicitthesuckingreflex. Allreflexeswereassessedusingafive-pointscalewithhigherscoresindicatinggreaterinhibitionofthereflexes.

Actionsandcommunicativegestureswereevaluatedusingathree-pointscale,withhigherscoresindicating better performance.Table1reportssomeexamplesofactionsandcommunicativegesturesproposedtotheinfants.

Finally,bothparentsofallinfantparticipantscompletedaprintedversionoftheﬁvesubscalesoftheAQquestionnaire (socialskills;attentionswitching;attentiontodetail;communication;imagination)(Baron-Cohenetal.,2001).HigherAQ scoresindicatehigherlevelsofautistictraits(thescalemeasurestraitsaboveandbelowtheclinicalthreshold).

2.3. Procedure

Infantswereobservedforapproximately25–30minduringasemi-structuredplaysession.

Intheﬁrstphaseinfantsplayedfreely;thisphasewasdesignedtofamiliarizethemwiththetworesearchers(asecond observerassessedinfants’behavior;wethusobtainedtwoindependentassessments).Theobservationphasebeganassoon astheinfantappearedtobecomfortablewiththetworesearchesandavailabletoplaywiththem.Duringthisphasethe infantwasseatedontheﬂoorinfrontofoneofthetworesearchers.Thisresearcherpresentedtheinfantwithsometoys andinvitedtheinfanttoimitateheractions(seeTable1).Toengagetheinfants’attentiontheactionswereintroducedas

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Table1

Examplesofactionsassessedduringtheobservationalmotoractionassessmentsession.

Action Playsession Score1 Score2 Score3

Voluntaryexhalation Theresearcherlightsacandle andthenblowsitoutwitha strongexhalation.The researcherrelightsthecandle andaskstheinfanttoblowas strongasthewindtoblowit out.

Theinfantdoesnot protrudehis/herlips.

Theinfantprotrudes his/herlipswithout sufﬁcientstrengthto blowoutthecandle

Theinfantprotrudes his/herlipsefﬁciently andblowsoutthe candle.

Theresearcherinsertsacoin intothetrayofacashregister. Shethenpressesabuttonto displaythecoininthetray. Finally,sheinvitestheinfantto pressthebuttoninordertosee thecoinagain.

Theinfantisnotableto pressthebuttonor usesthepalmof his/herhandtodoso.

Theinfantpressesthe buttonusingmore thanoneﬁnger.

Theinfantpressesthe buttonusingonly his/herforeﬁnger.

Disappearinggesture Theresearcherinsertsacoin intoamoneybox,thenopens herhandswiththepalms facingupwardsandsays“the money’snotanymore!”The researchertheninsertsanother coinandaskstothechild “whereisthecoin?”

Theinfantdoesnot imitatethe disappearinggesture, his/herhandareclosed

Theinfantopensthe handbuthis/her ﬁngersarebentand half-closed

Theinfantopensthe hand,his/herﬁngers arewellextended

behaviorsperformedbytheprotagonistinastory.Theresearcherdemonstratedthemotoractsseveraltimes(maximumof

ﬁvetimes).Reﬂexeswereevaluatedattheendoftheobservationphase.

2.4. Variablesandcoding

Thevariablesanalysedincluded:(1)totalscoreonreﬂexassessments,(2)totalscoreonthemotorassessmentand(3)

quantitativemeasureofparentalautistictraits(evaluatedusingtheAQquestionnaire).Twoindependentobserverscodedall

instancesofreﬂexesandactions.Theinter-rateragreementwascalculatedusingtwoindices:simplecorrelationbetween

thescoresgivenbythetwocoders(r=0.976;p<0.001;408observations)andCohen’sKappa(k=0.883);bothindicated

excellentinter-rateragreement.

3. Resultsanddiscussion

3.1. Preliminaryanalyses

Theaveragescoresfortheassessmentofinfants’reﬂexesandmotoractswererespectively20.59(SD=5.10)and27.41

(SD=4.68).

Theeffectofageonthepresenceofprimitivereﬂexeswasevaluatedaspartofthepreliminarystatisticalanalyses.Infant

age(expressedindays)andprimitivereflexscorewerecorrelated(r=0.394;p=0.021),confirmingthatprimitivereflexes

decreasewithincreasingage(Fig.1).

Theage effect suggested bythe correlation wasconﬁrmed by a t-test.Participants were divided into two differ-entageranges: youngerthan15 months(n=16,Mage=14months,SD=35days)and olderthan 15months(n=18,M age=17months, SD=28days). The t-test revealed that primitive reﬂex score differed between the two age groups

(t(19.3)=−2.644,p=0.016),indicatingthatolderparticipants(M=22.66,SD=2.52)showedgreaterinhibitionofprimitive

reﬂexesthanyoungerparticipants(M=18.25,SD=6.24).

Thispreliminaryanalysisconfirmedthatprimitivereflexesdecreasewithincreasingage.Thisfindingisconsistentwitha maturationalaccountoftheinhibitionprimitivereflexes.Interestingly,theresultsrevealedthepresenceofprimitivereflexes ininfantsolderthan15months,whichislaterthantheexpecteddateofreflexinhibition(12months).Furtheranalysesto determinewhetherthepersistenceofprimaryreflexesaffectedmotorperformanceirrespectiveinfantageweretherefore warranted.

Othervariables,suchasthesettinginwhichtheassessmenttookplace(i.e.,nurseryorhome)andparticipants’gestational ageatthetimeofbirthdidnotinﬂuencethedependentvariableandwerethereforeexcludedfromsubsequentstatistical analyses.

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Fig.1. Infant’reflexscorecorrelateswithage:olderchildrenhavelowerreflexscores;lowscoreindicatesinhibitionofreflexes.

3.2. Dataanalyses

3.2.1. Primitivereﬂexesandmotorrepertoire

Afterconfirmingtherelationshipbetweenthepersistenceofprimitivereflexesandage,weexploredwhetherpersistence ofgraspingandrootingreflexesaffectedinfants’abilitytoperformactionsandcommunicativegesturesthatrequiredfine handandmouthmovementsindependentlyofanyageeffects.Participantsweredividedintotwogroupsonthebasisoftheir scoreontheprimitivereflexesscale.Participantswhoscoredaboveaverage(i.e.,showedrelativehighpersistenceofprimary reflexes)madeupthe‘highpersistenceofreflexes’(HPR)group(n=13,Mreflexscore=15.69,SD=5.06),whereasthosewith belowaveragescorescomprisedthe‘lowpersistenceofreflexes’(LPR)group(n=21,Mreflexscore=23.62,SD=1.53).

Aone-wayANOVAonmotorscore(handandmouthactions),withreﬂexgroup(HPR;LPR)asabetween-subjectsfactor andageasacovariaterevealedamaineffectofreﬂexgroup(F(1,31)=14.514,p=0.001p2=0.319)whichwasindependent

ofage(F(1,31)=1.222,p>0.05).TheseﬁndingsrevealedthatLPRparticipantshadhighermotorscoresthanHPRparticipants

(t(32)=−4.814,p=0.0001;Cohen’sd=1.65),suggestingthatthepersistenceofprimitivereﬂexesreducesinfants’performance

ininteractionswithobjects(i.e.,actions)andpeople(i.e.,communicativegestures). 3.2.2. Primitivereﬂexesandsubclinicalautistictraits

Wealsoinvestigatedtherelationshipbetweenpersistenceofprimaryreflexesininfantsandparentalself-reportsof subclinicalautistictraits.Theseanalysesarebasedondatafrom28ofthe31participants,asinthecaseofthreechildren atleastoneparentprovidedanincompleteAQquestionnaire(missingresponsesformorethanfiveitems).The Shapiro-Wilkdistributiontestofmaternal(S-W=0.967,df=28,p=0.492)andpaternal(S-W=0.958,df=28,p=0.321)AQscores confirmedthatsubclinicalautistictraitswerecontinuouslydistributedinoursample,asinthegeneralpopulation.Using thenormativedatafromtheItalianvalidationofthequestionnaire(Ruta,Mazzone,Mazzone,Wheelwright,&Baron-Cohen, 2012)theparents’AQscoresweretransformedintoz-scores.Infants’reflexscoreswerealsotransformedintoz-scores. ThecorrelationsbetweeninfantreflexscoreandmaternalandpaternalAQscoreswerecalculated(allscoresexpressed asz-scores).InfantreflexscorewascorrelatedwithbothpaternalAQscore(r=−0.543;p=0.003)andmaternalAQscore (r=−0.388;p=0.041),suggestingthatparentswithhigherlevelsofsubclinicalautistictraitstendtohaveinfantswhoshow morepersistentprimitivereflexesthanparentswithlowerlevelsofsubclinicalautistictraits(Fig.2).

Toexploretherelationshipbetweenpersistenceofprimaryreﬂexesininfantsandparentallevelsofsubclinicalautistic traitsweconductedanANOVAwithmaternalandpaternalAQscoresascovariatesandinfantreﬂexscoreasthedependent variable.AsexpectedtherewasamaineffectofpaternalAQscore(F(1,24)=7699,p=0.011p2=0.243),indicatingthatinfant

reﬂexscoreisrelatedtopaternalAQscore.Thiseffecthasbeenconﬁrmedindependentlybyparticipants’age(F(1,24)=3.120,

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Fig.2. InfantreﬂexscoreiscorrelatedwithparentalAQscore;childrenwithmorepersistentprimaryreﬂexeshaveparentswithhigherlevelsofsubclinical autistictraits.

Table2

Correlationalmatrix.ThetableshowsthecorrelationsbetweeninfantreﬂexscoreandmaternalandpaternalscoresonthetwoselectedASQsubscales (seetablefootnoteforsigniﬁcancelevel).

ReﬂexesScore MaternalSocialSkillsAQ MaternalCommunicationAQ

ReﬂexesScore 1 −0.456** _−0.204

PaternalSocialSkillsAQ −0.421** _0.086 _0.273

PaternalCommunicationAQ −0.457** _0.055 _0.276

***_p_<_0.001. ** _p_<_0.05.

WefocusedontwooftheﬁveAQsubscales,socialskillsandcommunication,becausepreviousstudieshavefoundsocial andcommunicativeimpairmentsinthesiblingsandparentsofindividualswithASD(e.g.,Boltonetal.,1994;Constantino

etal.,2006;Pivenetal.,1997).Mostimportantly,recentevidencesuggeststhatthesedomainsaremainlyconnectedwith

thecharacteristicsoftheoffspring,whentheypresentsadiagnosisofautism(Bishopetal.,2004;Wheelwright,Auyeung,

Allison,&Baron-Cohen,2010).

Infantreflexscorewascorrelatedwithpaternalscoresonboththesocialskills(r=−0.421,p=0.026;n=28)and com-municationsubscale(r=−0.457,p=0.014;n=28)andwithmaternalscoreonlyonthesocialskillssubscale(r=−0.456, p=0.015;n=28).Takentogetherthesecorrelations(seeTable2)suggestthatinfantswithmorepersistentreflexestendto havefatherswhoshowmoreautistic-traitfeaturesinsocialskillsandcommunicationsubscales(anditsreverse),whereas motherswithlowersocialskillshaveinfantswithmorepersistentprimitivereflexes(anditsreverse).

3.3. Generaldiscussion

Thetargetofthecurrentresearchwastoidentifytherelationshipsbetweenthepersistenceofthreeprimitivereﬂexes (grasping,rootingandsucking)andboththemotorrepertoireof12-to17-month-oldinfantsandtheirparentalsubclinical autistic-liketraits.

Thistargetisrelevantforatleasttworeasons.First,thepersistenceofprimitivereﬂexesmightbeapromisingearlysign ofautismthat,togetherwiththeearlyattentionalsigns(Elsabbaghetal.,2013,2009;Ronconietal.,2014),mighthelpto characterizethedevelopmentalcourseofbroaderphenotypeofautismininfancy(e.g.,BAP,Pivenetal.,1997).Inlinewith theNeuroconstructivistapproach(Bishop,1997;Karmiloff-Smith,1998)webelievethatsmallvariationsintheearlystages

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ofthedevelopment(i.e.,thepersistenceofprimitivereﬂexes)mightexertnegativecascadingeffectsnotonlyonlatermotor skillsbutalsoinavarietyofotherdomains(i.e.,objectexplorationandsocialandcommunicativebehaviour).

Second,detectingearlymotorabnormalitiesmightbealsopromisingforstratificationofASD(Esposito&Pasca,2013). Indeeddependingonthetaskandthecohort,theproportionofASDschildrendisplayingmotordevelopmentabnormalities varies.Esposito,Venuti,Apicella,andMuratori(2011),foundthatpersistentposturalasymmetrieswerepresentonlyin ∼40%ofchildrenwithASDs.Thevariabilityinthesedeficitsacrossthespectrumisachallengethatlikelyreflectstheclinical andetiologicalheterogeneityofASDs.Atthesametime,itconstitutesauniqueopportunitytoidentifydiseasesubtypes.

Startingfromtheseconsiderations,weexaminedinageneralpopulationof12–17monthsoldinfantstherelationship betweenthepersistenceofprimitivereﬂexesthatinvolvetheuseofthehandandofthemouthand(1)infants’age,(2) infantsmotorrepertoireand(3)thesubclinicalautistictraitsmeasuredintheirparents.

Findingsrevealedahigherinhibitionofprimitivereflexesinolderthaninyoungerinfants.Thisresultsustainsa mat-urationalexplanationofprimitivereflexesinhibitions:asthenervoussystemdevelops,primitivereflexesareinhibitedor transformed.Resultsrevealedalsothepresenceofprimitivereflexesbeyondtheirnormaltimespan(12months),confirming apreviouswork(McPhillipsetal.,2000):theinhibitionofprimaryreflexescanbebroughtatalaterstageofthedevelopment thanisgenerallyaccepted.

Independentlybyparticipants’age,thepersistenceoftheprimitivereflexeswassignificantlyassociatedwithinfant’s performanceinboththeinteractionwithobjects(i.e.actions)andwithpeople(i.e.,communicativegestures),meaningthat lowscoresintheprimitivereflexesassessment,correspondingtoelevatedpersistenceofthereflexes,correlatewithlow scoresinmotorrepertoireirrespectiveoftheinfants’age.Thisfindingisconsistentwithpreviousstudies,revelingthatthe persistenceoftheAsymmetricalTonicNeckreflex,anotherprimitivereflex,reducesbothfine(suchasfingering,shaking, rotatingandtransferringobjectsacrossthemidline)andgross(suchasrolling,creeping,crawling,ridingabicycleand catchingorkickingaball)motorabilities(McPhillipsetal.,2000;McPhillips&Sheehy,2004).

Finally,ourresultsrevealedthatparticipants’persistenceofprimitivereflexesisrelatedtosubclinicalautistictraitsin theircloserelatives:parentswithhighersubclinicalautistictraitshaveinfantswithastrongerpersistenceofprimitive reflexesthanparentswithlowersubclinicalautistictraits.Morespecifically,ourdatasuggestthatinfantswithhigherlevel ofreflexespersistencehavefatherswithmoreautistic-likefeaturesinthesocialskillsandcommunicationsub-scales(and itsreverse)andmotherswithlowersocialskills(anditsreverse).Altogethertheresultsofthisstudyisinlinewithallthose studiesthathavesuggestedtoobservethemotordomainasapromisingearlysignofASD(Bhatetal.,2011,2012;Kaur

etal.,2015;Koterbaetal.,2014;LeBarton&Iverson,2013)andalsoforstratiﬁcationofASD(Esposito&Pasca,2013).

Therearelimitationsandcautionsassociatedwiththecurrentstudy.First,thefindingherereportedwerenotspecificto infantslaterdiagnosedwithASD,butconcernstherelationshipbetweenreflexpersistenceintypicalpopulationandASD endophenotypeoftheirparents.Endophenotypereferstoatraitthatoccursmorecommonlyinaffectedfamilymembers ofariskgroupthaninthegeneralpopulation.Thus,endophenotypesareheritablecharacteristicsthatmayhaveagenetic relationtoASDwithouthoweverpredictingfulldiagnosis(Szatmarietal.,2007;Viding&Blakemore,2007).Therefore,to betterunderstandtheroleofprimitivereflexespersistenceonlateratypicaldevelopment,futureresearchshouldbefocused onthereflexespresenceininfantswhoaremorelikelytodevelopASD(i.e.,infantswithsiblingsalreadydiagnosed).

Thesecondissueregardsthesamplesize(n=34)thatisrathersmallandthereforeitmaynotadequatelyrepresenta typicalpopulationofinfants.Ourfindingsrequirereplicationwithlargernumberofinfantsandlongerperiodofobservation. Thethirdissueregardstheexperimentaldesign.Herewecomparedtwogroupsofinfantswithdifferentage(i.e.,younger vs.olderthan15months),butitisclearthatadeeperunderstandingofdevelopmentaltrajectoriesrequiresindividual outcomesthatcanbeobtainedonlycollectingdatalongitudinallyacrossdifferentages.Forinstance,intypicaldevelopment theinhibitionoftheprimitivereflexespromotesefficientposturalcontrol:Howdoesthepersistenceofprimitivereflexes interferewithposturaldevelopment?Howmanyinfantswithahighpersistenceofprimitivereflexesshowalsopostural impairments?

Despitetheselimitations,andtakinginaccounttherelativeeasetoobserveprimitivereflexes(forbothparentsand paediatricians),webelievethatourfindingssuggestthatthepersistenceofprimitivereflexesmightbeapromisingmarker thatshowsthewayforwardindevelopingmoreeffectiveearlyidentificationandscreeningmeasures.

Conﬂictofinterests

Theauthorsdeclarethattheyhavenoconﬂictofinterests.

Acknowledgements

Weareextremelythankfultoallthefamiliesthattookpartinthepresentstudy.Wealsohavetothankthenurseries thathostedus.ThepresentresearchwassupportedbytheProgettidiEccellenzagrantfromtheCARIPAROFoundation,Italy (rep.no.1873/2012).

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References

Allen,M.C.,&Capute,A.J.(1989).Neonatalneurodevelopmentalexaminationasapredictorofneuromotoroutcomeinprematureinfants.Pediatrics, 83(4),498–506.

Baron-Cohen,S.(1995).Mindblindness:Anessayonautismandtheoryofmind.Cambridge,MA:MITPress. Baron-Cohen,S.(2002).Theextrememalebraintheoryofautism.TrendsCognitiveScience,6,248–254. Baron-Cohen,S.(2003).Theessentialdifference:Men,womenandtheextrememalebrain.London:Penguin.

Baron-Cohen,S.,Cassidy,S.,Auyeung,B.,Allison,C.,Achoukhi,M.,Robertson,S.,etal.(2014).Attenuationoftypicalsexdifferencesin800adultswith autismvs.3900controls.PLoSOne,9(7),e102251.

Baron-Cohen,S.,Wheelwright,S.,Skinner,R.,Martin,J.,&Clubley,E.(2001).Theautism-spectrumquotient(AQ):EvidencefromAsperger

syndrome/high-functioningautism,malesandfemales,scientistsandmathematicians.JournalofAutismandDevelopmentalDisorders,31(1),5–17. Belmonte,M.K.,Gomot,M.,&Baron-Cohen,S.(2010).Visualattentioninautismfamilies:‘unaffected’sibsshareatypicalfrontalactivation.Journalof

ChildPsychologyandPsychiatry,51(3),259–276.

Bhat,A.N.,Galloway,J.C.,&Landa,R.(2012).Relationbetweenearlymotordelayandlatercommunicationdelayininfantsatriskforautism.Infant BehaviorandDevelopment,35,838–846.

Bhat,A.N.,Landa,R.J.,&Galloway,J.C.(2011).Currentperspectivesonmotorfunctioningininfants,children,andadultswithautismspectrumdisorders. PhysicalTherapy,91(7),1116–1129.

Bishop,D.V.M.(1997).Cognitiveneuropsychologyanddevelopmentaldisorders:Uncomfortablebedfellows.TheQuarterlyJournalofExperimental PsychologySectionA,50,899–923.

Bishop,D.V.,Maybery,M.,Maley,A.,Wong,D.,Hill,W.,&Hallmayer,J.(2004).Usingself-reporttoidentifythebroadphenotypeinparentsofchildren withautisticspectrumdisorders:Astudyusingtheautism-spectrumquotient.JournalofChildPsychologyandPsychiatry,45(8),1431–1436. Bolton,P.,Macdonald,H.,Pickles,A.,Rios,P.A.,Goode,S.,Crowson,M.,etal.(1994).Acase-controlfamilyhistorystudyofautism.JournalofChild

PsychologyandPsychiatry,35(5),877–900.

Capute,A.J.,Palmer,F.B.,Shupiro,B.K.,Wuchtel,R.C.,Ross,A.,&Accurdo,P.J.(1984).Primitivereflexprofile:Aquantitationofprimitivereflexesin infancy.DevelopmentalMedicine&ChildNeurology,26(3),375–383.

Castiello,U.,Becchio,C.,Zoia,S.,Nelini,C.,Sartori,L.,Blason,L.,etal.(2010).Wiredtobesocial:Theontogenyofhumaninteraction.PLoSOne,5(10), e13199.

Constantino,J.N.,Lajonchere,C.,Lutz,M.,Gray,T.,Abbacchi,A.,McKenna,K.,etal.(2006).Autisticsocialimpairmentinthesiblingsofchildrenwith pervasivedevelopmentaldisorders.AmericanJournalofPsychiatry,163(2),294–296.

Constantino,J.N.,&Todd,R.D.(2003).Autistictraitsinthegeneralpopulation:Atwinstudy.ArchivesofGeneralPsychiatry,60(5),524–530.

Dawson,G.,Webb,S.,Schellenberg,G.D.,Dager,S.,Friedman,S.,Aylward,E.,etal.(2002).Deﬁningthebroaderphenotypeofautism:Genetic,brain,and behavioralperspectives.DevelopmentandPsychopathology,14(3),581–611.

Dawson,G.,Webb,S.J.,Wijsman,E.,Schellenberg,G.,Estes,A.,Munson,J.,etal.(2005).Neurocognitiveandelectrophysiologicalevidenceofalteredface processinginparentsofchildrenwithautism:Implicationsforamodelofabnormaldevelopmentofsocialbraincircuitryinautism.Developmentand Psychopathology,17(3),679–697.

Dubowitz,L.M.S.,Dubowitz,V.,&Mercuri,E.(1999).Theneurologicalassessmentofthepreterm&full-termnewborninfant(2nded.).London:MacKeith Press.

Elsabbagh,M.,Fernandes,J.,JaneWebb,S.,Dawson,G.,Charman,T.,&Johnson,M.H.(2013).Disengagementofvisualattentionininfancyisassociated withemergingautismintoddlerhood.BiologicalPsychiatry,74,189–194.

Elsabbagh,M.,Volein,A.,Holmboe,K.,Tucker,L.,Csibra,G.,Baron-Cohen,S.,etal.(2009).Visualorientingintheearlybroaderautismphenotype: Disengagementandfacilitation.JournalofChildPsychologyandPsychiatry,50(5),637–642.

Esposito,G.,&Pasca,S.P.(2013).Motorabnormalitiesasaputativeendophenotypeforautismspectrumdisorders.FrontiersinIntegrativeNeuroscience, 7(43),1–5.

Esposito,G.,Venuti,P.,Apicella,F.,&Muratori,F.(2011).Analysisofunsupportedgaitintoddlerswithautism.BrainandDevelopment,33,367–373. Esposito,G.,Venuti,P.,Maestro,S.,&Muratori,F.(2009).Anexplorationofsymmetryinearlyautismspectrumdisorders:Analysisoflying.Brainand

Development,31(2),131–138.

Fong,S.S.,Tsang,W.W.,&Ng,G.Y.(2012).Alteredposturalcontrolstrategiesandsensoryorganizationinchildrenwithdevelopmentalcoordination disorder.HumanMovementScience,31(5),1317–1327.

Fournier,K.A.,Hass,C.J.,Naik,S.K.,Lodha,N.,&Cauraugh,J.H.(2010).Motorcoordinationinautismspectrumdisorders:Asynthesisandmeta-analysis. JournalofAutismandDevelopmentalDisorders,40(10),1227–1240.

Gernsbacher,M.A.,Sauer,E.A.,Geye,H.M.,Schweigert,E.K.,&Goldsmith,H.H.(2008).Infantandtoddleroral-andmanualmotorskillspredictlater speechﬂuencyinautism.ChildPsychologyPsychiatry,49(1),43–50.

Geuze,R.H.(2003).Staticbalanceanddevelopmentalcoordinationdisorder.HumanMovementScience,22(4),527–548. GoddardBlythe,S.(2000).Earlylearninginthebalance:PrimingtheﬁrstABC.SupportforLearning,15(4),154–158. GoddardBlythe,S.(2002).Reﬂexes,learningandbehavior:Awindowintothechild’smind.FernRidgePress.

GoddardBlythe,S.(2011).Neuro-motormaturityasanindicatorofdevelopmentalreadlinessforeducation.TACJournal,4,12. Holt,K.S.(1994).Childdevelopment:Diagnosisandassessment.Newness:Butterworth-Heinemann.

Iverson,J.M.(2010).Developinglanguageinadevelopingbody:Therelationshipbetweenmotordevelopmentandlanguagedevelopment.Journalof ChildLanguage,37,229–261.

Iverson,J.M.,&Fagan,M.K.(2004).Infantvocal-motorcoordination:Precursortothegesture-speechsystem?ChildDevelopment,75(4),1053–1066. Iverson,J.M.,Capirci,O.,&Caselli,M.C.(1994).Fromcommunicationtolanguageintwomodalities.CognitiveDevelopment,9(1),23–43.

Iverson,J.M.,&Thelen,E.(1999).Hand,mouthandbrain.Thedynamicemergenceofspeechandgesture.JournalofConsciousnessStudies,6(11–12),19–40. Jordan-Black,J.A.(2005).Theeffectsoftheprimarymovementprogrammeontheacademicperformanceofchildrenattendingordinaryprimaryschool.

JournalofResearchinSpecialEducationalNeeds,5(3),101–111.

Karmiloff-Smith,A.(1998).Developmentitselfisthekeytounderstandingdevelopmentaldisorders.TrendsinCognitiveSciences,2(10),389–398. Kaur,M.,Srinivasan,S.,&Bhat,A.(2015).Atypicalobjectexplorationskillsininfantsat-riskforautismbetween6–15monthsofage.Frontiersin

Psychology,6(798).

Khan,O.A.,Garcia-Sosa,R.,Hageman,J.R.,Msall,M.,&Kelley,K.R.(2014).Coreconcepts:Neonatalneurologicalexamination.NeoReviews,15(8). Koterba,E.A.,Leezenbaum,N.B.,&Iverson,J.M.(2014).Objectexplorationat6and9monthsininfantswithandwithoutriskforautism.Autism,18(2),

97–105.

LeBarton,E.S.,&Iverson,J.M.(2013).Finemotorskillpredictsexpressivelanguageininfantsiblingsofchildrenwithautism.DevelopmentalScience, 16(6),815–827.

Leonard,H.C.,&Hill,E.L.(2014).Review:Theimpactofmotordevelopmentontypicalandatypicalsocialcognitionandlanguage:Asystematicreview. ChildandAdolescentMentalHealth,19(3),163–170.

Libertus,K.,&Landa,R.J.(2014).Scaffoldedreachingexperiencesencouragegraspingactivityininfantsathighriskforautism.FrontiersinPsychology,5, 1071.

McDufﬁe,A.,Turner,L.,Stone,W.,Yoder,P.,Wolery,M.,&Ulman,T.(2007).Developmentalcorrelatesofdifferenttypesofmotorimitationinyoung childrenwithautismspectrumdisorders.JournalofAutismandDevelopmentalDisorder,37(3),401–412.

(9)

McPhillips,M.,Hepper,P.G.,&Mulher,G.(2000).Effectsofreplicatingprimary-reflexmovementsonspecificreadingdifficultiesinchildren:A randomised,double-blind,controlledtrial.TheLancet,355(12),537–541.

McPhillips,M.,&Jordan-Black,J.A.(2007).Primaryreﬂexpersistenceinchildrenwithreadingdifﬁculties(dyslexia):Across-sectionalstudy. Neuropsychologia,45,748–754.

McPhillips,M.,&Sheehy,N.(2004).Prevalenceofpersistentprimaryreﬂexesandmotorproblemsinchildrenwithreadingdifﬁculties.Dyslexia,10(4), 316–338.

Nickel,L.R.,Thatcher,A.R.,Keller,F.,Wozniak,R.H.,&Iverson,J.M.(2013).Posturedevelopmentininfantsatheightenedversuslowriskforautism spectrumdisorders.Infancy,18(5),639–661.

Ozonoff,S.,Young,G.S.,Goldring,S.,Greiss-Hess,L.,Herrera,A.M.,&Rogers,S.J.(2008).Grossmotordevelopment,movementabnormalities,andearly identiﬁcationofautism.JournalofAutismandDevelopmentalDisorder,38(4),644–656.

Parfrey,K.,Gibbons,S.G.T.,Drinkwater,E.J.,&Behm,D.G.(2014).Effectofheadandlimborientationontrunkmuscleactivationduringabdominal hollowinginchroniclowbackpain.BMCMusculoskeletalDisorders,15(1).

Pavão,S.C.,NevesdosSantos,A.,Woollacott,M.H.,&CicutoFerreiraRocha,N.A.(2013).Assessmentofposturalcontrolinchildrenwithcerebralpalsy:A review.ResearchinDevelopmentalDisabilities,34(5),1367–1375.

Piven,J.,Palmer,P.,Landa,R.,Santangelo,S.,Jacobi,D.,&Childress,D.(1997).Personalityandlanguagecharacteristicsinparentsfrommultiple-incidence autismfamilies.AmericanJournalofMedicalGenetics,74(4),398–411.

Ronconi,L.,Facoetti,A.,Bulf,H.,Franchin,L.,Bettoni,R.,&Valenza,E.(2014).Paternalautistictraitsarepredictiveofinfantsvisualattention.Journalof AutismandDevelopmentalDisorders,44(7),1556–1564.

Ruta,L.,Mazzone,D.,Mazzone,L.,Wheelwright,S.,&Baron-Cohen,S.(2012).Theautism-spectrumquotient—Italianversion:Across-cultural conﬁrmationofthebroaderautismphenotype.JournalofAutismandDevelopmentalDisorders,42(4),625–633.

Ruzich,E.,Allison,C.,Smith,P.,Watson,P.,Auyeung,B.,Ring,H.,etal.(2015).Measuringautistictraitsinthegeneralpopulation:Asystematicreviewof theautism-spectrumquotient(AQ)inanonclinicalpopulationsampleof6,900typicaladultmalesandfemales.MolecularAutism,6(2),2–12. Schmitz,C.,Martineau,J.,Barthélémy,C.,&Assaiante,C.(2003).Motorcontrolandchildrenwithautism:Deﬁcitofanticipatoryfunction?Neuroscience

Letters,348(1),17–20.

Stone,W.L.,Ousley,O.Y.,Yoder,P.J.,Hogan,K.L.,&Hepburn,S.L.(1997).Nonverbalcommunicationintwo-andthree-year-oldchildrenwithautism. JournalofAutismandDevelopmentalDisorders,27(6),677–696.

Sucksmith,E.,Roth,I.,&Hoekstra,R.(2011).Autistictraitsbelowtheclinicalthreshold:Re-examiningthebroaderautismphenotypeinthe21stcentury. NeuropsychologyReview,21(4),360–389.

Szatmari,P.,Maziade,M.,Zwaigenbaum,L.,Mérette,C.,Roy,M.A.,Joober,R.,etal.(2007).Informativephenotypesforgeneticstudiesofpsychiatric disorders.AmericanJournalofMedicalGeneticsPartB:NeuropsychiatricGenetics,144(5),581–588.

Teitelbaum,O.,Benton,T.,Shah,P.K.,Prince,A.,Kelly,J.L.,&Teitelbaum,P.(2004).Eshkol–Wachmanmovementnotationindiagnosis:Theearly detectionofAsperger’ssyndrome.ProceedingsoftheNationalAcademyofSciencesoftheUnitedStatesofAmericaPNAS,101(32),11909–11914. Teitelbaum,P.,Teitelbaum,O.,Nye,J.,Fryman,J.,&Maurer,R.G.(1998).Movementanalysisininfancymaybeusefulforearlydiagnosisofautism.

ProceedingsoftheNationalAcademyofSciences,95(23),13982–13987.

Viding,E.,&Blakemore,S.J.(2007).Endophenotypeapproachtodevelopmentalpsychopathology:Implicationsforautismresearch.BehaviorGenetics,37, 51–60.

Wang,M.V.,Lekhal,R.,Aarø,L.E.,&Schjolberg,S.(2012).Cooccurringdevelopmentofearlychildhoodcommunicationandmotorskills:Resultsfroma population-basedlongitudinalstudy.ChildCareHealthandDevelopment,40(1),77–84.

Watson,L.R.,Crais,E.R.,Baranek,G.T.,Dykstra,J.R.,&Wilson,K.P.(2013).Communicativegestureuseininfantswithandwithoutautism:A retrospectivehomevideostudy.AmericanJournalofSpeechLanguagePathology,22(1),25–39.

Wheelwright,S.,Auyeung,B.,Allison,C.,&Baron-Cohen,S.(2010).Deﬁningthebroader,mediumandnarrowautismphenotypeamongparentsusingthe autismspectrumquotient(AQ).MolecularAutism,1(1),1.

Wilkinson,G.(1994).Therelationshipofprimitiveposturalreﬂexestolearningdifﬁcultyandunderachievement(UnpublishedM.Edthesis).Newcastle: UniversityofNewcastle-upon-Tyne.

Yang,M.(2004).Newbornneurologicexamination.Neurology,62(7),15–17.

Zafeiriou,D.(2004).Primitivereﬂexesandposturalreactionsintheneurodevelopmentalexamination.PediatricNeurology,1,1–8.

Zoia,S.,Blason,L.,D’Ottavio,G.,Bulgheroni,M.,Pezzetta,E.,Scabar,A.,etal.(2007).Evidenceofearlydevelopmentofactionplanninginthehuman foetus:Akinematicstudy.ExperimentalBrainResearch,176(2),217–226.