chapter 8 – autism symptoms exist but the disorder remains...

399Rethinking Autism ©2013ElsevierInc.http://dx.doi.org/10.1016/B978-0-12-415961-7.00008-3 Allrightsreserved.

CHAPTER

Autism Symptoms Exist but the Disorder Remains ElusiveContents

The Autism Male to Female Ratio is Likely to be a Composite 402The Extreme Male Brain Theory of the Autism Male/Female Ratio 402The X Chromosome Theory of the Autism Male/Female Ratio 403The Female Protective Factor Theory of the Autism Male/Female Ratio 403Many Risk Factors are Likely to Contribute Many Different Sex Ratios to Autism 403Initial Structural and Hormonal Differences Between Male and Female Brains 404Male Brain Vulnerability During the Prenatal Period 405Initial Male–Female Brain Function Differences may be Increased During Brain Development 406

Summary: The Male to Female Diagnosis Ratio in Autism is Likely to be a Composite Ratio 407

Much Research is Still Focused on Trying to Unify Autism as a Single Disorder 407The Quest to Find a Unifying Feature for Autism Persists 408Two Empirical Unifying Earliest-Feature Claims for Autism 408

Event-Related Potential Pattern to Eye Gaze Before 12 Months Predicts Autism 408Infant White Matter Development Pattern Predicts Autism 409

Two Empirical Unifying Superior Skills in Autism 410Superior Perceptual Integration in Autism 410Superior Discrimination of Visual Movement Speed in Autism 411

Two Empirical Multiple Gene Models of Autism 411The Multiple Hit Model of Autism 411Tumor Necrosis Factor and Beta-Estradiol Regulators as Priorities for Genetic Research in Autism 412

Summary: All Six Studies Sought to Find a Unifying Feature or Pattern in Autism 413Abandoning Autism as a Single Disorder would Eliminate Three Inferential

Problems in Autism Research 414Diagnostic Criteria that have Never been Validated would no Longer be Needed 414

Links Between Autism Diagnostic Symptoms have not been Validated or Explained 414Autism Diagnostic Symptom Set has not been Validated 415

Viewing Behavioral Symptom Heterogeneity as Comorbidity would be Unnecessary 416

The Problem of the Failure to Reconcile Data and Synthesize Theories in Order to Establish the Features of Autism would Disappear 418Lack of Subgroup Synthesis 419

The Hundreds of Theories Proposing a Unifying Feature for Autism would not Require Synthesis if Autism were no Longer Viewed as a Single Disorder 420Theory Predictions from Autism Data Sets Require Reconciliation 421

8

ELSEVIE

R

Rethinking Autism400

More than $1 billion has been spent over the past decade researching autism. In some ways, the search for its causes looks like a long-running fishing expedition, with a focus on everything from genetics to the age of the father, the weight of the mother, and how close a child lives to a freeway.

Stobbe (2012)

Thesymptomsofautismexist.However,thebilliondollarsspentonautismresearchinthepastdecadehasgeneratedevidenceforsignificantheteroge-neityinautism.Chapters1to6documentedheterogeneityinautismdiag-nosticbehaviors,associatednon-diagnosticbehaviors,braindeficits,onsetsymptoms,andgeneticandenvironmental risk factors.Thisevidencehasfoundnosharedpathogenesis,pathophysiology,orvalidatedsymptomset.Theincreasingevidenceforheterogeneitymakesautismaharderandharderproblemtosolve,whiletheincreasingprevalenceputsmoreandmorepres-sureonautismresearcherstosolvetheproblem.

Shockingly,FrancesandWidiger (2012)claimed thatmuchofautismwasafad.FrancesandWidiger(2012)stated,“fadsmeetadeeplyfeltneedto explain, or at least to label, what would otherwise be unexplainablehumansufferinganddeviance”(p.115).Fromthisdefinition,itwouldseemthatpsychiatry,withitsdeeplyfeltneedtoexplainandlabelhumansuffer-inganddeviance,mustbeafad.ThechargemadeagainstautismbyFrancesandWidiger (2012) is wrong.As outlined in Chapter 7, the increase inautismhasbeenshowntostemfromdiagnosticcriteriachanges,diagnosticsubstitution,specialeducationpolicychanges,increasedavailabilityofser-vices,andheightenedawarenessofautism,and,alsoperhapsatrueincreaseinincidence.Someportrayalsofautisminnovels,movies,orontelevisionmaybefaddish,butautismsymptomsarenotafad.

The Existing Quandary and the Argument for Autism as Symptoms 423The Existing Quandary: Should the Current Paradigm of Autism be Abandoned? 423

Rethinking Autism 427The Argument that Autism is Symptoms and not a Single Disorder or a

Spectrum of Related Disorders 427Claim One: Autism has not Been Validated as a Symptom Set, and Heterogeneity

in Symptoms, Brain Deficits, and Etiologies Argues that Autism is not a Single Disorder 427

Claim Two: Environmental and Genetic Risk Factors for Autism Cause Brain Disruptions that are not Causally Specific to Autism Symptoms 428

Claim Three: Because Risk Factors Tie Autism Symptoms to Non-Autism Symptoms, Behavioral Subgroups cannot be Uniquely Autism Subgroups 431

Summary: Autism Symptoms as Symptoms 431Conclusion: Autism Symptoms without a Disorder 432

ELSEVIE

R

Autism Symptoms Exist but the Disorder Remains Elusive 401

Themajorityofautismresearcherscurrentlyholdoneoftwocompetingtheories.Onetheoryisthatautismisasinglemulti-etiologyheterogeneousdisorder.Theothertheoryisthatautismisaspectrumofmanycloselyrelateddisorders.However,thesetwoviewsshadetogetherwhenresearchersdefineautism.Forexample,Satoetal.(2012)stated,“Autismistheprototypicformofagroupofconditions,alsoknownas‘autismspectrumdisorders’”(p.1).Walshetal.(2011)openedtheirpaperbystating,“Autismspectrumdisorderisthetermusedforadiversegroupofdevelopmentalconditionsthataffectaperson’sabilitytorelatetoandcommunicatewithothers”(p.603).Threepages laterWalsh et al. (2012) argued that researchers needed to develop“understandingof autism as a complex condition that is probably deter-minedbymultiple,yet tobeunderstoodpathways that lead toheteroge-neousoutcomes”(p.606).Evenreportsofaunitaryfeatureforautismopenwithatipofthehattothetheoryofmanyautisms.Forexample,Wolffetal.(2012)began theirpaper,“Autism spectrumdisorders (ASDs) are complex disorders of neurodevelopmentdefinedbyimpairedsocialcommunicationandrestricted,repetitivebehaviors”(p.1).Theresearchers,however,concluded,“aberrantdevelopmentofwhitematterpathwaysmay…[cause]thisneuro-developmentaldisorder”(p.1).Elsabbaghetal.(2012)expressedboththeoriesinthefirstfivewordsoftheirfirstsentence:“Autism spectrum disorders (hence-forth autism)arediagnosedinaround1%ofthepopulation”(p.1).

Unfortunately,aclearunderstandingofthenatureofautismhasnotbeengeneratedbythebilliondollarsinresearchfunding.Worsestillisthecostinmissingtranslationalfindingsfortreatmentandprevention.Ifautismismanydistinctdisorderswithmanyvariedcauses,thereisnotranslationalvalueinsearchingforoneunifyingbraindysfunctionforautism.Conversely,ifautismisasinglecomplexdisorder,therewillbenoultimatetranslationalresultsfromefforts to distinguish subgroups.Walsh et al. (2011) stated,“despite hugeadvancesinthebasicscientificunderstandingofautism,comparativelylittlehasbeenachievedtodatewithregardtotranslatingtheresultingevidenceintoclinicallyusefulbiomarkers”(pp.609–610).Unfortunately,mostofthe“hugeadvancesinthebasicscientificunderstanding”ofautismarefindingsformas-sive heterogeneity in genetic variants, chromosomal number variants, andenvironmentalriskfactors,andthese“hugeadvances”havenotsolvedthecorequestionofwhatentity“clinicallyusefulbiomarkers”wouldbeidentifying.

Thischapterhas five sections.The first sectionargues that thehigherprevalenceofmales than femalesdiagnosedwithautism is likely tobeacompositeratio,basedonthemaletofemaleratiosformanydifferentenvi-ronmentalandgeneticriskfactors.Thesecondsectiondemonstratesthat,

ELSEVIE

R


despite accumulated evidence to the contrary, most autism research hascontinuedtosearchforunifyingfeaturesandsinglepredictorsforautism.Thethirdsectionsummarizesthreecriticalinferentialproblemsthatwouldbeeliminatedbyabandoningtheefforttounifyautismasadisorder.Thefourthsectionpresentstheargumentforautismassymptoms.Thefifthandconcluding section proposes a way of seeing and documenting autismsymptomswithoutdefiningautismasadisorder.

THE AUTISM MALE TO FEMALE RATIO IS LIKELY TO BE A COMPOSITE

Noacceptedmodelhasexplainedthereasonforthegreaternumberofmalesthanfemalesdiagnosedwithautism.Recentestimatesoftheautismmaletofemaleratiohaveremainedatbetween2.5and4malesdiagnosedforeveryfemalediagnosed.However,Zwaigenbaumetal.(2012)studied319youngsiblingsofchildrenwithautismandreporteda significantly lowergenderdifferenceratioofonly1.65malesiblingsdiagnosedwithautismforeveryfemalesiblingdiagnosed.Theresearchersdiagnosedautismin57boysamongthe176at-riskmalesiblings,anddiagnosedautismin28girlsofthe143at-risk femalesiblings.Mostsurprisingwasthatboy/girlratios forcognitionandsymptomsintheautismsiblinggroupdidnotdifferfromtheboy/girlratiosforthesamemeasuresinacomparisongroupoftypicalchildren.

Satoetal.(2012)proposedtherewerethreetheoriesexplainingthehighernumberofmalesthanfemalesdiagnosedwithautism:theextrememalebrain,Xchromosomegenevariants,andaprenatalprotectivefactorfunctioninginfemales.

The Extreme Male Brain Theory of the Autism Male/Female RatioBaron-Cohenetal.(2011)theorizedthatautismsymptomswerecausedbydysregulatedfetal testosteronethatresultedinautismsymptomsbeinganexaggerationoftypicalmaletraits.Thistheoryofautismarguedthatfemalesaremoreempatheticthanmales,malesaremoreanalyticthanfemales,andmaleshaveagreaterdrive toconstruct rule systems than females.Autism, in thisview, is anextremeversionof typicalmale systematizing.ChallengestothisviewincludefindingslikethoseofBejerotetal.(2012),whoreportedthatwomenwithautismdisplayedfewerfemininecharacter-isticsthandidwomenwithoutautism,andmenwithautismdisplayedfewermasculinecharacteristicsthandidmenwithoutautism.Bejerotetal.(2012)furthernoted that autismbehaviors and traits correlatedwitheffeminatebodyfeaturesinmenwithautism,andwithlessfemininefacialfeaturesin

ELSEVIE

R


women.Conversely,James(2012)concludedthatthereportsofmoremalesiblingsborn tomothersof boysdiagnosedwith autism andmothersofboyswithdevelopmental languagedisorders supportedtheextrememalebraintheorybecausetheysuggestedthatthematernalproductionofhighandrogenlevelswaspersistent.James(2012)notedthatthereweretwocon-trollingfactorsfortypicalsexratiosatbirth—hormoneregulationatcon-ception, and sex-specific effects of stressors during pregnancy—anddysfunctionineitherfactormightcontributetodevelopmentaldisorders.

The X Chromosome Theory of the Autism Male/Female RatioNooretal.(2010)proposedthatthemaletofemaleratioinautismwasdueto effects of genes of the sex chromosomes. Zwaigenbaum et al. (2012)reportedthatmoregenevariantsontheXchromosomehavebeendiscov-eredinassociationwithautismsymptoms,eachofwhichmightconferahigher number of males with autism: neuroligins 3 and 4; PTCHD1;TMLHE;MECP2;somecasesoffragileXsyndrome;and,possibly,epigen-eticeffectsfrompaternallyimprintedX-linkedgenes.Baron-Cohenetal.(2011),however,arguedthatX-linkedmutationsareinsufficientlyprevalentinautismtoaccountfortheautismsexratio.

The Female Protective Factor Theory of the Autism Male/Female RatioSzatmarietal.(2012)proposedthatfemalespossessedsometraitthatpro-tectedbraindevelopment,suchthatmoregeneticriskfactorswereneededtotriggertheexpressionofautismsymptomsinfemales.Satoetal.(2012)reporteda rareautosomalSHANK1deletiononly inmaleswithautism.MutationsinSHANK2andSHANK3havebeenfoundinassociationwithautismsymptoms;however,Satoetal.(2012)foundautismsymptomsonlyinthemalesinafamilycarryingSHANK1deletions,andnotedthattheirfindingwasthefirstreportofanautosomalsex-limitedriskfactorforautism.BecausetheresearchersalsofoundamalewithautismwhocarriedadenovodeletionofSHANK1,theyconcludedthattheSHANK1deletioninthefamilystudiedwastheprimarycauseofautisminaffectedmalefamilymembers.Satoetal.(2012)reasonedthatcarrierfemalesinthisfamilydidnot express autism symptomsbecause theyhad someneural feature thatprotectedthemfromtheeffectsoftheSHANK1deletion.

Many Risk Factors are Likely to Contribute Many Different Sex Ratios to AutismGivenmultipleriskfactors,itislikelythatthemaletofemalesexratioinautismisacompositeofhundredsofseparatemaletofemalesexratios,each

ELSEVIE

R


ofwhichisdeterminedbyaspecificcausalrisketiologyandtheensuingmediationofbraindevelopment.

Asoutlined inChapters 4 and5,manyvariedgenetic, chromosomal,epigenetic,andenvironmentalriskfactorshavebeenlinkedtoautismsymp-toms.Autismsymptomsmayalsoresultfromprenatalinteractionofmater-nalandchildgenesandthegestationalenvironment,andmayresultfromtheeffectsoffetalimmunesystemgenesintheenvironmentofthedevelop-ingfetalbrain.Iftheautismmale/femaleratioisacompositeofmanyvariedratios, thengenevariantson theXchromosome,epigeneticeffects frompaternallyimprintedX-linkedgenes,therareautosomalSHANK1deletionfoundonly inmaleswith autism, and intrauterine testosteronemight allcontributetotheratioofmoremalesthanfemalesinautism.

Genetic and environmental risk factors have tied autism symptoms toschizophrenia,anxiety,attentiondeficit/hyperactivitydisorder,Tourettesyn-drome, intellectualdisability, and languagedevelopmentdisorders.Copeland,Shanahan, Costello, andAngold (2011) conducted a prospective populationstudyofpsychiatricdisorderprevalencein1400childrenaged9–16years.Theyfounda1.6to1ratioofmalestofemalesforanypsychiatricdiagnosis.Theneurocognitivedisorderswhosesymptomshavebeenlinkedtoautismthroughsharedriskfactorshavedemonstratedahigherprevalenceofdiagnosedmalesthanfemales.Attentiondeficit/hyperactivitydisorderhasa10to1maletofemaleratio,languagedevelopmentdisordershaveavariableratioof2to4malesfor1female,Tourettesyndromehasa6to1maletofemaleratio,andintellectualdisabilityhasanapproximately1.8to1ratioofmalestofemales.Therefore,whenautismsharesriskfactorswiththesedisorders,itislikelythoseriskfactorsmaycontributetothemale/femalediagnosisratiofoundforautism.

Notably, the twin study of Hallmayer et al. (2011) suggested thatenvironmentalfactorsmightaccountformorethanhalfthevarianceinautism,andtheresearchersarguedthatdisruptiveeventsintheprenatalenvironmentwerelikelytobeanimportantcauseforautism.AlthoughreplicationoftheHallmayeretal.(2011)twinstudyisneeded,findingsfor environmental risk factors outlined inChapter 5 suggest that sexratiosfortheseenvironmentalriskfactorswouldbelikelytocontributetothecompositemale/femaleratioforautism.

Initial Structural and Hormonal Differences Between Male and Female BrainsHines(2011)summarizedinitialdifferencesbetweenmaleandfemalehumanbrains.Ingeneral,thebrainislargerinmales.Theamygdalaisalsolargerin

ELSEVIE

R


males,butthehippocampusislargerinfemales.Femalebrainshavegreatercorticalthicknessinmanyregionsthandomalebrains.Humanfemalebrainsshowgreatergyrificationinpartsoffrontalandparietalcortex,andfemalebrainsappeartousewhitematterwithgreaterefficiencythandomalebrains.Itmaybethatdifferentialfeaturessuchascorticalthicknessandgreaterwhitematterefficiencyconferprotectionforthefemalebrain.

Differencesingonadalhormonesandthesocialneuropeptidesargininevasopressinandoxytocinbetweenmalesandfemalesmaycontributetothehighermaletofemaleratioinautism.Gonadalhormonesdifferentiatemalesand females. Insel (2010) and Gordon et al. (2011) proposed models ofsocialmotivationandsocialbehaviorsthatbeganfromgonadalhormonesandthesocialneuropeptides,argininevasopressinandoxytocin.Insel(2010)noted that theprocessofmammalianpairbondingdifferentially involvesargininevasopressin(AVP)inmales,andoxytocin(OT)infemales.Ebstein,Knafo,Mankuta,Chew, andLai (2012) argued that theOT–AVPneuralpathwaysregulatesocialbehaviorundertheinfluenceofsixcrucialgenes:AVP-neurophysin II, OXT neurophysin I, and their receptors, AVPR1a,AVPR1b,LNPEP,andCD38.Ebsteinetal.(2012)reviewedevidenceforabnormalities inAVPandOTinautism,andpresentedevidence for theassociation of autism with variants of these genes. Ebstein et al. (2012)argued,“thesegenesnotonlyaccountforindividualdifferencesinbehaviorinsociallyintactindividualsbutalsocontributethevulnerabilitytodisor-dersofsocialcognitionespeciallyautism”(p.374).

Initialsexdifferencesinbrainstructureandcirculatinghormones,whendisrupted may contribute to autism symptoms. Initial sex differences inbrainstructureandcirculatinghormonesmayalsoleavemalebrainsmorevulnerable to a rangeof disruptiveprocesses, andmay confer protectionfromdisruptiveprocessesforfemalebrains.

Male Brain Vulnerability During the Prenatal PeriodAsnotedabove,Hallmayeretal.(2011)proposedthatenvironmentalfactorscausingautismwerelikelytohavetheireffectduringtheprenatalperiod,andChapter5reviewedevidenceforprenatalriskfactorsforautismsymp-toms.Thehighmaletofemalesexratiofoundforautismmay,inpart,reflectthatmalebrains,ingeneral,aremorevulnerabletoinsultduringprenatallife (Howerton & Bale, 2012; James, 2012; Kent,Wright,Abdel-Latif, &NewSouthWalesandAustralianCapitalTerritoryNeonatalIntensiveCareUnitsAuditGroup,2012;Murphyetal.,2012;Peacock,Marston,Marlow,Calvert,&Greenough,2012).

ELSEVIE

R


For example,Murphy et al. (2012) reported thatmaternal cigarettesmokingsignificantlyaffectedtheepigeneticprocessofDNAmethylationonlyinmalenewborns.Theresearchersreportedthatonlymaleinfantsborntocurrentsmokersshowedsignificantlyelevatedmethylationrela-tivetothoseborntomotherswhoquitsmokingduringpregnancy,andthose born to mothers who never smoked. In addition, Peacock et al.(2012) reported that among 787 very preterm infants, a significantlyhigherpercentageof the428male infantsdied, requiredoxygen,hadapulmonaryhemorrhage,orhad amajor cranialultrasound abnormalitythandidverypretermfemaleinfantsinthetheirsample.Thesefindingswere significant even after adjusting fordifferences inmale and femalebirth weights and gestation duration. In addition, a follow-up of thesechildren found significantly more motor disability and cognitive delayamongboysthangirls.

Initial Male–Female Brain Function Differences may be Increased During Brain DevelopmentGiventheinitialdifferencesinmaleandfemalebrainstructure,gonadalhor-mones,andsocialneuropeptides,andgiventheriskfactordisruptionsmedi-ating autism symptoms, it is possible that interaction of the initial braindifferenceswiththedisruptionmayconfersomeadditionalharmformalebrainsorstimulateprotectionforfemalebrainsduringtheprocessesinvolvedin brain development.These processes include programmed brain altera-tions,veryearlylearning,andevendevelopmentalbrainchangesoccurringduringsleep(Karmiloff-Smith,2012;Reeb-Sutherland,Levitt,&Fox,2012).Wolffetal.(2012)stated,“Bothhighlyexperience-dependentandlessenvi-ronmentallymediatedprocessescontributetothefunctionalandstructuralorganizationofthebrain,andthedynamicinterplayoftheseprocessesovertimeyieldsspecializedcorticalcircuitsdesignedtooptimallyprocesscom-plex information”(p.8).Braindevelopmentproducesalterations inmanyvariedaspectsofthebrain.Forexample,theanteriorinsulaandtheanteriorcingulate cortex together contribute to social responsiveness in behavior.Uddin,Supekar,Ryali,andMenon(2011)reportedsignificantdevelopmen-talchangesinbraininterconnectednessforrightfronto-insularcortex,tissuethatcontributestoswitchingattentionbetweenoutsidetheselfandinsidetheself.Consequently,theanteriorinsula,acontributortosocialresponsive-ness, if disrupted earlier in development may suffer additional disruptionduringthisprogrammedchangeasthebraindevelops(Uddinetal.,2011).Sexdifferencesinthedisruptedbraininautismmaydifferentiallyinfluenceprogrammeddevelopmentalprocessessuchasthis.

ELSEVIE

R


Reeb-Sutherland et al. (2012) reported that individual differences inassociativelearningmeasuredat1monthofagewereassociatedwithlatermeasuresofsocialbehavior.Theresearchersfoundasignificantlinkbetween1-monthassociativelearningandbrainactivitypatterninresponsetofamil-iarandunfamiliarfaces.Reeb-Sutherlandetal.(2012)proposedthattheirfindingswerenottheresultofindividualdifferencesingeneralcognition,andarguedthatinfant“associativelearningmayserveasamajorbuildingblockforthedevelopmentofsocialbehavior”(p.2).Karmiloff-Smith(2012)notedthatimpairedsleepprocessescharacterizedmostneurodevelopmentaldisorders.Shepointedoutthatthebrainchangesduringsleep,consolidatingandreorganizinginformation.Becauseconsolidationofinformationduringsleep depends on gene expression, brain biochemistry, and psychologicalprocesses in response to environmental stimuli, abnormal sleep processesmaycontributetoaberrationinbrainfunction.

Sex differences in brain structure, function, gonadal hormones, andsocialneuropeptides,aswellasotherinitialsexdifferences,maycontributetosexdifferencesinprogrammeddevelopmentalchangesinthebrain,inassociativelearning,orinsleepprocessessubsequenttotheinitialeffectsofbraindisruptionsforautism.

Summary: The Male to Female Diagnosis Ratio in Autism is Likely to be a Composite RatioThereisevidencethatmalebrainsaremorevulnerabletoinsultsanddis-ruptions.Maleandfemaledifferencesinbrainstructure,function,gonadalhormones,andsocialneuropeptides,aswellasotherinitialsexdifferences,mayvariablycontributetomaleprenatalbrainvulnerabilitytoinsultanddisruption,andmayvariablyconfersomeprotectionagainstprenatalinsultordisruptionforfemalebrains.

Theexistingevidenceformultiplevariedriskfactorsforautismmakesitlikelythatthemaletofemaleratioinautismisnotgeneratedbyanysinglecause,butratherreflectsthecollocationofhundredsofseparatemaletofemaleprevalenceratios.Itislikelythatdifferentcausalriskfactorsforautismgener-atedistinctmaletofemaleratioseachofwhichisdeterminedbyaspecificcausalrisketiologyandconsequentmediationofbraindevelopment.

MUCH RESEARCH IS STILL FOCUSED ON TRYING TO UNIFY AUTISM AS A SINGLE DISORDER

Eventhoughmanyresearcherswoulddefineautismasaspectrumofrelateddisorders, most researchers have continued the quest to find unifying

ELSEVIE

R


features for autism as if autismwere a single disorder.Why this researchcontinuesisunclear.Tatsionietal.(2007)concludedthat“itcanbedifficulttodiscernwhetherperpetuatedbeliefsarebasedoncarefulconsiderationofallevidenceanddifferentialinterpretation,inappropriateentrenchmentofoldinformation,[or]lackofdisseminationofnewerdata”(p.2525).

The Quest to Find a Unifying Feature for Autism PersistsTherearehundredsofalternateunifyingfeatureclaimsforautism.Claimsforunifyingfeaturesinautismhaveoftennotbeenreplicated,orhavebeenfoundtobetrueonlyofasmallsubsetofindividualswithautism.Moreover,unifyingfeatureclaimsforautismhaveoftensidesteppedevidencethattheunifyingfeaturewasnotspecifictoautism.

Even in genetic research, where multiple genetic variants have beenexploredascausesfortheautismspectrum,manyresearchershaveworkedtocreateunifiedaccountsofthegeneticetiologyforautism.Unifyingmodelsofrelatedgenevariantsand/orchromosomalnumbervariantsforautismhaverarelybeenreplicated,andtherehasbeenarapidreplacementofonegeneticmodelwithanothersubsequenttothediscoveryofnewdata(Abrahams&Geschwind, 2010;Bill&Geschwind, 2009;Girirajan et al., 2010;Holt&Monaco,2011;Voineaguetal.,2011;Zhaoetal.,2007).

Followingarebriefdiscussionsof four selectedunifying featureclaims.Onereportsthatautismincludesasuperiormentalprocessoftouch-to-visionmemory (Nakano, Kato, & Kitazawa, 2012).A second reports that autismincludes a superior visual speed discrimination skill (Chen et al., 2012).Athirdassertsthatatypicalresponsetoeyegazeininfantspredictslaterautismdiagnosis(Elsabbaghetal.,2012).Afourthassertsthatanearlyatypicalpatternofthebrain’swhitematterdevelopmentpredictslaterautismdiagnosis(Wolffetal.,2012).Followingthediscussionsofthesefourunifyingfeatureclaimsarebriefdiscussionsoftwomulti-genemodels.

Two Empirical Unifying Earliest Feature Claims for AutismEvent-Related Potential Pattern to Eye Gaze Before 12 Months Predicts AutismElsabbaghetal.(2012)reportedthat40infantsatriskforautism,whencom-paredwith45healthycontrols,showedlessP400brainactivityat6–10monthswhileviewingfaceswitheyegazedirectedtowardversusawayfromtheinfant.Thus,aparticularbrainactivitypatternknowntobespecificallyresponsivetohumanfaces(P400)wasfoundtobeatypicallyrelativelylessactiveinindividu-alsatriskforautismininfancy.Theresearchersproposedthattheirfindings

ELSEVIE

R


wereconsonantwithevidencethatbrainfunctionmeasurescandistinguishinfantsatriskforautismfromtypicalchildren,andconsonantwithevidenceforvariousotherearlypredictorsofrisk,includingavisualprocessingmarker,anattention-switchingmarker,afaceresponsemarker,andamarkerbasedonsen-sitivitytoeyedirectiongaze.Elsabbaghetal.(2012)arguedthatatypicalbrainfunctionrelatedtoeyegazereactionprecedestheonsetofautismbehavior.

Limitations for the Claim that Event-Related Potential Pattern to Eye Gaze Before 12 Months Predicts AutismTheresearchersfoundthatneitherstaticgazenorface-versus-noisecontrastsreliablydistinguishedtheASDgroupfromthetwoothergroups.Thus,therewasonlyasinglesignificantdatapoint(P400ondynamicgazeshift),demonstratinglowerresponsivity,differentiatingchildrenatriskwholaterwerediagnosedwithautism.Moreover,Elsabbaghetal.(2012)didnotdiscusstheimplicationsofdelayedcognitivedevelopmentfoundforchildrenatriskforautism.

Infant White Matter Development Pattern Predicts AutismWolffetal.(2012)reportedthatimagingofwhitemattertractsrevealedthatdevelopmentofamajorityoftractsdifferedsignificantlybetween17infantsatriskandlaterdiagnosedwithautism,and33at-riskinfantsnotdiagnosedwithautism.The17infantswholaterwerediagnosedwithautismshowedevidenceoflargerwhitemattertractsat6months.However,these17infantsthenwerefoundtohaveslowerdevelopmentofwhitemattertractscom-paredwithinfantsnotdiagnosedwithautism,andat2yearsthebrainsofthe17diagnosedchildrenshowedevidenceforlesswhitematterinfibertractscomparedwithchildrenwithoutautism.Wolffetal.(2012)concluded,“MostfibertractsfortheASD-positiveinfantswerecharacterizedbyhigherfrac-tionalanisotropyat6monthsfollowedbyblunteddevelopmentaltrajectoriessuchthatfractionalanisotropywaslowerby24months”(p.6).

Limitations for the Claim that Infant White Matter Development Pattern Predicts AutismThe17childrenwhowerelaterdiagnosedwithautismdifferednotonlyindiagnosticfeatures.Thechildrenlaterdiagnosedwithautismhadsignificantlylower scoresonameasureofcognitivedevelopment at age6months,12months,and24months.Atypicalwhitematterdevelopmentislikelytobethecauseofbothdevelopmentaldelayandabnormalsocialbehavior.How-ever, theWolffet al. (2012) research reportdidnotdiscussdevelopmentaldelay.Alsopossibleisthatthepatternofwhitematterdevelopmentinthe17was a collection of different patterns of white matter development.The

ELSEVIE

R


reportofferedno analysis ordiscussionof individual variationwithin thegroupof17childrendiagnosedwithautism.

Wolffetal.(2012)citedthestudyofBarnea-Goraly,Lotspeich,andReiss(2010)withthecomment,“StudiesofASDsusingdiffusiontensorimaginghaveidentifiedevidenceofwidespreadabnormalitiesinwhitematterfibertractintegrity”(p.2).However,Barnea-Goralyetal.(2010)reportedthatthebrainsofchildrenwithautismandtheirunaffectedsiblingsbothhadreducedprefrontalwhitematter,andreducedwhitematterinthecorpuscallosum,cingulategyrus,thalamus,leftandrightsuperiortemporalgyrusapproach-ingthehippocampusandtheamygdala,andleftandrighttemporoparietaljunctions.Barnea-Goralyetal.(2010)foundwhitematterstructureinthechildrenwithautismandtheirunaffectedsiblingsdifferedsignificantlyfromthatoftypicalchildren,andtheyconcludedthatatypicalwhitematterwaslikelytobeafamilytrait“notdirectlyrelatedtotheactualpsychopathol-ogy” of autism (Barnea-Goraly et al., 2010, p. 1058).Wolff et al. (2012)includednodiscussionof these relevantBarnea-Goralyet al. (2010)dataandconclusionsintheinterpretationoftheirownwhitematterfindings.

Two Empirical Unifying Superior Skills in AutismSuperior Perceptual Integration in AutismNakano et al. (2012) reported that 14 adults with autism demonstratedsuperior performance on a test of touch-to-vision delayed matching ofshapecomparedwith20healthycontrols.Thestudyparticipantstouchedashapewithoutseeingit,andthenhadtoidentifyitvisuallyafteradelay.Theresearchersarguedthatsuccessonthistaskrequiredintegrationofsenso-rimotorperceptsofthefeltshapeintoanobjectrepresentationthatcouldbementallyvisualized.Nakanoetal.(2012)arguedthattheintegrationofsensorimotorperceptsofashapethatwaslatercorrectlyidentifiedvisuallycontradictedtheweakcentralcoherencetheoryofautism.HappéandFrith(2006)hadproposedtheweakcentralcoherencetheoryofautism,whichclaimedthatcognitiveprocessinginautismreliedonabnormallysuperiorprocessingofsensorydetailsintheabsenceofabilitytointegratesensoryinformation.Nakanoetal.(2012)notedthatthesuperiorityofadultswithautismonthetouch-to-visiontaskdidnotreflectasuperiorityoflocalordetail-focused processing because the adults with autism were no betterthantypicaladultsintheirabilitytodiscernobjectorientationorlength.Nakanoetal.(2012)proposedthatfuturestudieswerenecessarytoexplorewhether superior haptic-to-visual shape perception skill was linked tosavantskillsfound“in10–30%ofpersonswithASD”(p.7).

ELSEVIE

R


Superior Discrimination of Visual Movement Speed in AutismChenetal.(2012)reportedthat19adolescentswithautismhadbetterspeedvisualdiscriminationperformancescoresthan17healthycontrolswhenvisualcomparisonsweremadeafteradelay.Inthestudy,alladolescentshadtodeter-minewhichoftwodisplaysof200randomdotsonacomputerscreenwasmovingfaster.Theregularintervalbetweendotdisplaystobecomparedwasahalfsecond,andtheprolongedcomparisondelaywassixtimesaslong,3seconds.Theresearchersarguedthatsuperiordiscriminationfortheindividu-alswithautismcouldnotbetheresultofenhancedworkingmemorybecausepreviousstudieshadreportedimpairedworkingmemoryinautism.

Chenetal.(2012)theorizedthatsuperiorvisualdiscriminationskillinautismwasafunctionofanatypicallylongerprocessofvisualencodinginautism.Theresearchersproposedthatthevisualsysteminautismhadshiftedvisualspeedprocessingtoaslowspeedrange,suchthatbrainactivityinthevisualsystemhadlongerlatencieswithsmallerreceptivefields.Chenetal.(2012) argued that the 3 seconddelay allowed for extended coding that“wouldaffordadditionalprocessingofspeedsignalsandallowforapercep-tualadvantageinthisvisualmotiondomain”(p.737).

Limitations for the Findings of Nakano et al. (2012) and Chen et al. (2012)Shared limitations of the studies of Nakano et al. (2012) andChen et al.(2012)aresmallsamplesizeandisolationofthespecificfinding.Samplesizesof14and19individualscannotprovidecompellingevidence.Second,bothfindingsexistinisolationfromotherfindingsinthefield,andrepresentonedatapointofsuperioritywithintestingthatotherwisefoundnodifferencesbetweenthesamplewithautismandthecontrolsample.AsnotedinChapter2,Ioannidis(2005)stated,“Thereisincreasingconcernthatinmodernresearch,falsefindingsmaybethemajorityoreventhevastmajorityofpublishedresearchclaims….However,thisshouldnotbesurprising.Itcanbeproventhatmostclaimedresearchfindingsarefalse”(p.696).Ioannidisarguedthatsmallsamples,selectivemeasures,abiasforsignificance,andhighlycreativemeasures operating in a“hot” field all contribute to invalid significancemeasures.AllthefactorsidentifiedbyIoannidisapplytothesetwostudies.

Two Empirical Multiple Gene Models of AutismThe Multiple Hit Model of AutismLeBlondetal.(2012)studied260individualswithautismandfoundadele-tionwithintheSHANK2geneinoneindividualwithautismandmoderate

ELSEVIE

R


intellectualdisability.Becausetheaffectedindividual’sparentsdidnotcarrythisdeletion,thedeletionwasadenovoevent,newintheaffectedindivid-ual.LeBlondetal.(2012)reported,“Inpatients,theonlyfeatureassociatedwithcarriersofSHANK2mutationscomparedwithotherpatientswasatrendforlowIQ”(p.11).Theresearchersalsonotedthat5%oftheFinnishpopulation was heterozygous for a SHANK2 variant without negativeeffects,andthat“deleteriousSHANK2variantsweredetectedinaheterozy-gousstateinparentsandinthegeneralpopulationwithoutcausingseverephenotypicconsequences”(LeBlondetal.,2012,p.11).Theresearcherscon-cludedthattheco-occurrenceofdenovomutations,togetherwithinheritedvariations,might be the genetic source of autism. In a larger sample, theresearchersidentifiedthreepatientswithdenovoSHANK2deletionswhoalsocarriedinheritedCNVsat15q11–q13,aregionassociatedwithneuro-psychiatricdisorders.Theresearchersconcludedthatthesethreecasessup-portedthetheoryofautismasresultingfrommultiplegeneticmutations.

Limitations for the Multiple Hit Genetic Causal Model for AutismItislikelythatcasesofautismdoresultfrom“theco-occurrenceofdenovomutations,togetherwithinheritedvariations”(LeBlondetal.,2012,p.12).However,themultiplehittheorycannotapplytoallcasesofautism.Theevidenceforvariousformsofsyndromicautism,discussedinChapter4,hasdemonstratedthatautismsymptomscanappearastheresultofsinglegeneeffects.Inaddition,thereisevidencesuggestingdifferentformsof“myriadhits”whereinmanygenevariantscontributetoautismsymptoms.

Tumor Necrosis Factor and Beta-Estradiol Regulators as Priorities for Genetic Research in AutismLee,Raygada,andRennert(2012)proposedthatautismwaslinkedtogeneclusters related toPTEN/TSC1/FMR1 andmTOR/PI3K gene regula-tion.Leeetal.(2012)createdatheoreticalnetworkofpossiblegenesbyexamining35genesthathadbeenlinkedtoimpairedsocialinteraction,8geneslinkedtorepetitivebehavior,74geneslinkedtoobsessivebehavior,146geneslinkedtoimpairedcommunication,and98genestiedtointel-lectualdisability.Theresearchersanalyzedrelationshipsbetweentheaggre-gatedgenesandfoundcomplexregulatorynetworks.Twokeyfactorsintheregulatorynetworktheyconstructedweretumornecrosisfactor(TNF)andbeta-estradiol.

TheresearchersproposedthatTNFwouldbeexpectedtooperateinasystemic molecular network in autism becauseTNF decreases serotonin

ELSEVIE

R


transporterfunction.However,Leeetal.(2012)weresurprisedtofindbeta-estradiol-relatedeffectsintheconstructednetwork.Theynotedthatbeta-estradiol was involved in neuroprotective and neurotropic functionsmediatedbyestrogenreceptorsignalingcascades.

Theresearcherstriedtoreplicatetheconstructednetworksusingevi-dence of actual genes found in association with autism. However, theresearchersstatedthat,becausesofewgeneshadbeenidentifiedforautismingenome-wide association studies, they couldnot construct anetworkbasedongenesactuallyfoundinautism.Inathirdanalysis,theresearchersreportedfindingaclusterforincreasedexpressionofthePTEN,TSC1,andFMR1 genes, and a cluster including genes with deletions and reducedexpressionlinkedtothemTOR/PI3Ksignalingpathways.Theresearchersconcludedthatalargenumberofnon-overlappinggenenetworksmightbethebasisforautismheterogeneity.

Limitations of the Network ModelAlthoughtheresearchersstatedthatthegoaloftheirstudywasto“priori-tizemolecularinteractions”(Leeetal.,2012,p.9),itwasnotclearfromthereportoftheirstudyhowgeneticresearchprioritieshadbeenadvancedbytheirefforts,nordidtheyproposespecificallyhowtheirconstructednet-workinformationmightbeusedinfutureresearch.

Summary: All Six Studies Sought to Find a Unifying Feature or Pattern in AutismThis brief review reported four claims for behavioral unity in autism:infant diminished P400 wave to dynamic gaze shift predicting autism(Elsabbaghetal.,2012);abnormaltrajectoryofinfantwhitematterdevel-opment pattern predicting autism (Wolff et al., 2012); adult superiortouch-to-visiondelayedmatching(Nakanoetal.,2012);andadultsupe-riordotmovementdelayeddiscrimination(Chenetal.,2012).Elsabbaghetal.(2012)foundonepatternofbrainactivity,andWolffetal.(2012)foundonepatternofbraindevelopment.Eachfindingwasproposedasapredictiveearlysignalofautism.However,becauseneitherresearchteamconductedanexploratorydataanalysistolookforindividualvariation,possibleevidenceforvariationintheseproposedearlypredictorswasnotexplored.Althoughalldisordersundertheautismumbrellawouldbenefitfromearly intervention, autismvariationmight be crucially importantforinterventionstrategies,andthepatternsofindividualvariationcannotbeadequatelyexploredinsmallsamples.

ELSEVIE

R


This section also sketched a report supporting the multiple-gene-hitmodel(LeBlondetal.,2012),andagenenetworkmodel(Leeetal.,2012).Thetranslationalvalueforthesemodelsis,asyet,unclear.

ABANDONING AUTISM AS A SINGLE DISORDER WOULD ELIMINATE THREE INFERENTIAL PROBLEMS IN AUTISM RESEARCHDiagnostic Criteria that have Never been Validated would no Longer be NeededAsnotedinChapter7,Hymanhadworriedthat,asdirectorofNIMH,hehad fundedhundredsof studiespredicatedonDSMcriteria“thatalmostnever questioned the existing diagnostic categories despite their lack ofvalidation”(2010,p.157).

Links Between Autism Diagnostic Symptoms have not been Validated or ExplainedAsnotedinearlierchapters,Happéetal.(2006)providedevidencefromtwinstudiesoftypicalindividualsthatthethreeDSM-IVautismdiag-nostic symptomsof social impairment,communicationdifficulties,andrigid and repetitive behaviors were genetically unrelated, and resultedfromthreeseparatesetsofnon-overlappinggenes.Theyconcludedthatthe symptoms were independent of one another. Happé et al. (2006)stated,“Clearlyaquestionremainsofwhythesethreefeaturesco-occuratabove-chancerates”(p.1219)inautism.

Similarly,Robinsonetal.(2012)tested5944typicaltwinpairsandfoundalmostnogeneticcausaloverlap for theproposedDSM-5twosymptomgroups:socialimpairment,andrestrictedandrepetitivebehaviorsandinter-estsorsensoryabnormalities.Theresearchersnotedthatidenticalandfra-ternaltwinshadnon-significantcross-twincorrelationsrangingfrom.02to.19betweenthetwoDSM-5autismsymptoms.

Boucher (2011) noted that autism symptoms were not correlated, andexpressedconcernthattherewasnoexplanationforhowthevariedetiologies,braindeficits,anddiagnosticsymptomsdidmanagetoconvergeonasingleautismbrainabnormality.Shehypothesizedthatheterogeneousbraindeficits,heterogeneousetiologiesanddiagnosticsymptombehaviorsmust“fanin”toconvergeontoasinglebrainabnormality.Boucher(2011)proposedthattheautismdiagnosisberedefinedasaspectrumofmanyseparatesymptomsandphysicaldisordersthathappenedtooccurtogetherinautismmorethanwouldbeexpectedbychance.Similarly,LordandJones(2012)definedautismasan

ELSEVIE

R


“as-yet-not-understood combination of social-communication deficits andrepetitive/restrictedbehaviorsand interests that interact together to formapatternthatappearstobemorethanthesumofitsparts”(p.504).AsBoucher(2011)noted,researchhasnotdiscoveredhowthesymptoms“interacttogethertoformapatternthatappearstobemorethanthesumofitsparts.”

Autism Diagnostic Symptom Set has not been ValidatedKanner(1943)definedinfantileautismasasingledisorderwithtwokeysymptoms: theprofound failure tounderstand social interaction,withaninsistenceonsameness.Kannerhasrightfullybeenhonoredforhisidentificationofseveresocialimpairmentinchildren.However,neitherneuroscience nor genetics research has validated Kanner’s autism.Researchershavenotfoundanybraincircuitorregionthatwhendis-rupted will cause his two symptoms, insistence on sameness and theinabilitytounderstandsocialinteraction,andonlythesetwosymptoms(Campbelletal.,2011;Ebischetal.,2010;Leekametal.,2011;Lewis&Kim,2009;Lombardoetal.,2011;Schulte-Rütheretal.,2011).Simi-larly,researchershavenotfoundageneticorenvironmentalcausethatgeneratesallandonlyallthethreeDSMsymptomsofsocialinteractionfailure,communicationimpairment,andrestrictedandrepetitivebehav-iorsoractivities(Addington&Rapoport,2012;Geschwind,2011;State&Levitt,2011;Yrigollenetal.,2008).

Moreover, no animal models have been found that produce animalhomologuesofthethreeDSMsymptoms.Forexample,Peñagarikanoetal.(2011)reportedthatmicelackingtheCntnap2geneassociatedwithautismexhibitedabnormalvocalcommunication,repetitiveandrestrictedbehav-iors,andabnormalsocialinteractions.However,Peñagarikanoetal.(2011)reportedthatthemicewerealsohyperactiveandsufferedepilepticseizures.Malkova,Yu,Hsiao,Moore,andPatterson(2012)createdamousemodelofenvironmentalriskofautismbystimulatingtheimmunesystemoffemalemice.Maleoffspringoftheimmune-activatedmothershadtruncatedvocal-ization,decreasedsociability,andhighlevelsofrepetitivebehaviors.How-ever,Malkovaetal.(2012)notedthatoffspringofimmune-activatedmousemothers“alsodisplayfeaturesofschizophrenia.Theseincludeenlargedven-tricles,enhancedresponsestoamphetamineandhallucinogens,alterationsindopamineandserotonergicpathways,aswellas…enhancedanxietyandeyeblinkconditioning”(p.8).

Abandoningthequestforautismasasingledisorderwouldeliminatetheneedtovalidateautismdiagnosticcriteriathathaveneverbeenvalidated.

ELSEVIE

R


Viewing Behavioral Symptom Heterogeneity as Comorbidity would be UnnecessaryCoghillandSonuga-Barke(2012)arguedthatheterogeneityandcomorbiditymadeclassificationofdiagnosticgroupsdifficult.Theresearcherspointedoutthatcomorbidityiscommoninchildhoodmentaldisorders.Whencomor-bidityisreducedbyeliminatingsomediagnosticcategories,thentheremain-ingdiagnosticcategoriesnecessarilywillhaveincreasedheterogeneity.Inthecaseofautism,asarguedinChapters4and7,comorbidityhasoftenbeentheassignmentofselectedsymptomsofonegeneralbraindisruptiontoseparatedisorders.PushingoutselectedsymptomsofcomplexautismphenotypesintootherdisordershasbeenanerrorsimilartoMendel’ssettingasideanddiscard-ing pea phenotypes that seemed errantly and extraneously heterogeneousthusinterferingwiththeorderlyclarityofMendel’sinheritancemodel.

Infact,theextensivevariationinsymptomsfoundforindividualswithautismisrarelytheresultofthecomorbidityofatrulyindependentaddi-tionaldisorder(Addington&Rapoport,2012;Fernandezetal.,2012;Rom-melseetal.,2011;Tabetetal.,2012).Despiteclaimsoferrantclinicalpractice(Lord,2011),problems indiagnosisoftenreflect thedifficulty inassigningsimplifiedlabelstocomplexphenotypes.Diagnosticsocialimpairmentanddiagnosticmotorand sensorybehaviorsoccurwith intellectualdisabilityordevelopmentaldelay, epilepsy,motordelay, language impairment, attentiondeficit/hyperactivitydisorder,andothersymptomsbecausethebrainiscom-plex,braindevelopmentiscomplex,andbraindisruptionsaresovaried.

Equallyimportant,theexclusionofnon-diagnosticassociatedsymptomsfrom autism phenotypes leads to problematic inferences. For example,Guinchat et al. (2012a) reported that parents’ early concerns about theirchildrenatriskforautismdidnotincludeautismsymptoms:

We found that the earliest warning signs were frequently not specific to autism … . Motor peculiarities, sensory reactivity, atypical regulation of emotions, a lack of attention, an abnormal level of activity, or sleeping problems were some of the common features … and it is noteworthy that most of the concerns related to a diagnosis of autism were clearly not the earliest concerns evoked by parents.

Guinchat et al. (2012a, p. 598)

AlthoughGuinchatetal.(2012a)declaredthatmotorpeculiarities,sensoryreactivity,atypicalregulationofemotions,alackofattention,anabnormallevelofactivity,orsleepingproblemswerefeaturesnotspecifictoautismoradiagnosisofautism,thesefeatureshaveallbeenfoundincompleteautismphenotypes.IfGuinchatetal.(2012a)weretoviewthechildren’spheno-typesasincludingallexpressedsymptoms,theresearcherswouldthenfind

ELSEVIE

R


thatparentshadbeenreportingsymptomsrelevanttotheirchildren’sneu-rodevelopmentaldisorder.

AsdiscussedinChapter7,Closeetal.(2012)providedanotherexampleofaninferentialproblemthatoccurswhensymptomsareassignedtoadisorderthoughttobecomorbidwithautism.Theresearcherscomparedsymptomsofchildrenwho“lost”thediagnosisofautismwithsymptomsofchildrenwhodidnotlosethediagnosisofautism.Theresearcherslookedatdatafrom1366chil-drenwhere453ofthechildren’sparentsreportedapastbutnotcurrentdiag-nosisofautismspectrumdisorder.TheremainingparentsreportedacurrentdiagnosisofASDfortheirchild.Closeetal.(2012)foundthatchildrenaged2–5yearswithacurrentdiagnosisofautismwere9.20timesmorelikelytohavedevelopmentaldelayand4.76timesmorelikelytohavetwocurrentcomorbidconditionsthanchildrenwhohadaformerdiagnosisofASD.Childrenaged6–11yearswithacurrentdiagnosisofautismhada3.85timesgreateroddsofhavingapastspeechproblem,3.51greateroddsofhavingcurrentanxiety,andwere3.19timesmorelikelytohavetwocurrentcomorbidconditions.

DothesymptomsCloseetal.(2012)describedascomorbid“belongto”theautismphenotypeordotheybelongtoanothercomorbiddisorder?ABritishnewspaper,The Daily Mail, reportedtheCloseetal. (2012) studyfindings in an articleheadlined“Can somechildren simply growoutofautism?”(Naish,2012).England’sNationalHealthService(NHS)respondedtotheDaily Mailarticlebyarguingthatchildrendonotgrowoutofautism(NHSChoice,2012).TheNHSassertedthat“diagnosingASDischalleng-ing,especiallysincetheconditionisoftenaccompaniedbyotherneurode-velopmentaldisorderswithoverlappingsymptoms”(NHSChoice,2012).

TheNHS claim effectively proposed that a symptom such as speechdelaywouldbe an“overlapping symptom” in a childwith autismand acomorbid language disorder, because speech delay could result from thechild’sautismorresultfromthechild’scomorbidlanguagedisorder.How-ever,thebraindisruptioncausingthespeechdelaydoesnotrecognizeorrespect diagnostic assignment. More importantly, risk factors for autismsymptomsmaycausesocialimpairment,behavioralrigidity,sensoryabnor-malities, andattentiondeficit/hyperactivitydisorder,developmentaldelay,languagedevelopmentproblems,andmotorproblemsinthesameindivid-ual.Therefore,whenspeechdelayandsocialimpairmentbothoccurinonechild, it isunlikelythatthespeechdelayisanoverlappingsymptomofaseparatecomorbidlanguagedisorder.

AlthoughCloseetal.(2012)arguedthatfutureautismresearchshould“focusonthefactorsthatdiscriminatetheco-occurringconditionswhose

ELSEVIE

R


symptomsoverlapwithASD”(p.e315),thisdiscriminationwouldbelikelytobe scientifically counterproductive.Autismgenetic andenvironmentalrisk factorsproducenon-diagnosticanddiagnosticsymptomsinanindi-vidual because risk factors cause brain-wide disruptions (Gilman et al.,2011;Weietal.,2011).Therefore,co-occurringsymptomsaremostlikelytobe component impairments of the complete autism phenotype and areunlikelytobeevidenceofseparatecomorbiddisorders.

Abandoningthediagnosisofautismasadisorderwouldfreeresearcherstorecognizeandstudythecompletephenotypeofchildrenexpressingneu-rodevelopmentalsocialimpairment.

The Problem of the Failure to Reconcile Data and Synthesize Theories in Order to Establish the Features of Autism would DisappearAutismresearchhasspentlittleefforttoreconcilecompetingtheoriesandconflictingfindings(Waterhouse,2008,2009).Theoriesofautismasasingledisorder are replaced repeatedly without efforts to reconcile findings orsynthesizetheories.Becausenounifyingbraindysfunctionhasbeenestab-lished,manyofusconductingautismresearchhavegenerateda seriesofvariedtheoriesofautismbraindysfunction.

AsoutlinedinChapter1,theDuhem–Quineprincipleproposedthatnoscientifictheorywillfullyaccountforalltheexistingvariationinavailableevidence.Consequently,scientificunderstandingmovesforwardfromonenot-fully-explanatory theory to the next not-fully-explanatory theory.However,therearelimitstothescientificacceptabilityofnot-fully-explan-atorytheories.Theextremeheterogeneityofautismhasmeantthatfartoolittle of the variation in autismhas been explainedby theories claimingautismisasingledisorder.

Meehl(1990)arguedthatwhentheoriesexplaintoolittlevariation,theyaresoweakthattheycaneasilybereplacedinaprocessthatMeehlcalled“adhock-ery.”Theweaksupportforanexistingtheoryallowsforthecreationofanewadhoctheorywhenevernewempiricalevidenceisdiscovered.ViewedfromaMeehl(1990)perspective,therepeatedreplacementofonetheoryofautismafteranotherhasbeen“adhockery.”Rejectedadhoctheorieseventuallyrequiresynthesis, not replacement.Althoughnormal sciencedoes involve a“point–counterpoint”competitionbetweendataclaims,reconciliationofcontradictoryfindingsandcompetingtheoriesisnecessarytodriveproductiveresearch.

Meehl(1990)arguedthateventually,“Asmoreandmore‘adhockery’piles up” (p. 112), researchers begin to doubt that they have correctly

ELSEVIE

R


conceptualized the problem. Researchers begin to conclude, as Szatmari(2011)did,thattheresearchfieldshouldstartoverinconceptualizingautism.

Lack of Subgroup SynthesisTheproposedDSM-5autismcriteriahavecollapsedallformerDSM-IV-TRdiagnostic subgroups into one group, autism spectrumdisorder.Unfortu-nately,therationaleproposedforcollapsingtheindividualsubgroupswasthattheysharedacommonpathophysiology(Kupfer&Regier,2011),arationalethathasnotbeensupportedbyempiricalevidence(seeChapter7).

Veenstra-VanderWeele andBlakely (2012) argued thatbecause autismspectrumdisorderwasaheterogeneouscondition,researchersshouldcreatesubgroups“based on biomarkers, such as macrocephaly or indicators ofmitochondrial dysfunction,orgenetic findings, such as theneurexin–neuroliginsystem….[or]abnormalmTORand5-HTsignaling”(p.206).Eapen(2011)proposedthreegeneticsubgroupsofautism.Shedefinedsyn-dromicASDcausedbyrare,single-genedisordersashavingamorecomplexphenotype.ShedefineddenovomutationASDasasevereandspecificphe-notype.Eapen(2011)definedathirdgenetictypeasbroadautismcausedbygeneticvariationsinsingleormultiplecommongenesdistributedacrossthegeneralpopulation.

Manyindirectbiomarkersubgroupshavealsobeenproposedforautism.Aldridgeetal.(2011)conductedafacialfeatureanalysisofboyswithautism.Aldridgeetal.(2011)determinedthatalltheboyswithautismhadadistinctfacialphenotypecharacterizedbyanincreasedbreadthofthemouth,orbits,andupperface,combinedwithaflattenednasalbridgeandreducedheightofthespacebetweenthenoseandmouth.Aldridgeetal.(2011)notedthatthisfacialphenotypesignalsdisruptionoftheembryologicalfrontonasalprocessthatcontributestoformingtheface.Theresearchersalsofoundtwodistinc-tivefacetypeswithintheautismgroup.Onefacepatternsubgroupof12boyshadincreasedautismseverityscoresandlowercognitivescores.Asecondfacepatternsubgroupof5boyshadlesssevereautismsymptomsandlargerheads.

Fountain,Winter,andBearman(2012)proposedsixsubgroupsofautismbased on the course of development: high, bloomers, medium-high,medium,low-medium,low.Thelow-mediumandlowsubgroupsshowedlittleimprovementinbehaviorfromage3to14.Thehighandmedium-high groups demonstrated continuous improvement in behaviors duringthissameperiod.Theonesurprisinggroupcalled“bloomers”showedthesteepest upward development trajectory from low functioning to highfunctioningwithinthetimeperiod.

ELSEVIE

R


Itisnotclearhowevidenceforthesixdevelopmentaltrajectorysub-groupsproposedbyFountainetal.(2012)andthetwofacestructuresub-types proposed byAldridge et al. (2011) might be synthesized with thethreeproposedgenetic subgroups—syndromic autism,denovomutationautism,andbroadautism—proposedbyEapen (2011).Similarly, it isnotclearhowtheevidenceformanyhundredsofsubgroupsbasedonawidearrayofdifferentfeaturesmightbereconciled.

The Hundreds of Theories Proposing a Unifying Feature for Autism would not Require Synthesis if Autism were no Longer Viewed as a Single DisorderDatareconciliationandtheorysynthesishavebeenrareinautismresearch.Many researchersbelieve thevariation in autismwillbe resolvedby thenext,better,newunifyingbraindysfunction.Forexample,Kana,Libero,andMoore(2011)argued,“Giventhecomplexity,heterogeneity,andthedevel-opmentalnatureofASD,aglobalexplanationorasetofexplanationsseemsoptimal…disruptedcortical connectivitymaybeone suchexplanatorymodel”(p.428).ThusforKanaetal.(2011)thebestresponsetocomplexityandvariationwastoprovideabroadbutunifyingexplanatorytheory.

However,thedisruptedcorticalconnectivitytheoryespousedbyKanaet al. (2011) to explain all autismhas been counteredbyother findings.Barnea-Goralyetal.(2010)reportedthatindividualswithautismandtheirunaffected siblingshad the samepatternof atypicalwhitematter.Vissersetal.(2012)carefullyreviewedevidencefortheunderconnectivitytheoryofautism.Vissersetal.(2012)foundinsufficientevidenceforfrontalcortexlocaloverconnectivity.Moreimportantly,theyreportedthatvariedpatternsofabnormalfunctionalconnectivityfelloutsidetheboundsofthetheory,andthuswerenotexplainedbythetheory.Wass(2011)alsoreviewedtheunderconnectivitytheoryofautism.Wassarguedthatincreasedshort-rangeconnectivityanddecreasedlong-rangeconnectivityreflectedimmaturityofthe cortex, and are found inmanyotherdisorders, includingdepression,schizophrenia,Tourette’s,Williamssyndrome,anddevelopmentallanguagedisorder.Wass(2011)stated,“Theoverlapbetweenhowconnectivityisdis-ruptedinASDandinotherdisordersremainspoorlyunderstood”(p.25).

Ifautismcontinuestobeconceptualizedasasingledisorder,thesecon-tradictoryfindingsforconnectivityneedtobereconciled,andthetheoriesofunderconnectivityneedbesynthesized.

Kaiser and Pelphrey (2012) argued that although previous autismresearchhadnotfoundany“consistentneurochemical,neurophysiological,

ELSEVIE

R


orneuroanatomicalabnormality”(p.29)forautism,theresearchersnone-thelessarguedthat“disruptionsinthevisualperceptionofbiologicalmotionwereahallmarkofASDwhichmayserveasachanneltothepathogno-monicdeficitsofthedisorder”(p.33).

However,Koldewyn,Whitney,andRivera(2010)stated,“currentresultsdonotsupporteitherageneraldorsalstreamdeficitorabiastowardslocalperceptionasexplanationsforvisualperceptiondifferencesinthosewithautism”(p.608).Koldewynetal.(2010)andRutherfordandTroje(2012)foundthat thedetectionofbiologicalmotion in individualswithautismwascorrelatedwith intelligence level.Moresignificantly,RutherfordandTroje (2012) found no group differences in the detection of biologicalmotionbetweenindividualswithautismandcontrols,andreportedthatthepatternofdeclineacrosslevelsofmaskingwassimilarbetweengroups.

Canthecontradictoryfindingsforimpaireddetectionofbiologicalmotionbereconciledwiththecontradictory findings for thetheorythatautismiscausedbyunderconnectivity?Again,normalsciencedoesinvolvea“point–counterpoint”theorycompetition,butreconciliationofcontradictoryfind-ingsandtheorysynthesisarerequiredinordertodriveproductiveresearch.

Theory Predictions from Autism Data Sets Require ReconciliationNotedandproductiveautismresearcherEricCourchesnehasproposedmorethanadozenseparatetheoriesofautism.Onlyfourofthemaredescribedhere(Akshoomoff, Pierce,&Courchesne, 2002;Chow et al., 2012;Kennedy&Courchesne,2008;Schumann,Barnes,Lord,&Courchesne,2009).In2002,Akshoomoffetal.theorizedthatautismresultedfromaberranttimingofneu-rongrowthleadingtoalargerthannormalcerebrumandreducedcellnum-bersinthecerebellumandlimbicregions.In2008,KennedyandCourchesnereportedevidencethattheattentionnetworkregulatingattentiontoexternaleventswas intact in autism,but thedefaultmodenetwork regulating self-internalattentionwasdisruptedinautism.KennedyandCourchesne(2008)theorizedthatthespareddorsalexternalattentionnetworksupportedsparedandenhancedskillsinautism,whiletheimpairedself-internalattentionnet-workresultedinattentionbeingshiftedawayfrom“socialandemotionalpro-cessing, but toward a particular non-social and non-emotional cognitiveprocessingstyle”(p.1882).In2009,Schumannetal.reportedfindinglargeramygdalaeintoddlerswithautismandthatamygdalasizeinmaleswasassoci-atedwithseverityofautismsymptoms.Schumannetal.(2009)theorizedthatthelargeramygdalawashyper-arousedinpeoplewithautisminresponsetosociallyrelevantstimuli,thusimpairingsocialinteractionfunctioning.

ELSEVIE

R


In2012,Courchesneandhisresearchteam(Chowetal.,2012)comparedgeneexpressionlevelsinpostmortemfrontallobesamplesfrom9maleswithautismand7maleswithoutautismwhodiedwhentheywerebetween2and14yearsold.Theresearchersalsocomparedgeneexpressionlevelsinpost-mortemfrontallobesamplesfrom6maleswithautismand11maleswithoutautismwhodiedwhentheywerebetween15and56yearsold.Thistotalsampleof33wasselectedfromalargerinitialsampleof57individuals.Chowetal.(2012)foundthat2017geneshadsignificantlydifferentexpressionlev-els in the 15 autismbrain samples compared to the 18non-autismbrainsamples,andtheyreportedthat736genesweredifferentiallyexpressedinthetwoagegroupswithinthetotalautismsample.Chowetal.(2012)theorizedthatthegeneexpressiondifferencestheyfoundfortheyoungerautismsam-plereflectedabnormalbrainactivityregulatingcellnumber,proliferation,cellcycle, cortical patterning and differentiation, DNA damage response andapoptosisandsurvival.Theresearchersarguedthatthisdysregulationwasthepossiblecauseofthe67%excessofneuronstheyfoundintheprefrontalcor-texofchildrenwithautism(Courchesneetal.,2011).

All four theories proposed by Courchesne and colleagues were welldevelopedandsupportedbyempiricalevidence.However,thesefourtheo-ries effectively replacedone another in the adhoc fashiondescribedbyMeehl(1990)becauseCourchesneandcolleaguesdidnotattempttorec-oncile conflicting claims of their own research team’s four papers, or toreconciletheirfindingswithconflictingfindingsofothers.

Thefourtheoriesmakecontradictorypredictionsandreportcontradic-tory findings.Akshoomoff et al. (2002) theorized that abnormal growthpatternsledtoasmallercerebellumandsmallerlimbicregionsinautism.Thecoreelementsofthelimbicregionthatwouldbesmallerwouldbethehypothalamus,hippocampus,andtheamygdala.Conversely,Schumannetal.(2009) foundevidencefor largeramygdalae inchildrenwithautism,andtheorized thatautismsocial impairment reflectedhyper-activationof theamygdala.ForAkshoomoffetal.(2002),theamygdala,aspartofasmallerlimbicsystem,shouldbesmaller,not larger.Similarly,Chowetal. (2012)theorizedthatasetofaberrantlyexpressedgenesexplainedtheirownteam’sfindingforexcessneuronsandaberrantorganizationofthoseneuronsinautismfrontallobetissue.Ifthereismoretissueinthecerebruminautism,according toAkshoomoffet al. (2002), thecerebellumand theamygdalashouldbe smaller,butSchumannet al. (2009) foundevidence for largeramygdalaeinchildrenwithautism.Inaddition,Eckeretal.(2011)reportedfindingreducedamygdalasizeassociatedwithautismsymptomsinadults

ELSEVIE

R


withautism.Eckeretal.(2011)alsonotedthatstudieshavereportedlargeramygdalae,smalleramygdalae,andnormalsizedamygdalaeinautism.

IfthecerebrumwerelargerinautismasproposedbyAkshoomoffetal.(2002),itwouldbeexpectedthatheadsizewouldbelikelytoreflectthelarger cerebrum. However, Barnard-Brak et al. (2011) reported in theEarlyChildhoodLongitudinalStudyBirthCohort,anationallyrepresen-tative,community-basedsampleofapproximately9000children,thatthe100youngchildrenwithautismdidnotshowsignificantheadcircumfer-encedifference at age9months,24months, and36months comparedwiththeheadcircumferenceofthe8900childrenwithoutautism.

Kennedy andCourchesne (2008) reported evidence that the externalattentionnetworkwasnotdisruptedinautism.However,Chowetal.(2012)reportedthatmanybraindevelopmentgeneshaveaberrantexpressioninthefrontal lobe in autism and theorized that aberrantly expressed genesaccountedfortheirfindingsofmoreneuronsinfrontallobetissueinautism(Courchsneetal.,2011).Giventheimportanceoffrontallobefunctiontoexternalattention(Posner,2011),itissurprisingthatanaberrantlydevelopedfrontallobe(Chowetal.,2012)inautismwouldcausenodisruptionoftheexternal attention network (Kennedy & Courchesne, 2008). In addition,externalattentiondeficitshavebeenwidelyreportedforautism(Rommelse,2011).Thesediscrepantfindingsrequirereconciliation.

Chowetal.(2012)didnotethattheirgeneexpressionresultsdifferedtothoseofasimilarstudybyVoineaguetal.(2011),andsuggestedthatgeneticheterogeneityinautismandsamplecharacteristicsmightexplainthediffer-ences.However,Chowetal.(2011)offerednosynthesisoftheirfindingswiththoseofVoineaguetal.(2011).

Asexcitingandinterestingasthefourtheorieshavebeen(Akshoomoffetal.,2002;Chowetal.,2012;Kennedy&Courchesne,2008;Schumannetal.,2009),thisbriefexercisesuggeststhattheefforttoreconcilefindingsandtheories,ifundertaken,mighthavebeenproblematic.

THE EXISTING QUANDARY AND THE ARGUMENT FOR AUTISM AS SYMPTOMSThe Existing Quandary: Should the Current Paradigm of Autism be Abandoned?KendlerandFirstaskedthequestion:

At what point does it make sense to abandon one paradigm in favour of another? Ideally, the shift should be organic, occurring at a point at which the advantages of

ELSEVIE

R


the new paradigm become so overwhelming that to continue with the existing paradigm would make no sense. However, what happens if a shift is driven by a new paradigm whose advantages over the existing paradigm are tentative, more theoretical than practical, appealing but not “road tested”?

Kendler and First (2010, p. 264)

Whatparadigmofautismshouldresearchersfollow?Shouldresearcherskeepsearchingfortheunifyingpathophysiologyof

autism in samples defined byDSMcriteria andDSMdiagnostic instru-ments? Elsabbagh et al. (2012), Chow et al. (2012), Kaiser and Pelphrey(2012),Kanaetal. (2011),Wolffetal. (2012)andmanyotherresearchershavearguedforthiscourse.LordandJones(2012)notedthatfindingtheneuralbasisforautismsymptomswas“particularlyimportantifthefocusisonearlierorbetterdiagnosis…wedowanttolinktheneurobiologytothebehaviorsthatwearetryingtoexplaininASD”(p.492).

However,thesearchfortheneurobiologicalbasisforautismhasalonghistoryoffailure.Asnotedthroughoutthisbook,novalidatedpathophysiol-ogyhasbeendiscoveredforautism,andeventhecoreautismsymptomofsocialinteractionimpairmenthasnotbeenlinkedtoanysingleneurobiologi-calcause.Theexistingevidenceforheterogeneityofbehaviors,braindeficits,andetiologiesforautismarguesagainstthepossibilityoffindingautism-spe-cific“validpatternsofbrainfunctionthatareassociatedwithreliablymea-suredbehavioraldimensionsofASD”(Lord&Jones,2012,p.492).

Shouldresearchersattempttoexcludewhattheyinterpretasnon-diagnos-ticsymptomsfromautismsymptomsetsinthebeliefthatthereisaunitaryautismdisorderormeaningful spectrumof closely related autismdisorders?Closeetal.(2012),Guinchatetal.(2012a),LordandJones(2012),andtheAPADSM-5NeurodevelopmentalDisordersWorkGrouphavearguedforthisview.

LordandJones(2012)statedthat,incomparisonwithneurobiologicalresearch inautism, the researchon social impairmentwas“notable in itsconsistencyandreplicabilityacrossstudies”(p.494).However,thisconsis-tencycannotincludethemeasurementofindividualvariation.AsnotedinChapter1,JonesandKlin(2009)concluded,“Individualswithautismshowavastclinicalvariabilityintheexpressionandseverityoftheirsymptoms.ThisheterogeneityspanstheentirerangeofIQandlanguagefunctionandawidearrayofcommunicative,social,andbehavioraldisabilities”(p.471).Schultznoted,“Ifyou’veseenonechildwithautism,you’veseenonechildwith autism.Autism’s like a snowflake” (Scott, 2011). Even Lord (2011)observedthatanyonewhohasmetmorethanonepersonwithautismisstruckbythevariationbetweendiagnosedindividuals.

ELSEVIE

R


Lord and Jones (2012) proposed that “Finer-grained descriptions ofbehaviors associated withASD are still needed in order to better definedimensionsofsocial-communicationdeficitsandrestricted/repetitivebehav-iorsonanindividual level forbothclinicalandneurobiologicalpurposes”(p.504).Althoughfiner-graindescriptionsofautismsymptomswouldcer-tainlyyieldincreasingdetailthatwouldbetterinformdifferentiableclinicaldescriptions of individual variation within autism, finer-grain behavioraldescriptionsareunlikelytoaddinformationthatwouldhelptolinkbehaviortoneurobiology.Todate,novalidatedcausalspecificityforautismsymptomshas been determined from the wealth of heterogeneous neurobiologicalfindings.Becausefiner-grainsymptomdescriptionswillnotexplicatehowvariedneurobiologicalcausesconvergeononeclinical symptom,andwillnotexplicatehowdivergentclinicalsymptomsaregeneratedbyasingleneu-robiololgicalcause,finer-graindescriptionsofautismsymptomsareunlikelytobeusefulfordeterminingthecomplexitiesofautismneurobiology.

Shouldresearchersviewautismasa spectrumofrelateddisorders thatcanbe successfully divided into subgroups?Aldridge et al. (2011),Eapen(2011),Veenstra-VanderWeeleandBlakely(2012),andmanyotherresearch-ershaveheldthisview,butthisviewhasyettoprovideimprovedclarityindiagnosisandhasyettoestablishstandardsubgroupswithinautism.Thepro-posedDSM-5criteriaforautismhaveeliminatedalldiagnosticsubgroupsforlackofdistinguishingevidencetodifferentiatethediagnosticsubgroups,andbecauseasharedpathophysiologyforautismwasclaimedtoexist.

KendlerandFirst(2010)arguedthatpsychiatricdisorderscouldnotbedividedintoetiologicalsubgroupsbecausethegeneticbasesfordisordershaveproven tobe socomplex that finding singleetiology subgroupswouldbeunlikely.However,geneticsingleetiologysubgroupsalreadyexistinautism.Calledsyndromicautism,thediagnosisofautismhasbeenmadeinindividualswith fragile X syndrome, Rett syndrome, tuberous sclerosis, Joubert syn-drome, Timothy syndrome, Down syndrome, Klinefelter syndrome, andAngelmansyndrome,aswellasinmanyotherdefinedgeneticsyndromes.

Infact,syndromicautismdemonstratesthatautismsymptomsmayappearinassociationwithmanydifferentformsofneurobiologicalbraindisruptioncaused by many different genetic etiologies.The findings for syndromicautismalsosuggestthattheLordandJones(2012)goaloflinking“neurobi-ologytothebehaviorsthatwearetryingtoexplaininASD”(p.492)maybefraughtwithcomplexoverlappinglinks.

Shouldresearchersviewautismasmanyhundredsofdifferentautismsresultingfrommultiplegeneticcausesandmultipleenvironmentalcauses?

ELSEVIE

R


ColemanandGillberg(2012)havearguedforthisview,buttheprospectisdaunting.DameStephanieShirley,founderofAutismSpeaksinBritain,hadhoped that“the causes of the various autisms should be understood by2012”(Feinstein,2010,p.297).Thishasnothappened,andforgoodreason:thecausesaremanyandcomplex.

Mostimportantly,naturehasblockedanyeasypathtoinferenceforthediscovery of multiple autisms.As noted frequently in this book, autismsymptomsappearwithothersymptomsinassociationwithasharedriskfactor,andmanydifferentpatternsofbraindisruptionmayproducethesameautismsymptom.Togetherthesetwolinesofevidencemeanthatclearcausalmappingofriskfactortobraindisruptiontosymptomwillbeunlikely,andsuggestthatetiologicalagentsanddevelopmentalbraindisruptionshavenotcreatedhundredsofclearlydistinguishableautismsyndromes.

Anadditionalinferentialproblemforformingmultiplesubgroupsisthedifficultyinidentifyingdiscretebraindeficits.Thewidespreadbraindisrup-tionsfoundtodateinassociationwithautism,andthecomplexityofbrainnetworksboth standagainst the identificationofdiscretebraindeficits forautismsubgroups.AnexampleofthepotentialunderlyingcomplexityistheproposalthatSchilbachetal.(2012)madeforthreeoverlappingbrainnet-works.Theresearchersconductedameta-analyticstudyandconcludedthattherewasasocialcognitionnetworkreflectedinbrainactivationintheleftdorsomedialprefrontalcortex,theleftprecuneus,thetemporoparietaljunc-tion,theanteriortemporalcortex,andtheleftsuperiorfrontalgyrus.Theydefinedanetworkforemotionprocessingthatincludedbilateralactivationintheamygdala,theventralanddorsalstriatum,theanteriorcingulatecortexanddorsomedialprefrontalcortex,theposteriorcingulatecortex,precuneus,dorsalvisualareaV5,andinsularcortex(Schilbachetal.,2012).Finally,theydefinedanetworkforintrospection,thedefaultmodenetworkactivewhenapersonisnotfocusedonatask,includingposteriorcingulatecortex,pre-cuneus,anteriorcingulatecortex,ventromedialanddorsomedialprefrontalcortex,bilateralsupramarginalgyrus,bilateraltemporoparietaljunction,leftsuperiorandrightmiddletemporalgyrus,leftmiddleoccipitalgyrus,andleftmiddlefrontalgyrus.Schilbachetal.(2012)foundtwopointsofoverlapforall three systems—the precuneus and anterior medial prefrontal cortex—whichtheresearchersviewedashubsthatconnectedthethreesystems.

Giventheexistingevidenceforwidespreadbraindisruptioncausedbymany risk factors for autism, linking disrupted components of complexsystems as described by Schilbach et al. (2012) to discrete variations inautismsymptomsislikelytoproveimpossible.

ELSEVIE

R


Rethinking AutismInselandWangcalledonresearchers torethinkthenatureofpsychiatricdisorders:

With no validated biomarkers and too little in the way of novel medical treatments since 1980, families need science to provide more than hope. Genetics and neuro-science finally have the tools to transform the diagnosis and treatment of mental illness. But first, it is time to rethink mental disorders, recognizing that these are dis-orders of brain circuits likely caused by developmental processes shaped by a com-plex interplay of genetics and experience.

Insel and Wang (2010, p. 1971)

ThisbookhastakenInselandWang’scallseriously.Theresearchfindingsforautismhavebeenreconsideredhereinanefforttounderstandwhynoneofusconductingresearchinautismhasbeenabletofindavalidsharedbraindeficit inautism,ora standarddiagnostic symptompattern,or replicableandmeaningfulclinicalorneurologicalsubgroups.

LikeInselandWang(2010),Kendler(2012)calledforempiricalpluralisminpsychiatry.Kendler(2012)arguedthatpsychiatricdisorders“arestunninglycomplex”(p.385),andhe,too,claimedthat“havingoverlysimplifiedviewsofthem,oftenideologicallydriven,hasonlyhamperedourfield”(p.385).

Ifautismisnota singledisorder, ifautismisnothundredsofdistinctsubtypesofautism,whatistheentitybeingstudied?

The Argument that Autism is Symptoms and not a Single Disorder or a Spectrum of Related DisordersGiventhetotalityoftheexistingresearchevidence,Ibelievetheleastspec-ulativescientificpositionisthatautismsymptomsarejustthat,symptoms.Thefollowingseriesofclaimstogetherleadtotheconclusionthatautismsymptomsaresymptomsandnotasingledisorderormultipledisorders.

Claim One: Autism has not Been Validated as a Symptom Set, and Heterogeneity in Symptoms, Brain Deficits, and Etiologies Argues that Autism is not a Single DisorderKanner(1943)definedautismwithtwodiagnosticsymptoms:theprofoundfailuretounderstandsocialinteraction,andaninsistenceonsamenessintheenvironment.There has beenno validation of this pairing of symptoms.DSMcriteriabeforeDSM-5definedautismwiththreesymptoms:socialimpairment, communication impairment, and restricted and repetitivebehaviors.Therehasbeennovalidationofthistriadofsymptoms.Thepro-posedDSM-5criteria for autism spectrumdisorderhavedefined autismwithtwodiagnosticsymptoms:socialinteractionimpairment;andrestricted

ELSEVIE

R


or repetitive behaviors, interests, or activities, or sensory abnormalities.Givenpreviousfindings,thispairingisunlikelytobevalidated.

Inadditiontothelackofvalidationfortheconnectionbetweenautismdiagnosticsymptoms,theheterogeneityofdiagnosticandassociatedsymptoms,thewidevariationinbraindeficits,andtheimmenserangeofetiologiesmakeitimplausiblethatautismcouldbeonedisorder.Nounitarypathogenesisexistsforautism.Nounitarypathophysiologyexistsforautism.Noconsistentunitaryphenotypeexistsforautism.

Claim Two: Environmental and Genetic Risk Factors for Autism Cause Brain Disruptions that are not Causally Specific to Autism SymptomsGeneticandenvironmentalriskfactorsyieldautismsymptomsalongwithothersymptomsanddisorders.AsLordandJones(2012)posited,“themostsignificantscientificchallengetotheconceptofautismasone‘disease’oreven‘diseases’istheheterogeneityofthegeneticfindings”(p.491).FragileXsyndrome(Brayetal.,2011),Rettsyndrome(Goffinetal.,2012),andothergeneticriskfactorsforautismsymptomshavebeenassociatedwithvariedbraindisruptionsandarangeofphenotypes.Variantphenotypeshaveincludedcompleteautismphenotypes,partialautismphenotypes,andphe-notypescomprisedofnon-autismsymptomsalongwithorindependentofautismsymptoms(Hoeftetal.,2011;Wulffaert,VanBerckelaer-Onnes,&Scholte,2009).Forexample,Fernandezetal.(2012)reportedevidenceforthreelargedenovo(newanduniquetothesetofindividualsstudied)chro-mosomalcopynumbervariantsthatcausedbothautismsymptomsandticdisorders.Fernandezetal.(2012)arguedthattheirfindingssupportedtheideaofsharedgeneticbases fordifferentclinicaldiagnoses.AsAddingtonandRapoport(2012)noted,thestudyofmentaldisordershas“littlereasontoexpectphenotypicspecificityfromaparticulargeneticvariant”(p.2).

Talkowskietal.(2012)exploredbalancedchromosomalabnormalitiesthatindexsinglegenedisruptionsinalargesampleofindividualsdiagnosedwithautism and individuals diagnosed with other neurodevelopmental disorders.Theresearchersfoundpossiblecausalgenevariantspreviouslylinkedtoneuro-developmentaldisorders,singlegenecontributorstomicrodeletionsyndromes,newgenevariants,andgenesassociatedwithschizophreniaandbipolardisor-der.Talkowskietal.(2012)proposedapolygenicbasisforautism,inwhichdif-feringmutationsinthesamesetsofgenescontributedinanoverlappingfashiontoautism,schizophrenia,psychosis,bipolardisorder,andintellectualdisability.

State andLevitt (2011)made theessentialpoint about thewidespreadnatureofbraindisruptionscausedbygeneticvariants.Theystated,“Complex

ELSEVIE

R


functions… mediated by hierarchically organized circuitries that includesensory and motor, autonomic regulatory, social-emotional, and cognitivedomains”(State&Levitt,2011,p.1)arealteredinautismbyvarieddisrup-tionsinthe“neurodevelopmentalprocessesthatareguidedbythousandsofgenes” (State & Levitt, 2011, p. 1). In fact, alterations or combinations ofalterationsinorganizingfactors,includinggenevariants,chromosomalnum-bervariants, alteredepigeneticprocesses, anduntowardgene–environmentinteractionsmayimpairbraincircuitsformanybehaviors:social,perceptual,motor,cognitive,andothers(Goh&Peterson,2012;Sivakumaranetal.,2011).

Similarly,environmentalriskfactorsforautismsymptomshaveyieldedmany varied outcomes including individuals with all diagnostic autismsymptoms,with some autism symptoms, andwithmanyother symptompatterns,alongwithorindependentofautismsymptoms.Theseoutcomesincludeintellectualdisability,cerebralpalsy,motordisorders,andotherneu-rocognitiveimpairments(Guinchatetal.,2012b).Awiderangeofenviron-mental insults are possible, and evidence for environmental risk factorssuggeststhatenvironmentalriskfactorsareunlikelytodisruptonlybraincircuits that generate social impairment and aberrantmotor and sensorybehaviors.Mwaniki,Atieno,Lawn,andNewton(2012)reviewedoutcomesof intrauterine and neonatal insults.They reported that epilepsy, visionproblems,hearingproblems,cognitiveimpairment,motorimpairment,andsocial impairmentwereallpossibleoutcomesof insultsbeforeorduringdelivery.Reesetal.(2011)statedthatanadverseintrauterineenvironment,including fetalneuroinflammation fromanycause,couldconferdeathofgraymatterinthecerebellum,hippocampus,andcortex,andcerebralwhitematter damage causing long-termdeficits inneural connectivity.Lubsenetal.(2011)arguedthatglialandneuronalcelldeathinvariousbrainregionsoccurredforchildrendeliveredprematurely.Theresearchersalsofoundevi-dencesuggestingthattherewasdamagetoneurobiologicalprocessesdirect-ingaxonalgrowthandsynaptogenesis.

Anadditionalproblemisthatinterconnectednetworksincreasethevul-nerabilityofindividualcircuitstodevelopmentaldisruption.Themanybraincircuitsmediatingsocialbehaviorarewoventhroughthebrain’sintercon-nections(Akiletal.,2010;Berntsonetal.,2012;Koch,2012;Molenberghs,Cunnington, & Mattingley, 2012; Solari & Stoner, 2011;Van Essen &Ugurbil,2012).Forexample,considerthecentralautismsymptomofsocialinteraction impairment. As outlined in Chapter 3, social neuroscienceresearchhasdemonstratedthatsocialinteractiondependsonmanydifferentneurochemicals andmanybrain circuits, including thosemediating socialmotivation,socialcognition,behavioralflexibility,perceptualprocessing,and

ELSEVIE

R


manyothers.Evidencesuggeststherearemulti-purposeprocessingcenters,such as the amygdala, thatmediate both social and non-social behaviors.Even presumptively dedicated social brain processing centers such as thefusiformfaceareamayservemoregeneralprocessingfunctions,suchasdis-criminationandcategorizingofobjects.Ameta-analysisof125studiesofhuman mirror neuron system function conducted by Molenberghs et al.(2012)suggestedthat,dependingonthetasksinvolved,themirrorsystemprovides comprehension of action or comprehension of the emotions ofothers.Berntson,Norman,Hawkley,andCacioppo(2012)argued,“com-plexitiesassociatedwithnavigatingsocialsystemsinprimates…ledtotheevolutionarydevelopmentof someof themostcomplexnetworksof thebrain… thecomplexityof thesenetworkshas thus farprecludedaclearmappingbetweensocialandneurologicalprocesses”(p.65).

Insum,therearemanycircuitsmediatingsocialbehavior,manyofthesecircuitsaremulti-purpose,andcircuitsmediatingsocialbehaviorareinter-wovenwiththetotalityofcorticalandsubcorticalcircuits,systems,andnet-works.Therefore, in order for genetic and environmental risk factors toimpairsocialinteraction,riskfactorsmustnecessarilycausebraindisruptionsthatimpairnotonlysocial-behavior-mediatingbraincircuits,butalsobraincircuitsmediatingotherbehaviors.Abraindisruptionyieldingsocialimpair-mentwouldthereforebelikelytocausevariedadditionalsymptomssuchasdevelopmentaldelay,atypicalmotorbehaviors,andlanguageimpairmentordelay.Asnotedearlier,neuroscience findings for regionalcircuits, systems,andnetworkswithinthelargerconnectomedonotsuggestthattherecouldbeaneasymappingoftheseinterwoven,overlapping,andsharedcircuitstospecificsymptoms.

For example,Wei et al. (2011) hypothesized that three major braindevelopmentprocessesweredisruptedinautism:neuronmigration;thebal-anceofexcitatoryandinhibitorysynapses;andsynaptogenesis.Allthreeareglobalbraindevelopmentdisruptions.Consequently, thebraindisruptionmodeloutlinedbyWeietal.(2011)effectivelypredictsthatintellectualdis-ability, motor delay, language impairment, attention deficit/hyperactivitydisordersymptoms,andothernon-diagnosticsymptomswouldbelikelytoco-occurwithautismsymptoms.

Of course, theremaybe rare cases, like the famousHMofmemoryresearch, wherein an individual has severe neurodevelopmental socialimpairmentbecauseofaspecific lesion.However,therearemyriadbraincircuitsandneurochemicalsthatdeterminethemanyskillsneededfortypi-calsocialinteractionbehavior.AsoutlinedinChapter3,ourmanysocial

ELSEVIE

R


braincircuitsreflectthebehavioralevidencethathumanmeansforsocialcommunicationareoverbuilt.Wehavemanyalternatewaysofcommuni-catingwithoneanother,suchaseyegaze,facialexpressions,gestures,bodymovement,voicetoneandpattern,andlanguage.Consequently,aspecificfocal lesion is less likely to be able to cause severe developmental socialinteractionimpairment.

Insum,thetotalityofevidencedemonstratesthatdevelopmentalbraindisruptionscausedbygeneticandenvironmentalriskfactorsforautismwillnotmapone-to-onewithautismsymptoms.Thus,becausethesebraindis-ruptionswillnotbecausallyspecificforautism,effortstovalidateautismasasingledisorderwillcontinuetofail.Moreover,thepresenceofassociatedsymptoms with autism symptoms suggests that the autism spectrum ofsymptomsandthebroadautismphenotypewillalsocontinuetofailtobevalidated.

Claim Three: Because Risk Factors Tie Autism Symptoms to Non-Autism Symptoms, Behavioral Subgroups cannot be Uniquely Autism SubgroupsFinally,becausemostindividualsdiagnosedwithautismexpressoneormoreadditionalnon-diagnostic symptomsgeneratedby the causal risk factors forautism, associatednon-autism symptomscannotbeexcluded fromany sub-group formation. Consequently, subgroups formed would include variouscombinationsofsymptoms,andthuswouldnotbeuniquelyautismsubgroups.

Takentogether,thesethreeclaimsandassociatedlinesofevidenceargueagainsttheexistenceofautismasasingledisorder,spectrum,orsetofautismsubgroups.Ifautismsymptomsarenotonedisorder,andarenotmanydis-orders,whatarethey?Themostparsimoniousandleastspeculativeviewisthatautismsymptomsmustbesymptoms.

Summary: Autism Symptoms as SymptomsSanislowetal.(2010)proposed,

a diagnosis may turn out simply to be indicative of a range of possible patholo-gies … . for example, depression might be viewed akin to the way that a fever is viewed today, suggesting specific tests for a panel of potentially active diagnostic markers that will steer the clinician to the appropriate treatment among any number of possible disordered processes that might underlie the depression.

Sanislow et al. (2010, pp. 637–638)

Areautismsymptomssimilartothewayinwhichfeverisasymptom?Feverischaracterizedbyariseincorebodytemperature,andtheactivationof

ELSEVIE

R


immunesystems.Feverisgenerallytemporary;autismisnot.However,fever,likeautism symptoms, is a signofmanydifferentdiseases, and fever, likeautism symptoms, results from complex mechanisms. Gensini and Conti(2004)notedthatGalenbelievedthatfeverwasadiseaseinitself,andmanytheoriesoffeverasadiseaseexistedforseveralthousandyears.

Feverisnowunderstoodasaphysiologicresponsetodiseasemediatedby immunesystemagentscalledpyrogeniccytokines (Mackowiak,1998).Yang,Zhuang,andServaes(2012)noted,however,thatthereisstillmuchfeverofunknownorigin(FUO).

Thediscoveryofpathogenswasnecessaryinorderforfevertobeunder-stoodasasymptomofapathogen’seffectonthebody.Thepathogenistheetiology, thepathogen’sdisruptionofbody function is thedisease, and afever isoneobservablesymptomofthe immunesystem’sreactiontothepathogen,anditsdisruptionofbodyfunctions.

Similarly,thediscoveryofmanydifferentbraindeficitsassociatedwithautism,andthediscoveryofmanydifferentgeneticandenvironmentalriskfactorsascausesforthosevariousbraindeficitswereanecessaryprecondi-tioninorderthatautismsymptomscouldbeseenassymptomsandnotadisorder.Autismsymptomsaretheobservablebehaviorsthatreflecttheexis-tenceofdevelopmentalbraindisruptionsand thecausalchains leadingtothosebraindisruptionsthatbeginwithanetiologyormultipleetiologies.

CONCLUSION: AUTISM SYMPTOMS WITHOUT A DISORDER

Talkowskietal.(2012)reportedthata“profoundcollectivecontributionofthedisruptedgenesonneurodevelopment”(p.534)crossedmanydiagnos-ticboundaries,andLeckmanandPine(2012)askedwhatthebestnosologi-calapproachshouldbegiventhatgeneticriskvariantsaresharedbymanydifferentdisorders.

LordandJones(2012)arguedthatthefindingthatautismsharescausalriskvariantswithotherdisorders“isanimportantadditionto,butinnowayareplacementforabehavioraldiagnosis”(p.491).Infact,however,thefind-ings for themany shared risk factors for autism andother disorders, theresultantbroadandvariablebraindisruptions,andthemixedsymptomphe-notypes do argue that the behavioral diagnosis of autism as a disorder islikelytobewrong.Moreover,becausetheevidence,asreportedinthisbook,hasdemonstrated thatno formof thebehavioral diagnosisof autismhasbeenvalidated,andtheevidenceformanysharedriskfactors,broadbraindisruptions and multi-symptom phenotypes suggests that the behavioral

ELSEVIE

R


diagnosisofautismisunlikelyevertobevalidated,scientificprogresswillcontinue to be stalled if theDSM-5 diagnosis remains in use.ThemostsimpleandminimalsolutionwouldbetoreplacetheDSM-5diagnosiswithanopensetofsymptomsthatmakesnoclaimstobeadisorder.

Manychangesindiagnosticcriteria,clinicalpractice,andresearchprac-ticewouldresultfromtheacceptanceoftheviewthatautismsymptomsaresymptoms.Forexample,whileautismisunderstoodasadisorder,theco-occurrenceofthetwosymptomsofsocialimpairmentandintellectualdis-abilitydefyadiagnosticboundary.Butifsocialimpairmentandintellectualdisabilityareseenastwoobservablesymptomsofbraindisruption,thenjustasaphysicianwouldneversaythatapersonwhohadarashcouldnotbediagnosedwithafever,aclinicianwouldnolongersaythatachildwhohaddevelopmentaldelaycouldnotbeidentifiedashavingsocialimpairment.

Box8.1usestheproposedDSM-5firstcriterionforautismspectrumdisorder as an illustration of a possible starting point for describing twoneurodevelopmentalsocialimpairmentsymptomsets.TheproposeduseofDSM-5criterialistedinBox8.1includesboththedescriptionofasimpleneurodevelopmentalsocialimpairmentsymptomsetandthedescriptionofacomplexsymptomset.Thefirstsymptomsetisdefinedbyneurodevelop-mentalsocialimpairmentonly.Therationaleforthissymptomsetofsocialimpairment without other symptoms is that this phenotype has beenreportedinclinicalpopulations(Mandyetal.,2011;Mattilaetal.,2011).Ifthereisagroupwithsocialimpairmentandnootherneurodevelopmentalorpsychiatricdisorders,thisgroupwouldbeofimportanceforresearch.

Thesecondsymptomsetdocumentsautismsocialimpairmentwithalladditionalco-occurringneurodevelopmentalsymptoms.Therationaleforthiscomplexsymptomsetisthatheterogeneoussymptomshavebeenfoundwithgeneticandenvironmentalriskfactorsforautismandrequireexplana-tionascomplexsymptomsets.

The British Psychology Society recommended that any classificationsystemshouldbeginfromsymptoms.Theyclaimedthatbecause“twopeo-plewithadiagnosisof‘schizophrenia’or‘personalitydisorder’maypossessno two symptoms incommon, it isdifficult to seewhatcommunicativebenefit is servedbyusingthesediagnoses”(Alan,2011,p.3).TheBritishPsychologicalSociety stated,“Webelieve thatadescriptionofaperson’srealproblemswouldsuffice”(Alan,2011,p.3),andtheyarguedthatasymp-tomlistwouldbepreferabletoDSM-5.

Adequatedescriptionofsocialimpairmentandothersymptomsrequiresthatmanysymptomsmustbeincluded.Therangeofsymptoms,suchasthat

ELSEVIE

R


BOX 8.1 Two Possible Neurodevelopmental Social Impairment Phenotypes for a Transitional Symptom Nosology

Neurodevelopmental Social Impairment Only PhenotypeA. Persistent deficits in social communication and social interaction across

contexts for all three types of social impairment appearing in childhood:Deficits in social-emotional reciprocity; ranging from abnormal social approach and failure of normal back and forth conversation, through reduced sharing of interests, emotions, and affect and response, to total lack of initia-tion of social interaction.Deficits in nonverbal communicative behaviors used for social interaction; ranging from poorly integrated verbal and nonverbal communication, through abnormalities in eye contact and body language, or deficits in understanding and use of nonverbal communication, to total lack of facial expression or gestures.Deficits in developing and maintaining relationships, appropriate to develop-mental level (beyond those with caregivers); ranging from difficulties adjusting behavior to suit different social contexts, through difficulties in sharing imagi-native play and in making friends, to an apparent absence of interest in people.

B. Does not express any other neurodevelopmental symptoms includingAtypical sensory behaviors:

Hyper- or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment (such as apparent indifference to pain/heat/cold, adverse response to specific sounds or textures, excessive smelling or touching of objects, fascination with lights or spinning objects).

Atypical motor behaviors:Hypotonia, motor stereotypies, self-injurious behavior …

Atypical rigidity in behaviors and interests:Excessive adherence to routines, ritualized patterns of verbal or nonverbal behavior, or excessive resistance to change (such as motoric rituals, insis-tence on same route or food, repetitive questioning, or extreme distress at small changes).Highly restricted, fixated interests that are abnormal in intensity or focus (such as strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interests).

Atypical language development:Absence of languageDelayed onset of speechStereotyped or repetitive speech, echolalia, idiosyncratic phrases

Attention deficit/hyperactivity disorder symptomsIntellectual disability or developmental delaySeizures

ELSEVIE

R


Neurodevelopmental Social Impairment Multi-symptom PhenotypeA. Persistent deficits in social communication and social interaction

across contexts appearing in childhood:Deficits in social-emotional reciprocity; ranging from abnormal social approach and failure of normal back and forth conversation, through reduced sharing of interests, emotions, and affect and response, to total lack of initia-tion of social interaction.Deficits in nonverbal communicative behaviors used for social interaction; ranging from poorly integrated verbal and nonverbal communication, through abnormalities in eye contact and body language, or deficits in understanding and use of nonverbal communication, to total lack of facial expression or gestures.Deficits in developing and maintaining relationships, appropriate to develop-mental level (beyond those with caregivers); ranging from difficulties adjust-ing behavior to suit different social contexts, through difficulties in sharing imaginative play and in making friends, to an apparent absence of interest in people.

B. Neurodevelopmental deficits manifested in any to all subdomains:Atypical sensory behaviors:

Hyper- or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment (such as apparent indifference to pain/heat/cold, adverse response to specific sounds or textures, excessive smelling or touching of objects, fascination with lights or spinning objects).

Atypical motor behaviors:Hypotonia, motor stereotypies, self-injurious behavior …

Atypical rigidity in behaviors and interests:Excessive adherence to routines, ritualized patterns of verbal or nonverbal behavior, or excessive resistance to change (such as motoric rituals, insis-tence on same route or food, repetitive questioning, or extreme distress at small changes).Highly restricted, fixated interests that are abnormal in intensity or focus (such as strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interests).

Atypical language development:Absence of languageDelayed onset of speechStereotyped or repetitive speech, echolalia, idiosyncratic phrases

Attention deficit/hyperactivity disorder symptomsIntellectual disability or developmental delaySeizures

BOX 8.1 Two Possible Neurodevelopmental Social Impairment Phenotypes for a Transitional Symptom Nosology—cont’d

ELSEVIE

R


suggestedinBox8.1,couldbelistedandidentified.Theunderlyingbraindisruptionswouldbeknownorunknown.Currentunknownriskfactorswouldcontinuetobeidentifiedasnewfindingsforcausalenvironmentalinsultsdevelopedovertime,andasknowledgeofcausalgene,chromosomal,epigenetic, and gene–environment disruptions of brain developmentaccumulated.

Rutter(2005)warned,“Thereisnodisgraceinbeingwrong,butthereisadisgraceinpersistingwithatheorywhenempiricalfindingshavemadeitapparentthatthehypothesisorclaimwasmistaken”(p.255).Thisbookhasarguedthatempiricalfindingshavemadeitapparentthatthetheoryofautismasasingledisorderorspectrumwasmistaken.However,thecontin-uedquesttounifyautismisnotadisgrace,butadesperatesearchforasingleclarifyingsolutionwherenoneislikelytoexist.

Prassad,Cifu,andIoannidis(2012)pragmaticallyconcludedthatoften,“established standardsmust be abandonednot because a better replace-menthasbeenidentifiedbutsimplybecausewhatwasthoughttobeben-eficialwasnot”(p.37).Thisbookhasarguedthattheestablishedtheoryandstandarddiagnosisofautismshouldbeabandonednotbecauseabetterreplacement has been identified but because the totality of empiricalresearchhas failed tovalidate autismas adisorder, and theevidence forheterogeneoussymptomsforriskfactorsrequiresamoreinclusiveexpla-nation. Translational research requires a neurobiological mechanism.Becauseautismsymptomsaresymptomsofamultitudeofneurobiologicalmechanisms, the abandonment of belief that autism will eventually befoundtohaveasingleneurobiologicalmechanismshouldbebeneficialforresearch.

Thevisionsuggestedhereissimple.Neurodevelopmentalsocialimpair-mentisasymptom,sensoryabnormalitiesareasymptom,intellectualdis-ability is a symptom, restricted and repetitive interests andbehaviors aresymptoms, andotherneurodevelopmental associateddisorders are symp-toms, all of which result from varied complex developmental braindisruptions.

Althoughthedescriptiveshiftmaybesimple,andalthoughshiftingtoasymptomviewhasthepowertoendfruitlesseffortstoprovethatasetofsymptomsisauniquedisorder,theresultingresearchproblemisimmenselymoredifficultthansearchingforasingularunity.Etiologies,braindisrup-tions,theprocessofbraindevelopment,andthestructureandfunctionofthebrainareeachcomplexworlds.Findinglinesofcausalitythroughandacrosstheseworldswillbealengthyandextremelydemandingchallenge.

ELSEVIE

R


REFERENCESAbrahams,B.S.,&Geschwind,D.H.(2010).Connectinggenestobrainintheautismspec-

trumdisorders.Archives of Neurology,67,395–399.Addington,A.M.,&Rapoport,J.L.(2012).AnnualResearchReview:Impactofadvancesin

genetics inunderstandingdevelopmental psychopathology. Journal of Child Psychology and Psychiatry,53,510–518.

Akil,H.,Brenner,S.,Kandel,E.,Kendler,K.S.,King,M.C.,Scolnick,E.,etal.(2010).The future of psychiatric research: Genomes and neural circuits. Science, 327,1580–1581.

Akshoomoff,N.,Pierce,K.,&Courchesne,E.(2002).Theneurobiologicalbasisofautismfromadevelopmentalperspective.Development and Psychopathology,14,613–634.

Alan,C.A.(2011,June).The British Psychology Society Response to the American Psychiatric Asso-ciation: DSM-5 Development, 1–26.Bps.uk.org.RetrievedJanuary23,2012fromhttp://www.bps.org.uk/news/societys-critical-response-dsm-5.

Aldridge,K.,George,I.D.,Cole,K.K.,Austin,J.R.,Takahashi,T.N.,Duan,Y.,etal.(2011).Facialphenotypes in subgroupsofpre-pubertalboyswithautism spectrumdisordersarecorrelatedwithclinicalphenotypes.Molecular Autism,2(15),1–12.

Barnard-Brak,L.,Sulak,T.,&IveyHatz,J.K.(2011).Macrocephalyinchildrenwithautismspectrumdisorders.Pediatric Neurology,44,97–100.

Barnea-Goraly,N.,Lotspeich,L.J.,&Reiss,A.L.(2010).Similarwhitematteraberrationsinchildren with autism and their unaffected siblings:A diffusion tensor imaging studyusingtract-basedspatialstatistics.Archives of General Psychiatry,67,1052–1060.

Baron-Cohen,S.,Lombardo,M.V.,Auyeung,B.,Ashwin,E.,Chakrabarti,B.,&Knickmeyer,R.(2011).Whyareautismspectrumconditionsmoreprevalentinmales?PLoS Biology,9,e1001081.

Bejerot,S.,Eriksson,J.M.,Bonde,S.,Carlström,K.,Humble,M.B.,&Eriksson,E.(2012).Theextrememalebrainrevisited:Gendercoherence inadultswithautismspectrumdisorder. British Journal of Psychiatry. [Epub April 12, 2012]. doi: 10.1192/bjp.bp.111.097899.

Berntson,G.G.,Norman,G.J.,Hawkley,L.C.,&Cacioppo,J.T.(2012).Evolutionofneuroarchitecture,multi-levelanalysesandcalibrativereductionism. Interface Focus,2,65–73.

Bill, B. R., & Geschwind, D. H. (2009). Genetic advances in autism: Heterogeneityandconvergenceonsharedpathways.Current Opinion in Genetic Development,19,271–278.

Boucher,J.(2011).Redefiningtheconceptofautismasaunitarydisorder:Multiplecausaldeficitsofasinglekind?InD.Fein(Ed.),The neuropsychology of autism(pp.469–482).NewYork,NY:OxfordUniversityPress.

Bray,S.,Hirt,M.,Jo,B.,Hall,S.S.,Lightbody,A.A.,Walter,E.,etal.(2011).AberrantfrontallobematurationinadolescentswithfragileXsyndromeisrelatedtodelayedcognitivematuration.Biological Psychiatry,70,852–858.

Campbell,D.B.,Datta,D.,Jones,S.T.,Lee,E.B.,Sutcliffe,J.S.,Hammock,E.A.D.,etal.(2011).Associationofoxytocinreceptor(OXTR)genevariantswithmultiplepheno-type domains of autism spectrum disorder. Journal of Neurodevelopmental Disorders, 3,101–112.

Chen,Y.,Norton,D.J.,McBain,R.,Gold,J.,Frazier,J.A.,&Coyle,J.T.(2012).Enhancedlocalprocessingofdynamicvisualinformationinautism:Evidencefromspeeddis-crimination.Neuropsychologia,50,733–739.

Chow,M.L.,Pramparo,T.,Winn,M.E.,Barnes,C.C.,Li,H.R.,Weiss,L.,etal.(2012).Age-dependentbraingeneexpressionandcopynumberanomaliesinautismsuggestdistinctpathologicalprocessesatyoungversusmatureages.PLoS Genetics,8,e1002592.[EpubMarch22,2012].

ELSEVIE

R

http://Bps.uk.org

http://www.bps.org.uk/news/societys-critical-response-dsm-5

http://www.bps.org.uk/news/societys-critical-response-dsm-5


Close,H.A.,Lee,L.C.,Kaufmann,C.N.,&Zimmerman,A.W.(2012).Co-occurringcondi-tionsandchangeindiagnosisinautismspectrumdisorders.Pediatrics,129,e305–316.

Coghill,D.,&Sonuga-Barke,E. J.S. (2012).AnnualResearchReview:Categoriesversusdimensions in theclassificationandconceptualisationofchildandadolescentmentaldisorders:Implicationsofrecentempiricalstudy.Journal of Child Psychology and Psychiatry,53,469–489.

Copeland,W.,Shanahan,L.,Costello,E.J.,&Angold,A.(2011).Cumulativeprevalenceofpsy-chiatricdisordersbyyoungadulthood:AprospectivecohortanalysisfromtheGreatSmokyMountainsStudy.Journal of the Academy of Child and Adolescent Psychiatry,3,252–261.

Courchesne, E., Mouton, P. R., Calhoun, M. E., Semendeferi, K.,Ahrens-Barbeau, C.,Hallet,M.J.,etal.(2011).Neuronnumberandsizeinprefrontalcortexofchildrenwithautism.Journal of the American Medical Association,306,2001–2010.

DeJaegher,H.,DiPaolo,E.,&Gallagher,S.(2010).Cansocialinteractionconstitutesocialcognition?Trends in Cognitive Sciences,14,441–447.

Eapen,V.(2011).Geneticbasisofautism:Isthereawayforward?Current Opinion in Psychia-try,24,226–236.

Ebisch, S. J., Gallese,V.,Willem, R. M., Mantini, D., Groen,W. B., Romani, G. L., &Bekkering,H.(2010).Alteredintrinsicfunctionalconnectivityofanteriorandposteriorinsularegionsinhigh-functioningparticipantswithautismspectrumdisorder.Human Brain Mapping,32,1013–1028.

Ebstein,R.P.,Knafo,A.,Mankuta,D.,Chew,S.H.,&Lai,P.S.(2012).Thecontributionsofoxytocinandvasopressinpathwaygenestohumanbehavior.Hormones and Behavior,61,359–379.

Ecker,C.,Suckling,J.,Deoni,S.C.,Lombardo,M.V.,Bullmore,E.T.,Baron-Cohen,S.,etal.(2012).Brainanatomyanditsrelationshiptobehaviorinadultswithautismspectrumdisorder:Amulticentermagneticresonanceimagingstudy.Archives of General Psychiatry,69,195–209.

Elsabbagh,M.,Mercure,E.,Hudry,K.,Chandler,S.,Pasco,G.,Charman,T.,etal. (2012).Infantneuralsensitivitytodynamiceyegazeisassociatedwithlateremergingautism.Current Biology,22,1–5.

Feinstein,A.(2010).A history of autism: Conversations with the pioneers.NewYork,NY:WileyBlackwell.

Fernandez,T.V.,Sanders,S.J.,Yurkiewicz,I.R.,Ercan-Sencicek,A.G.,Kim,Y.S.,Fishman,D.O.,etal.(2012).RarecopynumbervariantsinTourettesyndromedisruptgenesinhis-taminergicpathwaysandoverlapwithautism.Biological Psychiatry,71,392–402.

Foss-Feig,J.H.,Heacock,J.L.,&Cascio,C.J.(2012).Tactileresponsivenesspatternsandtheirassociationwithcorefeaturesinautismspectrumdisorders.Research in Autism Spectrum Disorders,6,337–344.

Fountain,C.,Winter,A.S.,&Bearman,P.S.(2012).Sixdevelopmentaltrajectoriescharacter-izechildrenwithautism.Pediatrics.[EpubApril2,2012].

Frances,A. (2012, February 21). DSM 5 freezes out its stakeholders. Huffingtonpost.com.RetrievedFebruary21,2012fromhttp://www.huffingtonpost.com/allen-frances/dsm-5-freezes-out-its-sta_b_1269838.html.

Frances,A.J.,&Widiger,T.(2012).Psychiatricdiagnosis:LessonsfromtheDSM-IVpastandcautionsfortheDSM-5future.Annual Review of Clinical Psychology,27,109–130.

Gensini,G.F.,&Conti,A.A.(2004).Theevolutionoftheconceptof“fever”inthehistoryof medicine: From pathological picture per se to clinical epiphenomenon (and viceversa).Journal of Infection,49,85–87.

Geschwind,D.H.(2011).Geneticsofautismspectrumdisorders.Trends in Cognitive Sciences,15,409–416.

Gilman,S.R.,Iossifov,I.,Levy,D.,Ronemus,M.,Wigler,M.,&Vitkup,D.(2011).Raredenovo variants associated with autism implicate a large functional network of genes.Neuron,70,898–907.

ELSEVIE

R

http://huffingtonpost.com/

http://www.huffingtonpost.com/allen-frances/dsm-5-freezes-out-its-sta_b_1269838.html

http://www.huffingtonpost.com/allen-frances/dsm-5-freezes-out-its-sta_b_1269838.html


Girirajan,S.,Rosenfeld,J.A.,Cooper,G.M.,Antonacci,F.,Siswara,P.,Itsara,A.,&Eichler.,E.E.(2010).Arecurrent16p12.1microdeletionsupportsatwo-hitmodelforseveredevelop-mentaldelay.Nature Genetics,42,203–209.

Goffin,D.,Allen,M.,Zhang,L.,Amorim,M.,Wang,I.T.,Reyes,A.R.,etal.(2012).RettsyndromemutationMeCP2T158AdisruptsDNAbinding,proteinstabilityandERPresponses.Nature Neuroscience,15,274–283.

Goh,S.,&Peterson,B.S.(2012).Imagingevidencefordisturbancesinmultiplelearningandmemorysystemsinpersonswithautismspectrumdisorders.Developmental Medicine and Child Neurology,54,208–213.

Gordon,I.,Martin,C.,Feldman,R.,&Leckman,J.F.(2011).Oxytocinandsocialmotivation.Developmental Cognitive Neuroscience,1,471–493.

Guinchat,V.,Chamak,B.,Bonniau,B.,Bodeau,N.,Perisse,D.,Cohen,D.,etal.(2012a).Veryearlysignsofautismreportedbyparentsincludemanyconcernsnotspecifictoautismcriteria.Research in Autism Spectrum Disorders,6,589–601.

Guinchat,V.,Thorsen,P.,Laurent,C.,Cans,C.,Bodeau,N.,&Cohen,D.(2012b).Pre-,peri-,andneonatalriskfactorsforautism.Acta Obstetrica Gynecologica Scandanavia,91,287–300.

Hallmayer,J.,Cleveland,S.,Torres,A.,Phillips,J.,Cohen,B.,Torigoe,T.,etal.(2011).Geneticheritabilityandsharedenvironmentalfactorsamongtwinpairswithautism.Archives of General Psychiatry,68,1095–1102.

Happé,F.,&Frith,U.(2006).Theweakcoherenceaccount:Detail-focusedcognitivestyleinautismspectrumdisorders.Journal of Autism and Developmental Disorders,36,5–25.

Hoeft,F.,Walter,E.,Lightbody,A.A.,Hazlett,H.C.,Chang,C.,Piven,J.,etal.(2011).Neuro-anatomical differences in toddler boyswith fragileX syndrome and idiopathic autism.Archives of General Psychiatry,68,295–395.

Holt,R.,&Monaco,A.P.(2011).Linksbetweengeneticsandpathophysiologyintheautismspectrumdisorders.EMBO Molecular Medicine,3,438–450.

Howerton,C.L.,&Bale,T.L.(2012).Prenatalprograming:Attheintersectionofmaternalstressandimmuneactivation.Hormones and Behavior.[EpubMarch23,2012].

Hyman,S.E.(2010).Thediagnosisofmentaldisorders:Theproblemofreification.Annual Review of Clinical Psychology,6,155–179.

Insel,T.R.(2010).Thechallengeoftranslationinsocialneuroscience:Areviewofoxytocin,vasopressin,andaffiliativebehavior.Neuron,65,768–779.

Insel,T.R.,&Wang,P.S.(2010).Rethinkingmentalillness.Journal of the American Medical Association,303,1970–1971.

Ioannidis, J. P.A. (2005).Why most published research findings are false. PLoS Medicine,2.e124.

James,W.H.(2012).Therelevanceoftheepidemiologyofhumansexratiosatbirthtosomemedicalproblems.Paediatric Perinatology and Epidemiology,26,181–189.

Jones,W.,&Klin,A.(2009).Heterogeneityandhomogeneityacrosstheautismspectrum:Theroleofdevelopment.Journal of the American Academy of Child and Adolescent Psychiatry,48,471–473.

Kaiser,M.A.,&Pelphrey,K.A.(2012).Disruptedactionperceptioninautism:Behavioralevidence,neuroendophenotypes,anddiagnosticutility.Developmental Cognitive Neurosci-ence,2,25–35.

Kana,R.K.,Libero,L.E.,&Moore,M.S.(2011).Disruptedcorticalconnectivitytheoryas an explanatory model for autism spectrum disorders. Physics of Life Reviews, 8,410–437.

Kanner,L.(1943).Autisticdisturbancesofaffectivecontact.The Nervous Child,2,217–250.Karmiloff-Smith,A.(2012).Perspectivesonthedynamicdevelopmentofcognitivecapaci-

ties:insightsfromWilliamssyndrome.Current Opinion in Neurology,25,106–111.Kendler,K.(2012).Thedapplednatureofcausesofpsychiatricillness:Replacingtheorganic–

functional/hardware–software dichotomy with empirically based pluralism. Molecular Psychiatry,17,377–388.

ELSEVIE

R


Kendler,K.S.,&First,M.B.(2010).AlternativefuturesfortheDSMrevisionprocess:Iterationv.paradigmshift.British Journal of Psychiatry,197,263–265.

Kennedy,D.P.,&Courchesne,E.(2008).Theintrinsicfunctionalorganizationofthebrainisalteredinautism.NeuroImage,39,1877–1885.

Kent,A.L.,Wright,I.M.,Abdel-Latif,M.E.,NewSouthWalesandAustralianCapitalTerri-toryNeonatalIntensiveCareUnitsAuditGroup(2012).Mortalityandadverseneuro-logicoutcomesaregreaterinpretermmaleinfants.Pediatrics,129,124–131.

Koch,C.(2012).Neuroscience:Theconnectedself.[ReviewofthebookConnectome:Howthebrain’swiringmakesuswhoweare,byS.Seung],Nature,482,31.

Koldewyn,K.,Whitney,D.,&Rivera,S.M.(2010).Thepsychophysicsofvisualmotionandglobalformprocessinginautism.Brain,133,599–610.

Kupfer,D.J.,&Regier,D.A.(2011).Neuroscience,clinicalevidence,andthefutureofpsy-chiatricclassificationinDSM-5.American Journal of Psychiatry,168,672–674.

Lane,A.E.,Young,R.L.,Baker,A.E.Z.,&Angley,M.(2010).Sensoryprocessingsubtypesinautism:Associationwithadaptivebehavior.Journal of Autism and Developmental Disorders,40,112–122.

LeBlond, C. S., Heinrich, J., Delorme, R., Proepper, C., Betancur, C., Huguet, G., et al.(2012).GeneticandfunctionalanalysesofSHANK2mutationssuggestamultiplehitmodelofautismspectrumdisorders.PLoS Genetics,8,e1002521.

Leckman, J. F., & Pine, D. S. (2012). Editorial commentary: Challenges and potential ofDSM-5andICD-11revisions.Journal of Child Psychology and Psychiatry,53,449–453.

Lee,T.L.,Raygada,M.J.,&Rennert,O.M.(2012).Integrativegenenetworkanalysispro-vides novel regulatory relationships, genetic contributions and susceptible targets inautismspectrumdisorders.Gene,496,88–96.

Leekam,S.R.,Nieto,C.,Libby,S.J.,Wing,L.,&Gould,J.(2007).Describingthesensoryabnormalities of children and adultswith autism. Journal of Autism and Developmental Disorders,37,894–910.

Lewis,M.,&Kim,S.J.(2009).Thepathophysiologyofrestrictedrepetitivebehavior.Journal of Neurodevelopmental Disorders,1,114–132.

Lombardo, M. V., Chakrabarti, B., Bullmore, E. T., MRC AIMS Consortium, &Baron-Cohen,S.(2011).Specializationofrighttemporo-parietaljunctionformental-izinganditsrelationtosocialimpairmentsinautism.NeuroImage,56,1832–1838.

Lord,C.(2011).Unweavingtheautismspectrum.Cell,147,24–25.Lord,C.,&Jones,R.M.(2012).AnnualResearchReview:Re-thinkingtheclassificationof

autismspectrumdisorders.Journal of Child Psychology and Psychiatry,53,490–509.Linden,D.E.J.(2012).Thechallengesandpromiseofneuroimaginginpsychiatry.Neuron,

73,8–22.Lubsen,J.,Vohr,B.,Myers,E.,Hampson,M.,Lacadie,C.,Schneider,K.C.,etal.(2011).

Microstructuralandfunctionalconnectivityinthedevelopingpretermbrain.Seminars in Perinatology,35,34–43.

Mackowiak,P.A.(1998).Conceptsoffever.Archives of Internal Medicine,158,1870–1881.Malkova,N.V.,Yu,C.Z.,Hsiao,E.Y.,Moore,M. J.,&Patterson,P.H. (2012).Maternal

immuneactivationyieldsoffspringdisplayingmouseversionsofthethreecoresymp-tomsofautism.Brain, Behavior, and Immunity,26,607–611.

Mandy,W.P.L.,Charman,T.,Gilmour,J.,&Skuse,D.(2011).TowardspecifyingPervasiveDevelopmentalDisorder—NotOtherwiseSpecified.Autism Research,4,121–131.

Mattila,M.L.,Kielinen,M.,Linna,S.L., Jussila,K.,Ebeling,H.,Bloigu,R.,etal. (2011).Autismspectrumdisorders according toDSM-IV-TRandcomparisonwithDSM-5draftcriteria:Anepidemiologicalstudy.Journal of the American Academy of Child and Adolescent Psychiatry,50,583–592.

Meehl,P.E.(1990).Appraisingandamendingtheories:ThestrategyofLakatosiandefenseandtwoprinciplesthatwarrantit.Psychological Inquiry,1,1–141.

ELSEVIE

R


Molenberghs, P., Cunnington, R., & Mattingley, J. B. (2012). Brain regions with mirrorproperties:Ameta-analysisof125humanfMRIstudies.Neuroscience and Biobehavioral Reviews,36,341–349.

Murphy,S.K.,Adigun,A.,Huang,Z.,Overcash,F.,Wang,F.,Jirtle,R.L.,etal.(2012).Gen-der-specificmethylationdifferencesinrelationtoprenatalexposuretocigarettesmoke.Gene,494,36–43.

Mwaniki,M.K.,Atieno,M.,Lawn,J.E.,&Newton,C.R.(2012).Long-termneurodevelop-mentaloutcomesafterintrauterineandneonatalinsults:Asystematicreview.The Lancet,379,445–452.

Naish,J.(2012,February21).Can some children simply “grow out” of autism? One mother tells how her son’s life has been transformed. dailymail.co.uk.RetrievedFebruary22,2012fromhttp://www.dailymail.co.uk/health/article-2103940/Autism-Can-children-simply-grow-One-mother-tells-sons-life-transformed.html.

Nakano,T.,Kato,N.,&Kitazawa,S. (2012).Superiorhaptic-to-visual shapematching inautismspectrumdisorders.Neuropsychologia,50,696–703.

NHSChoices.(2012,February22).“Kidsgrowoutofautism”claimunfounded.NHS.uk.Retrieved February 22, 2012 from www.nhs.uk/news/2012/02February/Pages/children-grow-out-of-autism-claim.aspx.

Noor,A.,Whibley,A.,Marshall,C.R.,Gianakopoulos,P.J.,Piton,A.,Carson,A.R.,etal.(2010).DisruptionatthePTCHD1locusonXp22.11inautismspectrumdisorderandintellectualdisability.Science Translational Medicine,2.49ra68.

Norris,M.,Lecavalier,L.,&Edwards,M.C.(2011).ThestructureofautismsymptomsasmeasuredbytheAutismDiagnosticObservationSchedule.Journal of Autism and Devel-opmental Disorders,42,1075–1086.

Peacock,J.L.,Marston,L.,Marlow,N.,Calvert,S.A.,&Greenough,A.(2012).Neonataland infant outcome in boys and girls born very prematurely. Pediatric Research, 71,305–310.

Peñagarikano,O.,Abrahams,B.S.,Herman,E.I.,Winden,K.D.,Gdalyahu,A.,Dong,H.,etal.(2011).AbsenceofCNTNAP2leadstoepilepsy,neuronalmigrationabnormalities,andcoreautism-relateddeficits.Cell,147,235–246.

Pies,R.W.(2012,February8).Beyond DSM-5, psychiatry needs a “third way.”Thepsychiatrictimes.com.RetrievedFebruary8,2012 fromhttp://www.psychiatrictimes.com/blog/pies/content/article/101682029546.

Prasad,V.,Cifu,A.,&Ioannidis,J.P.(2012).Reversalsofestablishedmedicalpractices:Evi-dencetoabandonship.Journal of the American Medical Association,307,37–38.

Reeb-Sutherland,B.C.,Levitt,P.,&Fox,N.A.(2012).Thepredictivenatureofindividualdifference in early associative learning and emerging social behavior. PLoS ONE, 7,e30511,1–7.

Rees,S.,Harding,R.,&Walker,D.(2011).Thebiologicalbasisofinjuryandneuroprotectionin the fetal and neonatal brain. International Journal of Developmental Neuroscience, 29,551–563.

Robinson,E.B.,Koenen,K.C.,McCormick,M.C.,Munir,K.,Hallett,V.,Happé,F.,etal.(2012).Amultivariatetwinstudyofautistictraitsin12-year-olds:Testingthefraction-ableautismtriadhypothesis.Behavior Genetics,42,245–255.

Rommelse,N.N.J.,Franke,B.,Geurts,H.M.,Buitelaar,J.K.,&Hartman,C.A.(2011).Areviewoncognitiveandbrainendophenotypesthatmaybecommoninautismspec-trumdisorderandattention-deficit/hyperactivitydisorderandfacilitatethesearchforpleiotropicgenes.Neuroscience & Biobehavioral Reviews,35,1363–1396.

Rutherford,M.D.,&Troje,N.F.(2012).IQpredictsbiologicalmotionperceptioninautismspectrumdisorders.Journal of Autism and Developmental,42,557–565.

Rutter,M.(2005).Autismresearch:Lessonsfromthepastandprospectsforthefuture.Journal of Autism and Developmental Disorders,35,241–257.

ELSEVIE

R

http://dailymail.co.uk/

http://www.dailymail.co.uk/health/article-2103940/Autism-Can-children-simply-grow-One-mother-tells-sons-life-tran%20

http://www.dailymail.co.uk/health/article-2103940/Autism-Can-children-simply-grow-One-mother-tells-sons-life-tran%20

http://www.nhs.uk/news/2012/02February/Pages/children-grow-out-of-autism-claim.aspx

http://www.nhs.uk/news/2012/02February/Pages/children-grow-out-of-autism-claim.aspx

http://thepsychiatrictimes.com/

http://thepsychiatrictimes.com/

http://www.psychiatrictimes.com/blog/pies/content/article/101682029546

http://www.psychiatrictimes.com/blog/pies/content/article/101682029546


Sanislow,C.A.,Pine,D.S.,Quinn,K.J.,Kozak,M.J.,Garvey,M.A.,Heinssen,R.K.,etal.(2010).Developingconstructsforpsychopathologyresearch:Researchdomaincriteria.Journal of Abnormal Psychology,119,631–639.

Sato,D.,Lionel,A.C.,Leblond,C.S.,Prasad,A.,Pinto,D.,Walker,S.,etal.(2012).SHANK1deletionsinmaleswithautismspectrumdisorder.American Journal of Human Genetics,90,879–887.

Schilbach,L.,Bzdok,D.,Timmermans,B.,Fox,P.T.,Laird,A.R.,Vogeley,K.,etal.(2012).Introspectiveminds:UsingALEmeta-analyses to study commonalities in the neuralcorrelates of emotional processing, social& unconstrained cognition.PLoS ONE,7,e30920.

Schulte-Rüther,M.,Greimel,E.,Markowitsch,H. J.,Kamp-Becker, I.,Remschmidt,H.,Fink,G.R.,etal.(2011).Dysfunctionsinbrainnetworkssupportingempathy:AnfMRIstudyinadultswithautism.Social Neuroscience,6,1–21.

Schumann,C.M.,Barnes,C.C.,Lord,C.,&Courchesne,E.(2009).Amygdalaenlargementintoddlerswithautismrelatedtoseverityofsocialandcommunicationimpairments.Biological Psychiatry,66,942–949.

Singer,T.(2012).Thepast,presentandfutureofsocialneuroscience:AEuropeanperspective.Neuroimage,61,437–449.

Sivakumaran,S.,Agakov,F.,Theodoratou,E.,Prendergast,J.G.,Zgaga,L.,Manolio,T.,etal.(2011).Abundantpleiotropyinhumancomplexdiseasesandtraits.American Journal of Human Genetics,89,607–618.

Solari, S.V.,&Stoner,R. (2011).Cognitive consilience:Primatenon-primaryneuroana-tomical circuits underlying cognition. Frontiers in Neuroscience, 5, 65. [Epub]. doi:10.3389/fnana.2011.00065.

Spiker,M.A.,Lin,C.E.,VanDyke,M.,&Wood,J.J.(2012).Restrictedinterestsandanxietyinchildrenwithautism.Autism,16,306–320.

State,M.,&Levitt,P. (2011).Theconundrumsofunderstandinggenetic risks for autismspectrumdisorders.Nature Neuroscience,14,1–8.

Stobbe,M.(2012,April9).Autism research may be about to bear fruit.Associatedpress.com.RetrievedApril20,2012fromhttp://www.google.com/hostednews/ap/article/ALeqM5gXNsF87xp3fq4T2MKsWVZ3D5IwPA?docId=a87f8d58fe4a4875a5e3cc25392f038c.

Szatmari,P.(2011).Newrecommendationsonautismspectrumdisorder:Shiftingthefocusfromsubtypestodimensionscarriespotentialcostsandbenefits.British Medical Journal,342,d2456.

Szatmari,P.,Liu,X.Q.,Goldberg,J.,Zwaigenbaum,L.,Paterson,A.D.,Woodbury-Smith,M.,etal.(2012).Sexdifferencesinrepetitivestereotypedbehaviorsinautism:Implica-tionsforgeneticliability.American Journal of Medical Genetics B, Neuropsychiatric Genetics,159B,5–12.

Tabet,A.C.,Pilorge,M.,Delorme,R.,Amsellem,F.,Pinard,J.M.,Leboyer,M.,etal.(2012).Autismmultiplex familywith16p11.2p12.2microduplicationsyndrome inmonozy-gotic twins and distal 16p11.2 deletion in their brother. European Journal of Human Genetics,20,540–546.

Talkowski,M.E.,Rosenfeld,J.,Blumenthal,I.,Pillalamarri,V.,Chiang,C.,Heilbut,A.,etal.(2012). Sequencing chromosomal abnormalities reveals neurodevelopmental loci thatconferriskacrossdiagnosticboundaries.Cell,149,525–537.

Tanguay,P.E.(2011).AutisminDSM-5.American Journal of Psychiatry,168,1142–1144.Tatsioni,A.,Bonitsis,N.G.,&Ioannidis,J.P.N.(2007).Persistenceofcontradictedclaimsin

theliterature.Journal of the American Medical Association,298,2517–2526.Uddin,L.Q.,Supekar,K.S.,Ryali,S.,&Menon,V.(2011).Dynamicreconfigurationofstruc-

turalandfunctionalconnectivityacrosscoreneurocognitivebrainnetworkswithdevel-opment.Journal of Neuroscience,31,18578–18589.

ELSEVIE

R

http://associatedpress.com/

http://www.google.com/hostednews/ap/article/ALeqM5gXNsF87xp3fq4T2MKsWVZ3D5IwPA%3FdocId%3Da87f8d58fe4a4875a5e3cc25392f038c




VanEssen,D.C.,&Ugurbil,K.(2012).Thefutureofthehumanconnectome.NeuroImage.[EpubJanuary10,2012].doi:10.1016/j.neuroimage.2012.01.032.

Veenstra-VanderWeele,J.,&Blakely,R.D.(2012).Networkinginautism:Leveraginggenetic,biomarkerandmodelsystemfindingsinthesearchfornewtreatments.Neuropsychophar-macology,37,196–212.

Vissers,M.E.,Cohen,M.X.,&Geurts,H.M.(2012).Brainconnectivityandhighfunction-ing autism:A promising path of research that needs refined models, methodologicalconvergence, and stronger behavioral links. Neuroscience and Biobehavioral Reviews, 36,604–625.

Voineagu,I.,Wang,X.,Johnston,P.,Lowe,J.K.,Tian,Y.,Horvath,S.,etal.(2011).Transcrip-tomic analysis of autistic brain reveals convergent molecular pathology. Nature, 474,380–384.

Walsh,P.,Elsabbagh,M.,Bolton,P.,&Singh,I.(2011).Insearchofbiomarkersforautism:Scientific,socialandethicalchallenges.Nature Reviews Neuroscience,12,603–612.

Wass,S.(2011).Distortionsanddisconnections:Disruptedbrainconnectivityinautism.Brain and Cognition,75,18–28.

Waterhouse,L. (2008).Autismoverflows: Increasingprevalenceandproliferating theories.Neuropsychology Review,18,273–286.

Waterhouse,L.(2009).Autismisaportmanteausyndrome.Neuropsychology Review,19,275–276.Wei,H.,Malik,M.,Sheikh,A.M.,Merz,G.,Brown,W.T.,&Li,X.(2011).Abnormalcell

properties and down-regulated FAK-Src complex signaling in B lymphoblasts ofautisticsubjects.American Journal of Pathology,179,1–9.

Wolff,J.J.,Gu,H.,Gerig,G.,Elison,J.T.,Styner,M.,Gouttard,S.,etal.(2012).Differencesinwhitematterfibertractsdevelopmentpresentfrom6to24monthininfantswithautism.American Journal of Psychiatry,169,589–600.

Wulffaert,J.,VanBerckelaer-Onnes,I.A.,&Scholte,E.M.(2009).AutisticdisordersymptomsinRettsyndrome.Autism,13,567–581.

Yang,J.,Zhuang,H.,&Servaes,S.(2012).Feverofunknownorigin:TherolesofFDGPETorPET/CT.PET Clinics,7,181–189.

Yrigollen,C.M.,Han,S.S.,Kochetkova,A.,Babitz,T.,Chang, J.T.,Volkmar,F.R.,et al.(2008).Genes controlling affiliative behavior as candidate genes for autism.Biological Psychiatry,63,911–916.

Zhao,X.,Leotta,A.,Kustanovich,V.,Lajonchere,C.,Geschwind,D.H.,Law,K.,etal.(2007).Aunifiedgenetic theoryforsporadicandinheritedautism.Proceedings of the National Academy of Sciences of the United States of America,104,12831–12836.

Zwaigenbaum,L.,Bryson,S.E.,Szatmari,P.,Brian,J.,Smith,I.M.,Roberts,W.,etal.(2012).Sexdifferencesinchildrenwithautismspectrumdisorderidentifiedwithinahigh-riskinfantcohort.Journal of Autism and Developmental Disorders.[EpubMarch28,2012].

ELSEVIE

R

chapter 8 – autism symptoms exist but the disorder remains...

Documents