Kemner AUCTX EEG in Autis Biol Psych 95

8/12/2019 Kemner AUCTX EEG in Autis Biol Psych 95

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Auditory Event Related Brain Potentials in AutisticChildren and Three Different Control GroupsChantal Kemner Marinus N. Verbaten Juliane M. Cuperus Gert Cam fferman andHerman van Engeland

ER Ps to auditory stimuli, gene rated during an odd ball task, w ere obtained in a group o f autisticchildren and three control groups normal, ADD H, and dyslectic children, respectively). Thetask included the presentat ion of s tandards, deviants , and novels and had a between-group)passiv e vs. active counting) condition. It was examined w hethe r 1) i t was possib le to replicateseveral ear l ier f indings, 2) aut is t ics ma ni fes t an ab normal lateral izat ion pat tern of ERPs, 3)aut is tics have an abnormal mismatch negat iv ity MMN ), and 4) di fferences between aut ist icsand n ormals a re really specific to the autistic group. The only findin g that could be replicatedwas that aut is tics have a smal ler A/Pcz /300. There was no evidence fo r ab normal lateral izat ionor abnormal M MN ; however , there was an unexpected e f fect of the task manipulat ion on theamplitude of the P3: in autistics, the occipital P3 to deviant stimuli was significantly larger inthe active than in the pass ive condition, a finding, l ike the replication of the smaller A/Pcz/300 ,specific to the autistic group. It was su ggested that the auditory occipital task effect is related tounderstimula tion of the occipital lobe by visual stimuli in autistic children.Key W ord s : Aut is tic chi ldren, event-re la ted brain potentia ls, oddbal l task, audi tory s t imula-tion, occipital lobe, lateralization

IntroductionAutism is a severe developmen tal disorder which is biologi-cally partly genetically) based Folstein and Rutter 1977;Prior 1987; Rutter and Schopler 1987; Bolton and Rutter1990; G illberg 1990); howe ver, i t is not clear in which w aybiological factors re la te to aut is tic sym ptoms. Th e idea hasbeen put forward that in some w ay the process ing of s t imul iis distu rbed e.g., Orn itz 1985).Event-re la ted brain potent ia ls ERPs) have proven to be asens i t ive measure of several aspects of s t imulus process ing,

From the Departments of Child and Adolescent Psychiatry (CK, JMC, HvE) andPsychoph armacology (CK, MNV, GC), Rud olf Magnus Institute for Neuro-sciences. Utrecht University. Utrecht. The Netherlands.Address reprint requests to Dr. C. Kemn er, Dept. of Child and Adolescent Psychia-try/RMIN Utrecht University Hospital, Heidelberglaan 100, 3584 CX Utrecht,The Netherlands.Receive d January 12, 1993; Aug ust 26. 1994.

and this technique has been used to s tudy s t imulus proces-sing in autistics. In the present paper we shall present ERPresults , but first we will discuss other ERP studies in whichaudi tory s t imul i were presented in an oddbal l paradigm. Anoddbal l s tudy involves the presentat ion of a ser ies of fre-quent s tandard s t imul i in which infrequent other s t imul i ,called deviants, are inserted in a task-re levan t condition,the deviant is the target). Sometimes, a second type ofinfrequen t stimulus, the novel, is also presented. In contrastto the deviant , the novel occurs unexpectedly and differsmuch more from the s tandard than the deviant . In oddbal ls tudies w i th aut ist ics , reports on ER P waves hav e usual lybeen res t r ic ted to an early wave, the N1, which is mainlyinfluenced by stim ulus param eters, and a later wav e, the P3,which is more inf luenced by cogni t ive manipulat ions .

A nu mber o f audi tory oddbal l s tudies wi th aut ist ic sub-jects have been carr ied out Novic k et al 1979; Niwa et a l

1995 Society of Biological Psychiatry 0006-3223/95 / 09.50SSDI 0006-3223(94)00247-Z


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Aud it ory ER Ps in Aut ist ics BIOL PSYCHIATRY 1511995;38:150-165

Tab le 1. Resu l t s o f Oddba l l S tud ies wi th Au t i s t ic Sub jec tsN Age Control Mean

Study (autistics) Diagnosis (autistics) group IQ Task Performance NI MMN P3Novic k et al 3 9 adoles- nor 9 a) attend -- N 1P2 = (Cz)(1979) cents b) lift finger ? -- -- < target

missing stim. (parietal)Niwa et al 4 ? 14.11 nor aut 66 attend -- --

(1983) Down nor, Down ?Courche sne 7 own 13-21 nor aut PIQ 93 a) attend -- =

et al (1984) criteria aut VIQ 71 b) button- accura cy = = -- < targets (Pz)novels in cond. b) nor V1Q 106 press RT >

Courche sne 10 own 16.7 nor aut PIQ 93 a) attendet al (1985) criteria aut VIQ 71 b) button- accura cy = -- < targets (Pz)novels in cond. b) nor VIQ 106 press RT =

Daw son et al 17 DS M-I II 13.1 nor aut 71 raise(1986) nor 126 hand

Daws on et al 17 DS M-II I 13.1 nor aut 71 raise(1988) nor 126 hand

Oades et al 7 DSM- III 11.3 nor aut 90 button-(1988) nor 123 pressincluding nontarget deviants

Courche sne 11 DSM-I II 19.7 nor aut PIQ 90 a) button-et al (1989) RDL D aut VIQ 78 pressb) = missing nor VIQ 108 b) button-

stimulus condition RDL D VIQ 74 pressLincoln et al 8 DSM-II1-R 12.4 nor aut71 attend

(1993) RDL D nor 108 button-RDLD 82 press

accu racy L

accurac y < > deviants (Fz)

accuracy= --R T =accurac y -R T =

accurac y -R T =

< targets(central)

< t argets (Pz)

< targets (Pz)-- < targets (Pz)

-- P3b =-- P3b < standards/

deviants (Pz)MMN = mismatch negativity; nor = normal subjects; Down = subjects with Down s syndrome; RDLD = subjects with receptive developmental language disorder; P IQ =

performance IQ; VIQ = verbal IQ; RT = reaction time; = = no difference; > = longer reaction times, resp. larger ERPs; < = less accuracy, resp. smaller ERPs.

1983; Co urch esne et al 1984, 1985, 1989; Da wson et al1986, 1988; Oades et al 1988; Lincoln et al 1993), but thefindings are inconsistent with respect to P3 and N1 seeTable 1).

An explanation for these apparently conflicting resultsmight be the composi t ion of the experimental groups . Ascan be seen in Tab le 1, age and IQ of the autistic and controlgrou ps often differ, and IQ s of the autistic subjects differedacross studies. Also, in some earlier studies, small subjectsamples were invo lved and the diagnos is of aut ism has notbeen made according to DSM -III APA 1980), makingcomparison with other studies difficult . A problem is thatusual ly only the aut is t ic group and a group of normal con-t rols were compared. This puts severe res t ric t ions on con-clus ions wi th respect to the ques t ion of wh ether an abnor-mality in the autistic group is unique to this group orwhether i t might be found in other groups of chi ldren withdevelopm ental disorders as wel l .

Another problem is that i t is unclear why C ourchesne e t a l1984, 1985) found P3 differences between autistics and

controls with regard to deviant stimuli, but not with respectto novels, since this latter category also consists of infre-

quent s t imul i . For these reasons , repl icat ion of audi toryoddball studies including novels, with a strictly definedgroup of aut is tic chi ldren and several s t r ic t ly defined con-t rol groups , seems imperat ive . But there w ere several otherobjectives of the present study: firstly, in normal subjects,mismatch negat ivi ty MM N) is to be expected af ter thepresentat ion of infrequent s t imul i in the t ime domain be-tween the N 1 and the P3 N~i~it~en 1990). Since P3 abnor-malities are often found in autistics, especially in responseto deviant s t imul i , i t seems important to s tudy foregoingprocesses as wel l , and a l though this has been done for theN1, no data are know n with regard to the MM N in autis tics .

Secondly, because of the severe language problem s seenin autistic children, i t has been sugge sted that in these chil-dren the lef t hemisphe re which is essent ia l to languageprocess ing in mo st people) i s funct ioning impro perly, to beseen in the lateralization pattern. Abnormal lateralizationpat terns of ERP w aves have been reported in a few s tudiesTang uay 1976; Dawso n et al 1986). Daw son et al 1986)

found that a subgroup of aut is t ic chi ldren showed reversedasym metry of the N1 to audi tory phon emes normal chi l-dren sho wed larger r ight- than lef t -hemisphere ampli tudes) .


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152 BIOLPSYCHIATRY C. Ke m ne r et al1995;38:150-165

T a b l e 2 . C h a r a c t e r i s t i c s o f t h e S u b j e c t sN M e n W o m e n A g e ~ T I Q ~ V I Q P I Q ~

A u t i s t i c s 2 0 1 6 4 9 . 8 ( 1 . 5 ) 7 8 . 8 ( 1 8 . 9 ) 8 0 . 2 ( 1 9 . 4 ) 8 0 . 9 ( 2 0 . 4 )N o r m a l s 2 0 1 6 4 1 0 . 6 ( 1 . 2 ) 9 6 . 5 ( 9 . 2 ) 9 8 . 7 ( 1 1 . 0 ) 9 4 . 9 ( 1 5 . 2 )A D D H s 2 0 2 0 0 9 . 9 ( 1 . 8 ) 9 5 . 2 ( 1 2 . 9 ) 9 3 . 1 ( 1 2 . 4 ) 9 7 . 7 ( 1 5 . 1 )Dy slec t ic s 20 18 2 10 .0 (1 .5) 96 .3 (6 .8) 90 .3 (5 .8) 104 .0 (10 .7)

TIQ = total 1Q; VIQ = verbal IQ; P1Q = performance IQ ; ADDH = attention deficit disorder with hyperactivity.Values are expressed as mean ( _+ standard deviation).

N o e f f e c t s w e r e r e p o r t e d w i t h r e g a r d t o th e a m p l i tu d e o f th eP 3 i n a l a t e r pape r ( Dawson e t a l 1988) ; however , i n bo t hs t ud i es a r e s t r i c t ed e l ec t r ode mon t age w as used ; on l y Cz , al o c a t io n b e t w e e n C 3 a n d T 5 , a n d a lo c a t i o n b e t w e e n C 4 a n dT 6 , w e r e m e a s u r e d . T h e o n l y o t h e r k n o w n ( E R P ) l a t e ra l iz a -t i on s t udy i n au t i s t i c s i s t ha t by T anguay ( 1976) ; however ,t h i s s t udy i s an unusua l one , s i nce E RP s wer e de t e r mi nedd u r i n g s l e e p , a n d n o i n f o r m a t i o n o n s p e c i f i c w a v e s w a sg i ven . T h e r e f o r e , i t i s s ti l l no t c l ea r wh e t he r ab nor m al l a t e r-a l i z ed E R P p a t t e m s c o n s t i t u te a m a j o r f e a t u r e o f a u t is m .

S o , conc l ud i ng , f our po i n t s o f i n t e r e s t can be f o r mul a t ed .F i r s t, w he t he r i t is pos s i b l e t o r ep l i ca t e t he r e su l t s o f ea r l ie rs t ud i e s i n a g r oup o f we l l - de f i ned au t i s ti c ch i l d r en . S econ d ,whe t he r au t i s t i c s have abnor mal i t i e s i n E RP l a t e r a l i za t i oni n r e sponse t o l anguage s t i mul i . T h i r d , whe t he r au t i s t i c sh a v e a b n o r m a l i t i e s i n M M N . F i n a l l y , w h e t h e r a b n o r m a l i -t i e s be t ween au t i s ti c s and nor m a l s a r e spec i f i c t o au ti s t ic s ,o r whe t he r t hey a r e a l so f ound i n g r oups o f ch i l d r en w i t ho t h e r d e v e l o p m e n t a l d i s o rd e r s .

I n o r d e r t o b e a b l e t o p r o v i d e a n a n s w e r t o t h e se q u e s -t i ons , an aud i t o r y oddba l l t a sk , i nc l ud i ng s t anda r ds , de -v i an t s , and nove l s , was p r esen t ed t o a g r oup o f h i gh- f un c -t i on i ng au t i s t i c ch i l d r en , a nor ma l con t r o l g r oup , and t woc o n t r o l g r o u p s o f c h i l d r e n w i t h o t h e r d e v e l o p m e n t a l d i s -o r de r s . E RP wav es s t ud i ed i nc l ude t he N 1 , M M N, a nd P 3 .B o t h a p a s s i v e a n d a n a c t i v e v e r s io n o f th e o d d b a l l t a s k w e r eused . T he p as s i ve ve r s i on w as i nc l uded i n o r de r to be ab l e t os t u d y s t i m u l u s - p r o c e s s i n g n o t c o n f o u n d e d b y t a s k - re l a t e dac t i v i t y , and t he ac t i ve ve r s i on ( i n wh i ch t he t a r ge t s had t ob e c o u n t e d ) w a s i n c lu d e d t o a l l o w c o m p a r i s o n w i t h o t h e rs t u d i e s . T a s k r e l e v a n c e w a s m a n i p u l a t e d a s a b e t w e e n -g r o u p s f a c t o r t o p r e v e n t t h e t r a n s f e r o f t a s k r e l e v a n c e f r o mt he ac t i ve i n to t he pas s i ve cond i t i on . A coun t i ng i ns t r uc t i onr a t he r t han a bu t t on- pr es s i ns t r uc t i on wa s used i n the ac t i vecond i t i on t o exc l ude t he i n t e r f e r enc e o f mot o r po t en t i a l s . I nt h e s a m e e x p e r i m e n t , w e a l s o p re s e n t e d v i s u a l an d s o m a t o -sensor y oddba l l t a sks bes i des t he aud i t o r y one . W ep r e s e n t e d d a t a o n t h e f o r m e r t w o t a s k s in a s e c o n d p a p e r( Ke mn er e t a l 1994) . T he r eason f o r t h is i s twof o l d : f i r st l y ,t h e f o c u s o f th e r e s e a r c h q u e s t i o n s b e t w e e n t h e a u d i t o rym o d a l i t y o n t h e o n e h a n d a n d t h e t w o o t h e r m o d a l i ti e s o nt h e o t h e r h a n d , d i ff e r s s o m e w h a t ; s e c o n d l y , t h e a b u n d a n c yo f d a ta , i f o n l y o n e p a p e r w o u l d b e p r o d u c e d , w o u l d d e t r a c tf r om i t s c l a r it y .

e t h o dS u b j e c t sF ou r g r oups o f 20 ch i l d r en each par ti ci pa ted . nor m a l ch i l -d r en , au t i s t i c ch i l d r en , ch i l d r en w i t h a t t en t i on de f i c i t d i s -o r d e r w i t h h y p e r a c t i v i t y (A D D H ) , a n d c h i l d r e n w i t h d e v e l -opment a l r ead i ng d i so r de r ( dys l ex i a ) . T he d i agnos t i cc r i t e r i a f r om D S M - I I I f o r i n f an t i le au t i sm ( 299 .00) , a t t en -t i on de f ic i t d i so r de r w i t h hyp e r ac t i v i t y ( 314 .01) , and de ve l -o p m e n t a l r e a d i n g d i s o r d e r ( d y s l e x i a ) ( 3 1 5. 0 0 ) w e r e u s e d .E x t ens i ve d i agnos t i c eva l ua t i ons i nc l uded a ch i l d psych i a t -r ic o b s e r v a t i o n a n d a r e v i e w o f p r i o r r e c o rd s ( d e v e l o p m e n -t a l h i s t o r y , ch i ld psych i a t r i c and psych o l og i c a l obse r va t i onsand t e s t s , and neur o l og i ca l obse r va t i ons ) . Addi t i ona l l y ,e a c h g r o u p w a s s u b j e c te d t o s e v e r a l ( d i f f er e n t ) p s y c h o l o g i -ca l t e s t s mean t t o s t anda r d i ze t he d i agnoses . A l l pa r en t sf i l l ed i n a ques t i onna i r e on soc i a l compe t ence and emo-t i ona l and behav i o r a l p r ob l em s o f t he i r ch i l d , the Chi l dB e h a v i o r C h e c k l i s t ( C B C L ) ( A c h e n b a c h a n d E d e l b r o c k1983) , ma i n l y t o check on hyper ac t i v i t y . T wo t e s t s wer eused f o r t he au t i s t i c g r oup : t he Chi l dhood Aut i sm Ra t i ngS ca l e ( CARS ) ( S chop l e r e t a l 1980) and t he S chedu l e o fH a n d i c a p s , B e h a v i o r a n d S k i l l s ( W I N G - s c a l e ) ( W i n g1 98 0) . T h e C o n n e r s T e a c h e r s R a t i n g S c a l e ( C T R S ) ( C o n -n e r s 1 9 6 9) w a s u s e d f o r th e A D D H g r o u p . T o a s s e s s re a d i n g( d i s ) ab i l i t i e s i n t he dys l ec t i c g r oup , s t anda r d i zed r ead i ngt e s ts ( t he B R U S - 1 - m i n u t e t e s t o r th e A V I - c a r d s ) w e r e u s e da s i n p u t f o r t h e M o n t h s B e h i n d M o d e l ( R i s p e n s e t a l1 9 9 0) . C o m o r b i d i t y w a s a n e x c l u s i o n c r it e ri o n . T h e n o r m a lc o n t r o l g r o u p c o n s i s t e d o f s c h o o l c h i l d r e n w h i c h w e r ec h e c k e d o n s o c i a l c o m p e t e n c e a n d e m o t i o n a l a n d b e h a v -i o r a l p r ob l ems . Ages r anged be t ween 6 .8 and 13 .0 yea r s .G r o u p s d i d n o t d i f f e r w i t h r e s p e c t t o a g e . M e a n d a t a a n ds t a n d a rd d e v i a t io n s o f e a c h g r o u p w i t h r e s p e c t t o a g e , s e x ,a n d I Q a r e t o b e f o u n d i n T a b l e 2 . I Q s w e r e d e t e r m i n e du s i n g t h e W e c h s l e r I n t e l li g e n c e S c a l e f o r C h i l d r e n -R e v i s e d , D u t c h v e r s i o n ( W I S C - R N ) . I t sh o u l d b e n o t e d t h a tt he au t i st i c ch i l d r en had s i gn i f i can t l y l owe r I Qs ( T I Q , VI Q,as we l l a s P I Q) t han t he con t r o l ch i l d r en ; howe ver , t h i s wascon t r o l l ed by u s i ng T I Q as a cova r i a t e i n case o f si gn i f i can tGr oups i n t e r ac t i ons ( s ee a l so unde r Statistical Analysis .Vi sua l ac t i v i t y o f a l l ch i l d r en was nor ma l o r co r r ec t ed t on o r m a l ( c h i l d r en w e a r i n g g l a s s e s k e p t t h e m o n d u r i n g t h ee x p e r i m e n t ) . A l l c h i ld r e n w e r e p h y s i c a l l y h e a l th y a n d n o n e


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Auditory ERPs in Autistics BIOLPSYCHIATRY 1531995;38:150--165

of the normal, autistic, or dyslectic children used psychotro-pic, anticonvulsive, or related medications. ADDH childrenwhich normally were on medication stopped using it at leastthree days prio r to the test.StimuliAn oddball task was used with three different types ofstimuli: 80 frequent stimuli, which were presented to thesubject beforehand (standards); 10 infrequent stimuli,which were also presented beforehand (deviants); and 10infrequent stimuli, which were not presented beforehandand which appeared unexpectedly (novels). The latter typeof stimulus was much more different from the standardstimulus than the deviant stimulus. In the active condition,the deviant stimuli were task-relevant (targets), subjects hadto count the total number o f deviant stimuli. The first 14stimuli were standard stimuli, followed by the first deviantstimulus at trial 15. The presentation of the other infrequentstimuli (both deviants and novels) was semirandomized.Interstimulus intervals (ISis) were semirandomized be-tween 4 and 6 sec. The total number of stimuli was 140. Thestandard stimulus consisted of the phoneme oy and thedeviant stimulus of the phoneme ay. The novel was a morecomplex sound, like bbrrzzz. The stimuli were presentedbinaurally through earphones at 67 dB. All stimuli weregenerated by a speech chip (General Instrument). The stan-dard and deviant stimuli lasted 300 msec, the novel 360msec. During presentation of the series o f stimuli, the chil-dren had to look at a + sign on a TV screen, to prevent themfrom closing their eyes. This series o f auditory stimuli waspart of a larger study, in which series of visual and somato-sensory stimuli were also presented according to the sameoddball design. The presentation of these three series wasbalanced. Finally, subjects were presented with a secondseries o f visual stimuli. This condition was meant to gener-ate large saccadic eye movements, which were used to re-move EOG artifacts from the EEG by means o f a regressiontechnique (Woestenburg et al 1983a).ERP RecordingsElectroencephalographic activity was recorded from tinelectrodes by means of an electrode cap. Scalp locationswere at F3, Fz, F4, C3, Cz, C4, P3, Pz, P4, O1, Oz, and 02,according to the 10-20 system. Linked earlobe electrodeswere used as reference. The earlobes were connected with a15 KOhm resistor, to prevent distortion of hemisphericalasymmetries (Katznelson 1981). Horizontal EOG wasrecorded using tin electrodes in plastic cups attached to theouter canthus of each eye by means o f adhesive rings. Simi-larly, vertical EOG was recorded from infraorbital and su-praorbital electrodes in line with the pupil of the eye. Aground electrode was attached to Fpz. For both EOG and

Table 3. Counting Performance in the Active ConditionA B

Aut i s t i c s 8 12 .5N o r m a l s 6 1 4 . 9A D D H s 8 1 4 .5D y s l e c t i c s 7 4 . 0

AD DH = attention defici t d isorder with hyperactivity .A: Number of children that counted correctly . The cri terion for good perfor-mance w as the correct num ber of target s t imuli (14), p lus or minus 1 ( l 3 or 15 .

B: Mean numb er ofcotmted st imuli .

EEG, ECI (electro-gel) electrode paste was used. All EOGand midline EEG signals were amplified and filtered byElema tmiversal filters. Lateral EEG signals were amplifiedand filtered by Tonnis filters. A time constant of 5 sec wasemployed in conjunction with a low-pass filter setting of 30Hz. To suppress 50 Hz main frequency and harmonies,amplifier output was first sent through a 45 Hz passivelow-pass network, followed by a 50 Hz notch filter (band-width of 4-5 Hz). Subsequently, the signals were sent to theanalogue inputs of a PDP 11/23 computer for on-line ana-logue-digital conversion. Sampl ing started 100 msec beforestimulus onset and lasted 1024 msec, with a rate of 250 Hz.

The EEG and EOG channels were calibrated before ar-rival of the child; The PDP 11/23 was used to sample andmeasure a 1000 ~V pulse for the EOG channels, a 100 p,Vpulse for the EEG channels that were connected with theTonnis filters, and a 50 p~V pulse for the EEG channels thatwere connected with the Elema amplifier.ProcedureOn arrival, the child was familiarized with the procedure.After attachment of an electrode cap in the instrument room,which adjoined the experimental room, the child sat down ina dentist' s chair in an acoustical ly and electrically shieldedroom. This chair was adjustable, so that the child's headcould be positioned roughl y parallel to a TV moni tor (black& white, 26-inch screen), which was positioned above andin front of the child at a distance of about 70 cm from theeyes. A vacuum cushion was attached at the top of the chairfor fixing the child' s head in such a way that the child lookedat the center of the TV screen.Afterwards, the child received instructions with respectto the first block of stimuli. In the auditory condition, thestandard and deviant stimuli were presented through theearphones and the child was asked to repeat the stimuli, toensure that they were heard correctly. Each child was as-signed to one of two experimental conditions, a passive oran active condition. Children in the passive group were toldto attend the stimuli carefully. Children in the active condi-tion were told to count the deviant stimuli. The results of thecounting perfo rmance can be found in Table 3. All childrenwere told beforehand that they would receive a toy after the


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154 BIOL PSYCHIATRY C. Ke mn er et al1995;38:150 165

test if they conformed to instructions. In fact, during theat tachment of the e lect rode cap, they were intent ional lyplaced before a glass drawer containing the toys , in order toincrease thei r mot ivat ion. After this , the experim enter lef tthe room and the sess ion s tar ted. A t the end of the s t imuluspresentat ion, the experimenter entered the shie lded roomand asked the children in the task condition to report thenum ber of targets they had counted. Then the ins t ruct ionsfor the next block fol lowed. A parent or caretaker was seatedbehind the chi ld during the whole experiment .ScoringDue to l imited computer memory during the f i rs t threeblocks , data were only recorded during the presentat ion ofthe deviants , novels , and the s tandards that immediate lypreceded the deviants and novels . S ingle- t r ia l ERPs weredetermined fo r these categories , us ing an orthogo nal poly-nomial t rend analys is in the frequency domain (OPTA)(Woestenb urg e t a l 1983b). ERP peak s were scored re la t iveto a 100 msec pres t imulus (basel ine) level . The N1 wasscored f rom 50-200 msec . The P3 was s cored f rom 300-700 msec. The MMN was scored as a di fference wave,obtained by subtract ing from the infrequent s t imul i thei rimmediate ly preceding s tandards , in the la tency window150--325 msec.Statistical Ana lysisAnalyses were carr ied out for each ERP wave separate ly.Mult ivaria te analys is was performed o ver a l l between- andwithin-factors , by means of the program Mult ivariance(Finn 1978). A two-tailed level of significance of 5 wasadopted, except in the case of planned co mparison s where aone-ta i led level was adopted. There were two between-groups factors: Groups, including normal and autistic chil-dren (but see a lso below), and Task, including a pass ive andan active condition; and three within-groups factors:Stimuli, including standard, devian t, and novel stimuli; Lat-erality, including midline, left , and right sites; and An terior-ity/Posteriority (AnP os), including frontal, central, parietal,and o ccipital sites.

In order to enable comparison of our group effects wi thearlier studies, and to localize effects as well as possible,f i rs t only the normal and the aut is t ic gro up were compared.In case of an interact ion with groups , i t was determined onwhich level of a factor the normal and the aut is t ic groupdiffered. Only then the other control groups (ADDH anddyslect ic) were com pared to the aut is tic group. In case o f aninteract ion Group s x Task, further analys is s tar ted by deter-mining a t what level of the factor Groups , a s ignif icant Taskeffect was present . A set of planned com parisons was a lsocarried out.

In case of a s ignif icant di fference between the groups ,di fferences in IQ were control led b y tes t ing whether there

Table 4. Significant F values of the Multivariate Analysis withRespect to the N 1 AmplitudeN 1 ampli tude Task Groups Task x Group sF I,36 )) ~ 7.1Stimuli F 2 ,35)) 4 .2

Laterality F 2,35)) 5.2AnP os F 3,34)) 19.3Stimuli x Laterality F 4,33))St imuli x AnPos F 6 ,31)) 2 .7Laterality x AnP os F 6,31 )) 3.4Stimuli x Lateral ity x A nPos

/: 12,25))F values between effects.

was a s ignificant regression (s tandardized regress ion coef-f ic ient) of IQ on the ERP parameter . Al though there wereseveral Groups di fferences, no such s ignif icant regress ionswere found, and they wil l therefore not be ment ioned in theResults section.

With regard to effects which showed no interact ion withGroups , a hierarchy of ques t ions was determined, and theanalys is was di rected towards answering these ques t ions .Al though we w il l not present a l l s teps perform ed to inves t i-gate an interaction e ffect, i t should be n oted that these stepsincluded the testing of partial interactions, which should besignificant before either smaller partial interactions or pair-wise comparison s were cons idered. The f i rs t ques t ion washow ampli tudes in response to the di fferent types of s t imul idi ffered from each other (s t imulus effects ) . Secondly, wetr ied to determine the s i te of larges t ampli tude and lef t -r ig htdifferences ( topography effects ) . For reasons of economyAnPos results were first inspected visually, and afterwardsthe larges t ampli tude was com pared pairwise wi th the otherlevels . Third, we examine d whether there were effects of thetask manipulat ions w i th respect to di fferent s t imul i or di f-ferent AnPos levels ( task effects ) .

esu l tsFigure 1 shows the grand ave rage ERPs o f the pass ive andthe active condition. S ignificant F values with respec t to theanalys is of the NI, MM N, and P3 are to be found in Tables4, 6, and 8, respect ively. Mean ampli tudes o f the N1, MM N,and P3 are to be found in Table s 5, 7, and 9, respectively.NThe N 1 ampli tude in response to deviant s t imul i was largerthan to standard stimuli (Stimuli main effect). The N1 atcentral sites was foun d to be larger than the N1 at occipitaland frontal sites and marginally larger than the parietal N1(AnP os ma in effect). Only at parietal sites a laterality effec twas found, r ight s ide ampli tudes were smal ler than midl ineand left side amplitudes (Laterality x AnPos interactions).


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Figure 2. The amplitude of the N1, averagedover stimuli, anterior/posterior positions, andtask conditions, at the three levels of the factorlaterality left, middle, and right electrode posi-tions), for each group separately Groups x Lat-erality effect). ADDH = attention deficit dis-order with hyperactivity.

A u t i s ti c s N o r m a l s A D D H s D y s l e c t i c s

PP3 ampli tudes to deviant and n ovel s t imuli were larger thanto frequent stimuli at occipital, central, and parietal sites, butno such difference was found a t the fronta l si te S t imulimain effect , S t imuli x AnPos interact ion). The parie ta l P3was found to be s ignif icant ly larger than the centra l andfronta l P3, but to be equal ly large as the occipi ta l P3 AnPosmain effect) . A s ignif icant difference between left - andright-s ide ampli tudes was found only parie ta l ly, r ight-s ideampli tudes being larges t Latera l i ty main effect , Latera l i tyTable 6. Significant F values of the Multivariate Analysis WithRespect to the Mismatch Negativity MMN) Passive Condition)M M N ampl i tude G r oupF 1,18)) o

Stimuli F 1 ,18)) 9 .3Laterality F 2,17)) 3.6AnPos F 3 ,16))Stimuli x Laterality F 2,17))St imuli x AnPos F 3 ,16))Lateral ity x AnPos F 6 ,13))Stimuli x Laterality x AnP os F 6,13)) 4.7

F values between effects.

x AnPos interact ion). A s ignif icant lef t -r ight difference waspresent for deviant s t imuli , r ight-s ide ampli tudes beinglarger than left -side ampli tudes S t imuli x Latera l i ty inter-act ion). P3 ampli tudes in the act ive condit ion were largerthan in the pass ive condit ion, a t occipi ta l and parie ta l s i tesonly Task main effect , Task x AnPos interact ion). A Task xAnPos x Latera l i ty effect did not reveal any differencesbetween left and r ight hemisphe re amp li tudes .

A complex Groups x Task x Latera l i ty x AnPos interac-t ion was noted. I t appeared that an interact ion of Task xGrou ps was s ignif icant a t O1 F 1,36) = 6.7) . The presenceof a Task effect a t O1 was tes ted per group: the effect wass ignificant in the aut is t ic group only, and implic ated that theaut is t ics had larger P3 am pli tudes a t O 1 in the act ive than inthe pass ive condit ion. A Groups x Task x S t imuli x AnPosinteract ion was a lso noted. The Groups x Task interact ionwas found to be s ignif icant a t occipi ta l s i tes for deviants t imuli F 1,36) = 5.1) only. When tes ted per group, anoccipi ta l task effect on deviant s t imuli was only foun d in theautistic group F 1,1 8) = 25.4). In Figur e 5 it can be seen thatthis group showed larger P3 ampli tudes occipi ta l ly in re-sponse to deviant s t imuli in the act ive than in the pass ivecondit ion. Non e of the other groups sh owed such an effect .


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Fig u re 5 . T h e a m p l i t u d e o f t h e o cc i -p ital P3 averag ed over O1, Oz, and0 2 to deviant s t imuli , in the pass iveas well as in the act ive condit ion , forea ch g ro u p s ep a ra t ely Gro u p s xTask x St imuli x AnPos ef fect) .ADDH = attent ion def icit d isorderwith hyperact iv ity .

cally significant, striking, acou stic stimuli nov els) Cour -chesne et al 1985). It resembles the P3a, as manifest inadults, which a lso occurs to deviant, auditory stimuli see,e.g. , N~t~inen 1991); however, there are also differences,mainly with respect to topography, which sug gest that P3aand A/P cz/3 00 are different wa ves Courchesne 1983). It isnot likely that developmen tal factors account for this topo-graphical difference, since ER Ps in childhood usually havea more posterior distribution, as compar ed to adults e.g.,Taylor 1988; Mullis et al 1985). This leav es the question ofthe meaning of the A/Pcz/300. A problem is also that it isTable 9. Me an Amplitudes of the P3 Amplitude

unclear why an abnormal A/Pcz/30 0 to novels does not leadto an abnormal P3 to novels , s ince the MPcz/300 occursearlier in time, assum ing, at least partially, serial pro cessin gof the presented stimuli. Therefore, the importance of thiseffect m ay be limited; but, as far as this wa ve is concerned,the results of the Courch esne et al studies 1984, 1985) werereplicated.

No differences between autistic and normal childrenwere noted with respect to the N1 or P3, after plannedcomparisons. The fact that we have not been succesful inour attempts to replicate the NI and P3 results of Cour-

Normals Autistics ADDH s Dyslecticspas act pas act pas act pas act

Standards Fz 4,0 3.3 3.7 4.4Cz 6.0 6.1 7.5 9.2Pz 9.1 10.0 8.3 10.5Oz 5.6 8,3 7.3 9.3

Deviants Fz 3.9 6.3 4.5 6.8Cz 9.2 13.3 11.5 11,0Pz 14.3 24.7 15.7 22.5Oz 13.3 17.7 9.4 21.2

Novels Fz 5.8 9.3 4.6 8.4Cz 9.7 17.6 12.9 13.1Pz 16.4 24.7 18.4 25.8Oz 13.3 15,0 12.9 22.0

4.9 5.1 4.5 2.89.2 7.9 5.6 5.39.4 8.9 7.3 8.37,8 9.0 7.4 5.84.1 7.2 3.3 3.65.6 10.6 6.2 11.58.4 16.2 11.3 22.87,7 14.3 10.1 15.43.0 6.7 4.2 6.77,6 15.2 7.7 15.8

12.8 20.3 15.0 18.39.1 14.2 13.4 9.4

ADDH =attention deficit disorder with hyperactivity; pas = passive condition; act = active condition.


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Au ditory ER Ps in Autistics BIOLPSYCHIATRY 631995;38:150 165

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0A u t i s t i cs N o r m a l s A D D H s D y s l e c t i c s

c h e s n e e t a l 1 9 8 4 , 1 9 8 5 , 1 9 8 9 ) c o u l d b e d u e t o o n e o r m o r ef a c t o r s ) w h i c h h a v e b e e n d i s c u s s e d i n t h e Introductions u c h a s d i a g n o s i s o f t h e a u t is t ic c h i l d r e n , I Q d i f f e r e n c e sb e t w e e n t h e a u t i s t i c g r o u p a n d c o n t r o l g r o u p s , a n d a g e o ft h e s u b j e c t s . E v e n m o r e i m p o r t a n t m a y b e t h e o b s e r v a t i o nt h a t a t ro p h y o f t h e p a r ie t a l l o b e w a s f o u n d i n a s u b g r o u p o fa u t i st i cs C o u r c h e s n e e t al 1 9 9 3 ). P 3 a c ti v i t y p r o b a b l y m a n -i f e s t s m a i n l y n e o c o r t i c a l a c t i v i t y , a l t h o u g h t h e r e i s n oa g r e e m e n t o n t h e q u e s t i o n o f w h e r e i n th e b r a i n t h e P 3g e n e r a t o r i s l o c a t e d s e e K a t z n e l s o n 1 9 8 1 a n d P i c t o n 1 9 9 2 ,f o r a m o r e e x t e n s i v e d i s c u s s i o n o f th i s t o p i c ), a n d n o a g r e e -m e n t o n w h e t h e r t h e re a r e o n e o r m o r e P 3 g e n e r a t o r s s e e ,e . g . , Fa b i a n i e t a l 1987 ) . I t i s t he r e f o r e h i gh l y l i ke l y t ha t t hepa r i e t a l t a r ge t ) P3 r e fl e c t s a c t i v i t y o f t he pa r i e t a l lobe . I nc a s e o f a t r o p h y o f th e p a r i e ta l l o b e , a s f o u n d i n a s u b g r o u p o fa u t i s t i c s , s ma l l e r pa r i e t a l P3 a m p l i t ude s a r e to be e xpe c t e d .I f t h i s s ubg r o up i s p r e s e n t i n s om e s t ud i e s e . g . , t he s t ud i e sb y t h e C o u r c h e s n e g r o u p ) a n d n o t i n o t h e r s e . g. , t h e p r e s e n to n e ) , t h i s c o u l d a c c o u n t f o r t h e d i f f e r e n c e s i n P 3 e f f e c t sb e t w e e n s t u d ie s .Mismatch ProcessesA s e c o n d m a i n q u e s t i o n i n t h e p r e s e n t p a p e r w a s w h e t h e rt h e a b n o r m a l P 3 a m p l i t u d e s f o u n d i n e a r l i e r s t u d ie s i n a u ti s -t ic c h i ld r e n a r e p r e c e d e d , o r c a u s e d , b y a b n o r m a l m i s m a t c hp r o c e s s e s ; h o w e v e r , a s s t a te d a b o v e , t h e s e p a r i et a l) P 3a b n o r m a l i t i e s i n t h e a u t i s ti c g r o u p c o u l d n o t b e r e p l i c a te d ,

a n d n o d i f f e r e n c e s b e t w e e n t h e a u t i s t i c s a n d t h e n o r m a l sw e r e f o u n d w i t h r e g a r d t o t h e M M N . W e m a y t h e r e f o r ec o n c l u d e t h a t t he o n l y P 3 d i f f e r e n c e s b e t w e e n g r o u p s f o u n dt o b e d i s c u s s e d h e r e a f t e r ) w a s n o t d u e t o a b n o r m a l m i s -

m a t c h p r o c e s s e s .LateralizationA t h i r d a s p e c t o f t h e s t u d y w a s r e l a te d t o t h e q u e s t i o n o fw h e t h e r E R P a c t i v i t y i n a u t i s t ic s i s d i f f e r e n t l y l a t e r a l iz e dw h e n c o m p a r e d t o t h e a c t iv i t y o f n o r m a l c h i l d r e n . A f t e ri n s p e c t i o n o f t h e r e s u l ts o f t h e a n a l y s i s , it h a s t o b e c o n -c l u d e d t h a t i n o u r d a t a t h e re i s n o i n d i c a t io n w h a t s o e v e r t h a ta n a b n o r m a l E R P l a t e r a l i z a t i o n p a t t e r n c o n s t i t u t e s a m a j o rf e a t u r e o f a u ti s m . T h i s a g r e e s w i t h t h e s t u d y b y O a d e s e t a l1 9 8 8 ) , w h o a l s o d i d n o t f i n d a d i f f e r e n c e i n l a t e r a l iz a t i o n

b e t w e e n n o r m a l s a n d a u t i s ti c s w h e n t o n e s t i m u l i w e r e u s e d ,n e i t h e r o n t h e N 1 , o r N 2 , n o r o n t h e P 3 .Unexpected FindingsA n u n e x p e c t e d P 3 e f f e c t w a s f o u n d i n t h e o v e r a l l a n a l y s i s.Tw o i n t e r a c t i on s r e ve a l e d t ha t t he a u t i st i c s , i n c on t r a s t t o a l lt h r e e c o n t r o l g r o u p s , s h o w e d a t a s k e f f e c t t h a t w a s l o c a t e do c c i p i t a l l y t h e e ff e c t w a s l a r g e s t a t O 1 , a n d w i t h r e s p e c t tod e v i a n t s t im u l i ) . T h e m e a n i n g o f t h is f i n d i n g i s n o t c le a r .T h e o c c i p i t a l l o b e p r o b a b l y r e f l e c t s a c t i v it y f r o m t h e v i s u a lc o r t e x , a n d t h e r e f o r e a t a s k - r el a t e d e n l a r g e m e n t o f o c c i p i t a l


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164 BIOLPSYCHIATRY C. Kemn er et al1995;38:150 165

act ivi ty in react ion to audi tory s t imuli is not to be expected.Probab ly the aut ist ic group, for an unkn own reason, uses a llavai lable cort ical potent ia l u nder the pressure of a task, butthis leaves us with the ques t ion of wh y the occipi ta l cortex is

avai lab le to provi de this potent ia l ; howe ver, there migh tbe a re la t ionship with othe r f indings . I t has been f ound thataut is t ic chi ldren do not properly f ixate faces , which can beobserved even a t a very young age (Dawson et a l 1990), aswell as nonsocia l s t imuli (V erbaten e t a l 1991), and that theyshow abnormal saccadic act ivi ty (Kemner e t a l submit ted).I t has been kn own long s ince tha t abnorm a l v i sua l expe r i -ence can m o di fy the b ra ins o f ca ts (Hube l and W iese l 1962)and hum ans (F reem an and Thibos 1973) . In a s tudy byKujala e t a l (1992), i t was found that early-bl ind peopleshowed an N2b to aud i to ry s t im ul i which w as m ore pos te r i -orly dis tr ibuted than in the s ighted control subjects . Theauthors su gges t that the bl ind may use parie ta l, and perh apseven occipi ta l bra in areas in the proces s ing of audi torys t imuli to a larger extent than the nor mal con trols . So, thereare indicat ions that i t is poss ible to use the occipi ta l cortex inthe process ing of audi tory s t imuli , in case the occipi ta lcor tex has no t deve loped norm a l ly . The fac t tha t the occ ip i -ta l task effect has not been reported before could be due tomore res tr ic ted e lectrode montages in earl ier s tudies , inwhich occipi ta l e lectrodes were not included. Also, the ef-fect of task has not been s tudied sys tem atical ly.O t h e r G r o u p sIn the present s tudy, aut is t ic chi ldren were comparednot only with normal chi ldren, but a lso with chi ldren withdys lex ia and w i th a t t en t ion de f ici t d i so rde r . Th i s was do nein o rde r to exam ine w he the r a d i f fe rence be tween the nor -Reference sAchen bach TM, Edelbrock C ( 1983): Manual for the Child Behav-ior Checklist and Revised Child Behavior Profile. Burlington:University of Vermont, Department of Psychiatry.American Psychiatric Association (1980): Diagnos tic and Statisti-cal Manual of Mental Disorders 3rd ed. Washington DC:American Psychiatric Association.Bolton P, Rutter M (1990): Genetic influences in autism, lnt RevPsychiatry. 2:67-80.Conn ers KC (1969): A teacher rating scale fo r use in drug-studieswith children. Am JPsychiatry 126:152-156.Courchesne E (1983): C ognitive com ponents o f the event-relatedpotential: C hang es associated with development. In GaillardA W K Ritter W (eds), Tutorials in Event-Related PotentialResearch: Endogenous Components. Amsterdam: North-Hol-land, pp 329-344 .Courchesne E (1987): A neurophysiological view of autism. InSchopler E, Mesibov GB (eds), Neurobiological Issues in Au-tism. New York: Plenum, pp 285-324 .Courchesne E, Kilman BA, Galam bos R, Lincoln AJ (1984): Au-tism: processing of novel auditory information assessed by

m al and the au t is t i c g roup w as un ique to the l at t e r g roup , o rwhe the r i t cou ld be found in o the r ch i ld ren wi th deve lop-m enta l d i so rde rs a s we l l . In bo th e f fec t s desc r ibed (P 3occipi ta l task effect , and A/Pcz/300 effect) , aut is t ics dif-fe red no t on ly f rom norm a ls , bu t f ro m the o the r two con t ro lg roups a s we l l . The re fore , i t c an be conc luded tha t theeffects described in this paper are highly specif ic to theaut is t ic group.

onc lu s ionAfte r p re sen ta t ion o f aud i to ry s t im uli , au t i s t ic ch i ld renshow no s igns o f abnorm a l p roces s in g in the N 1 and M M Nrange , bu t they do show a d i f fe rence wi th o the r g ro ups wi threga rd to ac t iv i ty in the P 3 range . Wi th re spec t to th i seffect , an increased occipi ta l P3 to task-re levant s t imuli , i twas specu la ted tha t the occ ip i t a l lobe o f au t i s ti c s has de -ve loped an abnorm a l s ens i t iv i ty to aud i to ry , t a sk- re la teds t im ul i . Th i s specu la t ion m igh t be s tud ied in fu tu re s tud ie swhere t a sk load i s va r ied sys tem a t ica l ly , to exam inewhe the r the re i s a re la t ionsh ip be tween inc reas ing t a skload and inc reased occ ip i t a l ac t iv i ty to aud i to ry s t im ul i .This f ind ing is high ly specif ic to the aut is t ic grou p. There isno ind ica t ion o f abnorm a l l a te ral i za t ion o f ERP s in an t i s -t i cs . The im p or tance o f ca re fu l s e lec t ion o f the expe r im en-ta l g roups i s em phas ized ; d i f fe rences in com pos i t ion o fgroups m igh t exp la in m a ny of the incons i s tenc ie s foun dbetween s tudies .

The authors gratefully acknowledge the v aluable comments of Dr. H.S.Koelega on earlier versions of the present paper.

event-related potentials. Electroencephalogr Clin Neurophy-sio159:238-248.Courchesne E, Lincoln AJ, Kilman BA, Galambos R (1985):Event-related brain correlates of the processing of novel visualand auditory information processing in autism. J Aut i sm D evDisord 15:55-76.Courchesne E, Lincoln AJ, Yeung-Courchesne R, Elmasian R,

Grillon C (1989): Pathophysiologic findings in nonretardedautism and receptive developmental disorder. J Autism DevDisord 19:1-17.Courchesne E, Press GA, Yeung-Courchesne R (1993): Parietallobe abnormalities detected w ith MR in patients w ith infantileautism. Am J Roentgenol 160:387-393.Dawson G, Finley C, Phillips S, Galpert L (1986): Hemisphericspecialization and the languag e abilities o f autistic children.Child Dev 57:1440-1453.Dawson G, Finley C, Phillips S, Galpert L, Lewy A (1988): Re-duc ed P3 amplitude o f the event-related brain potential: itsrelationship to languag e ability in autism. JAut i sm Dev Disord18:493-504.


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