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Unimodal and crossmodal reactivity in autism: Presence of auditory evoked responses and effect of the repetition of auditory stimuli
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Unimodal and Crossmodal Reactivity in Autism: Presence of Auditory Evoked Responses and Effect of the Repetition of Auditory Stimuli J. Martineau, S~ Roux, B. Garreau, J. L. Adrien, and G. Lelord
Using auditory evoked responses, this work compares the reactivities to unimodal and crossmodal stimuli and the main neurocognitive functions most often disturbed in autism. With the aim of testing the hypothesis that the deficit in the ability to form crossmodal associations in autism is linked to a cognitive abnormality, audiwry evoked responses to simple and to crossmodal (auditivo-visual) stimuli were recorded in 30 autistic children and compared with those of 30 normal and 30 mentally retarded children. Relationships between electrophysiological reactivity and neurocognitive functions showed that the cognitive deficit in the ability to maintain crossmodal associations is preceded by a more elementary perceptive abnormality in autistic children.
Introduction For some authors, the ability to acquire speech is dependent on the ability to form crossmodal associations, both visual-auditory and tactile-auditory (Geschwind 1965; Bryson 1970). One approach to investigate this ability in forming auditory-visual associations is to examine the modifications of auditory evoked responses (AERs) when the auditory stimulus is followed by a strong visual or tactile stimulus (Lelord and Maho 1969). In these conditions, the crossmodai phenomenon depends on the establishment of a cross. modal association between the auditory and visual stimuli over time. Such a paradigm does not require the pe,rticipation of the subject and can be used in young and/or pathological children. Normal adults and children show an increase in the auditory-evokedresponse amplitude in the occipital region when the sound is followed by the flash (Martineau et al 1984; Bruneau et al 1990). This spread of the AER over the occipital visual-cortical area was considered characteristic of the crossmodal association phenomenon (Lelord and Maho 1969; Bruneau et al 1990). A deficit in the ability to form crossmodal associations needed for the devclopmcnt of language, was reported in children with autistic behavior. Hermelin and O'Connor (1970), on the basis of an extensive series of laboratory studies, concluded that autistic children displayed an impaired ability to integrate input and output data and to process
From INSERM U316, the Department of Psychopathology and Neurophysiology of Development, CHRU Bretonneau, Cedex, France. Address reprint requests to .L Martineau, INSERM U316, Department of Psychopathology and Neurophysiology of Devel. opment, CHRU Bretonneau, 37044 TOURS Cedex, France. Received May 20, 1991, revised February ! 1, 1992.
© 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
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information from various sources. In a study of sensory processing, Bryson (1970) used matching-to-sample tasks to test the ability of autistic children to make visual, w~cal, and fine motor responses to visual and auditory stimuli. She found that the auditory-tovisual and visual-to-vocal performances were poorer than visual-to-visual and auditoryto-vocal performDnces in autistic children, suggesting a dysfunction of the connections between the temporal and occipital lobes. Morton-Evans and Hensley (1978) found that autistic and aphasic children had significantly lower performances in matching auditory stimuli to visual stimuli than normal children of similar nonverbal mental age. There was no difference between groups in performing visuo-visual associations. Instead of increases in occipital responses amplitudes in normal children, Lelord et al (1973) found very small modifications of auditory evoked responses in autistic children when the auditory stimulus was followed by a strong visual stimulus. Several studies have found that the auditory evoked components are smaller in autistic children compared with n o ~ a l (Novick et al 1980; Martineau et al 1981; Dawson et al 1988). However, most of the studies performed on sensory-evoked responses emphasized the great intraindividual and interindividual variability (Ornitz et al 1968; Walter 1969; Novick et al 1979; Martineau et al 1980, 1981, 1984, 1987; Friedman et al 1982) More recently, in order to study this great intraindividual variability, Courchesne (1987) looked at the A/Pc~/300 amplitude (the fronto-central P3 and orienting to novelty) to the first novel trial and to each of the following five novel trials. He found that autistic subjects usually have normal amplitude A/Pcz/300 responses to the very first novel stimulus and that, after this first trial, each of the following responses is usually very much smaller, and the wave shape changes radically from trial to trial. He concluded that the neural generators involved in detecting novelty have the capacity for normal functioning, and occasionally, they do respond normally. For Courchesne, this evidence raises the possibility that the operation of this apparently otherwise normal neural system is usually abnormally interfered with or hindered by some other system. The evoked-potential variability can be evaluated by studying the standard deviation of the evoked-potential waveform and not just the peaks and troughs in the individual waveform (Hatter and Guido 1980). By studying the standard deviation (SD) of AERs, ~ve showed some slight abilities in auditory-visual association in autistic children compared to retarded ones (Martineau et al 1987). Even though the amplitude modifications observed when stimuli are paired did not reach a significant level, the pattern of autistic responses looked like the pattern of normal ones, with an increase of evoked potential amplitudes at both occipital (Oz) and vertex (Cz) sites during crossmodal association series. It was noted that the inverse pattern was observed in mentally retarded children. Moreover, evoked-potential variability is high in schizophrenia and young children (Callaway et al 1970). Among schizophrenics, evoked-potential variability is greatest in those who show inaccurate and variable perceptual performances (Inderbitzen et al 1970). Evoked-potential variability decreases with maturation in normal children (Callaway 1972; Callaway and Halliday 1973) and with clinical improvement in schizophrenic (Jones et al 1966j and autistic children (Martineau et al 1989). Using standard deviation to evaluate auditoryevoked-response amplitudes and a signal-to-noise ratio method applied to individual evoked responses to evaluate the variability of evoked responses, we demonstrated the interindividual variability in autistic children (Martineau et al 1992). The present work thoroughly studies mechanisms by comparing, on one hand, the reactivities to unimodal and crossmodal stimuli and, on the other hand, the main neu-
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Table 1. The Composition of the Autistic Group and the Two Control Groups. Chron Age
Devel Age
Verb DQ
N Verb DQ
Groups
n
G
B
M
SEM
M
SEM
M
SEbl
M
SEM
Autistic Normal Retarded
30 30 30
13 13 11
17 17 19
6;11 6;6 6;3
0;6 0;4 0;4
2;9
0;3
42
5
50
5
3;0
0;3
47
6
49
4
n, number of children; G, girls; B, boys; M : mean age in years and months (y; m). Chron Age : chronological age; Devel Age : developmental age; Verb DQ : verbal developmental quotient; N Verb DO : Nonverbal developmental quotient.
rocognitive functions most often disturbed in autism. The aim is to test the hypothesis that the deficit in the ability to form crossmodal associations in autism is linked to a cognitive abnormality. Subjects Thirty autistic subjects (17 boys and 13 girls) ranging in age from 3 years 4 months to 11 years were involved in this study. A mentally retarded group (n = 30) matched the autistic sample on chronological age and developmental age (Table 1). The psychomotor development scale of Brunet and Lezine (1976), a French version of Gesell and Amatruda's scale (1947), was used to determine developmental quotients (DQ). Forty-five percent of autistic children and 55% of mentally retarded children were capable of spoken language. Each child was a patient from the day-care child psychiatry unit of Centre Hospitalier Universitalre Regional TOURS. Each child received an extensive evaluation, including a detailed developmental history, using a questionnaire, a videotaped psychiatric assessment, psychological and linguistic testing, pediatric and neurological examination, and audiological assessment. Examinations were carried out by a professional team consisting of child psychiatrists and child psychologists, language pathologists, a neurologist, social worker, and pediatrician, all expert in dealing with autistic children. A diagnosis of infantile autism was reached only if at least all but one of the members of the team agreed that the child's condition met all the criteria for early infantile autism listed in the DSM III-R ([APA] American Psychiatric Association 1987). These criteria include qualitative impairment in reciprocal and social interaction, qualitative impairment in communication and imaginative activity, and markedly restricted repertoire of activities and interests. Children of the mentally retarded group were mixed in their etiology, but none of these children exhibited withdrawal signs or bizarre responses. They were classified 317.00, 318.00, 318.10, and 318.20 by DSM III-R criteria. All children were in excellent physical health, audiologicaily intact, and none had a history of endocrine and systemic disease. None showed gross neurological disorders or had seizures or pathological electroencephalograms (EEG) with either slow waves or paroxysmal spikes. An evaluation of disturbances affecting the major neurocognitive functions was carried out based on the Behavior Summarized Evalaation scale (BSE, Lelord et al 1981, Bar-
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Table 2. Neurocognitive Functions Attention Unstable attention, easily distracted Perception Abnormal eye contact Bizarre responses to auditory stimuli Autoaggressiveness Association Inappropriate relating to inanimate objects or to doll Disturbances of feeding behavior No attempt to control urine and feces Intention Lack of initiative, poor activity Agitation, restlessness Uses objects in a compulsive and/or ritualistic way Motility Stereotyped sensori-motor activity Bizarre posture and gait Emotion Resistance to change and to frustration Soft anxiety signs Mood difficulties Heteroaggressiveness Instinctual disturbances Sleep disturbances Masturbation Contact Is eager to be alone Ignores people Poor social interaction Communication Does not make an effort to communicate using voice Lack of appropriate facial expressions and gestures Stereotyped vocal and voice utterances, echolalia Regulation Behavioral variability The scores of the BehaviorSummarizedEvaluationscale (Lelordet al 1981; Barthelemyet al 1990)are not classed accordingto the headingsadaptedfromthe DSM-Ill,but accordingto the mainneurocognitivefunctionsmostoftendisturbed in autism.
thelemy 1986), which supplied information on the actual behavior of the child. The content validity, using a principal component factor analysis without and with Varimax rotation and interrater reliability, using the Kappa statistic of the BSE scale have been recently published (Barthelemy et al 1990). ' ~ i s scale is commercialized by the "Etablissements d'Applications Psychotechniques" (France). It consists of 25 items rated on a 5-point scale ranging from never (0) to always (4), and grouped under 10 headings corresponding to the neurocognitive functions most often disturbed in autism (Table 2). Each autistic and mentally retarded child was rated once a week by nurses who knew the children for several months and who had daily contact with them. A group of 30 children with no known neurological or auditory dysfunction was drawn from children in the normal school population, matched to the autistic and mentally retarded samples on chronological age, and used as the normal control group.
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Materials and M e t h c d s Each subject was isolated in a dark, soundproof room and seated in a comfortable armchair beside his usual nurse or his mother. Recordings of the EEG were made from the midline central, or vertex (Cz), the midline frontal (Fz), the midline occipital (Oz), the left (T3) and right (T4) temporal electrode loci of the international 10-20 system. These active electrodes were referred to linked electrodes placed on the earlobes. Subjects were earthed via the forehead and the electrooculogram (EOG) was monitored from supraorbital linked electrodes, using the same references (earlobes). All electrode impedances were less than 5 Kf~. On each trial, the EEG and EOG were amplified by a Minihuit Alvar Polygraph (3dB bandwidth, 0.5-2000 Hz~. The EEG was digitized every 4 msec for a 2.3-see period that began 500 msec prior to stimuli presentation. The presentation of stimuli was stopped whenever the child moved or spoke. All trials contamined by ocular movements were rejected on-line (criteriz~ 100 ~volts). The percentages of rejected trials in the unimodal condition were between 1% and 12% in the normal children, between 1% and 13% in the autistic children, and between 1% and 12% in the mentally retarded children. The percentages of rejected trials in the crossmodal condition were between 1% and 13% in the normal children, between 1% and 15% in the autistic children, and between 1% and 14% in the mentally retarded children. Auditory stimuli were presented through two speakers placed 35 cm directly beside each ear, a flash was positioned 30 cm from the subject's face. Auditory evoked responses (AERs) were recorded during two sessions on 2 consecutive days at the same time of the dav. session 1 included 180 nonrejected trials, session 2 included 120 nonrejected trials. The first day, a weak tone burst (S = 50 dB SPL, 750 Hz, 100-msec duration with 20-msec rise time) was presented alone on the first 60 trials (1 to 60, SI) in order to study unimodal AERs. To study crossmodal association between the auditory and visual stimuli over time, a strong flash of light (L = 1200 lux, 200 I~sec) was then presented 800 msec after S on trials 61 to 180 (SLI, day 1). The second day, the strong flash of light was presented after S on trials I to 120 (SLII, day 2). Intertrial intervals varied randomly between 4 and 12 see. Each averaged auditory evoked response was obtained by averaging 20 auditory evoked responses, using a PDP 11/24 computer. The SD, which was more appropriate than the amplitude to determine the absence or presence of a response and to characterize this response, was computed across time (Callaway 1975) during 250 msec-averaged presound and 250 msec-averaged postsound EEGs (Martineau et al 1987). The ratio of the SD from the 250msec-averaged postsound EEG to 250 msec-averaged presound EEG was chosen as the criterion for determining the presence (if ratio > 1.3, Bruneau et al 1990; Martineau et al 1991) of the averaged evoked response. The SD is known to give a correct estimation of the peak-to-peak amplitude of AER and especially of N I and P2 waves. An electrophysiological scale was utilized to evaluate anomalies of the electrophysiological reactivity (Figure 1). This comprised four headings: the presence of AERs in the unimodal condition, the effect of the repetition of stimuli in the unimodal condition, the presence of AERs in the crossmodal condition, and the effect of the repetition of stimuli in the crossmodal cc,,ldition, scored on a 3-point scale. In the unimodal condition, the AERs were recorded on the four centro-temporo-frontal electrode sites, 60 simple stimuli were given and AERs were averaged by 20 trials. So, 3 averaged AERs can be obtained on 4 sites in the optimal conditions and 3 x 4 = 12
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ANOMALIES IN UNI - MODAL REACTIVITY Presence of AERs Score NbAERst 9112 [5-28 [ 1~4~
[
Effect of repetition ]Score/ 1 ] 2 I I Effect 1>2>3 I--2=3 1 ~r32<3 2>3 1<2<3
ANOMALIES IN CROSS-MODAL REACTIVITt Presence of Oz AERs ScoreI : Ozresponsesand modificationson Cz,Fz,T3,1"4 Score2 : Ozresponsesand no modiflcaqonon Cz,Fz,T3,1"4 Score3 : NoOzresponse Effect of repetition
Figure 1. Electrophysiological scale utilized to evaluate anomalies of the electrophysiological reactivity. Top: the anomalies in the unimodal condition were observed on the four centro-temporo, frontal electrode sites (Cz, T3, T4, Fz). Bottom: the anomalies in the crossmodai condition were observed on the occipital electrode site (Oz) and on the other derivations for the presence, and only on the occipital electrode site for the effect of repetition of stimuli.
I
was the maximum of recorded AERs. Concerning the presence of AERs in the unimodal condition, score 1 was given for a number of AERs between 9 and 12, score 2 for the number between 5 and 8, score 3 for the number between 1 and 4. The repetition of stimuli produced a decrease in AER amplitude in most of the subjects (Bruneau et al 1990): the amplitude of the first AER (Sl) was greater than the second ($2), which was greater itself than the third ($3). Regarding the effect of the repetition of stimuli in the unimodal condition, score 1 was given if SI was greater than $2, which was itself greater than $3, or if S 1 was identical to $2 and $2 greater than $3. Score 2 was given if S 1 was identical to $2 and to $3. Score 3 was given if S 1 or $2 was smaller than $3, or if S 1 was smaller than $2, which was itself smaller than $3. In the crossmodal condition, the appearance (or the increase) of AER was observed in the occipital region when the sound was followed by the flash, and a decrease or an increase of AER amplitude was observed on the other derivations (Martineau et al 1984; Bruneau et al 1990). Concerning the presence of Oz AERs in the crossmodal condition, score 1 was given if an Oz response appeared with a decrease or an increase of AER amplitudes on the other derivations. Score 2 was given if an Oz response appeared without modification of AER amplitudes on the other derivations. Score 3 was given if no modification was observed at Oz site during the crossmodal condition compared to the unimodal condition. In the crossmodal condition, the maximum number of Oz responses recorded was 12 (6 in the first session, 6 in the second session). With regard to the effect of the repetition of stimuli in the crossmodal condition, score 1 was given if the number of present Oz responses was higher than 4. Score 2 was given if the number was between 1 and 3. Score 3 was given if no Oz response was recorded. This scale was rated by two independant raters. Reliability of each heading was tested
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by calculating the Kappa statistic. The evaluation of reliability coefficient was based on guidelines given by Cicchetti and Sparrow (1981): the four headings had excellent reliability (presence of AERs in the unimodal condition: 0.78; effect of the repetition of stimuli in the unimodal condition: 0.79; presence of AERs in the crossmodal condition: 0.79; effect of the repetition of stimuli in the crossmodal condition: 0.81). Frequency comparisons of the scores under each heading using X2, intragroup comparisons using Kruskal-Wallis (1-way analysis variance [ANOVA]), and Mann-Whitney U test were performed. For clinical evaluation, a discriminant analysis was performed using a stepwise variable selection procedure. SPSS subprograms were used. Results
Electrophysiological Evaluation Figure 2 shows the grand average of AERs in the three groups in the unimodal condition S (1-3) and in the crossmodal condition SL (1-6) on the first and second days; Figure 3 shows the ratings of the electrophysiological evaluation.
Anomalies in the Unimodal Reactivity. Significant differences were found concerning the presence of AERs between the three groups (X2 = 21.99, df = 4, p < 0.0001). Fifteen out of the 30 normal children were rated with score 1, 9 with score 2, and 6 with score 3. The same distributions were found in the normal and the mentally retarded children (15 mentally retarded children were rated with score 1, 5 with score 2, 10 with score 3, X2 = 2.14, df = 2, NS). On the contrary, this predominance of score 1 was not found in the autistic children: 1 out of the 30 autistic children were rated with score 1, 10 with score 2, and 19 with score 3 (X2 = 19.06, df = 2, p < 0.001 between autistic and normal children, X2 --- 16.71, df = 2, p < 0.001 between autistic and mentally retarded children). Concerning the repetition of stimuli, significant differences were observed between the three groups (~(2 = 27.22, df = 4, p < 0.001). A decrease of AER amplitudes with the lepetition of stimuli was observed in 19 out of the 30 normal children (score 1), no modification of AER amplitudes was observed in 5 of the normal children, and an increase of AER amplitudes in 6 out of the 30 normal children. The ?ame distributions were found in the normal and the mentally retarded children (17 mentally retarded children were rated with score 1, 7 with score 2, 6 with score 3, ×2 = 0.44, df = 2, NS). This predominance of score 1 was not found in the autistic children: 3 out of the 30 autistic children were rated with score 1, 5 with score 2, and 22 with score 3 (X:' = 20.78, df = 2, p < 0.001 between autistic and normal children, X2 = 19.28, df = 2, p < 0.001 between autistic and mentally retarded children). Anomalies in the Crossmodal Condition. Concerning the presence of Oz AERs, significant differences were observed between the three groups (X2 = 53.69, df = 4, p < 0.001). In all normal children, an Oz response appeared (scores 1 and 2); in almost all autistic children, an Oz response appeared in the crossmodal condition (29 out of the 30 autistic children were scored I or 2, X2 = 0.65, df = 1, NS); in mentally retarded children, no Oz response was recorded in 20 out of the cases scored 3 (×2 = 37.39, df = 2, p < 0.001 between normal and mentally retarded children, X2 = 34.37, df = 2, p < 0.0001 between autistic and mentally retarded children).
Unimodal and Crossmodal Reactivity in Autism
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Normal children (n = 30) S(I-3)
SL(I-6)
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(n = 30)
$L ( I -ep
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? U IqI~W~LI|
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Figure 2. Grand average of AERs in the three groups of children (30 normal, 30 autistic and 30 mentally retarded children) in the uni-modal condition S (1-3) and in the crossmodal SL (1--6) condition on the first and the second days. An Oz response appeared in all normal children (apparent in the waveform on the first and the second days) and in almost all autistic children (apparent principally in the waveform on the second day).
Significant differences were observed with regard to the repetition of crossmodal stimuli (X2 = 71.69, df = 4, p < 0.001). The Oz response was relatively well-maintained with the repetition of stimuli in normal children (23 of the normal children had more than 4 responses). In autistic children, this Oz response was not maintained (20 of the 30 autistic children had less than 3 0 z responses, X 2 = 11.38, df = 2, p < 0.001 between normal and autistic children). No Oz response was recorded in 20 mentally retarded children and less than 3 0 z responses for the 10 others (×2 = 43.53, df = 2, p < 0.001 between
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Nb 25
~Anomalies in uni-modal reactivity[ Presence 2s Repetition 20
20 15 10
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123 Aut
1 2 3 Nor
123 Nor
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Figure 3. Electrophysiological evaluation. In the unimodal condition, on the left, normal children (NOR) were mainly rated with score 1 (dotted piles on the left), as were the mentally retarded children (RET). Autistic children (AUT) displayed few AERs with a failure to decrease AER amplitudes during the repetition of stimuli. In the crossmodal condition, on the left, an Oz response appears in normal and autistic children (score 1) while a disappearance or no Oz response was mainly observed in mentally retarded children. This Oz response was maintained in normal children, whereas 67% of autistic childl'en had fewer than 3 0 z responses.
normal and mentally retarded children, X2 = 33.33, df = 2, p < 0.001 between autistic and mentally retarded children).
Functional Evaluation Figure 4 gives the mean of each neurocognitive function in the two groups of pathological children. Autistic children differed from mentally retarded children on Attention (z = 2.29; df = 58; p < 0.02), Perception (z = 6.11; df = 58; p < 0.0001), Association (z = 6.46; df = 58; p < 0.0001), Intention (z = 4.79; df = 58; p < 0.0001), Motility (z = 4.58; df = 58; p < 0.0001), Emotion (z = 2.53; df = 58; p < 0.01), Contact (z = ~.72, df = 58; p < 0.0001), Communication (z = 5.82; df = 58; p < 0.0001) and Regulation (z = 6.78; df = 58; p < 0.0001). They did not differ on Instinctual Disturbances. A discriminant analysis between the two pathological groups was then performed on the ratings of the 10 headings corresponding to the neurocognitive functions most often disturbed in autism. Two variables were sufficient for the discriminant analysis procedure. They entered the linear function in the following order: Contact, Regulation. The ratings
Unimodal and Crossmodal Reactivity in Autism
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4
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Figure 4. Functional evaluation: mean and SEM of each aeumcognitive function. Autistic children (AUT) differed from mentally retarded children (RET) on each neurocognitive function except on
instinctual disturbances (Inst.). Contact (Cont.) and regulation (Reg.) were sufficient for the discriminant procedure and the ratings of these two functions allowed to correctly classified all the children. Art, Attention; Perc, Perception; Ass•c, Association; Int, Intention; Mot, Motility; Emot,
Emotion; Inst, Instinctual disturbances; Cont, Contact; Comm, Communication; Reg, Regulation.
disturbed in autism• Two variables were sufficient for the discriminant analysis procedure. They entered the linear function in the following order: Contact, Regulation. The ratings of the heading: Contact allowed the accurate classification of 96•7% of children (2 autistic children were not correctly classified). When the heading Regulation was added, the percentage of correctly classified children increased to 100%.
Functional and Electrophysiological Evaluations Kruskai-Wallis nonparametric tests (l-way ANOVA) were performed on the ratings of the 10 neurocognitive functions in order to test differences between children who scored 1, 2, or 3 on each heading of the electrophysiological scale for the two pathological groups• The autistic children having the higher scores on the anomalies of presence of AERs in the unimodai condition were the more disturbed in Association (Kruskal-Wallis test, X2 corrected for ties = 7.42; p = 0.0244). The autistic children having the higher scores on the anomalies of the repetition of stimuli in the unimodal condition were the more disturbed in Attention (X2 corrected for ties = 6.05; p = 0.0451) and Perception (X2 corrected for ties = 6.14; p = 0.0464). The autistic children having the higher scores on the anomalies of the repetition of stimuli in the crossmodal condition were the more disturbed in Attention (X2 corrected for ties = 5.49;p = 0.0190), Perception (X2 corrected for ties: 4.40; p = 0.0358) and Association (X2 corrected for ties = !3.21; p = 0.0003). No significant Kruskal-Wallis test result was found with the other psychological functions. No significant Kruskal-Wallis test result was found in the mentally retarded group.
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Discussion This study shows that the reactivity of autistic children to unimodal and crossmodal stimuli is different from the reactivity of both normal and mentally retarded children. Differences among groups in the frequency distribution of the EEG may account for the evoked response data, but spectral analyses were not available and this can be a limitation of the present study. However, compared with normal children, the autistic children have less well-differentiated auditory evoked responses to unimodal stimuli. This confirms previous studies showing that the number of present evoked responses in autistic children is alwavs weaker than normal (Ornitz et al 1968; Novick et al 1979; Martineau et al 1981, 1987; Friedman et al 1982). Moreover, autistic children differ from normal children i~ she effects of the repetition of simple auditory stimu!i. In normal children, the repetition of simple stimuli produced a decrease in amplitude of the AERs (19 children). Autistic children did not show this decrease and some even showed an increase of AER amplitudes (22 children). This confirms the failure to habituate, largely observed and described in autistic children with electrodermal studies (Palkovitz and Wiesenfeld 1980; James and Barry 1980, 1984; Stevens and Gruzelier 1984; Barry and James 1988) and studies of evoked potentials (Saletu et al 1975). Concerning the reactivity to unimodal stimuli, no difference was observed between the normal and the mentally retarded children: the mentally retarded children had the same number of AERs and the same response to the repetition of unimodal stimuli, with a decrease in amplitudes of AERs, as the normal children. Autistic children differed from mentally retarded children and also from normal children in the unimodal condition. However, in the crossmodal condition, autistic children did not differ from normal children in the presence of crossmodal phenomenon, but differed from them in the effect of the repetition of crossmodal stimuli. Crossmodal associations exist in autistic children, but they are unable to maintain them. In the crossmodal condition, autistic children differed largely from mentally retarded children: very few Oz responses are recorded in mentally retarded children and the repetition of crossmodal stimuli did not allow the observation of Oz AERs. The mentally retarded children differed largely from autistic children in this condition. Regarding disturbances affecting the neurocognitive functions, autistic children differed largely from mentally retarded children on most of the ratings. Only the Instinctual Disturbances were almost rated higher in mentally retarded than in autistic childrea. The tests performed between electrophysiological and functional data showed significant results only in the autistic group. There was no significant result in the mentally retarded group. In the autistic group, the functions Attention and Perception were scored signi',icantly higher in the autistic children showing the higher anomalies in the effect of repelition in unimodal and crossmodal conditions. The autistic children showing the more unstable attention and the more perceptual abnormalities have the greater failure to habituate. This confirms numerous studies performed with electrodermal recordings (James and Barry 1980, 1984; Stevens and Gruzelier 1984; Barry and James 1988) and showing evidem:e of a dysfunction in attentional responses in autistic children. The results obtained between the function Association and the unimodal condition showed that the children more impaired in their association abilities were the children displaying fewer AERs. A highly significant result was found between the function Association and the effect of repetition of crossmodal stimuli but not with the presence of Oz AERs in the crossmodal condition. This showed that autistic children ~ e capable
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of crossmodal associations, but the children more clinically disturbed on the Association function were not able to maintain these associations. It seems that autistic children can form crossmodal associations but cannot maintain them. This deficit in sustaining abilities can be related to clinical observations on the cognitive aspects of autism. Adrien (1983) found evidence that autistic children are capable of object permanence, but with irregularities in the object placement. Sigman and Mundy (1987) showed that the sensorimotot skills of autistic children are not delayed relative to normal children of comparable mental age and that they are capable of certain forms of representational thought. In mentally retarded children, hyperresponsiveness to unimodal stimuli was observed with large AERs on all derivations and even on the occipital lead (Figure 2). A decrease of AER amplitudes was observed with the repetition of unimodal stimuli as in normal children. Global inhibition was observed during crossmodal stimuli with a decrease of AER amplitudes on all derivations and disappearance on the occipital lead. It seems that these children "inhibit" the responses to sound when it is followed by the light. It may be possible that the mentally retarded children selected the visual stimuli and persevered in their attention to this stimuli, inhibiting their responses to the auditive stimuli. Mentally retarded children appear to have a limited capacity for information processing. Ellis (1963) proposed that the generally low performance of retarded people is due to a limited capacity for information intake and a more rapid decay of that information over time. It can be suggested that the interstimulus interval between auditive and visual stimuli was too long to allow mentally retarded children to perform crossmodal associations. It would be of great interest to compare the modifications of visual evoked responses to unimodal visual stimuli and to crossmodal visuo-auditory stimuli in these mentally retarded children and to shorten the interstimulus interval in order to determine their ability to perform sensorial associations. In summary, autistic children fail to habituate to repetition of simple unimodal stimuli, can form crossmodal associations, but cannot maintain them. This suggests that a more elementary perceptual abnormality precedes the inability to maintain crossmodal associations in autism. These observations can be related to hypotheses put forward by Ornitz (1983) on the faulty modulation of sensory input and by Lelord (1990) showing that the characteristic disorders of autism are linked with abnormalities in the filtering and the sensorial, emotional, posturomotor regulation, resulting ":.~ genuil~e "brain regulating insufficiences." It seems that the autistic child does not perceive brief, intense stimuli like a door banging or a gunshot, whereas they are intolerant of longer stimuli like the blast of a hooter, the noise of flushing the toilet, or the buzz of a vacuum cleaner. Some of these clinical observations may be related to electrophysiological data such as insufficient responses to the first stimuli or absence of habituation. This research was supported by INSERMU 316 (The nervous systemfrom the foetusto the child: development, circulation and metabolism), R~seau INSERM n. 489 001, Fondation Langlois, CRAMTSn. 2748/88, FRM and CNAM.
References Adrien JL (1983): La permanence de l'objet chez l'enfant pr~sentant des troubles autistiques et psychotiques. R Descartes University Paris; Thesis. American Psychiatric Association (1987): Diagnostic and Statistical Manual for Mental Disorders, 3rd Revised Edition. Washington, DC: American Psychiatry Press.
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Ban3' RJ, James AL (1988): Coding of stimulus parameters in autistic, retarded and normal children: Evidence for a two-factor theory of autism. Int J Psychophysiol 6:139-149. Barthelemy C (1986): Evaluations cliniques quantitatives en P6dopsychiatrie. Neuropsychiat Enfance Adolesc 34:63-91. Barthelemy C, Adrien JL, Tanguay P, et al (1990): The Behavioral Summarized Evaluation: Validity and reliability of a scale for the assessment of autistic behavior. J Autism Dev Disord 2" 189204. Bruneau N, Roux S, Martineau J, Garreau B, Ornitz, EM, Lelord G (1990): Cortical evoked potentials as indicators of auditivo-visual cross-modal association in young adults. Pavlov J Biol Sci 25:201-206. Brunet O, Lezine I (1976): Echelle de d6veloppement psychomoteur de la premi6re enfance. In Brunet O, Lezine I (eds), Le ddveloppement Psychologique de la Premidre Enfance, 2d ed. Paris: PUF. Bryson CQ (1970): Systematic identification of perceptual disabilities in autistic children. Percept Mot Skills 31:239-246. Callaway E (1972): Brain potentials and cognitive potentials. In J Prescott (ed), Malnutrition and Brain Function: Neuropsychological Methods of Assessment. Washington DC: NICHD. Callaway E (1975): Brain Electrical Potentials and Individual Psychological Differences. New York: Grune and Stratton. Callaway E, Jones RT, Donchin E (1970): Auditory evoked potential variability in schizophrenia. Electroencephalogr Clin Neurophysiol 29:421-428. Callaway E, Halliday RA (1973): Evoked potential v~u'iability: Effects of age, amplitude and methods of measurement. Electroencephalogr Clin Neurophysiol 34:125-133. Cicchetti DV, Sparrow SA (1981): Developing criteria for establishing interrater reliability of specific items: Applications to assessment of adaptative behavior. Am J Ment Def 86:127-137. Courchesne E (1987): A neurophysiological view of autism. In Schopler E, Mesibov (3 (eds), Neurobiological issues of Autism. New York: Plenum, pp 285-324. Ellis NR (ed) ( ! 963): Handbook of Mental Deficiency: Physiological Theory and Research. London: Mc Graw Hill. Dawson G, Finley C, Phillips S, Galpert L, Lewy A (1988): Reduced P3 amplitude of the eventrelated brain potential: its relationship to language ability in autism. J Autism Dev Disord 18:493504. Friedman D, Vaughan HG, Erlenmeyer-Kimling L (1982): Cognitive brain potentials in children at risks for schizophrenia: Preliminary findings. Schizophr Bull 8:514-530. Gesell A, Amatruda CS (1947): Developmental Diagnosis, Normal and Abnormal Development: Clinical methods and pediatric applications. New York: Paul B Hoeber. Geschwind N (1965): Disconne×ion syndromes in animals and man. Brain 88:237-294, 585-644. Hatter MR, Guido W (1980): Attention to pattern orientation: Negative cortical potentials (Oz, Cz, Fz) reaction time and the selection process. Electroencephalogr Clin Neurophysio149:461475, Hermelin B, O'Connor N (1970): Psychological Experiments with Autistic Children. London: Pergamon Press. Inderbitzen LB, Buchsbaum M, Silvermann J f1970): EEG-averaged evoked response and perceptual variability in schizophrenics. Arch Gen Psychiat 23:438-444. James AL, Barry RJ (1980): Respiratory and cardiovascular responses to simple visual stimuli in autistics, retardates and normals. Psychophysiology 17:541-547. James AL, Barry RJ (1984): Cardiovascular and electrodermal responses to simple stimuli in autistic, retarded and normal children, lnt J Psychophysiol 1:179-193. Jones RT, Blacker KH, Callaway E (1966): Perceptual dysfunction in schizophrenia: clinical and auditory evoked response findings. Am J Psychiatry 123:639-4545. Lclord G (1990): Physiopathologie de l'autisme. Les insuffisances modulatrices c(~r6brales. Neuropsychiatr Enfance Adolesc 38:43-49.
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Lelord G, Maho C (1969): Modifications des activit6s ~voqu6es corticales et thalamiques au cours d'un conditionnement sensoriel. Electroencephalogr Clin b.;europhysiol 27:258-269. Lelord G, Laffont F, Jusseaume P, Stephant JL (1973): Comparative study of conditioning of averaged evoked responses by coupling sound and light in normal and autistic children. Psychophysiology 10:415-427. Lelord G, Muh JP, Barthelemy C, Martineau J, Garreau B (1981): Effects of pyridoxine and magnesium on autistic symptoms. Initial observations. J Autism Dev Disord 11:219-230. Martineau J, Laffont F, Bruneau N, Roux S, Lelord G (1980): Event-related potentials evoked by sensory stimulation in normal, mentally retarded and autistic children. Electroencephalogr Clin Neurophysio148 :140-15 3 . Martineau J, Garreau B, Barthelemy C, Callaway E, Lelord G (1981): Effects of vitamin B6 on averaged evoked potentials in infantile autism. Biol Psychiatry 16:625-639. Martineau J, Tanguay P, Garreau B, Roux S, Lelord G (1984): Are there sex differences in averaged evoked respo..ases (AERs) produced by coupling sound and light in children and adults? lnt J Psychophysiol 2:117-183. Martineau J, Gan'eau B, Roux S, Lelord G (1987): Auditory evoked responses and their modifications during conditioning paradigm in autistic children. J Autism Dev Disord 17:525-539. Martineau J, Barthelemy C, Roux S, Garreau B, Lelord G (1989): Electrophysiological effects of fenfluramine or combined vitamin B6 and magnesium on children with autistic behavior. Dev Med Child Neurol 31:721-727. Martineau J, Roux S, Adrien JL, Garreau B, Barthelemy C, Lelord G (1992): Electrophysiological evidence of different abilities to form cross-modal associations in children with autisti.~ behavior. Electroencephalogr Ciin Neurophysiol 82:60-66. Morton-Evans A, Hensley R (1978): Paired associate learning in early infantile autism and receptive developmental aphasia. J Autism Dev Disord 8:61-69. Novick B, Kurtzberg D, Vaughan HG (1979): An electrophysiologic indication of defective information storage in childhood autism. Psychiatry Res 1:101-108. Novick B, Vaughan HG, Kurtzberg D, Simson R (1980): An electrophysiologic indication of auditory processing defects in autism. P.~,chiatry Res 3:107-114. Ornitz EM (1983): The functional neuroanatomy of infantile autism, lnt J Neurosci 19:85-124. Ornitz EM, Ritvo ER, Panman LE, Lee YH, Carr EM, Walker RD (1968): The auditory evoked responses in normal and autistic children during sleep. Electroencephal~gr Clin Neurophysiol 25:221-230. Palkovitz RJ, Wiesenfeld AR (1980): Differential autonomic responses of '~utistic and normal children. J Autism Dev Disord 10:347-360. Saletu B, Saletu M, Itil TM, Simeon J (1975): Brain function analysis in childhood psychosis: evoked responses. Clin Electrencephalogr 6:44-53. Sigman M, Mundy P (1987): Social and cognitive deficits in young autistic children. In Gremy F, Tomkiewicz S, Ferrari P, Lelord G (eds)Autisme Infantile/Infantile Autism. Paris: INSERM, 146 pp 169-174. Stevens S, Gruzelier J (1984): Electrodermal activity to auditory stimuli in autistic, retarded and normal children. J Autism Dev Disord 14:245-260. Walter WG (1969): Can "attention" be defined in psychological terms? In Evans CR, Mulholland B (eds), Attention in Neurophysiology. London: Butterworths, pp 27-39.
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Unimodal and Crossmodal Reactivity in Autism: Presence of Auditory Evoked Responses and Effect of the Repetition of Auditory Stimuli J. Martineau, S~ Roux, B. Garreau, J. L. Adrien, and G. Lelord
Using auditory evoked responses, this work compares the reactivities to unimodal and crossmodal stimuli and the main neurocognitive functions most often disturbed in autism. With the aim of testing the hypothesis that the deficit in the ability to form crossmodal associations in autism is linked to a cognitive abnormality, audiwry evoked responses to simple and to crossmodal (auditivo-visual) stimuli were recorded in 30 autistic children and compared with those of 30 normal and 30 mentally retarded children. Relationships between electrophysiological reactivity and neurocognitive functions showed that the cognitive deficit in the ability to maintain crossmodal associations is preceded by a more elementary perceptive abnormality in autistic children.
Introduction For some authors, the ability to acquire speech is dependent on the ability to form crossmodal associations, both visual-auditory and tactile-auditory (Geschwind 1965; Bryson 1970). One approach to investigate this ability in forming auditory-visual associations is to examine the modifications of auditory evoked responses (AERs) when the auditory stimulus is followed by a strong visual or tactile stimulus (Lelord and Maho 1969). In these conditions, the crossmodai phenomenon depends on the establishment of a cross. modal association between the auditory and visual stimuli over time. Such a paradigm does not require the pe,rticipation of the subject and can be used in young and/or pathological children. Normal adults and children show an increase in the auditory-evokedresponse amplitude in the occipital region when the sound is followed by the flash (Martineau et al 1984; Bruneau et al 1990). This spread of the AER over the occipital visual-cortical area was considered characteristic of the crossmodal association phenomenon (Lelord and Maho 1969; Bruneau et al 1990). A deficit in the ability to form crossmodal associations needed for the devclopmcnt of language, was reported in children with autistic behavior. Hermelin and O'Connor (1970), on the basis of an extensive series of laboratory studies, concluded that autistic children displayed an impaired ability to integrate input and output data and to process
From INSERM U316, the Department of Psychopathology and Neurophysiology of Development, CHRU Bretonneau, Cedex, France. Address reprint requests to .L Martineau, INSERM U316, Department of Psychopathology and Neurophysiology of Devel. opment, CHRU Bretonneau, 37044 TOURS Cedex, France. Received May 20, 1991, revised February ! 1, 1992.
© 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
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information from various sources. In a study of sensory processing, Bryson (1970) used matching-to-sample tasks to test the ability of autistic children to make visual, w~cal, and fine motor responses to visual and auditory stimuli. She found that the auditory-tovisual and visual-to-vocal performances were poorer than visual-to-visual and auditoryto-vocal performDnces in autistic children, suggesting a dysfunction of the connections between the temporal and occipital lobes. Morton-Evans and Hensley (1978) found that autistic and aphasic children had significantly lower performances in matching auditory stimuli to visual stimuli than normal children of similar nonverbal mental age. There was no difference between groups in performing visuo-visual associations. Instead of increases in occipital responses amplitudes in normal children, Lelord et al (1973) found very small modifications of auditory evoked responses in autistic children when the auditory stimulus was followed by a strong visual stimulus. Several studies have found that the auditory evoked components are smaller in autistic children compared with n o ~ a l (Novick et al 1980; Martineau et al 1981; Dawson et al 1988). However, most of the studies performed on sensory-evoked responses emphasized the great intraindividual and interindividual variability (Ornitz et al 1968; Walter 1969; Novick et al 1979; Martineau et al 1980, 1981, 1984, 1987; Friedman et al 1982) More recently, in order to study this great intraindividual variability, Courchesne (1987) looked at the A/Pc~/300 amplitude (the fronto-central P3 and orienting to novelty) to the first novel trial and to each of the following five novel trials. He found that autistic subjects usually have normal amplitude A/Pcz/300 responses to the very first novel stimulus and that, after this first trial, each of the following responses is usually very much smaller, and the wave shape changes radically from trial to trial. He concluded that the neural generators involved in detecting novelty have the capacity for normal functioning, and occasionally, they do respond normally. For Courchesne, this evidence raises the possibility that the operation of this apparently otherwise normal neural system is usually abnormally interfered with or hindered by some other system. The evoked-potential variability can be evaluated by studying the standard deviation of the evoked-potential waveform and not just the peaks and troughs in the individual waveform (Hatter and Guido 1980). By studying the standard deviation (SD) of AERs, ~ve showed some slight abilities in auditory-visual association in autistic children compared to retarded ones (Martineau et al 1987). Even though the amplitude modifications observed when stimuli are paired did not reach a significant level, the pattern of autistic responses looked like the pattern of normal ones, with an increase of evoked potential amplitudes at both occipital (Oz) and vertex (Cz) sites during crossmodal association series. It was noted that the inverse pattern was observed in mentally retarded children. Moreover, evoked-potential variability is high in schizophrenia and young children (Callaway et al 1970). Among schizophrenics, evoked-potential variability is greatest in those who show inaccurate and variable perceptual performances (Inderbitzen et al 1970). Evoked-potential variability decreases with maturation in normal children (Callaway 1972; Callaway and Halliday 1973) and with clinical improvement in schizophrenic (Jones et al 1966j and autistic children (Martineau et al 1989). Using standard deviation to evaluate auditoryevoked-response amplitudes and a signal-to-noise ratio method applied to individual evoked responses to evaluate the variability of evoked responses, we demonstrated the interindividual variability in autistic children (Martineau et al 1992). The present work thoroughly studies mechanisms by comparing, on one hand, the reactivities to unimodal and crossmodal stimuli and, on the other hand, the main neu-
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Table 1. The Composition of the Autistic Group and the Two Control Groups. Chron Age
Devel Age
Verb DQ
N Verb DQ
Groups
n
G
B
M
SEM
M
SEM
M
SEbl
M
SEM
Autistic Normal Retarded
30 30 30
13 13 11
17 17 19
6;11 6;6 6;3
0;6 0;4 0;4
2;9
0;3
42
5
50
5
3;0
0;3
47
6
49
4
n, number of children; G, girls; B, boys; M : mean age in years and months (y; m). Chron Age : chronological age; Devel Age : developmental age; Verb DQ : verbal developmental quotient; N Verb DO : Nonverbal developmental quotient.
rocognitive functions most often disturbed in autism. The aim is to test the hypothesis that the deficit in the ability to form crossmodal associations in autism is linked to a cognitive abnormality. Subjects Thirty autistic subjects (17 boys and 13 girls) ranging in age from 3 years 4 months to 11 years were involved in this study. A mentally retarded group (n = 30) matched the autistic sample on chronological age and developmental age (Table 1). The psychomotor development scale of Brunet and Lezine (1976), a French version of Gesell and Amatruda's scale (1947), was used to determine developmental quotients (DQ). Forty-five percent of autistic children and 55% of mentally retarded children were capable of spoken language. Each child was a patient from the day-care child psychiatry unit of Centre Hospitalier Universitalre Regional TOURS. Each child received an extensive evaluation, including a detailed developmental history, using a questionnaire, a videotaped psychiatric assessment, psychological and linguistic testing, pediatric and neurological examination, and audiological assessment. Examinations were carried out by a professional team consisting of child psychiatrists and child psychologists, language pathologists, a neurologist, social worker, and pediatrician, all expert in dealing with autistic children. A diagnosis of infantile autism was reached only if at least all but one of the members of the team agreed that the child's condition met all the criteria for early infantile autism listed in the DSM III-R ([APA] American Psychiatric Association 1987). These criteria include qualitative impairment in reciprocal and social interaction, qualitative impairment in communication and imaginative activity, and markedly restricted repertoire of activities and interests. Children of the mentally retarded group were mixed in their etiology, but none of these children exhibited withdrawal signs or bizarre responses. They were classified 317.00, 318.00, 318.10, and 318.20 by DSM III-R criteria. All children were in excellent physical health, audiologicaily intact, and none had a history of endocrine and systemic disease. None showed gross neurological disorders or had seizures or pathological electroencephalograms (EEG) with either slow waves or paroxysmal spikes. An evaluation of disturbances affecting the major neurocognitive functions was carried out based on the Behavior Summarized Evalaation scale (BSE, Lelord et al 1981, Bar-
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Table 2. Neurocognitive Functions Attention Unstable attention, easily distracted Perception Abnormal eye contact Bizarre responses to auditory stimuli Autoaggressiveness Association Inappropriate relating to inanimate objects or to doll Disturbances of feeding behavior No attempt to control urine and feces Intention Lack of initiative, poor activity Agitation, restlessness Uses objects in a compulsive and/or ritualistic way Motility Stereotyped sensori-motor activity Bizarre posture and gait Emotion Resistance to change and to frustration Soft anxiety signs Mood difficulties Heteroaggressiveness Instinctual disturbances Sleep disturbances Masturbation Contact Is eager to be alone Ignores people Poor social interaction Communication Does not make an effort to communicate using voice Lack of appropriate facial expressions and gestures Stereotyped vocal and voice utterances, echolalia Regulation Behavioral variability The scores of the BehaviorSummarizedEvaluationscale (Lelordet al 1981; Barthelemyet al 1990)are not classed accordingto the headingsadaptedfromthe DSM-Ill,but accordingto the mainneurocognitivefunctionsmostoftendisturbed in autism.
thelemy 1986), which supplied information on the actual behavior of the child. The content validity, using a principal component factor analysis without and with Varimax rotation and interrater reliability, using the Kappa statistic of the BSE scale have been recently published (Barthelemy et al 1990). ' ~ i s scale is commercialized by the "Etablissements d'Applications Psychotechniques" (France). It consists of 25 items rated on a 5-point scale ranging from never (0) to always (4), and grouped under 10 headings corresponding to the neurocognitive functions most often disturbed in autism (Table 2). Each autistic and mentally retarded child was rated once a week by nurses who knew the children for several months and who had daily contact with them. A group of 30 children with no known neurological or auditory dysfunction was drawn from children in the normal school population, matched to the autistic and mentally retarded samples on chronological age, and used as the normal control group.
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Materials and M e t h c d s Each subject was isolated in a dark, soundproof room and seated in a comfortable armchair beside his usual nurse or his mother. Recordings of the EEG were made from the midline central, or vertex (Cz), the midline frontal (Fz), the midline occipital (Oz), the left (T3) and right (T4) temporal electrode loci of the international 10-20 system. These active electrodes were referred to linked electrodes placed on the earlobes. Subjects were earthed via the forehead and the electrooculogram (EOG) was monitored from supraorbital linked electrodes, using the same references (earlobes). All electrode impedances were less than 5 Kf~. On each trial, the EEG and EOG were amplified by a Minihuit Alvar Polygraph (3dB bandwidth, 0.5-2000 Hz~. The EEG was digitized every 4 msec for a 2.3-see period that began 500 msec prior to stimuli presentation. The presentation of stimuli was stopped whenever the child moved or spoke. All trials contamined by ocular movements were rejected on-line (criteriz~ 100 ~volts). The percentages of rejected trials in the unimodal condition were between 1% and 12% in the normal children, between 1% and 13% in the autistic children, and between 1% and 12% in the mentally retarded children. The percentages of rejected trials in the crossmodal condition were between 1% and 13% in the normal children, between 1% and 15% in the autistic children, and between 1% and 14% in the mentally retarded children. Auditory stimuli were presented through two speakers placed 35 cm directly beside each ear, a flash was positioned 30 cm from the subject's face. Auditory evoked responses (AERs) were recorded during two sessions on 2 consecutive days at the same time of the dav. session 1 included 180 nonrejected trials, session 2 included 120 nonrejected trials. The first day, a weak tone burst (S = 50 dB SPL, 750 Hz, 100-msec duration with 20-msec rise time) was presented alone on the first 60 trials (1 to 60, SI) in order to study unimodal AERs. To study crossmodal association between the auditory and visual stimuli over time, a strong flash of light (L = 1200 lux, 200 I~sec) was then presented 800 msec after S on trials 61 to 180 (SLI, day 1). The second day, the strong flash of light was presented after S on trials I to 120 (SLII, day 2). Intertrial intervals varied randomly between 4 and 12 see. Each averaged auditory evoked response was obtained by averaging 20 auditory evoked responses, using a PDP 11/24 computer. The SD, which was more appropriate than the amplitude to determine the absence or presence of a response and to characterize this response, was computed across time (Callaway 1975) during 250 msec-averaged presound and 250 msec-averaged postsound EEGs (Martineau et al 1987). The ratio of the SD from the 250msec-averaged postsound EEG to 250 msec-averaged presound EEG was chosen as the criterion for determining the presence (if ratio > 1.3, Bruneau et al 1990; Martineau et al 1991) of the averaged evoked response. The SD is known to give a correct estimation of the peak-to-peak amplitude of AER and especially of N I and P2 waves. An electrophysiological scale was utilized to evaluate anomalies of the electrophysiological reactivity (Figure 1). This comprised four headings: the presence of AERs in the unimodal condition, the effect of the repetition of stimuli in the unimodal condition, the presence of AERs in the crossmodal condition, and the effect of the repetition of stimuli in the crossmodal cc,,ldition, scored on a 3-point scale. In the unimodal condition, the AERs were recorded on the four centro-temporo-frontal electrode sites, 60 simple stimuli were given and AERs were averaged by 20 trials. So, 3 averaged AERs can be obtained on 4 sites in the optimal conditions and 3 x 4 = 12
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ANOMALIES IN UNI - MODAL REACTIVITY Presence of AERs Score NbAERst 9112 [5-28 [ 1~4~
[
Effect of repetition ]Score/ 1 ] 2 I I Effect 1>2>3 I--2=3 1 ~r32<3 2>3 1<2<3
ANOMALIES IN CROSS-MODAL REACTIVITt Presence of Oz AERs ScoreI : Ozresponsesand modificationson Cz,Fz,T3,1"4 Score2 : Ozresponsesand no modiflcaqonon Cz,Fz,T3,1"4 Score3 : NoOzresponse Effect of repetition
Figure 1. Electrophysiological scale utilized to evaluate anomalies of the electrophysiological reactivity. Top: the anomalies in the unimodal condition were observed on the four centro-temporo, frontal electrode sites (Cz, T3, T4, Fz). Bottom: the anomalies in the crossmodai condition were observed on the occipital electrode site (Oz) and on the other derivations for the presence, and only on the occipital electrode site for the effect of repetition of stimuli.
I
was the maximum of recorded AERs. Concerning the presence of AERs in the unimodal condition, score 1 was given for a number of AERs between 9 and 12, score 2 for the number between 5 and 8, score 3 for the number between 1 and 4. The repetition of stimuli produced a decrease in AER amplitude in most of the subjects (Bruneau et al 1990): the amplitude of the first AER (Sl) was greater than the second ($2), which was greater itself than the third ($3). Regarding the effect of the repetition of stimuli in the unimodal condition, score 1 was given if SI was greater than $2, which was itself greater than $3, or if S 1 was identical to $2 and $2 greater than $3. Score 2 was given if S 1 was identical to $2 and to $3. Score 3 was given if S 1 or $2 was smaller than $3, or if S 1 was smaller than $2, which was itself smaller than $3. In the crossmodal condition, the appearance (or the increase) of AER was observed in the occipital region when the sound was followed by the flash, and a decrease or an increase of AER amplitude was observed on the other derivations (Martineau et al 1984; Bruneau et al 1990). Concerning the presence of Oz AERs in the crossmodal condition, score 1 was given if an Oz response appeared with a decrease or an increase of AER amplitudes on the other derivations. Score 2 was given if an Oz response appeared without modification of AER amplitudes on the other derivations. Score 3 was given if no modification was observed at Oz site during the crossmodal condition compared to the unimodal condition. In the crossmodal condition, the maximum number of Oz responses recorded was 12 (6 in the first session, 6 in the second session). With regard to the effect of the repetition of stimuli in the crossmodal condition, score 1 was given if the number of present Oz responses was higher than 4. Score 2 was given if the number was between 1 and 3. Score 3 was given if no Oz response was recorded. This scale was rated by two independant raters. Reliability of each heading was tested
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by calculating the Kappa statistic. The evaluation of reliability coefficient was based on guidelines given by Cicchetti and Sparrow (1981): the four headings had excellent reliability (presence of AERs in the unimodal condition: 0.78; effect of the repetition of stimuli in the unimodal condition: 0.79; presence of AERs in the crossmodal condition: 0.79; effect of the repetition of stimuli in the crossmodal condition: 0.81). Frequency comparisons of the scores under each heading using X2, intragroup comparisons using Kruskal-Wallis (1-way analysis variance [ANOVA]), and Mann-Whitney U test were performed. For clinical evaluation, a discriminant analysis was performed using a stepwise variable selection procedure. SPSS subprograms were used. Results
Electrophysiological Evaluation Figure 2 shows the grand average of AERs in the three groups in the unimodal condition S (1-3) and in the crossmodal condition SL (1-6) on the first and second days; Figure 3 shows the ratings of the electrophysiological evaluation.
Anomalies in the Unimodal Reactivity. Significant differences were found concerning the presence of AERs between the three groups (X2 = 21.99, df = 4, p < 0.0001). Fifteen out of the 30 normal children were rated with score 1, 9 with score 2, and 6 with score 3. The same distributions were found in the normal and the mentally retarded children (15 mentally retarded children were rated with score 1, 5 with score 2, 10 with score 3, X2 = 2.14, df = 2, NS). On the contrary, this predominance of score 1 was not found in the autistic children: 1 out of the 30 autistic children were rated with score 1, 10 with score 2, and 19 with score 3 (X2 = 19.06, df = 2, p < 0.001 between autistic and normal children, X2 --- 16.71, df = 2, p < 0.001 between autistic and mentally retarded children). Concerning the repetition of stimuli, significant differences were observed between the three groups (~(2 = 27.22, df = 4, p < 0.001). A decrease of AER amplitudes with the lepetition of stimuli was observed in 19 out of the 30 normal children (score 1), no modification of AER amplitudes was observed in 5 of the normal children, and an increase of AER amplitudes in 6 out of the 30 normal children. The ?ame distributions were found in the normal and the mentally retarded children (17 mentally retarded children were rated with score 1, 7 with score 2, 6 with score 3, ×2 = 0.44, df = 2, NS). This predominance of score 1 was not found in the autistic children: 3 out of the 30 autistic children were rated with score 1, 5 with score 2, and 22 with score 3 (X:' = 20.78, df = 2, p < 0.001 between autistic and normal children, X2 = 19.28, df = 2, p < 0.001 between autistic and mentally retarded children). Anomalies in the Crossmodal Condition. Concerning the presence of Oz AERs, significant differences were observed between the three groups (X2 = 53.69, df = 4, p < 0.001). In all normal children, an Oz response appeared (scores 1 and 2); in almost all autistic children, an Oz response appeared in the crossmodal condition (29 out of the 30 autistic children were scored I or 2, X2 = 0.65, df = 1, NS); in mentally retarded children, no Oz response was recorded in 20 out of the cases scored 3 (×2 = 37.39, df = 2, p < 0.001 between normal and mentally retarded children, X2 = 34.37, df = 2, p < 0.0001 between autistic and mentally retarded children).
Unimodal and Crossmodal Reactivity in Autism
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Normal children (n = 30) S(I-3)
SL(I-6)
02,~,,~
l&.
c ~ ~ ~ ~
,L~'~
~
-
3L(!-6)
_
"~
r ] ~''~
Autisticchildren(n = 30) SOl-S)
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Figure 2. Grand average of AERs in the three groups of children (30 normal, 30 autistic and 30 mentally retarded children) in the uni-modal condition S (1-3) and in the crossmodal SL (1--6) condition on the first and the second days. An Oz response appeared in all normal children (apparent in the waveform on the first and the second days) and in almost all autistic children (apparent principally in the waveform on the second day).
Significant differences were observed with regard to the repetition of crossmodal stimuli (X2 = 71.69, df = 4, p < 0.001). The Oz response was relatively well-maintained with the repetition of stimuli in normal children (23 of the normal children had more than 4 responses). In autistic children, this Oz response was not maintained (20 of the 30 autistic children had less than 3 0 z responses, X 2 = 11.38, df = 2, p < 0.001 between normal and autistic children). No Oz response was recorded in 20 mentally retarded children and less than 3 0 z responses for the 10 others (×2 = 43.53, df = 2, p < 0.001 between
1198
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BIOL PSYCHIATRY 1992;31:! 190-1203
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Figure 3. Electrophysiological evaluation. In the unimodal condition, on the left, normal children (NOR) were mainly rated with score 1 (dotted piles on the left), as were the mentally retarded children (RET). Autistic children (AUT) displayed few AERs with a failure to decrease AER amplitudes during the repetition of stimuli. In the crossmodal condition, on the left, an Oz response appears in normal and autistic children (score 1) while a disappearance or no Oz response was mainly observed in mentally retarded children. This Oz response was maintained in normal children, whereas 67% of autistic childl'en had fewer than 3 0 z responses.
normal and mentally retarded children, X2 = 33.33, df = 2, p < 0.001 between autistic and mentally retarded children).
Functional Evaluation Figure 4 gives the mean of each neurocognitive function in the two groups of pathological children. Autistic children differed from mentally retarded children on Attention (z = 2.29; df = 58; p < 0.02), Perception (z = 6.11; df = 58; p < 0.0001), Association (z = 6.46; df = 58; p < 0.0001), Intention (z = 4.79; df = 58; p < 0.0001), Motility (z = 4.58; df = 58; p < 0.0001), Emotion (z = 2.53; df = 58; p < 0.01), Contact (z = ~.72, df = 58; p < 0.0001), Communication (z = 5.82; df = 58; p < 0.0001) and Regulation (z = 6.78; df = 58; p < 0.0001). They did not differ on Instinctual Disturbances. A discriminant analysis between the two pathological groups was then performed on the ratings of the 10 headings corresponding to the neurocognitive functions most often disturbed in autism. Two variables were sufficient for the discriminant analysis procedure. They entered the linear function in the following order: Contact, Regulation. The ratings
Unimodal and Crossmodal Reactivity in Autism
BIOL PSYCHIATRY 1992;3h1190-1203
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Figure 4. Functional evaluation: mean and SEM of each aeumcognitive function. Autistic children (AUT) differed from mentally retarded children (RET) on each neurocognitive function except on
instinctual disturbances (Inst.). Contact (Cont.) and regulation (Reg.) were sufficient for the discriminant procedure and the ratings of these two functions allowed to correctly classified all the children. Art, Attention; Perc, Perception; Ass•c, Association; Int, Intention; Mot, Motility; Emot,
Emotion; Inst, Instinctual disturbances; Cont, Contact; Comm, Communication; Reg, Regulation.
disturbed in autism• Two variables were sufficient for the discriminant analysis procedure. They entered the linear function in the following order: Contact, Regulation. The ratings of the heading: Contact allowed the accurate classification of 96•7% of children (2 autistic children were not correctly classified). When the heading Regulation was added, the percentage of correctly classified children increased to 100%.
Functional and Electrophysiological Evaluations Kruskai-Wallis nonparametric tests (l-way ANOVA) were performed on the ratings of the 10 neurocognitive functions in order to test differences between children who scored 1, 2, or 3 on each heading of the electrophysiological scale for the two pathological groups• The autistic children having the higher scores on the anomalies of presence of AERs in the unimodai condition were the more disturbed in Association (Kruskal-Wallis test, X2 corrected for ties = 7.42; p = 0.0244). The autistic children having the higher scores on the anomalies of the repetition of stimuli in the unimodal condition were the more disturbed in Attention (X2 corrected for ties = 6.05; p = 0.0451) and Perception (X2 corrected for ties = 6.14; p = 0.0464). The autistic children having the higher scores on the anomalies of the repetition of stimuli in the crossmodal condition were the more disturbed in Attention (X2 corrected for ties = 5.49;p = 0.0190), Perception (X2 corrected for ties: 4.40; p = 0.0358) and Association (X2 corrected for ties = !3.21; p = 0.0003). No significant Kruskal-Wallis test result was found with the other psychological functions. No significant Kruskal-Wallis test result was found in the mentally retarded group.
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Discussion This study shows that the reactivity of autistic children to unimodal and crossmodal stimuli is different from the reactivity of both normal and mentally retarded children. Differences among groups in the frequency distribution of the EEG may account for the evoked response data, but spectral analyses were not available and this can be a limitation of the present study. However, compared with normal children, the autistic children have less well-differentiated auditory evoked responses to unimodal stimuli. This confirms previous studies showing that the number of present evoked responses in autistic children is alwavs weaker than normal (Ornitz et al 1968; Novick et al 1979; Martineau et al 1981, 1987; Friedman et al 1982). Moreover, autistic children differ from normal children i~ she effects of the repetition of simple auditory stimu!i. In normal children, the repetition of simple stimuli produced a decrease in amplitude of the AERs (19 children). Autistic children did not show this decrease and some even showed an increase of AER amplitudes (22 children). This confirms the failure to habituate, largely observed and described in autistic children with electrodermal studies (Palkovitz and Wiesenfeld 1980; James and Barry 1980, 1984; Stevens and Gruzelier 1984; Barry and James 1988) and studies of evoked potentials (Saletu et al 1975). Concerning the reactivity to unimodal stimuli, no difference was observed between the normal and the mentally retarded children: the mentally retarded children had the same number of AERs and the same response to the repetition of unimodal stimuli, with a decrease in amplitudes of AERs, as the normal children. Autistic children differed from mentally retarded children and also from normal children in the unimodal condition. However, in the crossmodal condition, autistic children did not differ from normal children in the presence of crossmodal phenomenon, but differed from them in the effect of the repetition of crossmodal stimuli. Crossmodal associations exist in autistic children, but they are unable to maintain them. In the crossmodal condition, autistic children differed largely from mentally retarded children: very few Oz responses are recorded in mentally retarded children and the repetition of crossmodal stimuli did not allow the observation of Oz AERs. The mentally retarded children differed largely from autistic children in this condition. Regarding disturbances affecting the neurocognitive functions, autistic children differed largely from mentally retarded children on most of the ratings. Only the Instinctual Disturbances were almost rated higher in mentally retarded than in autistic childrea. The tests performed between electrophysiological and functional data showed significant results only in the autistic group. There was no significant result in the mentally retarded group. In the autistic group, the functions Attention and Perception were scored signi',icantly higher in the autistic children showing the higher anomalies in the effect of repelition in unimodal and crossmodal conditions. The autistic children showing the more unstable attention and the more perceptual abnormalities have the greater failure to habituate. This confirms numerous studies performed with electrodermal recordings (James and Barry 1980, 1984; Stevens and Gruzelier 1984; Barry and James 1988) and showing evidem:e of a dysfunction in attentional responses in autistic children. The results obtained between the function Association and the unimodal condition showed that the children more impaired in their association abilities were the children displaying fewer AERs. A highly significant result was found between the function Association and the effect of repetition of crossmodal stimuli but not with the presence of Oz AERs in the crossmodal condition. This showed that autistic children ~ e capable
Unimodal and Crossmodal Reactivity in Autism
BIOL PSYCHIATRY 1992;31:1190-1203
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of crossmodal associations, but the children more clinically disturbed on the Association function were not able to maintain these associations. It seems that autistic children can form crossmodal associations but cannot maintain them. This deficit in sustaining abilities can be related to clinical observations on the cognitive aspects of autism. Adrien (1983) found evidence that autistic children are capable of object permanence, but with irregularities in the object placement. Sigman and Mundy (1987) showed that the sensorimotot skills of autistic children are not delayed relative to normal children of comparable mental age and that they are capable of certain forms of representational thought. In mentally retarded children, hyperresponsiveness to unimodal stimuli was observed with large AERs on all derivations and even on the occipital lead (Figure 2). A decrease of AER amplitudes was observed with the repetition of unimodal stimuli as in normal children. Global inhibition was observed during crossmodal stimuli with a decrease of AER amplitudes on all derivations and disappearance on the occipital lead. It seems that these children "inhibit" the responses to sound when it is followed by the light. It may be possible that the mentally retarded children selected the visual stimuli and persevered in their attention to this stimuli, inhibiting their responses to the auditive stimuli. Mentally retarded children appear to have a limited capacity for information processing. Ellis (1963) proposed that the generally low performance of retarded people is due to a limited capacity for information intake and a more rapid decay of that information over time. It can be suggested that the interstimulus interval between auditive and visual stimuli was too long to allow mentally retarded children to perform crossmodal associations. It would be of great interest to compare the modifications of visual evoked responses to unimodal visual stimuli and to crossmodal visuo-auditory stimuli in these mentally retarded children and to shorten the interstimulus interval in order to determine their ability to perform sensorial associations. In summary, autistic children fail to habituate to repetition of simple unimodal stimuli, can form crossmodal associations, but cannot maintain them. This suggests that a more elementary perceptual abnormality precedes the inability to maintain crossmodal associations in autism. These observations can be related to hypotheses put forward by Ornitz (1983) on the faulty modulation of sensory input and by Lelord (1990) showing that the characteristic disorders of autism are linked with abnormalities in the filtering and the sensorial, emotional, posturomotor regulation, resulting ":.~ genuil~e "brain regulating insufficiences." It seems that the autistic child does not perceive brief, intense stimuli like a door banging or a gunshot, whereas they are intolerant of longer stimuli like the blast of a hooter, the noise of flushing the toilet, or the buzz of a vacuum cleaner. Some of these clinical observations may be related to electrophysiological data such as insufficient responses to the first stimuli or absence of habituation. This research was supported by INSERMU 316 (The nervous systemfrom the foetusto the child: development, circulation and metabolism), R~seau INSERM n. 489 001, Fondation Langlois, CRAMTSn. 2748/88, FRM and CNAM.
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