Auditory associative cortex dysfunction in children with autism: evidence from late auditory evoked potentials (N1 wave–T complex)

Clinical Neurophysiology 110 (1999) 1927±1934 www.elsevier.com/locate/clinph

Auditory associative cortex dysfunction in children with autism: evidence from late auditory evoked potentials (N1 wave±T complex) Nicole Bruneau*, Sylvie Roux, Jean Louis Adrien, Catherine BartheÂleÂmy INSERM Unite 316, Service Universitaire d'Explorations Fonctionnelles et de Neurophysiologie en PeÂdopsychiatrie, 2, Bd TonnelleÂ, 37 044 Tours CeÂdex, France Accepted 2 June 1999

Abstract Objectives: Auditory processing at the cortical level was investigated with late auditory evoked potentials (N1 wave±T complex) in 4±8year-old autistic children with mental retardation and compared to both age-matched normal and mentally retarded children (16 children in each group). Methods: Two negative peaks which occurred in the 80±200 ms latency range were analyzed according to stimulus intensity level (50 to 80 dB SPL): the ®rst culminated at fronto-central sites (N1b) and the second at bitemporal sites (N1c, equivalent to Tb of the T complex). The latter wave was the most prominent and reliable response in normal children at this age. Results: Our results in autistic children indicated abnormalities of this wave with markedly smaller amplitude at bitemporal sites and pronounced peak latency delay (around 20 ms). Moreover, in both reference groups the intensity effect was found on both sides whereas in autistic children it was absent on the left side but present on the right. Conclusion: These ®ndings in autistic children showing very disturbed verbal communication argue for dysfunction in brain areas involved in N1c generation i.e., the auditory associative cortex in the lateral part of the superior temporal gyrus, with more speci®c left side defects when auditory stimulus have to be processed. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Autism; Mental retardation; Children; Late auditory evoked potentials; N1 wave; T complex; Auditory modulation; Stimulus intensity

1. Introduction Autism is a severe developmental disorder characterized by impairment in reciprocal social interactions and verbal and non-verbal communication, and by a restricted repertoire of activities and interests (Rutter and Schopler, 1987). Disordered reaction to sensory input also constitutes a striking aspect of autistic disorder. While all modalities are affected, these abnormalities are particularly evident in the auditory modality (Bergman and Escalona, 1949; Goldfarb, 1963; Ornitz and Ritvo, 1968; Ornitz, 1974, 1989; Hayes and Gordon, 1977; Dahlgren and Gillberg, 1989). Indeed many autistic children seem to be deaf in their early years when in fact they are later diagnosed as autistic (Wing,

* Corresponding author. Tel: 133-2-47-47-47-47 Ext. 4304; fax: 1332-47-47-38-46. E-mail address: [email protected] (N. Bruneau)

1966). This hyporeactivity is apparent in the disregard of both verbal commands and loud sounds. Contrasting to this hyporeactivity are markedly exaggerated reactions to auditory stimuli of both mild and low intensity (Grandin and Scariano, 1986). Although individuals with autism are abnormal in their ability to regulate auditory input, evidence of dysfunction of the systems responsible for such regulation has not been identi®ed. Possible disorders that can affect various levels of central auditory processing can be evaluated by studying auditory evoked potentials (AEPs). Although brainstem AEP abnormalities are present in a higher proportion of autistic children than in normal children, they are not a necessary condition for autism since most autistic children display normal brainstem AEPs (review in Klin, 1993). Middle-latency AEPs representing initial activation of the primary auditory cortex have also been reported to be normal in adults with autism (Courchesne et al., 1985a; Grillon et al., 1989) although no ®ndings have yet been reported on children.

1388-2457/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1388-245 7(99)00149-2

CLINPH 99526

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The present study focuses on the later auditory responses which occur between 80 and 200 ms after stimulus onset. The responses recorded in this latency period have been extensively studied in adults (for reviews, see NaÈaÈtaÈnen and Picton, 1987; Woods, 1995). In fact two negative waves are recorded in this latency period. They differ in both peak latency and scalp topography: the ®rst peak culminates at fronto-central sites at around 100 ms and the second culminates around 30 ms later at bitemporal sites. In adults, the fronto-central peak is very prominent and reliable whereas the temporal peak is of smaller amplitude and less constant. The terminology commonly used is N1b for the ®rst peak and N1c for the second peak (McCallum and Curry, 1980; Woods, 1995); N1c also corresponds to the negative Tb wave of the T complex previously described by Wolpaw and Penry (1975). These waves are particularly interesting because the cerebral regions involved in their generation have been relatively well identi®ed (review in NaÈaÈtaÈnen and Picton, 1987). The fronto-central N1b wave mainly corresponds to activation of generators situated in the supratemporal plane of the auditory cortex (Vaughan and Ritter, 1970); non-speci®c brain regions (Hari et al., 1982; Velasco and Velasco, 1986) involving frontal areas (Giard et al., 1994). The temporal N1c (or Tb) wave originates from sources in the secondary auditory cortex on the lateral aspect of the temporal lobe (Wolpaw and Penry, 1975; Celesia, 1976; Wood and Wolpaw, 1982). The responses obtained in normal 4 to 8 year old children have recently been described in detail and compared to adults' responses (Bruneau et al., 1997; Bruneau and Gomot, 1998). Both peaks culminate later in children than in adults, i.e. 170 ms for N1c and 140 ms for N1b. Moreover, at this age children show a reverse pattern to that of adults: the temporal N1c is very prominent and reliable, whereas the fronto-central N1b is of smaller amplitude and more inconstant and culminates at the frontal site instead of at the vertex as in adults. Data reported in autistic disorder concern only the fronto-central N1 peak i.e. N1b. This wave has been found to be normal in autistic adolescents (Novick et al., 1980) whereas it has been described as reduced in amplitude and without a signi®cant shift in peak latency in autistic adults (Courchesne et al., 1985b). Contradictory results have been reported for the N1b wave in children with autism. This could be due in part to the different paradigms used and to the wide age ranges of the population studied. In an oddball target detection task N1b displayed shorter latency and greater amplitude in children with autism than in normal children at age 6±18 years (Oades et al., 1988), whereas it was reported to be normal in children with autism aged 7±13 years (Kemner et al., 1995) and aged 8±14 years (Lincoln et al., 1995). However, in the latter work N1b was found to be smaller than normal at high intensity levels of stimulation in children with autism, as previously described by Bruneau et al. (1987) at age 3±8

years. Martineau et al. (1992) emphasized the wide variability of the N1b response in patients aged 3.4±11 years compared to controls when sound was delivered alone or paired with light. Data have never been reported concerning N1c in adults or children with autism. However the high reliability of the temporal N1c wave in 4±8 year old normal children and the cortical areas involved in its generation make it a potentially relevant index to evaluate cortical auditory processing in autism. The present study was therefore designed to evaluate the cortical responses to auditory stimuli evoked in the 80±200 ms latency range in children with autism aged 4±8 years. As these children were also mentally retarded, two control groups were studied for comparisons, one comprising mentally retarded children without autistic symptoms and one comprising normal children. Since abnormal behavioral reactivity to auditory stimulation is often reported in autism in relation to the intensity of the sound, the present study considers the changes in cortical auditory responses with varying stimulus intensity.

2. Methods 2.1. Subjects Three groups of 16 children (12 male, 4 female in each group) aged 4±8 years participated in this study: a group of autistic children with mental retardation (AUT) and two control groups comprising mentally retarded children without autistic symptoms (RET) and normal children (NOR). All the patients were diagnosed according to criteria de®ned in The Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. revised: DSM III-R (American Psychiatric Association, 1987). Autistic children displayed severe or mild mental retardation as assessed by the psychomotor development scale of Brunet and LeÂzine (1976), a French adaptation of Gesell and Amatruda's scale (Gesell and Amatruda, 1947): verbal developmental quotients ranged from 12 to 41 (mean ^ SEM: 25 ^ 3) and non-verbal developmental quotients ranged from 24 to 65 (mean: 41 ^ 3). The mentally retarded group (RET) matched the autistic group on gender, chronological age and non-verbal developmental age (from 20 to 65; mean: 43 ^ 4). Their verbal developmental quotients ranged from 13 to 70 (mean: 42 ^ 5). All patients included in this study were recruited from the Child Psychiatry Day-Care Unit of the Centre Hospitalier ReÂgional in Tours. All children were of normal physical development and were in good physical health. They were all audiologically normal as assessed using brainstem auditory evoked potential (BAEP) criteria as previously detailed in Garreau et al. (1984). None had a history of endocrine or systemic disease. None showed neurological

N. Bruneau et al. / Clinical Neurophysiology 110 (1999) 1927±1934

disorders or had seizures or abnormal electroencephalograms (EEG) with either slow waves or epileptiform discharges. A group of normal children (NOR) with no psychological problems was drawn from children in the normal school population and constituted the normal control group. All were right-handed and had normal hearing, also assessed by BAEPs. 2.2. Procedure The conditions were similar to those previously used and detailed in Bruneau et al. (1997). The subjects sat in a comfortable armchair in a dimly lit, sound-insulated room. Children were accompanied by their nurse, their mother or a person known to them. The behavior of each child was monitored by a video system throughout the session. The EEG was recorded from 5 Ag±AgCl cup electrodes (Cz, Fz, Pz, T3, T4) with linked earlobes as reference. Eye movements were recorded from two supraorbital linked electrodes, also referred to linked earlobes. The EEG was sampled on-line at a rate of 250 Hz for 1 s duration (500 ms pre- and post-stimulus). The stimuli comprised 750-Hz tone bursts of 200 ms duration with rise/fall times of 20 ms delivered through two speakers placed 50 cm directly in front of each ear. Each subject received a randomized series of tones of varying intensity. Interstimulus interval varied from 3 to 5 s. All trials contaminated by ocular movements were rejected on-line (criterion 100 mV) and the sequence was then prolonged (the stimuli always being delivered in a pseudo-random order) until a total of 40 non-contaminated trials for each stimulus intensity had been collected. The percentages of rejected (and secondarily compensated for) trials were between 5% and 25% in normal children and between 10% and 35% in patients. Data analysis was performed on auditory evoked potentials recorded at stimulus intensity levels of 50, 60, 70 and 80 dB SPL. The negative peaks occurring during the 80±200 ms period after stimulus onset were measured at each electrode site. Manual scoring using a cursor program was used to

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measure amplitude and latency of the peaks according to the mean of the 500-ms prestimulus baseline. Two peaks were individualized in all children: the ®rst culminated at around 140 ms at fronto-central sites and the second culminated at around 170 ms at temporal sites; they were labeled N1b and N1c, respectively, according to the currently used nomenclature (McCallum and Curry, 1980; Woods, 1995) and were measured (amplitude, latency) at Fz, Cz and Pz for N1b and at T3 and T4 for N1c. 2.3. Data analysis Repeated-measures ANOVAs were performed separately for amplitude and latency data of both the midline N1b peak and the temporal N1c peak. The betweensubjects variable was group (3 levels: AUT, RET, and NOR). The two within-subject variables were site (either at midline for N1b: Fz, Cz and Pz or at both left and right temporal sites for N1c: T3 and T4) and intensity (4 levels: 50, 60, 70, 80 dB SPL). Signi®cant levels were determined using degrees of freedom adjusted by the Geisser±Greenhouse corrections when appropriate, the correction factor (1 ) being reported. Newman±Keuls tests were used for post hoc comparisons. 3. Results Fig. 1 shows the grand average AEPs elicited by 60 dB SPL tones at both midline and temporal sites for NOR, AUT, and RET children. 3.1. N1b 3.1.1. Latency (Table 1) A signi®cant main effect of group was found for N1b peak latency measured at midline electrodes (F…2; 45† ˆ 4:06, P , 0:02) due to longer N1b peak latency for RET than for both AUT and NOR which did not differ. As indicated on Table 1, N1b culminated around 15 ms later for RET at the frontal site. Moreover, the N1b peak latency

Fig. 1. Grand averaged AEPs elicited by 60 dB SPL tones for normal (NOR), autistic (AUT) and mentally retarded (RET) children (16 children in each group).

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Fig. 2. Mean amplitude and SEM of both fronto-central N1b and temporal N1c in normal (NOR), autistic (AUT) and mentally retarded children (RET) as a function of stimulus intensity (50 to 80 dB SPL) (n ˆ 16 in each group).

exhibited a signi®cant effect of electrode (F…2; 90† ˆ 14:41, P , 0:00001, 1 ˆ 0:80) and intensity (F…3; 135† ˆ 5:68, P , 0:001, 1 ˆ 0:81) as well as a signi®cant Intensity £ Electrode interaction (F…6; 270† ˆ 3:26, P , 0:004). The strong effect of electrode was due to an antero-posterior gradient for N1b peak latency (Fz . Cz . Pz) for all 3 groups. The effect of intensity varied according to electrode site; indeed, with increasing intensity level, N1b peak latency decreased at the 3 sites and at all intensity levels except at the frontal site where latency increased at the greatest intensity of 80 dB after decreasing between 50 and 70 dB. 3.1.2. Amplitude (Fig. 2) The amplitude of N1b exhibited signi®cant main effects of group (F…2; 45† ˆ 34:54, P , 0:0001), electrode (F…2; 90† ˆ 14:09, P , 0:0001, 1 ˆ 0:80) and intensity (F…3; 135† ˆ 12:73, P , 0:0001, 1 ˆ 0:85), as well as signi®cant Group £ Electrode interaction (F…4; 90† ˆ 3:09, P , 0:03, 1 ˆ 0:80). Post hoc tests indicated that N1b amplitude was greater for RET than for both AUT and

NOR at the 3 electrode sites. They also indicated that AUT differed from NOR at the frontal site where AUT displayed smaller responses than NOR at all intensity levels. At central sites differences between AUT and NOR were only signi®cant at the lowest level of intensity (50 dB). No between-group difference (AUT/NOR) was found at parietal sites. Moreover, N1b predominates at frontal sites for both NOR and RET. Indeed post hoc tests indicated signi®cant differences (Fz . Pz and Cz $ Pz) at all intensity level for both NOR and RET. In the AUT group the small frontocentral N1b amplitude did not differ from amplitude at the parietal site. The intensity effect was due to increase in amplitude with increasing stimulus intensity which did not differ signi®cantly according to group or electrode. 3.2. N1c 3.2.1. Latency: (Table 1) The overall ANOVA revealed signi®cant main effects for

N. Bruneau et al. / Clinical Neurophysiology 110 (1999) 1927±1934 Table 1 Mean (SEM) peak latency (ms) for N1b and N1c waves measured at midline (Fz, Cz, Pz) and temporal (left:T3; right: T4) sites, respectively, in normal (NOR), autistic (AUT) and mentally retarded children (RET) (n ˆ 16 in each group) a

N1b Fz b Cz Pz N1c T3 c T4

50 dB

60 dB

70 dB

80 dB

NOR AUT RET* NOR AUT RET* NOR AUT RET*

150 (6) 150 (6) 162 (3) 143 (6) 145 (7) 161 (4) 134 (6) 140 (7) 152 (5)

145 (6) 144 (6) 158 (4) 143 (7) 135 (5) 152 (3) 133 (7) 132 (7) 148 (6)

136 (6) 139 (5) 158 (5) 135 (6) 139 (4) 154 (3) 130 (6) 135 (7) 150 (4)

151 (8) 145 (5) 158 (4) 132 (7) 135 (5) 148 (3) 130 (6) 132 (7) 148 (4)

NOR AUT(*) RET NOR AUT(*) RET

176 (3) 193 (6) 178 (5) 176 (3) 197 (5) 178 (6)

168 (3) 187 (6) 177 (4) 169 (5) 187 (6) 173 (5)

163 (3) 180 (6) 171 (5) 167 (3) 183 (6) 167 (5)

170 (3) 179 (6) 169 (4) 167 (5) 183 (6) 164 (4)

a

RET displayed signi®cantly longer N1b peak latency at midline sites whereas AUT displayed signi®cantly longer N1c peak latency at temporal sites. b N1b-Midline sites: *overall ANOVA (F…2; 45† ˆ 4:06; P , 0:02) RET . AUT and RET . NOR (post hoc tests signi®cant). c N1c-Temporal sites: (*)overall ANOVA (F…2; 45† ˆ 17:5; P , 0:0001) AUT . RET and AUT . NOR (post hoc tests signi®cant).

group (F…2; 45† ˆ 4:75, P , 0:01) and intensity (F…3; 135† ˆ 21:61, P , 0:0001, 1 ˆ 0:82). The group effect was due to longer N1c peak latency for AUT than for both NOR and RET, which did not differ. As indicated by the mean values in Table 1, the N1c peak latency was 15 to 20 ms later (depending on stimulus intensity) for AUT than for both NOR and RET. The intensity effect was due to decrease in latency with increasing stimulus intensity at both temporal sites for all 3 groups. 3.2.2. Amplitude (Fig. 2) The overall ANOVA performed on N1c amplitude revealed a main effect for group (F…2; 45† ˆ 17:53, P , 0:0001) and intensity (F…3; 135† ˆ 30:59, P , 0.0001, 1 ˆ 0:79). The Group £ Intensity interaction was signi®cant (F…6; 135† ˆ 4:93, P , 0:0004, 1 ˆ 0:79). Post hoc tests indicated that the group effect was mainly due to smaller temporal N1c for AUT than for both NOR and RET on both sides and for all intensity levels. The intensity effect varied according to group. With increasing stimulus intensity, the amplitude displayed a greater increase for RET than for AUT and for RET than for NOR (Group £ Intensity interaction F…3; 90† ˆ 4:37, P , 0:007, 1 ˆ 0:73 and F…3; 90† ˆ 8:35; P , 0:0001, 1 ˆ 0:87, respectively). Comparison between NOR and AUT indicated a signi®cant Group £ Electrode £ Intensity interaction (F…3; 90† ˆ 3:02, P , 0:05). Between-group

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comparison performed on each side separately indicated signi®cant differences for intensity effect on the left side (signi®cant Group £ Intensity interaction: (F…3; 90† ˆ 3.36, P , 0:04, 1 ˆ 0:78); indeed at T3, the amplitude of the left temporal response did not vary with intensity for AUT (F…3; 45† ˆ 2:39, not signi®cant) whereas it increased with increasing intensity for NOR (F…3; 45† ˆ 6:96, P , 0:0006). On the right side, the effect of stimulus intensity (F…3; 90† ˆ 6:71, P , 0:0004, 1 ˆ 0:88) was similar for both AUT and NOR (Group £ Electrode interaction: F…3; 90† ˆ 0:30, not signi®cant). 4. Discussion The late auditory evoked potentials recorded in 4- to 8year-old children were found different in AUT children compared to both NOR and RET children. Concerning the N1b wave recorded at midline sites, differences between AUT and NOR children are localized at the frontal electrode where N1b of AUT children was of smaller amplitude without latency shift. The slight predominance of N1b at the frontal site in normal children compared to the central predominance in adults has previously been discussed (Bruneau et al., 1997). The hypothesis proposed for this frontal shift is that the temporal generators situated in the supra-temporal cortex responsible for N1b have a different orientation in young children than in adults. This hypothesis was con®rmed by our results from a scalp potential distribution study of N1b in children (Bruneau and Gomot, 1998). Smaller N1b peak amplitude found in the AUT group could therefore correspond to different orientations of these temporal generators (indeed despite their normal head circumference, abnormal macroscopic features of the cortical areas involved cannot be excluded) and/or abnormal activation of these generators. The possibility of abnormal functioning of non-speci®c areas and/or frontal areas cannot be excluded since they are also involved in the generation of the N1b wave in adults (Giard et al., 1994) but have not yet been demonstrated in children. Responses of the RET group mainly differed from both other groups at midline sites since they showed signi®cantly greater amplitude and longer latency at all 3 sites and for all intensity levels. Moreover, RET displayed a clear fronto-central gradient for both amplitude and latency (Fz . Cz . Pz). Since the younger the child the greater the frontal predominance (Bruneau et al., 1997), the pattern shown by the RET group therefore corresponded to that of younger children. Moreover, in normal children, the younger the child, the greater the N1b peak latency, due to the immaturity of mediating structures (different level of myelination, different neurotransmitter activity, etc.). The longer N1b peak latency found in the RET group could therefore indicate a maturational delay of the cortical structures involved in the generation of N1b wave. The pattern

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of the RET group at midline sites could also indicate that components involved in N1b generation are different from those involved in the NOR group. Further studies using topographical analyses are needed to clarify this. The main differences between AUT and both NOR and RET groups concerned the temporal N1c wave; these differences are prominent at bitemporal sites where the N1c wave of the AUT group displayed smaller amplitude and longer latency than the N1c wave of both NOR and RET groups. Several reports have suggested that the secondary auditory cortex on the lateral aspect of the superior temporal gyrus is involved in the generation of these temporal waves. This derives from recordings from cortical surface in man (Celesia, 1976), from scalp-distribution analysis (Wood and Wolpaw, 1982) and from spatio-temporal dipole model analysis of scalp-recorded AEP activity (Scherg and Von Cramon, 1985, 1986). The pronounced delayed peak latency of temporal N1c could be interpreted as re¯ecting slower transmission of information in neuronal pathways and/or in synaptic connections in the secondary auditory cortex in autism. The lengthening of the temporal N1c peak in AUT children without a shift in N1b peak latency and the reverse for RET might indicate that the cortical activating processes involved in the generation of these two waves are parallel rather than sequential. This hypothesis will have to be considered in further studies performed to elucidate the different cortical stages of auditory processing in humans. No such electrophysiological data concerning the temporal N1c wave have previously been reported in autism. Indeed, as emphasized above, the data reported concerned only N1b. Similar bitemporal N1c abnormalities (attenuated amplitude and delayed peak latency) were recently reported in non-autistic language-impaired children (Tonnquist-Uhlen, 1996; these authors referred to Tb of T-complex in their study corresponding to N1c in the present work). Although autism and language impairment represent distinct entities, their electrophysiological similarities may point to certain common pathophysiological mechanisms. However further studies are needed before concluding that abnormalities found in both groups of children correspond to similar cerebral dysfunctioning. Our electrophysiological ®ndings might be related to those described with functional brain imaging. Chugani et al. (1996) individualized a subgroup of infants with spasms, all having in common a particular metabolic pattern consisting of bitemporal lobe hypometabolism assessed by PET. The clinical prospective follow up study indicated that these children became autistic and displayed severely impaired verbal and non-verbal communication. A bitemporal hypoperfusion was also observed with PET in 16 idiopathic children with autism (mean age: 8 ^ 2:6 years) (Zilbovicius et al., 1998). Our present results in children with autism also indicate inter-hemispheric differences when considering the effect of varying stimulus intensity. Such effects on temporal N1c

have previously been reported both in 4- to 8-year-old normal children (Bruneau et al., 1997) and in adults (Connolly, 1993). Indeed, N1c peak amplitude increased with increasing stimulus intensity at both temporal sites in the NOR group (with greater increase on the left side) and in the RET group (symmetric effect). This effect was present on the right side but non signi®cant on the left side in the AUT group. At the highest level of 80 dB SPL the activation of the secondary auditory cortex as indexed by N1c amplitude was greater on the left than on the right side in normal children whereas the reverse was found in autistic children (see Fig. 2). This is in agreement with previous data obtained by SPECT on 5±11 year old autistic children after activation by repeated 80 dB SPL tone stimulation (Garreau et al., 1994). Posterior associative temporal areas were found to be activated on the left side in normal children and on the right side in autistic children. Our results are also in accordance with other data reporting a right hemisphere dominance in the processing of verbal and non-verbal auditory stimuli by autistic subjects. Such evidence derives from dichotic listening studies (Prior and Bradshaw, 1979), neuropsychological testing (Hoffmann and Prior, 1982), electrophysiological studies using EEG (Small, 1975), auditory responses during sleep (Tanguay et al., 1976), auditory responses to verbal stimulation (Dawson et al., 1982, 1988) and cerebral blood ¯ow studies (Bruneau et al., 1992). These results argue for a reorganization of the respective roles of the left and right hemispheres for auditory information processing during early brain development rather than dysfunction of the left hemisphere alone. Further studies are needed for better understanding of N1 wave abnormalities in autism. The comparison between autistic children with poor and better language abilities will be valuable; more informative electrophysiological methods such as scalp potentials and scalp current density distribution of auditory responses are needed to clarify the temporal dysfunctions proposed from the present electrophysiological results. Acknowledgements This study was supported by INSERM U316 `The nervous system from the foetus to the child' (Pr Pourcelot), INSERM network no. 4R002B, and France Telecom. References American Psychiatric Association. Diagnostic and statistical manual for mental disorders. 3rd revised edition, American Psychiatry Press, 1987. Bergman P, Escalona SK. Unusual sensitivities in very young children. Psychoanal Study Child 1949;3-4:333±352. Bruneau N, Gomot M. Auditory evoked potentials (N1 wave) as indices of cortical development throughout childhood. In: Garreau B, editor.

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