Interstimulus interval and auditory event-related potentials in children: evidence for multiple generators

Electroencephalography and clinical Neurophysiology 108 (1998) 345–354

Interstimulus interval and auditory event-related potentials in children: evidence for multiple generators R. Cˇeponiene˙*, M. Cheour, R. Na¨a¨ta¨nen Cognitive Brain Research Unit, Department of Psychology, P.O. Box 13, 00014-FIN, University of Helsinki, Helsinki, Finland Accepted for publication: 29 September 1997

Abstract In the present study, the component structure of auditory event-related potentials (ERP) was studied in children of 7–9 years old by presenting stimuli with different interstimulus intervals (ISI). A short-term auditory sensory memory, as reflected by ISI effects on ERPs, was also studied. Auditory ERPs were recorded to brief unattended 1000 Hz frequent, ‘standard’ and 1100 Hz rare, ‘deviant’ (probability 0.1) tone stimuli with ISIs of 350, 700 and 1400 ms (in separate blocks). With the 350 ms-ISI, the ERP waveform to the standard stimulus consisted of P100-N250 peaks. With the two longer ISIs, in addition, the frontocentral N160 and N460 peaks were observed. Results suggested that N160, found with the longer ISIs, is a correlate of the adult auditory N1. In difference waves, obtained by subtracting ERP to standard stimuli from ERP to deviant stimuli, two negativities were revealed. The first was the mismatch negativity (MMN), which is elicited by any discriminable change in repetitive auditory input. The MMN data suggested that neural traces of auditory sensory memory lasted for at least 1400 ms, probably considerably longer, as no MMN attenuation was found across the ISIs used. The second, later negativity was similar to MMN in all aspects, except for the scalp distribution, which was posterior to that of the MMN.  1998 Elsevier Science Ireland Ltd. All rights reserved Keywords: Auditory event-related potentials (ERP); Mismatch negativity (MMN); Late difference negativity (LDN); Interstimulus interval (ISI); Auditory sensory memory; Children

1. Introduction Auditory event-related potentials (ERP) change dramatically from infancy to adolescence. These changes, however, do not consist of a simple reduction of ERP latencies due to the ongoing myelinization or amplitude decrease due to the synaptic loss (Courchesne, 1990). They reflect complex processes of sculpturing the efficient neural networks for higher stimulus-specificity, automaticity of information processing, maturation of adaptive and attention-related processes, emerging formation of associations, learning and memory. These cause profound changes in ERP component-structure, resulting in changing ERP waveform during the development. In adults, simple unattended auditory stimulus elicit P1-

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0168-5597/98/$19.00  1998 Elsevier Science Ireland Ltd. All rights reserved PII S0168-5597 (97 )0 0081-6

N1-P2 waves. The auditory N1 (‘vertex’ potential) was regarded as a modality-nonspecific response in the early ERP studies (Walter, 1964). Later it was found that the N1 wave has multiple generators, most of them residing in the temporal lobe (Vaughan and Ritter, 1970; Woods, 1995; for a review, see Na¨a¨ta¨nen and Picton, 1987). According to Na¨a¨ta¨nen and Picton, 1987, there are 3 obligatory components of the auditory N1: component 1 is stimulusspecific and is thought to be involved in the short-term neural sensory-memory processes. Component 2 is largest in temporal recordings and its generator is radially oriented (Wolpaw and Penry, 1975). Component 3 has a long refractory period, well beyond 10 s, is vigorous when elicited, and has a scalp topography, posterior to that of component 1. Evidence for this component was provided by Hari et al. (1982) who recorded a negativity which continued to increase only in central areas when the ISI was prolonged up to 8 and 16 s. This component is regarded as nonspecific, serving transient CNS arousal and, thus, facilitation of sti-

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mulus-related neural processes. In particular, components 1 and 3 were assumed to be related to the orienting response and to be responsible for the most of N1 attenuation at short vs. very long ISIs (also see Imada et al., 1997). In children, however, data addressing the auditory ERP component structure and ISI effects are very scarce. ERP peaks, commonly found in children, are the P85-120 and N200-240 (Courchesne, 1990; Cse´pe et al., 1992; Korpilahti and Lang, 1994). However, they do not correspond to the adult P50-N100-P200 in terms of a latency/polarity. The equivalents of the adult auditory ERP components in children are unclear. Some authors name the negativity at 200– 250 ms the N1 (Kurzberg et al., 1995), while others call it N2, regarding it as different from the adult auditory N1 wave (Cse´pe, 1995), which is thought to emerge only at the age of 9–10 years (Cse´pe et al., 1992). In contrast, Korpilahti et al. (1996b) suggested that the N1 and N250 peaks of their study with children might represent two subcomponents of the auditory N1 wave. Recently, several children studies have reported a more complex ERP waveform in response to tone stimuli, presented with long ISIs. In their magnetoencephalographic (MEG) recordings, Paetau et al. (1995) found an early negative peak at about 100–230 ms, but in young children (3–5 years) it was present only with the longest ISI used (they were 0.9, 1.2 and 2.4 s). In addition to their N260, Neville et al. (1993) observed a negative wave, peaking at 140 ms, and a late negativity, peaking at 440 ms, with 1- and 2-s ISIs in 9-year-old children. Similarly, Pa¨a¨kko¨nen et al. (1996) found a late negative component, which peaked at 400–800 ms and was prominent in the response to the first stimulus, but was absent already in the ERP to the second stimulus in a sequence. In contrast to above mentioned, Korpilahti et al. (1996b) found a very small early negativity with a slow stimulation rate (ISI 1500 ms) in 7–9-year-old children. The N1, as well as the N250 peak of their study, decreased in amplitude at their long (1500 ms), compared with short (500 ms), ISI. These results are contradictory to adult data on ISI effects on exogenous ERPs. As most other children studies have employed only one ISI, a direct comparison of ERPs recorded at different ISIs is not possible. One of the issues, addressed in the present study, is whether the previously reported differences in children auditory ERPs could be, at least partially, attributed to differences in the ISIs employed. The ISI has a crucial effect also on the auditory-change specific ERP component, the mismatch negativity (MMN) (Na¨a¨ta¨nen et al., 1987a; Bo¨tther-Gandor and Ullsperger, 1992; Sams et al., 1993). The MMN is elicited by a discriminable change in any physical feature of a frequently presented stimulus. It is considered to represent an automatic neuronal change-detection process, occurring when a physically different and rare stimulus (‘deviant’) encounters a well-established, recent neural representation of a frequent (‘standard’) stimulus (Na¨a¨ta¨nen et al., 1978; Na¨a¨ta¨nen, 1992; Cowan et al., 1993; Tiitinen et al., 1994). The enhan-

cing effect of short ISIs on the MMN amplitude, shown in adults, is assumed to be due to a stronger neural memory trace for the standard stimulus with faster stimulation (Na¨a¨ta¨nen, 1992). Prolonging the ISI in the sequences of standard and deviant stimuli gives an estimate of the shortterm sensory memory duration for the standard stimulus, as MMN cannot be elicited after the neural memory trace for the standard stimulus has decayed to a certain degree (Na¨a¨ta¨nen et al., 1987a; Imada et al., 1993). The longest ISI, at which MMN has been elicited in adults, is 10 s. (Sams et al., 1993). A similar estimate in children is unknown. Several studies have reported a prominent MMN in children (Cse´pe et al., 1992; Kraus et al., 1993; Korpilahti and Lang, 1994; Cse´pe, 1995). Unlike the other ERP components, the MMN is relatively mature at the age of 5–7 years and even earlier (Cse´pe, 1995). Response of this kind was found in newborns (Alho et al., 1990b; Cheour-Luhtanen et al., 1995) and even in pre-term infants (Cheour-Luhtanen et al., 1996). MMN enables one to test the processing of auditory sensory and phonetic discrimination at the cortical level. Such features as automaticity and high stimulus-specificity render MMN an excellent tool to test hearing and speech disorders (Na¨a¨ta¨nen and Alho, 1995). It was suggested that at fast stimulus rates the subtle auditory discrimination deficits might interfere with perception along the altered dimension, which may not happen with low auditory input rates, however (Reed, 1989). This phenomenon may play a role in speech and language disabilities, as rapid temporal dynamics are characteristic of human speech. Namely, several studies have reported reduced performance in auditory (Neville et al., 1993) or phonological (Mody et al., 1997) discrimination with fast stimulation in language/reading impaired children. In contrast, studying MMN with long ISIs, the duration of auditory sensory memory was found to be shorter in CATCH patients (suffering from cognitive, speech, and language deficits), compared with that in healthy children (Cheour et al., 1997). In this context, a clarification of ISI effects on the MMN in healthy children is very important. Nevertheless, the only ERP study addressing this issue is that of Korpilahti et al. (1996b). These authors reported an inverse relationship between the ISI and the MMN amplitude at the age of 5–6 vs. 7–9 years: at short ISIs the MMN was larger in amplitude in younger, but smaller in elder children. This is in contrast with adult data, in which the MMN amplitude is larger at faster stimulation rates. Furthermore, Korpilahti et al. (1996a) reported a second difference negativity, a ‘late MMN’ (lMMN), peaking over 350 ms after stimulus onset. As lMMN was significantly larger for deviant word than to tone stimuli, it was suggested to represent, in addition to phonological discrimination, a ‘more cognitive’ process, operating within a realm of a ‘mental lexicon’. In the present study, we tested whether ISI effects on MMN, found by Korpilahti et al. in 7–9-year-old children, are replicable, and whether a late

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difference negativity could be reliably elicited by sine tones as the stimuli. Concisely, the aims of the present study were to determine the effects of systematic ISI prolongation on (1) the exogenous components of auditory ERPs; (2) the endogenous discriminative potential, MMN, in healthy 7–9-year-old children.

2. Materials and methods 2.1. Subjects Fifteen healthy, 7–9-year-old children with normal hearing originally participated in the study. The data recorded from 4 of them were excluded from further analysis because of the extensive contamination by movement artifacts; in one case the alpha rhythm was seen in the average waveform, obscuring ERPs. The mean age of the remaining 10 subjects (5 boys) was 8 years 1 month, range being 7 years 3 months–9 years 4 months. The control group consisted of 7 children (mean age 8 years 2 months, range 7 years 2 months–9 years 5 months; 4 boys). Informed consents to participate in the experiment were obtained from subjects, their parents and principals of their schools.

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self-chosen soundless cartoons. They were asked to concentrate on the video and not to pay attention to sounds. During experiments the subjects were visually monitored. The EEG was recorded in an electrically shielded and sound dampened chamber. The duration of the experiment was 1.5 h. 2.3. EEG recording and averaging The EEG (bandpass 0.5–30 Hz) was recorded using a Neuroscan PC-3.0 based system. Silver/silver chloride electrodes were placed at the scalp sites F3, F4, C3, C4, P3, P4, T3, and T4, according to the International 10–20 System. Eye movements were monitored with two electrodes—one below and one at the outer corner of the right eye. The righthemisphere electrodes were referred to the right mastoid and the left-hemisphere electrodes to the left mastoid. This was chosen in order to avoid lateral bias that is possible when one-side reference is used. EEG epochs of 850 ms, including a 50 ms pre-stimulus interval, were averaged off-line at a 250 Hz sampling rate. Epochs, contaminated by artifacts of eye or body movements, blinks, or peak to peak deflections exceeding 150 mV in any channel were automatically omitted from averaging, as were the first 3 epochs in each block. The data included an average of 120–145 responses for the deviant stimulus for each subject.

2.2. Stimuli and procedure 2.4. Data analysis Auditory stimuli were frequent, ‘standard’ sinusoidal tones of 1000 Hz and rare, ‘deviant’ tones of 1100 Hz (probabilities 0.9 and 0.1, respectively). Stimuli were produced and delivered by the NeuroStim equipment. They were presented through two loudspeakers, each placed at 45° to the right and left from the sagittal plane in front of the subject at the distance of 90 cm from his/her head. Subjects heard stimuli as coming from the midline space. Stimulus intensity was 75 dB SPL at the subject’s head, duration - 100 ms, including rise and fall times of 10 ms. Stimuli were presented in blocks with three within-block constant ISIs (offset to onset): 350, 700 and 1400 ms (‘short’, ‘middle’, and ‘long’, respectively). Each block contained 500 stimuli. Three blocks with each ISI were presented. The different blocks were administered in a random order. The results of the main experiment lead us to run two control conditions: (1) the oddball condition with the 2000-ms ISI, with the purpose to check whether the ISI effects found in the main conditions would enhance with this, longer ISI, and (2) the Deviants-Alone condition, in which deviant stimuli occurred with the same temporal intervals as with the short ISI but without intervening standards (mean ISI 4393 ms), to demonstrate the absence of the MMN component in response to stimulation with only one type of stimulus. An additional aim was to investigate the effects of a very long ISI on the exogenous ERP components. Children were sitting in a reclining chair and watching

Latencies of separate ERP peaks were measured in each subject’s grand-average waveform at the frontal electrode sites, where the peaks were largest and most distinct, in the latency periods, defined by the distributions of those peaks in all subjects’ grand-average waveforms. Latencies of peaks from F3 and F4 electrodes were used for the leftand right-hemisphere calculations, respectively. The latency windows for mean amplitude calculations were centred around them. The mean amplitudes were calculated over the latency window of 50 ms for all peaks of interest, with the exception of a 10 ms latency window for the N160 peak due to its short duration. Measurements were made with reference to the 50 ms prestimulus baseline. Latencies of ERP peaks, obtained over temporal areas, were measured from T3- and T4- electrode recordings and data were analysed separately. The difference waves for the MMN component analysis were obtained by subtracting ERPs to standard tones from those to deviant tones. The presence of peak/component was tested using twotailed t tests. Comparisons of peak/component amplitude with different ISI-conditions and scalp distributions of MMN vs. LDN were made with two-way ANOVA (ISI/ electrode or component/electrode) for repeated measures (BMDP 2V program). The Greenhouse-Geisser test was applied when appropriate. For the scalp-distribution comparison, data were scaled by the corresponding vector length, according to McCarthy and Wood (1985): the

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Fig. 1. ERPs to 1000 Hz ‘standard’ stimuli with different ISIs, in a control situation of 2000 ms ISI and to Deviants-Alone. An emergence and separation of the N160 and N460 peaks occurred with ISI lengthening.

mean amplitude at each electrode site was divided by the square root of the sum of the squares of the mean amplitude values at all electrode sites in comparison. The procedure was performed separately for each subject. Thereafter the data were subjected to statistical analysis. The data set consisted of measurements from the left and right paramedian line electrodes.

3. Results 3.1. Responses to standard stimuli The ERP to the 1000 Hz standard stimuli consisted of the frontocentrally dominant P100-N160-N250-N460 peaks. However, the ISI effects were considerable and differential for separate peaks (Fig. 1). In the short-ISI condition, only

the P100 and N250 deflections were found. The most salient transformation that occurred with the ISI prolongation was the separation from the N250 and the enhancement of a clear negative peak with the maximum at around 160 ms. It was the largest peak of the ERP curve with the longest ISI (4393 ms, Deviants-Alone condition). The N460 was clearly present with the middle and longest ISIs. The P100 peak was distinct with all ISIs, decreasing in amplitude with ISI prolongation up to the 2000-ms ISI condition (Table 1, Fig. 1). The amplitude decrease was statistically significant at long vs. middle ISIs (t(1,9) = 13.79, P , 0.005). The latency of P100 was not affected by the ISI length (Table 2). The N160 deflection in the short ISI condition was fused with the largest peak of the ERP - the N250, and was seen only as a minor protuberance at its upgoing limb. With the longest ISI, the N160 was clearly separated from the N250 peak, forming a distinct peak at the latency of 160 ms and being predominant over the frontocentral areas. Its amplitude significantly increased with the 1400-ms ISI compared to the 700-ms ISI (F(1,8) = 10.93, P , 0.02). In the 2000and 4393-ms ISI conditions the N160 continued to increase in amplitude. Being not detectable in the short-ISI recordings, with the 4393-ms ISI of the Deviants-Alone condition the N160 became a largest peak of the ERP waveform. The peak latency of N160 significantly decreased with ISI lengthening (F(2,16) = 6.17, P , 0.01). The N250 peak was of considerable size with all ISIs (Table 1) and in general tended to increase in amplitude with ISI lengthening, though rather moderately. An exception was the 1400-ms ISI condition, in which the N250 amplitude tended to be smaller than in the 700-ms ISI condition. Neither the amplitude nor latency of the N250 peak did change reliably as a function of the ISI (Table 2). The N460 peak formed a third negative peak of the ERP to standard stimuli. It was of a small amplitude in short-ISI recordings, not significantly different from 0 mV (Table 1), but grew significantly larger in the middle- (F(1,9) = 6.82, P , 0.03) and long- (F(1,9) = 8.20, P , 0.02) ISI conditions with a clear frontocentral predominance (the main effect for electrode ,0.01). The peak latency of the N460 peak tended to increase with longer ISIs, but this effect did not reach statistical significance (F(2,18) = 3.37, P , 0.057), (Table 2). The morphology of the ERP waveform to the standard stimulus at the temporal leads was different from that at the

Table 1 Mean amplitudes ( ± SD) of ERP peaks at the F4 electrode with all ISIs ISI (ms)

P100

N160

N250

N460

MMN

LDN

350 700 1400

5.17 ± 2.48 3.71 ± 1.1 2.44 ± 1.3***

– −2.65 ± 2.1 −4.52 ± 3.0**

−6.10 ± 1.6 −8.37 ± 3.9 −7.60 ± 5.4

−0.32 ± 1.4 −2.38 ± 2.9* −3.84 ± 4.1**

−5.10 ± 3.7 −4.00 ± 2.4 −3.43 ± 3.2

−5.17 ± 3.2 −3.66 ± 2.4 −3.94 ± 2.6

*P , 0.03; **P , 0.02; ***P , 0.005. The probability level indicates the difference in amplitude, compared with the previous, shorter, ISI.

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Table 2 Mean latencies ( ± SD) of ERP peaks at the F4 electrode with all ISIs ISI (ms)

P100

N160

N250

N460

MMN

LDN

350 700 1400 ISI difference

106 ± 7.6 98 ± 7.8 95 ± 8.7 n.s.

– 164 ± 16 156 ± 14 P , 0.02

248 ± 13 243 ± 13 246 ± 14 n.s.

374 ± 51 388 ± 70 419 ± 52 P , 0.06

220 ± 49 225 ± 46 230 ± 40 n.s.

514 ± 61 487 ± 58 544 ± 53 n.s.

parasagittal locations. The main peaks were P100/130– N190 (Fig. 2). The P100/130 was shallow and decreased in amplitude with longer ISIs. The main deflection of the temporal ERP was the N190 negativity, peaking at around 190 ms, latency of which decreased from short to longer ISIs: 199 ± 18 ms for the short ISI vs. 190 ± 16 ms for the middle ISI (F(1,9) = 8.28, P , 0.02), and 182 ± 23 ms for the long ISI (n.s.). Its amplitude steadily increased as the ISI was prolonged: −1.19 ± 0.85 mV, −2.27 ± 1.37 mV and −3.40 ± 2.19 mV, respectively (for the short vs. middle ISI F(1,9) = 5.88, P , 0.05; for the middle vs. long ISI F(1,9) = 15.35, P , 0.005). In the control recordings, the N190 had a sharply-defined waveform, its mean amplitude being −5.26 mV with the 2000 ms ISI and −7.49 mV in the Deviants-Alone condition. The negativity at around 480 ms was also recorded, although it was not well-defined and of a small amplitude with ISIs shorter than that in the Deviants-Alone condition. In fact, only in the latter condition it was clearly present. A comparison of temporal and frontal ERPs revealed two main findings (Fig. 2). Firstly, although the waveshape and ISI dependence of the temporal N190 corresponded to that of the frontocentral N160 peak, the temporal N190 peaked 26–30 ms later (F(1,9) = 9.09 and 8.24, P , 0.02 for the middle and long ISIs). Secondly, no clear negativity was observed at the latency of the N250 peak at the temporal electrode sites. The ERP curve rather tended to invert polarity at 250–350 ms from stimulus onset. 3.2. Responses to deviant stimuli The response to deviant stimuli showed a similar structure and dependence on the ISI, as did the response to standards (Fig. 3). The P100 amplitude was decreased as the ISI was prolonged. The N160, obtained with the middle and long ISIs, was seen only in central and parietal recordings. The amplitude of the N250 peak increased from the short to the middle ISI, but was slightly decreased from the middle to the long ISI. The N460 peak, however, was large with all ISIs and showed a systematic increase in amplitude when ISIs were longer, with the amplitude maximum over the frontal areas. 3.3. Difference negativities The difference waves revealed two prominent negative components (Figs. 3 and 4). The first was the mismatch

negativity (MMN), and for the second we use term the late difference negativity (LDN). MMN. The MMN component was distinct and statistically significant at all ISIs at all parasagittal leads, except the parietal electrode sites with the middle ISI. It was predominant in frontal recordings (Fig. 4). The MMN amplitude tended to be larger over the right hemisphere, although this difference did not reach statistically significant levels. The ISI effects on MMN amplitude were not uniform. The MMN was larger with the short than with the middle ISI, but the amplitude difference was not statistically significant (Table 1). A more complex picture was displayed by the long-ISI recordings. At the frontal electrode sites the MMN had a tendency to further diminish, but at the central and parietal sites it was larger than both in the short and middle ISIs (F(1,9) = 6.81, P , 0.03). The mean peak latency of MMN tended to increase from the short to the middle and long ISIs (220, 225, and 230 ms, respectively, at the F4 electrode, n.s.). Inspection of the difference waves, superimposed on the waveforms of ERP to standard stimuli, revealed that MMN peaked later than N160, but earlier than the N250 peak, with all stimulation rates. The difference between the MMN and N250 peak latencies was significant for the short ISI (28 ms, F(1,9) = 5.1, P , 0.05), close to significance for the middle ISI (18 ms, F(1,9) = 4.62, P , 0.06), but was not statistically significant in the long-ISI condition (16 ms). LDN. The second negative component peaked at 400– 500 ms in the short, 400–550 ms in the middle and 460–560 ms in the long ISI conditions (Figs. 3 and 4). With the short ISI, however, in some subjects it could be overlapped by the

Fig. 2. Right frontal (F4) and temporal (T4) recordings superimposed in the 1400 and 2000 ms ISIs conditions. The temporal N190 peaked later than the frontocentral N160 peak. The N250 peak tended to invert polarity over temporal areas.

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grew larger (Fig. 1). Both difference negativities, however, decreased in amplitude (Fig. 3). In addition, the difference waves of this condition revealed a frontocentrally dominant P3a component (Fig. 5, top). 2. The ERP waveform, elicited by Deviants-Alone, was of the same structure, as of the ERPs to standard stimuli with ISIs of 1400 and 2000 ms - the P100-N160-N250N460 complex. The largest peak now, however, could be found at 160 ms (Fig. 1). Its amplitude was as large as −11.17 mV at F4 electrode. Nevertheless, ERPs to Deviants-Alone were more positive than ERPs to deviant stimuli in the oddball paradigm with the 350-ms ISI at the latency range of 200–250 ms, typical for the MMN in the present study (Fig. 5, bottom). 4. Discussion 4.1. Responses to standard stimuli

Fig. 3. ERPs to 1000 ‘standard’ and 1100 ‘deviant’ stimuli and difference waves at different ISIs. A P3a wave was elicited with the 2000 ms ISI, as can be seen in the difference wave.

ERP to the next stimulus. A second peak of the LDN, peaking after 500 ms and seen only with the short ISI, was caused by the MMN to the consecutive stimulus. Therefore, measurements with this ISI were constrained within limits of 500 ms. The LDN partially overlapped the N460 peak of the obligatory response, but peaked considerably later (Table 2). The LDN amplitude was highly significantly different from 0 mV at the frontal and central leads with all ISIs (P , 0.001–0.05) and at the parietal sites with the long ISI. The LDN was maximal at the frontal electrode sites with all stimulation rates, and only there the diminishing effect of longer ISIs was visible. However, the LDN amplitude differences across the conditions did not reach statistical significance. A comparison of MMN and LDN scalp distributions with the middle ISI revealed posterior topography of the LDN relative to that of the MMN (F(2,18) = 6.32, P , 0.02, for the right-hemisphere recordings). 3.4. Control conditions

1. The 2000-ms ISI condition revealed a further amplitude decrease of the P100, while all the remaining peaks

One of the main findings of the present study was the emergence of the N160 and N460 peaks in ERPs to standard stimuli, when the ISI was prolonged from 350 to 1400 ms. The N160 peak was presumably elicited also at the 350 ms ISI, but because of its small amplitude and longer latency with this ISI, it was fused with the N250 peak. With the 700 and 1400 ms ISIs the N160 amplitude increased rather moderately, which could be accounted for by the release from refractoriness. However, with the longest ISI of 4393 ms the N160 was the largest peak of ERP, indicating that some of its generators have very long recovery cycle. Therefore, a high susceptibility to the stimulus rate, the long refractory period and the frontocentrally dominant scalp distribution implied a strong parallelism between the present N160 and

Fig. 4. Difference waves with the short, middle, and long ISIs. The first negative peak was the mismatch negativity (MMN). The MMN enhancement, found with long ISI, was present over the centro-parietal areas only. In addition, with all ISIs a late difference negativity (LDN) was recorded. The LDN was similar to MMN in all aspects, except of the scalp distribution, which was posterior to that of MMN.

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the adult auditory N1 wave. However, the adult N1 is assumed to contain at least 3 obligatory subcomponents (Na¨a¨ta¨nen and Picton, 1987), which makes one ask, how they are represented in the ERPs of the present study. As mentioned above, Korpilahti et al. (1996b) hypothesized that both negativities—the N250, and the one peaking before 200 ms, could be equivalents of the components of adult N1 wave. In the present study, however, the N250 peak did not reveal dependence on the ISI, so characteristic for the adult N1: the N250 amplitude was large already with the 350 ms ISI and did not reliably increase with longer ISIs. Furthermore, the mismatch negativity (MMN) (see discussion below) peaked significantly earlier than did the N250, while in similar experimental conditions the MMN peaks usually later than the N1 wave. Therefore, it was unlikely that the present N250 could be a precursor of any subcomponents of the N1. The N160, recorded with the (700)1400 ms ISI could mainly represent a stimulus-specific response, which was implied for the component 1 of adult N1 wave by Na¨a¨ta¨nen and Picton (1987). The fact that in the DeviantsAlone condition the N160 grew unproportionally to the rest of the ERP peaks implied an addition of a vigorous extra component, elicited exquisitely with very long ISIs. Consistently with this, Karhu et al. (personal communication) in 9year-old children found that a prominent negative response at around 100 ms was elicited by the first stimulus in a train, and this negativity remarkably decreased with the consecutive stimuli. The aforementioned characteristics resemble well those attributed to the nonspecific component of auditory N1. With longer ISIs, peak latency of the N160 shortened, resulting in its increasing overlap with the P100, which could account for the decrease of the measured amplitudes of the latter. Further information on the component structure of auditory N1 precursor in children is provided by the temporal recordings. The main negative peak at the temporal leads, the N190, showed a similar dependence on the ISI as did the N160, but peaked 26–30 ms later (Fig. 2). In adults, the temporal negativity peaks later than the frontocentral N1, and is assumed to be generated by a radially oriented neuronal pool in the temporal lobe. The MEG study of Paetau et al. (1995) has shown only one N1m generator source in the temporal lobe, which accords to the here reported N160. Therefore, it is likely, that the later-peaking N190 of the present study represents activity of a radially oriented generator, residing in the temporal lobe and not detectable by MEG. Thus, N190 presumably is a children correlate of a Tb wave in adults, described by Wolpaw and Penry (1975), or component 2 of the model of Na¨a¨ta¨nen and Picton (1987), or N1c of McCallum and Curry (1980). In conclusion, present results suggested that all 3 subcomponents of auditory N1, listed by Na¨a¨ta¨nen and Picton (1987), are represented by the N160/N190 peaks of the present study. An interesting finding concerning the N250 peak was its

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amplitude decrease at the 1400-vs. 700-ms ISI (Table 1). This, in part, replicates the results of Korpilahti et al. (1996b), which demonstrated, in their older subjects, decline of the N250 amplitude with longer (1500 ms) ISI. However, the present data highlight this issue as not age but ISI-related phenomenon. At high stimulus rates, the N160 and N250 overlapped, resulting in the enhanced amplitudes of the N250. With the 1400-ms ISI, however, the N160 peaked significantly earlier, while the N250 latency did not change. As a consequence, these peaks separated, and the N250 became apparently smaller in amplitude. Further, with the 2000- and 4393-ms ISIs, the N250 amplitude again continued to slightly increase (Fig. 1). Note, that both N160 and N250 peaks of present study peaked by 50–60 ms later than the N1 and N2 in adults. Therefore, the N250 in children seems to correspond the ‘basic’ N2 in adults (Na¨a¨ta¨nen and Picton, 1986). The N460 peak was very small at fast stimulation rates, increasing in amplitude with longer ISIs. A negativity at 440 ms in attend conditions was reported by Neville et al. (1993), who suggested that this response was related to the specific location-related task of their experiment. In the present study, however, the N460 was elicited by unattended stimuli. The functional significance of this component remains to be revealed. However, the long latency and refractory period suggested that this peak could have been generated in auditory association (Lu et al., 1991) or polymodal cortices. In summary, the stimulation rate affects childrens’ auditory ERPs to the extent that with different ISIs different

Fig. 5. Control conditions. Top: ERPs to standard and deviant stimuli, and difference waves with the 2000 ms ISI. Note the P3a wave in the difference curves. Bottom: ERPs to 1100 Hz stimuli as deviants in the oddball paradigm with the 350 ms ISI and as Deviants-Alone, without intervening standard stimuli (mean ISI 4393 ms). The ERP to deviant stimulus in the odd-ball paradigm, containing MMN, was more negative than the response to Deviants-Alone at the latency range, typical for MMN in the present study.

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components can be recorded. Interestingly, recent experiment in our laboratory has shown, that this is even more the case in newborns, in whom exogenous negativity can be recorded only with ISIs of several seconds. This offers an opportunity to selectively study compartments of children ERPs by manipulating study-design. In contrast, in adults the only frontocentral negative peak, that is N1, is recordable under the all comparable conditions.

Therefore, in general the MMN component tended to decrease with longer ISIs, as in adults. A moderate slope of this phenomenon in part can be accounted for the increasing temporal probability of the deviant stimuli with shorter ISIs (Na¨a¨ta¨nen et al., 1987a). In addition, we suggest, that in children MMN should be recorded with ISIs shorter than 700 ms and evaluated from the frontal recordings to avoid the possible overlap with the other endogenous components.

4.2. The mismatch negativity (MMN) 4.3. Late difference negativity (LDN) We assume, that the first negative component of difference wave is mismatch negativity (MMN), as: (1) it was elicited by the unattended stimuli in the oddball paradigm (Na¨a¨ta¨nen et al., 1978); (2) it was largest over the right frontal areas (Paavilainen et al., 1991); (3) it tended to decrease with longer ISIs, similarly as in adults (Bo¨ttherGandor and Ullsperger, 1992; Sams et al., 1993); (4) it preceded the P3a wave, elicited in the 2000-ms ISI condition (Na¨a¨ta¨nen, 1990). However, as two difference negativities were elicited, one could argue, that the first is an N1 enlargement, generated by the new afferent neurons. Possibly, the N1 enhancement was present in the early part of it. Nevertheless, it appears that the first difference negativity represents mainly MMN, because of the following: firstly, with the frequency deviance of 10%, as in the present study, the N1 enhancement is known to be negligible (Na¨a¨ta¨nen, 1992). Secondly, the negativity under discussion peaks at 220–230 ms, while the N1 enhancement should peak at around 160 ms. And, thirdly, this negativity had frontally in the right predominant scalp distribution, which is known to be characteristic for the MMN. An important finding was the larger MMN amplitudes in the 1400-ms ISI condition (Table 1), than with the 700-ms ISI (Fig. 4). This in part resembles results of Korpilahti et al. (1996b) of the larger MMN amplitudes in longer than shorter ISI conditions (1500 vs. 500 ms) in 7–9-year-olds. The authors interpreted this as an age-specific phenomenon. Notably, in the present study, with the 1400-ms ISI the MMN was larger and tended to peak later only over the centro-parietal areas. The other negative ERP component of this latency range, known to be distributed posterior to the MMN, is N2b (Na¨a¨ta¨nen and Gaillard, 1983; Na¨a¨ta¨nen and Picton, 1986). In adults, the N2b component commonly is elicited in the attend-conditions and is followed by the P3a wave. Nevertheless, it can also be evoked in ignore conditions (Ritter et al., 1992) or without succeeding P3a (Na¨a¨ta¨nen, 1992). However, in the present 2000-ms ISI condition the P3a wave was also recorded (Fig. 5, top), testifying an involuntary attention switch (Na¨a¨ta¨nen, 1990). This strongly suggests that the N2b component could have been elicited with the 1400-ms ISI, in which case it would have contributed to the enlargement of MMN amplitudes in this condition. Note, that MMN tended to further decrease at all leads in the 2000-ms ISI condition.

Obtaining of a second difference negativity in response to tone stimuli contradict the hypothesis of Korpilahti et al. (1996a) that the ‘late MMN’ is a ‘mental-lexicon’ specific response. In adults, two negativities in the difference waves have also been reported: Alho et al. (1992) found two auditory difference negativities in conditions of visual attentional task. The second peaked at 400 ms, was frontally dominant and appeared to be independent on the attentional load. Likewise, Trejo et al. (1995) found a late difference negativity, peaking at 200–300 ms, in the oddball paradigm in their non-attend conditions. The authors of both studies suggested a MMN-like functional significance for this component. Alho et al. (1992) however, noted, that this negativity could be caused by the MMN to standards, immediately following deviant stimuli. The LDN of the present study seem to resemble above-mentioned findings in the elicitation conditions, latency and scalp distribution, although findings in adults and 7–9-year-olds may bear a different underpinnings. The other negative endogenous ERP components, sharing the latency range of present LDN, are the processing negativity (PN) and Nc. The Nc wave is elicitable in infants, children and adolescents by surprising and novel stimuli. As an ‘auditory discriminative potential’, it was referred to as representing orienting response to the unexpected auditory stimuli in infants (Kurzberg, 1985), and possibly corresponding to the P3a in adults (Vaughan and Kurzberg, 1992). Its amplitude is inversely correlated to the ‘precision or stability of the memory trace for an event’ and shows long-term habituation as the novelty value of the repeated stimulus decreases (Courchesne, 1978, 1990). Over 450 identical deviant stimuli were presented in the present experiment, and they evidently lost their novelty feature during the test. Therefore, it is very unlikely, that LDN of the present study could represent the Nc wave. On the other hand, most of the research on Nc has been done in the visual modality. Little is known about the auditory Nc at the age of 7–9 years, as most of the studies were conducted on infants. Therefore, further studies are needed to reliably show prerequisites and attributes of auditory Nc. The PN is elicited by the attended ‘channel’ stimuli and represents a neuronal ‘match’ process between a current stimulus and an ‘attentional trace’ (Na¨a¨ta¨nen et al., 1978). It was impossible, however, that in the present study deviant

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stimuli formed a ‘channel’, which was exclusively attended, because of the unattend-conditions and long interdeviant intervals of experiment (Alho et al., 1990a). This implies, that LDN can not be regarded as a PN-like response. The LDN of the present study was similar to the MMN in the elicitation conditions, dependence on the ISI and in the right frontal predominance. Nevertheless, the LDN had a posterior scalp topography to that of the MMN. Timing of the LDN, related to that of the N460 peak, suggested that in part LDN could constitute an enhancement of the N460 peak, caused by the release from refractoriness and/or discharge of a new afferent neurons. Nevertheless, it is also possible that the LDN reflects further processing of, or response to, the detected change in auditory input. However, whether the LDN is an MMN-like response, remains to be tested by, e.g. using intensity deviations (Na¨a¨ta¨nen et al., 1987b), different probabilities of deviant events (Na¨a¨ta¨nen et al., 1987a), LDN relation to behavioural discrimination thresholds, attentional load and learning effects (Na¨a¨ta¨nen, 1992). Of major importance would be to follow a developmental course of this negativity, as well as to possibly localize its generation areas in the brain (MEG). Acknowledgements This study was supported by Centre for International Mobility (CIMO, Helsinki, Finland) and Academy of Finland. References Alho, K., Lavikainen, J., Reinikainen, K., Sams, M. and Na¨a¨ta¨nen, R. Event-related brain potentials in selective listening to frequent and rare stimuli. Psychophysiology, 1990a, 27: 73–86. Alho, K., Woods, D.L., Algazi, A. and Na¨a¨ta¨nen, R. Intermodal selective attention. II. Effects of attentional load on processing of auditory and visual stimuli in central space. Electroenceph. clin. Neurophysiol., 1992, 82: 356–368. Alho, K., Sainio, K., Sajaniemi, N., Reinikainen, K. and Na¨a¨ta¨nen, R. Event-related potentials of human newborns to pitch change of an acoustic stimulus. Electroenceph. clin. Neurophysiol., 1990b, 77: 151–155. Bo¨tther-Gandor, C. and Ullsperger, P. Mismatch negativity in ERPs to auditory stimuli as a function on varying interstimulus interval. Psychophysiology, 1992, 29: 546–550. Cheour-Luhtanen, M., Alho, K., Sainio, K., Rinne, T., Reinikainen, K., Pohjavuori, M., Renlund, M., Aaltonen, O., Eerola, O. and Na¨a¨ta¨nen, R. The ontogenetically earliest discriminative response of the human brain. Psychophysiology, 1996, 33: 478–481. Cheour-Luhtanen, M., Alho, K., Kujala, T., Sainio, K., Reinikainen, K., Renlund, M., Aaltonen, O., Eerola, O. and Na¨a¨ta¨nen, R. Mismatch negativity indicates vowel discrimination in newborns. Hear. Res., 1995, 82: 53–58. Cheour, M., Haapanen, M-L., Hukki, J., Cˇeponiene˙, R., Kurjenluoma, S., Alho, K. and Na¨a¨ta¨nen, R. The first cognitive dysfunction in CATCH children. NeuroReport, 1997, 8, 1785–1787. Courchesne, E. Chronology of postnatal human brain development: eventrelated potential, positron emission tomography, myelinogenesis, and synaptogenesis studies. In: Event-Related Brain Potentials. Basic Issues and

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