Clinical Neurophysiology 111 (2000) 546±551 www.elsevier.com/locate/clinph

The individual replicability of mismatch negativity at short and long inter-stimulus intervals

Carles Escera*, Elena Yago, M. Dolores Polo, Carles Grau

Neurodynamics Laboratory, Department of Psychiatry and Clinical Psychobiology, University of Barcelona, P. Vall d'Hebron 171, 08035 Barcelona, Catalonia, Spain Accepted 4 October 1999

Abstract Objectives: The individual replicability of the mismatch negativity (MMN) event-related potential (ERP) was studied at two different inter-stimulus intervals (ISIs), to establish its potential value for routine clinical evaluation of sound discrimination and auditory . Methods: Ten healthy young subjects were presented sequences of 3 stimulus trains, in two recording sessions approximately 1 month apart. The stimuli in the trains were delivered at an ISI of 300 ms, whereas the inter-train intervals (ITIs) were 0.4 s and 4.0 s in different blocks. ERPs were averaged to standard (75 ms) and deviant (25 ms) tones started equiprobably the stimulus trains. Results: Signi®cant Pearson product±moment correlations coef®cients were found between sessions at all scalp locations for the short ITI, when the MMN was quanti®ed as the mean amplitude in the 100±200 ms latency window around its peak. However, none of the correlations reached signi®cance for the longer ITI. Conclusions: MMN appears to be a reliable measure for single-case assessment and follow-ups when obtained at short ISIs and quanti®ed as an integrated window of neuroelectric activation over a temporal span. q 2000 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Mismatch negativity; Sensory memory; Auditory event-related potentials; N1; Cognitive assessment; Test±retest reliability

1. Introduction indicates that MMN provides a unique objective measure to evaluate, without behavioural demands, the accuracy of Recent research indicates that most of the objective central sound representation (NaÈaÈtaÈnen and Alho, 1997), evaluation of cognitive brain functions for clinical practice automatic auditory discrimination (Tiitinen et al., 1994), will be largely based on functional neuroimaging methods. and auditory sensory memory (Grau et al., 1998). In addi- However, clinical neurophysiological tools may still be tion, a frontal contribution found to MMN (Giard et al., valuable for such clinical purposes. Indeed, the non-inva- 1990) suggests its involvement in involuntary attention sive recording of electrical brain activity provides high- (SchroÈger, 1996; Escera et al., 1998). temporal resolution information on the sequence of cerebral Studies of MMN in several groups of patients have shown events leading to cognitive functions and their disorders. In auditory discrimination de®cits in Parkinson's disease particular, a very promising tool in this context is the (Pekkonen et al., 1995a) and schizophrenia (Javitt et al., mismatch negativity (MMN) event-related brain potential 1995). In addition, attenuation of MMN to stimuli delivered (ERP) (Tervaniemi and Escera, 1998), elicited to infrequent at long inter-stimulus intervals (ISIs) has revealed auditory deviant stimuli appearing in a sequence of repetitive stan- sensory memory impairments in Alzheimer's disease dard sounds (NaÈaÈtaÈnen et al., 1978). MMN is generated in (Pekkonen et al., 1994), chronic alcoholism (Grau, 1998), the supratemporal (Alho, 1995) by a sensory and children with CATCH-22 syndrome (Cheour et al., memory system automatically detecting violations of regu- 1997). For single individuals, MMN recording may become larity in the acoustic stream (NaÈaÈtaÈnen, 1992). Evidence a useful tool for detection of language disorders in children with learning disabilities (Kraus et al., 1996) or develop- mental dysphasia (Korpilahti and Lang, 1994). It may also * Corresponding author. Tel.: 134-93-402-1100 ext. 3047; fax: 134-93- be used to assess the success of cochlear implants (Kraus et 403-4424. al., 1993; Ponton and Don, 1995), to monitor developmental E-mail address: [email protected] (C. Escera)

1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. CLINPH 99563 PII: S1388-2457(99)00274-6 C. Escera et al. / Clinical Neurophysiology 111 (2000) 546±551 547 brain processes in pre-term new-borns (Cheour-Luhtanen et 2. Methods al., 1996), and to complement the prognosis of recovery from coma (Kane et al., 1993). However, a critical issue 2.1. Subjects before introducing MMN into routine clinical practice is its individual replicability. If MMNs obtained from the Ten healthy paid university students, between 19 and 24 same individual subject in the same experimental conditions years old (mean age ˆ 21 ^ 1.5; 7 female), participated in vary considerably from recording to recording, the use of two identical recording sessions separated by approximately MMN for clinical practice will be questionable. 1 month (mean ˆ 35 ^ 12 days; range 20±64 days). Several studies have shown that reliable MMNs can be Informed written consent was obtained from subjects prior recorded from session to session in a particular group of to their participation. subjects, thus showing its group-level replicability (Pekko- nen et al., 1995b; Escera and Grau, 1996; Joutsiniemi et al., 2.2. Stimuli and procedure 1997). This makes MMN suitable for clinical research. Stimuli were pure sine-wave tones of 700 Hz generated However, the individual replicability of MMN is still to by a Stim unit (Neuroscan Inc., USA). Standard and deviant be proven. Indeed, signi®cant correlation coef®cients tones were 75 ms and 25 ms in duration respectively, includ- between individual MMN recordings have been obtained ing 5 ms of rise and fall times. Tones were delivered binau- only at some scalp locations, indicating low individual rally through headphones at an intensity of 85 dB SPL. replicability (Pekkonen et al., 1995b; Escera and Grau, Trains of 3 stimuli, starting on a random basis with a 1996; Joutsiniemi et al., 1997). The best replicability results deviant (P ˆ 0:5) or a standard tone (P ˆ 0:5), and have been obtained for MMNs elicited to duration devian- followed by two standard tones, resulting in an overall prob- cies (Pekkonen et al., 1995b; Joutsiniemi et al., 1997; Terva- ability of deviant stimuli of 16.7%, were delivered to the niemi et al., 1998). The lack of individual replicability of subjects (Grau et al., 1998). The stimuli in a train were MMN contrasts with highly reliable indexes obtained to the separated by short intervals of 300 ms (onset-to-onset) in N1 elicited to standard tones (Michalewski et al., 1986; order to create the sensory memory trace of the standard- Shelley et al., 1991; Pekkonen et al., 1995b; Escera and tone features in the shortest possible time. In separate Grau, 1996). Some authors have suggested that the differ- blocks, stimulus trains were presented at short (0.4 s) or ence in the replicability level of both ERPs is due to the long (4.0 s) ITIs (onset-to-onset). larger number of stimuli averaged for N1 in comparison A total of 400 stimulus-trains in each ITI condition were with that averaged for MMN, and that increasing the presented to the subjects in separate blocks spaced by short number of ERPs averaged to deviant tones to obtain the breaks. Subjects were instructed to read a book of their own MMN would lead to better MMN reliability (Pekkonen et choice and to ignore the auditory stimulation, while sitting al., 1995b; Escera and Grau, 1996). in a comfortable armchair, in an electrically shielded and In the present study, two identical recording sessions soundproof room. Subjects were also instructed to avoid eye separated by approximately 1 month were carried out with movements and blinking during the recording sessions. a group of 10 healthy young subjects, in order to clarify the individual replicability of MMN further. MMN was elicited 2.3. Recording and analysis to duration deviant stimuli according to the new faster para- digm developed by Grau et al. (1998). Stimuli were The EEG was recorded from standard 10/20 scalp loca- presented in trains of 3 tones, starting with identical prob- tions at Fz, F3, F4, Cz, C3, C4, and from the left (LM) and ability of standard or deviant stimuli, at short (0.4 s) and right (RM) mastoids. Vertical eye movements and blinks long (4.0 s) inter-train intervals (ITIs). With this paradigm, were controlled from electrodes located at Fp1 and Fp2. the tones within a train are delivered at a very short ISI, Horizontal EOG was monitored from an electrode attached whereas the ITIs can be varied to evaluate the duration of to the outer canthus of the left eye. All electrodes were auditory sensory memory. Thus, MMN recording time is referenced to the tip of the nose. EEG and EOG were shortened by 2/3, particularly for long intervals, when continuously sampled at 500 Hz and stored on computer compared with conventional procedures delivering the for off-line analysis. Epochs with EOG or EEG exceeding stimuli at a constant ISI. Signi®cant correlations between ^100 mV were automatically excluded from averaging. sessions were obtained at all scalp locations for the short ITI ERPs were averaged for only those stimuli starting a 3 when MMN was quanti®ed as the mean voltage of a latency tone train, separately for deviant and standard tones, for window centred at its peak. This indicates that MMN is a each subject and for each session and ITI condition. The reliable measure when obtained at short ISIs and quanti®ed epoch was of 400 ms, including 100 ms as the pre-stimulus as an integrated amplitude of neuroelectric activation over a baseline. After averaging, ERPs were digitally band-pass temporal span. However, further studies are to be under- ®ltered between 0.5 and 15 Hz and re-referenced to the taken to clarify the reliability of MMN at long ISIs, where RM electrode. the memory processes involved in MMN generation appear MMN was identi®ed separately for each individual, to add additional variability. session, and ITI condition by 3 experienced observers, as 548 C. Escera et al. / Clinical Neurophysiology 111 (2000) 546±551 the largest negative peak in the 100±200 ms latency window conditions). Highly signi®cant correlations were obtained of the difference wave obtained by subtracting the ERPs for between sessions for all N1 parameters at all scalp locations standard tones from those for deviant tones. Agreement in both ITI conditions (Pearson's r ranging from 0.85 to between observers was approximately 98% (range: 78± 0.98; P , 0:02 in all cases). 100%). For statistical analysis, MMN peak amplitude and latency, as well as the mean amplitude in the 100±200 ms latency window, were determined at all scalp locations. The 4. Discussion N1 response was identi®ed in the ERPs to standard tones as the most prominent negativity occurring between 80 and The present study addressed the individual replicability 130 ms, and its peak amplitude, latency and mean amplitude of MMN elicited to stimuli presented at short and long ISIs, in the 80±130 ms latency window were determined at all in order to clarify its potential value as routine clinical tool electrodes. All ERP and deviant minus standard difference for neurophysiological evaluation of sound discrimination wave amplitudes were measured in relation to the mean (Kraus et al., 1993, 1996; Korpilahti and Lang, 1994; voltage of the pre-stimulus baseline. Ponton and Don, 1995; NaÈaÈtaÈnen and Alho, 1997) and audi- ANOVAs, including session and ITI conditions as tory sensory memory (Pekkonen et al., 1994; Grau, 1998; factors, were used to compare overall peak amplitudes and Grau et al., 1998). It was found that MMN correlated signif- latencies, and mean amplitudes of MMN (Fz) and N1 (Cz). icantly between sessions when the ITI was 0.4 s, but not To analyse the individual replicability of MMN and N1, when it was 4.0 s. Thus, reliable MMN recordings can be Pearson product±moment correlations between sessions obtained from two different sessions separated by a period were calculated for each ITI condition at each of the 6 of time, i.e. approximately 1 month, to stimuli delivered at electrode positions. short ISIs. The highest correlation coef®cients were obtained at all 6 scalp locations, when the MMN was measured as the mean 3. Results amplitude of a latency window around its peak. As in the present data, signi®cant correlations were obtained in Similar MMNs were elicited to deviant tones in both previous studies at only some of the electrodes used in the sessions and ITI conditions (Fig. 1, right bottom). recordings when MMN amplitude was identi®ed at its peak ANOVA revealed no signi®cant differences for MMN (Escera and Grau, 1996; Joutsiniemi et al., 1997). Conse- peak amplitude (22.8 ^ 1.14 mV, averaged across subjects, quently, the present results indicate that measuring inte- sessions and ITI conditions at Fz) and latency (167 ^ 26.9 grated amplitudes of neuroelectric activation over a ms), nor for the mean amplitude in the 100±200 ms latency temporal span provides a reliable estimation of the auto- window (21.5 ^ 1.2 mV). MMN could be identi®ed in all matic sound-discrimination mechanism associated with individuals and conditions, except in Subject 3 (S3) in the MMN generation. Pekkonen et al. (1995b) found signi®cant 0.4 s ITI condition of the ®rst session (Fig. 1). correlations at only one electrode (F4), however, they Fig. 2 illustrates the correlation coef®cients between measured the MMN as the mean amplitude in a 50 ms sessions at each electrode for peak and mean MMN ampli- latency window (from 125 to 175 ms). The fact that these tudes in the two ITI conditions. In the 0.4 s ITI condition, authors used a narrower time window may explain the less MMN mean amplitudes in the 100±200 ms latency window reliable MMN obtained in comparison with the present correlated signi®cantly at all scalp locations (Pearson's r study. It also raises the question of, which is the optimal ranging from 0.68 to 0.87; P ranging from 0.04 to 0.002), interval to integrate MMN amplitude. whereas the peak parameters reached signi®cance only in Several studies have reported a shortening in MMN two occasions: at Fz (r ˆ 0:72; P , 0:03) for MMN peak latency to increased differences between the standard and amplitude and at F3 (r ˆ 0:68, P , 0:05) for its peak deviant stimuli, at least for frequency (Novak et al., 1990; latency. In the longer ITI condition (4.0 s), none of the Tiitinen et al., 1994) and intensity (NaÈaÈtaÈnen et al., 1989a) correlations reached statistical signi®cance. differences, but not for stimulus duration (Kaukoranta et al., The N1 elicited to standard tones was also similar in the 1989; NaÈaÈtaÈnen et al., 1989b). Preliminary evidence from two recording sessions and for both ITI conditions (Fig. 1, our lab (Amenedo and Escera, 1999) corroborates this ®nd- left bottom). Due to its small amplitude in the 0.4 s ITI ing, and indicates that MMN latency to either increasing or condition, N1 was dif®cult to identify in 3 subjects (S4, decreasing duration deviancies, ranging from 5 to 60%, is S5, S9) in both sessions and in an additional subject (S3) rather stable (approx. 200 ms). Thus, stimulus duration in the ®rst session (Fig. 1). These subjects were discarded appears as the critical feature to change in order to obtain from subsequent analyses using the peak parameters. The stable and reliable MMN data in clinical contexts, as it N1 peak amplitude was signi®cantly larger in the 4.0 s provides the most stable MMN latency and the best replic- (26.7 ^ 3.22 mV, at Cz) than in the 0.4 s ITI condition ability results (Pekkonen et al., 1995b; Tervaniemi et al., (21.2 ^ 1.76 mV) (F 1; 5†ˆ137:7; P , 0:001), but had 1998; the present data). the same latency (108 ^ 13.4 ms, across sessions and ITI In contrast with the high individual replicability of MMN C. Escera et al. / Clinical Neurophysiology 111 (2000) 546±551 549

Fig. 1. ERPs to standard tones (left) and difference waves (right) from Session 1 (thick line) and Session 2 (thin line). Individual recordings at the top and grand-averages at the bottom. obtained in the 0.4 s ITI condition, the MMNs obtained at the ISI may be caused by additive variability of the two the long ITI were not so reliable, as no signi®cant correla- mechanisms involved in MMN generation. Indeed, MMN tions were obtained at any of the electrodes in the 4.0 s ITI is elicited by a comparison process between the incoming condition for any of the peak parameters, nor for the mean stimuli and neural representation of the standard stimuli amplitude in the 100±200 ms latency window. Pekkonen et features, resulting in disparity (NaÈaÈtaÈnen, 1992). In addi- al. (1995b) also reported the loss of individual replicability tion, this comparison mechanism requires a sensory when their short ISI of 0.5 s was increased to 1.5 s. The loss memory system keeping neural traces of these features for of the individual replicability of the MMN when increasing a period of time (NaÈaÈtaÈnen, 1992), i.e. of approximately 10 s 550 C. Escera et al. / Clinical Neurophysiology 111 (2000) 546±551 features in a sensory memory trace for a longer period. This may result in the overall higher variability of the MMN signal caused by the intrinsic variability of the comparison mechanism and an increased instability of the neural trace of the standard stimuli for being maintained a longer period in sensory memory. Consequently, further studies on the individual replicability of MMN at long ISIs are to be conducted before using MMN for sensory memory evaluation purposes at an individual level. Some authors have suggested that the lack of individual replicability of MMN may be due to the small number of deviant stimuli averaged in comparison to the number of stimuli considered to study the N1 replicability in the ERPs to standard tones (Pekkonen et al., 1995a,b; Escera and Grau, 1996). In the present study, the correlation coef®- cients found for the N1 peak and mean amplitudes were higher than those obtained for the MMN parameters, despite the fact that the same number of stimuli was averaged to identify the N1 in the ERP to the standard tones and the MMN in response to the deviant tones. This suggests that whereas 200 stimuli are enough to obtain a reliable N1 response, reliable MMN peak parameters (i.e. amplitude and latency) may require a larger number of stimuli included in the averages. This leads to an increase in the length of the recording session. However, the use of the new MMN paradigm developed by Grau et al. (1998) may help in this context to shorten the recording time up to 2/3. In summary, the present results indicate that reliable MMN estimates can be obtained at short ISIs when using a temporal window of neuroelectric activation, thus provid- ing a useful tool for single-case evaluation of sound discri- mination abilities in the absence of behavioural demands.

Acknowledgements

The authors wish to thank the constructive comments of Fig. 2. Pearson product±moment correlations (r) between recording sessions at all 6 scalp electrodes, for MMN peak amplitudes (upper Risto NaÈaÈtaÈnen and Mari Tervaniemi and to Elise Mengler panel) and mean amplitudes (lower panel), in the 0.4 s (light) and 4.0 s for language revision. Supported by BIOMED-2 contract (dark) ITI conditions. **P , 0:01; *P , 0:05. BMH4-CT96-0819-COBRAIN of the European Union. in young healthy subjects (Sams et al., 1993). The dissocia- References tion between these two processes is also supported by results obtained in clinical populations. For instance, it has been Alho K. Cerebral generators of mismatch negativity (MMN) and its reported that schizophrenic subjects present an impairment magnetic counterpart (MMNm) elicited by sound changes. Ear Hear in the comparison process leading to MMN generation, but 1995;16:38±51. no alteration in the underlying sensory memory mechanism Amenedo E, Escera C. Accuracy of sound duration representation in the (Shelley et al., 1996). On the other hand, chronic alcoholics human brain determines the accuracy of behavioral perception. Psycho- physiology 1999;36(Suppl):S25. appear to suffer from the opposite effect: an intact discrimi- Cheour M, Haapanen ML, Hukki J, Ceponiene R, Kurjenluoma S, Alho K, nation mechanism, re¯ected in similar MMNs to control Tervaniemi M, Ranta R, NaÈaÈtaÈnen R. The ®rst neurophysiological subjects to stimuli delivered at short ISIs, but a shorter evidence for cognitive brain dysfunctions in children with CATCH. sensory memory duration, as indicated by an attenuation NeuroReport 1997;8:1785±1787. of MMN to stimuli delivered at longer ISIs (Grau, 1998). Cheour-Luhtanen M, Alho K, Sainio K, Rinne T, Reinikainen K, Pohja- vuori M, Renlund M, Aaltonen O, Eerola O, NaÈaÈtaÈnen R. The onto- Compared with short ISIs, increasing the ISI to obtain the genically earliest response from the human brain. Psychophysiology MMN requires the maintenance of the standard-stimulus 1996;33:478±481. C. Escera et al. / Clinical Neurophysiology 111 (2000) 546±551 551

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