Frequency specificity of 40-Hz auditory steady-state responses

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Hearing Research 186 (2003) 57^68 www.elsevier.com/locate/heares

Frequency speci¢city of 40-Hz auditory steady-state responses Bernhard Ross a

a;b;

, Rossitza Draganova a , Terence W. Picton b , Christo Pantev

b

Institute of Biomagnetism and Biosignalanalysis, University Hospital, Kardinal von Galen Ring 10, 48129 Mu«nster, Germany b Rotman Research Institute for Neuroscience, Baycrest Centre for Geriatric Care, Toronto, ON, Canada M6A 2E1 Received 27 June 2003; accepted 2 September 2003

Abstract Auditory steady-state responses (ASSR) to amplitude modulated (AM) tones with carrier frequencies between 250 and 4000 Hz and modulation frequencies near 40 Hz were recorded using a 37-channel neuro-magnetometer placed above the auditory cortex contralateral to the stimulated right ear. The ASSR sources were likely in the primary auditory cortex, located more anteriorly and more medially than the N1m sources. The ASSR amplitude decreased with increasing carrier frequency, the amplitude at 250 Hz being three times larger than at 4000 Hz. The amplitude of the ASSR to a test sound decreased in the presence of an interfering second AM sound. This suppression of the ASSR to the test stimulus was greater when the carrier frequency of the interfering stimulus was higher than that of the test tone and was greater when the test stimulus had a lower carrier frequency. Similar frequency specificity was observed when the interfering sound was a non-modulated pure tone. These results differ from those found for the ASSR elicited by modulation frequencies above 80 Hz or for the transient brainstem and middle-latency responses and suggest substantial interactions between phase-locked activities at the level of the primary auditory cortex. 7 2003 Elsevier B.V. All rights reserved. Key words: Auditory steady-state responses; Frequency speci¢city ; Amplitude modulation; Primary auditory cortex ; Magnetoencephalography

1. Introduction Auditory evoked responses re£ect the cerebral processing of speci¢c properties of the auditory environment. The frequency-speci¢c processing of an auditory stimulus has been widely investigated for the various components of the evoked responses. Frequency speci¢city indicates the degree of independence of an evoked response to an individual stimulus frequency with respect to responses elicited by stimuli at other frequencies. This is an important measure if a frequency-spe-

* Corresponding author. Tel.: +49 (251) 83 52543; Fax: +49 (251) 83 56874. E-mail address: [email protected] (B. Ross). Abbreviations: ABR, auditory brainstem response; AEP, auditory evoked potential; AM, amplitude modulation; ASSR, auditory steady-state responses; EEG, electroencephalography; MEG, magnetoencephalography; MLR, middle-latency response

ci¢c hearing threshold has to be assessed by means of evoked potential audiometry (Stapells et al., 1993). The experimental procedure for determining frequency speci¢city measures the changes in the response to a test stimulus in relation to an interfering stimulus, which either precedes the test stimulus or is presented simultaneously with it. By means of magnetoencephalography (MEG), Sams and Salmelin (1994) explored the relation between the changes of the N1m amplitude (the magnetic counterpart of the most pronounced auditory evoked electric potential (AEP) peaking around 100 ms after stimulus onset) and the width of a spectral notch in a white noise masker. The spectral notch was centered at the stimulus frequency and the masker was continuously presented. The results showed a substantial reduction of the N1m amplitude only if the stop-band slopes of the masking noise were close to the stimulus frequency. A corresponding equivalent rectangular bandwidth of about 250 Hz was found for a stimulus of 1 kHz and a bandwidth of 600 Hz for 2 kHz. Also, Na«a«ta«nen et al. (1988) reported a sharply de¢ned

0378-5955 / 03 / $ ^ see front matter 7 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0378-5955(03)00299-5

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frequency tuning for the N1 amplitude of the AEP in relation to the frequency of pure tone intervening stimuli. In this case, the main e¡ect on the N1 amplitude in response to 1-kHz stimuli, which were presented at a relatively fast rate of two stimuli per second, was observed only for the frequency of the intervening tone between 925 and 1250 Hz. At ¢rst glance these observations of a sharp frequency tuning seem to be in contrast to the wider frequency characteristics found for the N1 amplitude by Butler (1968) and Picton et al. (1978a,b). In both studies the authors inserted three intervening tone bursts of varying frequencies between the test stimuli of 1000 Hz, which were presented every 5 s (Butler) or every 4 s (Picton et al.) with the same intensity of 80 dB HL for the test and the intervening tones. In both studies the N1 amplitude was signi¢cantly reduced even if the frequency of the intervening tones was two octaves above or below the test frequency. However, these experiments di¡er from those conducted by Sams et al. and Na«a«ta«nen et al. in two obvious ways. First, the inter-stimulus interval was di¡erent (Butler and Picton : 1.25 and 1 s; Na«a«ta«nen et al.: 460 ms). Second, the continuously presented masker of Sams et al. did not elicit an N1, whereas both the test and intervening stimuli evoked an N1 response (Butler, 1968; Picton et al., 1978a,b). Studies of earlier evoked response components have used continuous masking sounds. Sharply de¢ned tuning curves were obtained for the wave V^VP of the auditory brainstem evoked responses (ABR) and the waves Na^Pa of the middle-latency responses (MLR) using a high-pass masking noise (Oates and Stapells, 1997a,b) and the method of derived response technique (Oates and Stapells, 1997a,b). Also pure-tone masking pro¢les of human ABR and MLR in response to clicks (Pantev and Pantev, 1982; Pantev et al., 1985) or brief tone bursts at 2000 Hz (Mackersie et al., 1993) and 500 Hz (Wu and Stapells, 1994) exhibited sharp frequency tuning. Herdman et al. (2002) demonstrated by means of derived responses that auditory steady-state responses (ASSR) evoked by modulations above 80 Hz show similar frequency speci¢city. The tonotopic organization of the auditory nervous system, which is established along the basilar membrane in the cochlea and preserved along the auditory pathway, including the auditory cortex (Romani, 1986; Pantev et al., 1988), supports the concept of auditory processing in parallel frequency-speci¢c channels. Following this concept, multiple amplitude-modulated (AM) sounds at modulation frequencies above 80 Hz were presented simultaneously in order to investigate multiple ASSR to di¡erent carrier frequencies at the same time (Lins and Picton, 1995; John et al., 1998). If the simultaneously recorded ASSR were mutually in-

dependent this technique could substantially reduce the time required to assess hearing thresholds (John et al., 1998, 2002; John and Picton, 2000; Perez-Abalo et al., 2001). Little interaction between the multiple AM components occurred if the carrier frequencies were separated by one octave or more (Lins and Picton, 1995). However, when the di¡erence between the carrier frequencies became smaller, there was a signi¢cant reduction in amplitude, with the response to the lower frequency stimulus more a¡ected than the response to the higher frequency stimulus. When two modulation rates are used for stimuli with the same carrier frequency, the 40-Hz responses are decreased in amplitude. ASSR amplitudes with 78% of the value obtained in the single AM case were reported in an electroencephalography (EEG) study (Picton et al., 1987) (1000 Hz carrier, 39 and 49 Hz modulation), 66% in another EEG study (John et al., 1998) (1000 Hz carrier, 42.7 and 44.7 Hz modulation), and 73% in a MEG experiment (Draganova et al., 2002) (250 Hz carrier, 38 and 40 Hz modulation). However, little is known about how the human 40-Hz ASSR change their amplitude, when a second AM stimulus at a di¡erent carrier frequency is simultaneously present. John et al., 1998 found that the 1-kHz electrical response was smaller in the presence of a 2-kHz interfering AM sound and slightly larger with a 500Hz interfering AM sound. The objective of this study was to investigate in more detail the behavior of the 40Hz ASSR when two stimuli are presented simultaneously over a wide range of di¡erent carrier frequencies. The experimental results may answer the question whether multiple ASSR in the 40-Hz range could also be used for objective examination of the audiometry threshold, similarly to the multiple 80-Hz ASSR. Furthermore, information about the frequency speci¢city of the human 40-Hz ASSR may contribute to the ongoing discussion about the mechanisms of ASSR generation.

2. Methods 2.1. Subjects Six right-handed volunteers (two female) aged between 24 and 34 years participated in this study. None of them had a history of otological or neurological disorders. The subject’s air conduction hearing thresholds were less than 10 dB HL between 250 Hz and 4 kHz. The subjects consented to participate after being given written information about the study. The study was approved by the Ethics Commission of the University of Mu«nster and was conducted in accordance with the Declaration of Helsinki. Subjects were paid for their participation.

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2.2. Stimulation The stimuli were sinusoidal AM tones with modulation frequencies of fm1 = 39 and fm2 = 41 Hz and carrier frequencies fc1 and fc2 ranging between 250 and 4000 Hz. In all cases the modulation depth was set to 100%. Two AM sounds were presented simultaneously. A sample stimulus pair with fc1 = 500 Hz, fm1 = 39 Hz, fc2 = 1000 Hz, and fm2 = 41 Hz is displayed in Fig. 1a. The complex temporal structure (Fig. 1b) is concisely de¢ned by a simple amplitude spectrum (Fig. 1c), containing peaks at both carrier frequencies fc1 and fc2 and additional side-band frequencies for each carrier at fc1 O fm1 and fc2 O fm2 . The stimuli were prepared as sound-¢les by a computer program. Therefore, the frequency ratio fc1 /fc2 was always exact and in the special case of equal carrier frequencies no beats or phase shifts occurred during continuous presentation of the stimuli. In this study the ASSR amplitude in response to one AM stimulus was investigated in the presence of a second sound. The stimulus that evoked the observed ASSR amplitude was referred to as the test stimulus.

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Hence, the carrier frequency of the test stimulus was labeled fct . The second stimulus, which caused a change in the ASSR amplitude of the response to the test stimulus, was termed the interfering stimulus. The carrier frequency of the interfering stimulus was consequently labeled fci . First, ¢ve single AM sounds with octave-spaced frequencies between 250 and 4000 Hz were investigated in order to describe the relations between the ASSR amplitude and the carrier frequency. Furthermore, the ASSR amplitudes to these single AM sounds served as references when investigating the suppression caused by a second sound. Second, 15 measurements were carried out with all combinations of the ¢ve octave-spaced frequencies between 250 and 4000 Hz, including the cases of equal carrier frequencies. This allowed us to study interactions when the carrier frequencies were identical or far apart. Third, extra combinations of adjacent frequencies were investigated around fct = 1000 and 500 Hz and above fct = 250 Hz with fci /fct = 3/4, 7/8, 15/16, and 31/ 32 as well as fci /fct = 32/31, 16/15, 8/7, and 4/3.

Fig. 1. (a) Time-series of a two-component AM stimulus composed of the sum of a 500-Hz tone modulated at 39 Hz and a 1000-Hz tone modulated at 41 Hz. The displayed waveform of 1 s duration is the shortest common period of the 39 and 41 Hz modulation. (b) A section extracted from the stimulus time-series corresponding to the horizontal bar around 0.1 s in panel a shown on an enlarged time scale exhibits the complex temporal structure of the stimulus signal. (c) Amplitude spectrum of the stimulus signal (right) and the corresponding response signal obtained with MEG (left). The stimulus spectrum mainly consists of two groups of spectral peaks around the carrier frequencies of 500 and 1000 Hz. The peak amplitudes at 39 or 41 Hz above and below the carrier frequencies are 6 dB smaller than the largest peaks at the carrier frequencies. The response spectrum shows two most pronounced peaks at 39 Hz corresponding to the 500-Hz stimulus and at 41 Hz corresponding to the 1000-Hz stimulus.

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Fourth, eight measurements were carried with the combinations of an fct = 250 Hz AM test stimulus and a non-modulated pure tone interfering stimulus at fci /fct = 1, 16/15, 8/7, 4/3, 2, 4, 8, and 16. This control measurement allowed us to determine whether the effects were related to the carrier frequency of the interfering tone or its modulation. Additional MEG measurements were performed for N1 source localization using 500-Hz tone bursts of 500ms duration, which were presented with an inter-stimulus interval of 3 s. The AM stimuli were presented continuously in blocks of 200-s duration. In order to keep the total duration of each MEG session below 1 h, not more than 12 di¡erent frequency combinations were investigated in one session and one block of 128 tone bursts. Two sessions with a half-hour break in between were carried out on the same day. In the second session the carrier-frequency combinations of the ¢rst session were repeated with the modulation frequencies exchanged. The order of the di¡erent carrier-frequency combinations was randomized between the two sessions and the subjects. For the entire experiment four pairs of sessions were performed with each subject on succeeding days. The stimuli were presented to the subject’s right ear through a magnetically silent delivery system consisting of speakers mounted outside the magnetically shielded room and connected through 6.3 m of echo-less plastic tubing (16 mm inner diameter) to silicon ear pieces. For each AM sound combination the individual hearing thresholds were determined for both single AM components prior to the MEG measurement using the MEG auditory stimulation equipment. Thereafter, the amplitudes of each of the components of the combined stimulus were adjusted to 70 dB above individual sensation thresholds, which corresponds to about 80 dB sound pressure level. The measurement inside the silent magnetically shielded room and the used ear plugs reduced the ambient noise close to hearing threshold. 2.3. Data acquisition MEG recordings were carried out in a magnetically shielded and acoustically silent room using a 37-channel neuromagnetometer (MAGNES, 4D-Neuro-Imaging, San Diego, CA, USA). The detection coils of this instrument are arranged in a circular concave array with a diameter of 144 mm and a spherical radius of 122 mm with distances between the centers of coils of 22 mm and coil diameters of 20 mm. The sensors are con¢gured as ¢rst-order axial gradiometers with a baseline of 50 mm. The spectral density of the intrinsic noise of each channel was between 5 and 7 fT/kHz in the frequency range above 1 Hz. The 37-channel MEG signals

were bandpass-¢ltered between 1 and 200 Hz before sampling at a rate of 520 s31 . The subjects rested in right lateral position with their head and body ¢xed on a vacuum mattress to provide a stable position throughout the whole experimental session. The sensor array was centered over the point about 1.5 cm superior to the position T3 of the international 10^20 system for electrode placement and was positioned as close as possible to the subject’s head, contra-lateral to the stimulated right ear. A sensor-position indicator system determined the spatial locations of the sensors relative to the head. In order to keep the subjects in an alert state during the MEG measurement they watched a soundless cartoon video. This also reduced their eye movements, which could be monitored from the MEG channels located near the left eye. 2.4. Data analysis Signal averaging in the time domain was applied to the magnetic ¢eld data of each experimental run of 200-s duration in order to extract the evoked ASSR. The epoch length for averaging was 1.0 s, which is the shortest common multiple of the period durations of the modulation frequencies of 39 and 41 Hz (Fig. 1a). Signal epochs were considered as artifact-contaminated and rejected from the averaging procedure if the amplitude £uctuations exceeded a 3 pT (picoTesla, 10312 T) threshold. The averaged data were approximated separately with sine-wave signals of 39 and 41 Hz to obtain 37 magnetic ¢eld time-series at both modulation frequencies. For the source analysis, a single moving equivalent current dipole was ¢tted to the averaged time domain data in order to estimate the spatial coordinates (x, y, z) of the underlying source. For each subject the median values of these source coordinates and the orientations were calculated across all experimental conditions and repeated measurements. Only those source locations were included in this analysis that were in agreement with the following anatomical and statistical considerations : distance from the midsaggital plane greater than 3.0 cm, and goodness of ¢t of the dipolar source s 90%. This procedure provides a reliable estimate of the cortical source location and orientation of the ASSR that were used as an individual reference for the source-space projection method, which was applied to all averaged magnetic ¢eld data. The source-space projection is a linear combination of the measured magnetic ¢eld strength in fT at the 37 sensor positions outside the head weighted with the sensitivity of each sensor for the magnetic ¢eld at the speci¢ed source localization. It results in a single time-series of the magnetic dipole moment measured in nAm. This is a measure of the source strength of activity in the speci¢ed brain area and is independent of the sensor posi-

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tions. The source-space projection allows calculating grand averages of dipole moment time-series across different subjects and sessions and enhances the signal-tonoise ratio (Ross et al., 2000). Especially the sensor noise, which is independent for all channels, is reduced in the combined dipole moment signal. The method is maximally sensitive for brain activity from sources at the selected origin and orientation. Unwanted activity from distant sources or sources with di¡erent orientation is combined less optimally and is therefore reduced in the dipole moment waveforms. An amplitude spectrum of the ASSR obtained in source space is shown together with the stimulus spectrum on the common frequency scale in Fig. 1c. The evoked ASSR contains pronounced peaks at both modulation frequencies. The arrows indicate for the given example that the 39-Hz response amplitude refers to the 500-Hz AM component and the 41-Hz amplitude to the 1000-Hz component of the stimulus. This method of frequency tagging was previously used to di¡erentiate between the responses related to the stimuli at corresponding carrier frequencies (Fujiki et al., 2002) even in the case of a common carrier frequency (Draganova et al., 2002). Estimates for the response amplitudes at the modulation frequencies were obtained from ¢tting sine waves to the source waveforms. For each combination of carrier frequencies and each subject the mean of response amplitudes at 39 and 41 Hz and repeated measurements were calculated. For the group statistic the mean amplitudes were calculated for all experimental conditions. Two-sided 95% con¢dence limits for the mean amplitudes were obtained using bootstrap statistics. For this non-parametric test the sample distribution is estimated from repeated samples of the data itself (Efron and Tibshirani, 1993). Two main experimental ¢ndings were analyzed. First, the e¡ect of carrier frequency on the response amplitude when a single stimulus was presented was investigated. This resulted in a frequency characteristic showing the ASSR amplitude versus the carrier frequency of the single AM stimulus. Second, the e¡ect of an interfering stimulus on the ASSR amplitude to the test stimulus was measured when both test and interfering stimuli were presented simultaneously. The results were presented for each test frequency as frequency-speci¢city curves, which exhibited the amplitude of the ASSR to the test stimulus versus the carrier frequency of the interfering sound. Each monotonic branch of the curve was approximated by an exponential function of the form W(g) = asingle (13p exp(3qg2 )) with the single AM amplitude asingle , the normalized frequency g = log(f/fct ) on a logarithmic scale and two parameters p and q, modeling the decrement of the amplitude at f = fct and the steepness of the slope, respectively (Sams and Salmelin, 1994). Because of the

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observed frequency asymmetry di¡erent values for the parameter q were used above and below fct .

3. Results Auditory steady-state magnetic ¢elds were recorded from all subjects. The signal-to-noise ratio was su⁄cient ( s 20) for reliable source estimation if the ¢eld amplitudes in the maximally responding channels were about 10 fT. This occurred at least 15 times for each subject from the repeated measurements under various stimulus conditions. The median source location over these measurements was used for the source-space projection for each individual subject. The grand average of the estimated source coordinates of the eight subjects was 1.20 cm in the posterior^anterior direction (x), 4.56 cm in the medio-lateral direction (y), and 5.71 cm in the inferior^superior direction (z). Compared to the N1m sources (x = 0.65 cm, y = 4.90 cm, z = 5.86 cm), which were obtained with the 500-Hz tone-burst stimulation, the ASSR sources were 0.54 cm more anterior (p(df = 7) = 0.0077) and 0.34 cm more medial (n.s.). After source-space projection was applied to the magnetic ¢eld data the ASSR amplitudes were mea-

Fig. 2. ASSR amplitudes in response to single AM stimuli versus the carrier frequency. (a) Individual amplitude characteristics (thin lines) and the corresponding grand average (thick line). The gray shaded area denotes the 95% con¢dence interval of the mean. (b) Mean amplitude characteristic (square symbols) ¢tted by a regression line in comparison to a characteristic obtained in a previous study (triangles) (Ross et al., 2000).

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sured for all experimental conditions. The amplitudes of the ASSR to single AM stimuli served as a reference for the amplitudes observed in the case of multiple AM stimuli. The individual ASSR amplitudes for single AM stimuli are shown in Fig. 2a in combination with the mean across all subjects and the 95% con¢dence limits of the mean. The relation between amplitude and carrier frequency shows a clear decrement of the ASSR amplitude with increasing carrier frequency. The regression line (r2 = 0.946, F(1,3) = 52.17, P = 0.0055) ¢tted to the characteristic shown in Fig. 2b has a slope of 0.50 nAm/octave, which corresponds to a 30% amplitude increment or decrement for an octave step below or above 1000 Hz. This distinct preference for the low carrier frequency range was also observed under similar experimental conditions with another group of subjects in a previous study (Ross et al., 2000). The ASSR amplitudes of this study were scaled with respect to the mean ASSR amplitude obtained in the present study and overlaid on Fig. 2b for comparison. The bar graph shown in Fig. 3a demonstrates how

the ASSR amplitude of the test stimulus with the frequency fct changed compared to the value at single AM stimulation (dark gray bars), if an interfering AM component at fci was presented simultaneously. A signi¢cant (P 6 0.025, one-sided bootstrap statistic) amplitude reduction was found for the frequency combinations, which are marked with an asterisk in Fig. 3a. Obviously, the e¡ect of the interfering AM sound is strongest in absolute and relative measure for low-frequency test stimuli. A clear asymmetry related to the frequency fci of the interfering sound can also be observed in Fig. 3a. At test frequencies fct = 0.5, 1, and 2 kHz the amplitude reduction is larger if fci is one octave above fct than one octave below. The data shown in Fig. 3a are rearranged in Fig. 3b in order to demonstrate how the interfering stimulus a¡ects the response to the test stimulus. The example of fct = 0.25 kHz and fci = 0.5 kHz demonstrates that low-frequency components are mostly reduced in case of a second component with higher frequency. The comparison of the bar graphs in the left column shows

Fig. 3. Group averages of ASSR amplitudes evoked with dual-component AM stimuli compared to the amplitudes in response to singe AM stimuli. (a) The ¢ve bar diagrams related to constant test frequencies fct between 0.25 and 4 kHz display the ASSR amplitudes to the test stimulus in the presence of interfering AM sounds with carrier frequencies fci (light gray) and the ASSR amplitude in response to a single AM stimulus at fct (dark gray). The error bars show the 95% con¢dence limits of the mean. The asterisks denote signi¢cant amplitude reduction at fct in the presence of fci compared with responses to single AM stimuli. (b) The data from panel a rearranged into ¢ve diagrams with constant frequency fci of the interfering stimulus show how the ASSR amplitudes of the test stimuli are a¡ected by the interfering stimulus. The ASSR amplitudes in case of single AM stimulation are given with dark gray bars.

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Fig. 5. Frequency-speci¢city characteristics obtained as smooth approximations to the characteristics shown in Fig. 4 and normalized to the response amplitude in case of a single AM stimulus. The characteristics show the reduction of the ASSR amplitude in response to the test AM stimulus at fct from its amplitude in the single AM condition in the presence of an interfering AM stimulus with the carrier frequency fci .

Fig. 4. Group averages of ASSR amplitudes corresponding to the test frequencies fct = 250, 500, and 1000 Hz of a dual-component AM stimulus versus the carrier frequency fci of the interfering sound. The horizontal lines denote the ASSR amplitude in case of a single AM stimulus at fct . The error bars show the standard error of the mean. The thin lines are approximations of the characteristics by smooth exponential functions excluding the case of equal carrier frequencies.

large e¡ects of interfering stimuli with higher frequencies on the 250-Hz test response (Fig. 3a), in contrast to the small e¡ect of a 250-Hz interfering stimulus on the responses to test stimuli of higher frequencies (Fig. 3b). In case of a common carrier frequency a signi¢cant amplitude reduction was found for all frequencies. Both ASSR amplitudes at 39 and 41 Hz were reduced by 19% of the single AM response at 250 Hz, 17.4% at 500 Hz, 16% at 1 kHz, 18% at 2 kHz, and 25% at 4 kHz. At no frequency this amplitude reduction was signi¢cantly different from the mean of 22%. The ASSR amplitudes obtained with combined AM stimuli for carrier frequencies separated less than one octave are shown in Fig. 4 together with the corresponding octave separations. The response amplitudes were smaller if the frequency di¡erence was smaller than one octave. However, the amplitudes did not decrease monotonously if both carrier frequencies were in close vicinity. Also, the case of equal carrier frequencies fci = fct seemed to be an exception. This point was therefore excluded when the data were approximated by smooth exponentials. The normalization of these exponential functions to the amplitudes obtained from single AM stimulation

and the test frequency fct resulted in the frequency-speci¢city curves shown in Fig. 5. These curves were narrow for high fct and widest for the lowest fct = 250 Hz. Also, the broader extension of the frequency-speci¢city curves above fci /ct = 1 compared to the lower frequency branches became obvious. The frequencies at which the amplitude decrements reach half of their maximum values were measured as 1077 Hz (4.31fct ) at fct = 250 Hz, 320 and 1570 Hz (0.64 and 3.14 times fct ) at 500 Hz, and 780 and 2060 Hz (0.78 and 2.06 times fct ) at 1000 Hz. The suppression of the ASSR amplitude in response

Fig. 6. Amplitude of a fct = 250-Hz AM test stimulus normalized to the amplitude at single AM stimulation versus the normalized frequency fci /fct , an interfering pure tone (thick line with square symbols) and the frequency-speci¢city characteristic for an fct = 250-Hz AM test stimulus interfering with a pure tone at fci (dashed line) in comparison with the frequency-speci¢city characteristics obtained for interfering AM stimuli (thin solid lines for fct = 250, 500, and 1000 Hz).

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to an AM sound with fct = 250 Hz in the presence of an interfering non-modulated pure tone with fci between 250 and 4000 Hz is shown in Fig. 6. If the pure tone frequency fci was equal to the AM carrier frequency fct , the carrier amplitude is e¡ectively increased and the modulation depth reduced by about 10 dB (the modulation depth, calculated as (max3min)/(max+min), reduces to 1/3). Compared to the single AM response the corresponding ASSR amplitude was only little reduced to 81.7%. In contrast, if the pure tone frequency fci was only slightly di¡erent from the test frequency fct , the ASSR amplitude was suppressed to about one-third of the single AM response. With increasing distance between the pure tone frequency and the AM sound the ASSR amplitude recovered, reaching the value of the single AM response at 2 kHz, which is three octaves above fct .

4. Discussion Since no structural magnetic resonance images were available from the test subjects, a comparison of the source localization results with individual anatomical structures was not feasible. However, since the ASSR sources were more anterior and more medial to N1 sources, which is most likely generated from sources in lateral parts of Heschl’s gyrus and the planum temporale (Pantev et al., 1995; Godey et al., 2001), the ASSR sources are assumed to be located along the Heschl’s gyrus. This result is consistent with previous observations under the same experimental conditions (Engelien et al., 2000; Draganova et al., 2002; Ross et al., 2002). Thus, the cortical sources of the ASSR obtained in this study are assumed to originate mainly from the primary auditory cortex. In order to obtain a high signal-to-noise ratio for the ASSR all MEG measurements were performed at the stimulus intensity of 70 dB above sensation level. Up to this stimulus level the ASSR amplitude rises with increasing intensity and saturates at higher intensity (Ross et al., 2000). Investigations of lower intensities, which might show di¡erent frequency dependences (John et al., 1998), were not feasible due to limitation of total measurement time. Our results showed that the 40-Hz response is much larger when the carrier frequency of the stimulus is low (Fig. 2). Since the 40-Hz ASSRs were reported for the ¢rst time in the auditory system (Galambos et al., 1981) they were discussed in close relation to the auditory MLR responses. However, clearly enhanced MLR amplitudes for low-frequency stimuli have never been described. When comparing the responses to brief 500 and 2000 Hz tone bursts no signi¢cant di¡erences in MLR amplitudes were found (Oates and Stapells, 1997a,b). In

contrast, in the present study the ASSR amplitude at 500 Hz was twice as large as the 2000 Hz ASSR. This preference for low carrier frequencies replicates previous studies (Ross et al., 2000). A reduction of the ASSR amplitude by a factor of two, when the stimulus frequency increased from 1000 to 4000 Hz was reported by Pantev et al. (1996). However, no amplitude di¡erences were found for frequencies between 250 and 1000 Hz in their study, in which brief tone-burst stimuli were used instead of AM sounds. Furthermore, lower ASSR amplitude was found at 500 Hz carrier frequency as compared to 1000 Hz when the modulation frequencies were above 80 Hz (John et al., 2002). The strong e¡ect of low carrier frequency on the 40-Hz response to AM tones demonstrated in the current study is therefore quite di¡erent from the MLR, the ASSR elicited by brief tones or the ASSR at more rapid modulation rates. This is di⁄cult to explain in terms of peripheral e¡ects in the auditory system. One speculation is that it might represent some cortical enhancement of responses that follow low frequencies. This might be important in following the pitch of the human voice while speaking or singing. Such a pitch might serve as a carrier for the spectral information at higher frequencies determining phonetic content. An enhanced representation of low stimulus frequencies also became evident from larger amplitudes of the N1 and mismatch negativity responses to low-frequency stimuli (Wunderlich and Cone-Wesson, 2000). The experimental results demonstrate strong interactions between ASSRs in the 40-Hz range when two AM sounds were presented simultaneously. The interaction was visualized as a frequency-speci¢city characteristic, describing the decrement of the ASSR amplitude evoked by a test stimulus in the presence of an interfering stimulus as a function of the frequency of the interfering stimulus. The frequency-speci¢city characteristics showed deepest amplitude decrement and widest extension on the relative frequency scale for ASSR evoked by a low carrier frequency (250 Hz) AM sound. Furthermore, the frequency-speci¢city characteristics were asymmetrical. Interfering stimuli with frequencies above the test frequency fct suppressed the ASSR amplitude more strongly than the interfering stimuli with frequencies below fct . This asymmetry is opposite to the asymmetry of tuning curves obtained from auditory nerve ¢bers, which show that much larger stimulus intensity is necessary for activation above the characteristic frequency than below. Psychoacoustical tuning curves also show an asymmetry opposite to the asymmetry of frequency-speci¢city characteristics found in this study. Stimuli with greater frequency than the test tone have less masking e¡ect on the threshold for the test tone than stimuli with frequencies lower than the test tone.

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In addition, the response to a low-frequency test stimulus was more strongly suppressed by an interfering stimulus than a test stimulus with higher frequency. The larger e¡ect on ASSR in response to low carrier frequency AM stimuli corresponds to generally larger ASSR amplitudes for low-frequency stimuli, even in the case of a single AM sound. More likely both peripheral cochlear mechanisms and central neural interactions are involved in this phenomenon and the e¡ects are superimposed in the observed evoked ASSR. An asymmetrical frequency characteristic of amplitude suppression in a dual AM experiment as found in our study was also reported by John et al. (1998) at modulation frequencies of 80 and 97 Hz. However, a signi¢cant amplitude reduction to the 1000-Hz test stimulus was only observed if the masker frequency was below 1500 Hz or above 900 Hz. Thus, at the higher modulation frequency the interaction between the pair of AM sounds is restricted to a narrower frequency band of roughly half of the extent seen at 40 Hz modulation frequency. In the same study John et al. (1998) found for 40-Hz responses to a 1000-Hz test stimulus even a slightly enlarged amplitude at 500-Hz interfering stimulus and an amplitude reduction to 87% when the interfering stimulus was 2000 Hz. Their results showed a similar asymmetry; however, the e¡ect was small and did not reach signi¢cance. It is possible that the electrical response is a combination of brainstem and cortical responses (Herdman et al., 2002) and that the magnetic response is mainly of cortical origin. Therefore, di¡erent frequency speci¢city of the responses may result in di¡erences between EEG and MEG observations. Similar asymmetrical frequency interaction characteristic between AM stimuli or two tone stimuli and a second modulated or pure tone were reported by Dolphin and Mountain (1993), Dolphin et al. (1994) and Dolphin (1997) from anesthetized Mongolian gerbils for a wide range of modulation frequencies from 50 to 500 Hz. In these experiments similar frequency characteristics were found when the interfering stimulus was either a modulated sound or a pure tone. Possible explanations were given by multiple interactions between spectral stimulus components if both stimuli were closely spaced or in general a distortion of the periodic envelope of the AM stimulus in the presence of a second tonal stimulus. However, it is not clear whether this animal model is valid for the human 40-Hz ASSR, which are known to be strongly depressed under anesthesia. Studies of the frequency speci¢city of the N1 response have shown the importance of changes in the experimental conditions. Sharply de¢ned frequency speci¢city was found when a notched noise masker was added continuously (Sams and Salmelin, 1994) to

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the N1 eliciting tone-burst stimulus or when the interfering stimuli were presented very rapidly (Na«a«ta«nen et al., 1988). However, widespread interaction was reported when the stimuli and masker were sequentially presented at slower rates (Butler, 1968; Picton et al., 1978a,b). Obviously, both types of experiments described di¡erent e¡ects. The continuously presented masker did not elicit an onset-related N1 response. More likely, the masker interacts with the stimulus sound in the auditory periphery and it seems that the N1 response mainly re£ects the frequency characteristics of the auditory periphery. When the test and masker tone bursts were presented sequentially, the onset of both stimuli evoke N1 responses when the rate is slow. In this case, the widespread interactions between stimulus and masker frequencies are likely related to the N1-generating neural network rather than to e¡ects at the auditory periphery. The interactions between our stimuli depended on the carrier frequency and not on the modulating frequency of the interfering stimulus. When two AM sounds with di¡erent modulation frequencies are presented simultaneously, the two evoked ASSR might interact at the level of the envelope-following mechanism and cause the suppression of the response amplitudes. If this is true, the amplitude decrement should be much less if the second sound was a non-modulated sound, which does not evoke an ASSR. However, our experimental results have shown that this is not the case. The e¡ect on the ASSR amplitude was similar when the second sound was a high-pass masking noise (Mauer and Do«ring, 1999). When using tonal or high-pass noise masker, sharply tuned frequency characteristics were found for a wide range of auditory evoked responses. The frequency characteristics of the V^VP ABR wave were identical to those found for the Na^Pa wave of the MLR. Even the N1 response of much longer latency showed a sharply tuned frequency characteristic. For ASSR above 80 Hz it was con¢rmed that the sharply tuned characteristic is preserved in the case of multiple AM stimuli (Herdman et al., 2002). It seems that for different evoked responses the observed frequency characteristics mainly re£ect the properties of the auditory periphery. However, it is unlikely that the peripheral processing of multiple AM in the 40-Hz range is di¡erent from multiple AM above 80 Hz. There is no reason to assume a wider-spread interaction of the AM components in the periphery for 40-Hz modulated sounds compared to higher modulation frequencies. The interaction observed in the present study was much wider spread in frequency domain than expected from a possible interaction between a pure tone and an AM sound in the auditory periphery. The e¡ect of

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masking noise on the 40-Hz ASSR amplitudes has been investigated in previous studies. Because of high variability of the ASSR amplitudes the high-pass masking pro¢les reported by Gri⁄ths and Chambers (1991) were not signi¢cantly di¡erent from peripheral tuning curves. However, a tendency toward a broader frequency characteristic at 250-Hz carrier frequency and in general smaller ASSR amplitudes at higher frequencies became evident. Frequency characteristics showing more pronounced interaction over wide frequency ranges were obtained by Mauer and Do«ring (1999), who observed the ASSR evoked by a 40-Hz modulated 240-Hz tone as a function of the lower cut-o¡ frequency of a continuously added high-pass or bandpass noise masker. The ASSR amplitude was reduced to 28% of the single AM amplitude, 35% at one, 47% at two, 68% at three, and 92% at four octaves above the 240-Hz carrier frequency. This behavior ¢ts exactly to the one observed in this study. Obviously, a common carrier frequency for both AM sounds constitutes a special case of dual AM stimulation. The obtained ASSRs in this case were described in detail by Draganova et al. (2002), who demonstrated an almost linear representation of the complex stimulus envelope waveform in the activity evoked from the primary auditory cortex including the low-frequency component related to the interfering beat between the 39and 41-Hz modulation frequency. Also in this case both single stimulus components were set to equal intensity of 70 dB SL, which resulted in a 6-dB larger intensity compared to the single AM stimulation. Assuming a linear dependence of the ASSR on the intensity in dB, the ASSR amplitude should increase by 8.5% when the intensity increases from 70 to 76 dB. The ASSR amplitudes at common carrier frequency were each 78% of the single AM amplitudes. The combined signal power of both responses was about 10% larger than the signal power of a single response. Very similar results were obtained in the EEG study of Picton et al. (1987) with 1000-Hz carrier and 39- and 49-Hz modulation frequencies. Therefore, it seems reasonable to describe the amplitude e¡ect in the case of common carrier frequencies as a ‘distribution of the total response onto the two spectral components’ instead of ‘amplitude suppression’, even though both ASSR amplitudes were reduced by roughly 25% compared to a single AM stimulation. Also, the combination of an AM sound and a pure tone with fci = fct can be explained as a single AM sound with reduced modulation depth because of the increased carrier amplitude. In this case the ASSR amplitude reduction by about 20% was similar to the one expected from the relation between ASSR amplitude and modulation depth (Ross et al., 2000). In summary, the suppression of the 40-Hz ASSR by a

sound masker with a di¡erent carrier frequency is much greater than the e¡ects on the ASSR above 80 Hz. The frequency e¡ects were also quite di¡erent from those expected from the known frequency characteristics of MLR and ABR. The enhanced low-frequency ASSR amplitude and the stronger interaction between multiple AM stimuli at low frequencies cannot be explained with the characteristics of the auditory periphery. Thus, it seems reasonable to assume an additional e¡ect of interaction of the stimuli in more central neuronal structures. An interaction between probe and masker sound is possible at any level of the ascending auditory pathway, at which phase locking between neural activity and the stimulus is preserved. In general, the phase locking degrades at higher levels. Recently, Krishnan (2002) recorded in humans frequency following responses (FFR), which is stimulus phase-locked activity, to steady-state English vowels. Signi¢cant responses corresponding to the second formants (F2) with frequencies between 840 and 1098 Hz were demonstrated. These FFR were interpreted as evidence that neural encoding based on phase locking is preserved at higher levels, most likely the lateral lemniscus and the inferior colliculus. Phase-locked responses to pure tones even in the primary auditory cortex were reported for the guinea pig (Wallace et al., 2002) and were related to the ¢rst formant of guinea pig voicing. If the spectral components of the auditory signal are represented in a phaselocked manner in neural activity of brainstem and midbrain structures then also the temporal structure of the sound is preserved there. This might be of great importance for speech processing. In general, pure-tone tuning curves of single neurons in the auditory pathway show a steep slope towards high frequencies and a shallower slope at low frequencies. The frequency-speci¢city characteristics found in this study showed a reversed shape. This apparent contradiction may be dissolved when considering that speci¢c auditory neurons can respond to AM sounds in di¡erent frequency bands than to pure tones. Evidence for across-frequency channel interactions was provided by Biebel and Langner (2002), who demonstrated in awake chinchilla that neurons in the inferior colliculus, which were tuned to low-frequency pure tones (e.g. 180 Hz), responded to low-intensity AM stimuli at carrier frequencies far above the characteristic frequency. The classical model for ASSR to AM sounds or envelope-following responses in general is the demodulation through the non-linearity of hair cells (Regan, 1989) and envelope extraction after low-pass ¢ltering of the demodulated signal. However, if the spectral composition of an AM sound especially at low carrier frequencies is preserved in a phase-locked manner in the

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brainstem and midbrain and even the primary auditory cortex, it is not unreasonable to assume further demodulation at higher levels of the auditory system. For lowfrequency AM sounds interaction between the spectral components, which result in an activity pattern following the sound envelope, in more central structures have to be considered. These additional activity patterns may explain the enhanced ASSR amplitudes at low carrier frequencies. However, it is still an open question why the interaction with a second sound extends over a wide frequency range. A possible mechanism is the active suppression of neighboring frequency components for contrast enhancement. A similar active mechanism is known in the cochlea as two-tone suppression. The two-tone suppression could largely explain the interaction of closely spaced AM sounds with modulation frequencies in the 80^100 Hz range (John et al., 1998). However, the interaction between concurrently presented sounds extended over a wider range, as in this study, cannot be explained by two-tone suppression in the cochlea. It is possible that the ASSR recorded from the primary auditory cortex represents the overall temporal structure of the sound regardless of the carrier signal. Then, a second sound added to an AM sound would disturb its periodical envelope and the corresponding ASSR amplitude would decrease. However, the results from multiple AM of a single carrier showed that the rather complex envelope caused by very similar modulation frequencies is represented in the ASSR. The strong interaction occurs only if the carrier frequencies are di¡erent. The suppression of the high-frequency, partially in favor of the low-frequency sound, may be related to an active selection process in the central auditory system. Such selection may relate to an enhanced representation of fundamental spectral components of speech sound.

5. Conclusions The enhanced ASSR amplitude at low carrier frequencies of the AM stimulus and the amplitude suppression in the presence of an interfering sound over a wide frequency range are in contrast to the frequency speci¢city observed for evoked responses recorded from di¡erent levels of the auditory pathway. The observed characteristics are also di¡erent from the ASSR above 80 Hz. A possible explanation is the demodulation and ASSR generation in the central auditory system in addition to the demodulation at the cochlear level. Gathering more knowledge about these phenomena will make the ASSR an important tool for studying the processing of complex sound in the central auditory system.

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Acknowledgements This work was supported by grants from the Deutsche Forschungsgemeinschaft (No. Pa392/7-2,3) and the Canadian Institutes for Health Research, the Ontario Innovation Trust and the Canadian Foundation for Innovation.

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