Cortical generators of slow evoked responses elicited by spatial and nonspatial auditory working memory tasks

Clinical Neurophysiology 116 (2005) 1644–1654 www.elsevier.com/locate/clinph

Cortical generators of slow evoked responses elicited by spatial and nonspatial auditory working memory tasks Irina Anurovaa,g, Denis Artchakova,b,g, Antti Korvenojac,d,g, Risto J. Ilmoniemic,f,g, Hannu J. Aronene,g, Synno¨ve Carlsona,b,g,* a

Neuroscience Unit, Institute of Biomedicine/Physiology, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland b Department of Basic Veterinary Science/Physiology, University of Helsinki, Helsinki, Finland c BioMag Brain Research Unit, BioMag Laboratory, Helsinki University Central Hospital, Helsinki, Finland d Functional Brain Imaging Unit, Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland e Cognitive Brain Research Unit, Department of Psychology, University of Helsinki, Helsinki, Finland f Nexstim Ltd, Helsinki, Finland g Helsinki Brain Research Center, Helsinki, Finland Accepted 20 February 2005

Abstract Objective: Slow evoked responses have been extensively studied using electrophysiological and neuroimaging methods, but there is no consensus regarding their generators. We investigated the generators of the P3 and positive slow wave (PSW) in the evoked responses to probes recorded during auditory working memory tasks to find out whether there is dissociation between functional networks involved in the generation of the P3 and PSW and between spatial and nonspatial auditory processing within this time window. Methods: Whole-head magneto-(MEG) and electroencephalography (EEG); analysis of MEG data using minimum-norm current estimates. Results: The associative temporal, occipito-temporal and parietal areas contributed to the generation of the slow evoked responses. The temporal source increased while the occipito-temporal source diminished activity during transition from the P3 to PSW. The occipitotemporal generator of the P3 was activated more during the spatial than nonspatial task, and the left temporal generator of the PSW tended to be more strongly activated during the nonspatial task. Conclusions: These findings indicate that partially distinct functional networks generate the P3 and PSW and provide evidence for segregation of spatial and nonspatial auditory information processing in associative areas beyond the supratemporal auditory cortex. Significance: The present results support the dual-stream model for auditory information processing. q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Auditory working memory; Location; Pitch; P3; Positive slow wave

1. Introduction The neuronal mechanisms underlying the processing of sound content and its spatial location have attracted research interest over the last few years. Several lines of evidence

* Corresponding author. Address: Neuroscience Unit, Institute of Biomedicine/Physiology, Biomedicum Helsinki, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland. Tel.: C358 9 19125316; fax: C358 9 19125302. E-mail address: [email protected] (S. Carlson).

support a dual-stream theory which assumes segregation of ‘what’ and ‘where’ auditory information processing. Histological and single-cell studies in nonhuman primates provide an anatomical basis for the segregation of spatial and nonspatial auditory processing (Kaas and Hackett, 1998, 2000; Kaas et al., 1999; Rauschecker and Tian, 2000; Rauschecker et al., 1997; Romanski et al., 1999). Reports on patients with selective deficits in sound localization and recognition following focal hemispheric lesions (Clarke et al., 2000, 2002) and results from neuroimaging (Alain et al., 2001; Maeder et al., 2001; Warren and Griffiths, 2003),

1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2005.02.029

I. Anurova et al. / Clinical Neurophysiology 116 (2005) 1644–1654

electrophysiological (Alain et al., 2001; Anourova et al., 2001, 2003; Novitski et al., 2003) and psychophysical studies (Anourova et al., 1999; Clarke et al., 1998) support the idea of segregation, suggesting that different brain structures are specifically involved in the processing of spatial and nonspatial information. Results from a recent study by Warren and Griffiths (2003) employing functional magnetic resonance imaging (fMRI) during auditory spatial and nonspatial perceptual tasks demonstrate that within the planum temporale, variation of sound pitch activated anterolateral areas, while the processing of spatial locations preferentially involved posteromedial sites. This finding is in line with our earlier results demonstrating that the generator of the N1m component is more medial during location than pitch task performance (Anourova et al., 2001), suggesting that the dissociation between spatial and nonspatial auditory information processing occurs within the supratemporal plane as early as at about 100 ms from stimulus onset. Results from an elaborate meta-analysis (Arnott et al., 2004) comparing the activation patterns obtained in several spatial and nonspatial fMRI and positron emission tomography (PET) studies provided evidence for segregation between ‘what’ and ‘where’ processing within the frontal, temporal and parietal associative structures. Because of their relatively poor temporal resolution, PET and fMRI are not optimal methods for studying the timing of activity. We employed electro- and magnetoencephalography (EEG and MEG) to study the spatiotemporal dynamics during location and pitch auditory information processing, particularly in the higher-order associative areas. Although there is no consensus yet regarding the location of the generators of slow evoked responses, results of studies employing different source localization techniques and intracranial recordings have suggested several associative cortical areas as possible sources of the P3, including areas in the parietal (Halgren et al., 1995a; Horovitz et al., 2002; Kiehl et al., 2001; Kiss et al., 1989; Linden et al., 1999; Menon et al., 1997; Moores et al., 2003; Smith et al., 1990), temporal (Halgren et al., 1995b, 1998; Horn et al., 2003; Kiehl et al., 2001; Linden et al., 1999), and frontal cortices (Kiehl et al., 2001; Kirino et al., 2000; Linden et al., 1999; McCarthy et al., 1997; Menon et al., 1997). Evidences from studies employing intracranial recordings indicate that medial temporal lobe structures, including the hippocampus and parahippocampal gyrus, have a role in target detection (Kanovsky et al., 2003; Paller et al., 1992; Smith et al., 1990). Polarity reversals along the surface of the medial temporal lobe may indicate local sources of recorded P3-like potentials, however, these potentials were 50 ms delayed compared to scalp-recorded P3 (Halgren et al., 1995b, 1998). Although some clinical observations reported local attenuation of the P3 after temporal lobectomy (Daruna et al., 1989), generally, results from lesion studies are highly inconsistent (Moores et al., 2003). Therefore, it is not clear whether medial temporal lobe structures have a considerable contribution to the scalp-recorded P3 (Moores et al., 2003).

1645

In addition to the medial temporal sources, intracranial recordings have also revealed P3 generators within the parietal lobuli (Halgren et al., 1995a; Smith et al., 1990), the superior temporal sulcus (Halgren et al., 1995b, 1998) and the parieto-occipital region (Kiss et al., 1989). The development of source localization techniques such as the equivalent current dipole-fitting and minimum-norm estimates has provided the possibility to determine the generators of the components of evoked responses obtained in multichannel EEG and MEG recordings. In the studies employing the dipole-fitting algorithms, both cortical (mainly in the temporal lobes) and deep subcortical (thalamus) structures have been suggested to generate the P3 in target recognition tasks (Hegerl and Frodl-Bauch, 1997; Mecklinger et al., 1998; Rogers et al., 1991; Tarkka et al., 1995). However, referring to the results from simulation studies (George et al., 1995), it has been pointed out that the use of the dipole-fitting algorithm might result in errors concerning the depth of broad and extended sources (Moores et al., 2003). Another limitation of dipole modelling is the requirement of a priori assumptions of the number and possible locations of the estimated sources (Moores et al., 2003; Tarkka et al., 1995). Thus, algorithms that do not require any a priori knowledge about the number of active sources or their spatial locations, such as minimum current estimates (MCE), seem to be suitable tools for the analysis of the slow components of evoked responses (e.g., Moores et al., 2003; Raij et al., 1997). Recent combined electrophysiological and neuroimaging studies have enabled the analysis of correlations between the amplitudes of evoked responses and regional hemodynamic responses. Activation in the supramarginal gyri, right medial frontal gyrus, insula, and thalamus correlated with the P3 amplitude as a function of target probability in a combined EEG—fMRI study (Horovitz et al., 2002), suggesting that these regions are probable sources of the P3. In a combined EEG–PET study (Perrin et al., 2005), regional blood flow in the posterior part of the right superior temporal sulcus, the precuneus, and medial prefrontal cortex correlated with the amplitude of the P3 elicited by the subject’s own name. In event-related potentials (ERP) recorded during complex tasks involving either perceptual difficulty (Ruchkin et al., 1988) or a high working memory load (Garcia-Larrea and Cezanne-Bert, 1998), the P3 component may be followed by a positive slow wave (PSW) (Squires et al., 1975). However, it is still unclear whether these two peaks represent different components of the evoked response or a single event. The P3 and PSW may be dissociated on the basis of their distinct relationships with such experimental manipulations as variations in perceptual and conceptual difficulty (Ruchkin et al., 1988), emotional content of stimuli (Keil et al., 2002) or memory load (Garcia-Larrea and Cezanne-Bert, 1998; Pelosi et al., 1992), or on the basis of their different correlations with reaction times (RT) (Roth et al., 1978; Ruchkin et al., 1980). In our previous

1646

I. Anurova et al. / Clinical Neurophysiology 116 (2005) 1644–1654

2.2. Experimental stimuli

study, in which we investigated responses to the memory items obtained during the performance of spatial and nonspatial auditory working memory tasks (Anurova et al., 2003), both the P3 and PSW increased in parallel with memory load. However, these potentials were differentially affected by the type of task (spatial or nonspatial). While the amplitude of the P3 did not change between the location and pitch tasks, the amplitude of the PSW was higher in the location than pitch task in the lowload condition. This finding motivated us to analyze the P3 and PSW elicited by the probes in the above experiment in order to test how the responses change with respect to the type of task (location vs. pitch) and probe (match vs. nonmatch). The results of this analysis are presented here.

Pure tones (duration 200 ms, including 10 ms rise and fall times) with a frequency of 220, 440 or 880 Hz were presented binaurally through plastic tubes and earpieces. Left and right locations were simulated by an interaural intensity difference of 13 dB and an interaural time difference of 500 ms. For the left and right sounds, the intensity in the ipsilateral side was 75 dB SPL and 62 dB in the contralateral side. The middle location was simulated by binaural presentation of symmetrical 70 dB tones. Furthermore, the subjective loudness of the sounds was adjusted by attenuating the intensity bilaterally by 3 dB for the sounds with the frequency of 440 Hz and by 6 dB for 880 Hz. The delivery of the stimuli was controlled by a computer program (Presentation 0.31, Neurobehavioral Systems, Inc., San Francisco, USA), which was also used for collecting the behavioral data (correct and incorrect responses, and reaction times).

2. Materials and methods The subjects, behavioral paradigms, and experimental procedure were identical to those reported in the article by Anurova et al. (2003), which focused on the responses to memory items. Here we report results from the analysis of slow components, the P3 and PSW, of the evoked responses to the probe stimuli, recorded during the experiment as described in the above-mentioned paper, but not reported earlier.

2.3. Behavioral tasks One trial of the task consisted of six stimuli (Fig. 1); the first three were memory items, and the last three were probes. The 4th stimulus was to be compared with the 1st, the 5th with the 2nd, and the 6th with the 3rd. The subjects performed location and pitch versions of the task. Similar blocks of stimuli were used in both tasks: three frequencies and three locations were mixed in a pseudorandom order. The tasks differed from each other only with respect to the instruction: in the pitch task the subjects had to attend to the frequency of the cue irrespective of its location and in the location task to its location irrespective of the frequency.

2.1. Subjects Nineteen healthy right-handed volunteers (10 males), aged 21–32 years (mean age 27 years) with no history of hearing disorders participated in the study.

REST

Pitch task: R

L

M

R

R

L

M

R

M

M

L

M

R

R

M

L

L

M

R

R

M

L

REST

Location task: M

M

1 trial + 0.2 s 1s

1.8 s

1.8 s

1.8 s

1.8 s

Cue I

Cue II

Cue III

Match

1.8 s

1.8 s

Non-match Match +

Fig. 1. The behavioral tasks and experimental design. The height of the bar represents the frequency of the tone (220, 440 or 880 Hz). LZleft, MZmiddle and RZright presentation locations. Triangles (;) indicate match trials, CZfixation cross; vertical arrows indicate time points when the fixation cross turned on (up) and off (down). Motor response (button pressing) is symbolised with a computer mouse.

I. Anurova et al. / Clinical Neurophysiology 116 (2005) 1644–1654

The trials started when a fixation cross appeared on the screen. After a fixation time of 1 s, the first cue was presented. The time between the onsets of successive stimuli within one trial was 2 s. Motor responses were required only for the probe stimuli. The subjects were instructed to press the left button of a response pad with the right index finger if the probe stimulus was of the same frequency as the cue in the pitch task or in the same location as the corresponding cue in the location task (match condition). In the nonmatch condition, the subjects were instructed to press the right button with the right middle finger. Matching and nonmatching probes were presented with an equal probability. The subjects were instructed to respond as fast and as accurately as possible and to continue visual fixation until the fixation cross was turned off 2 s after the onset of the last stimulus of the trial. After a 2 s intertrial interval (rest) a new trial started. Each experimental session consisted of 12 blocks of 30 trials: 6 blocks of the location task and 6 of the pitch task. The order of the location and pitch blocks was counterbalanced across the session and across subjects. At the end of the experiment, the subjects filled a questionnaire indicating, on a five-point scale, the subjective difficulty level of the tasks (1Zvery easy, 2Zeasy, 3Zintermediate, 4Zdifficult and 5Zvery difficult). They also described the strategies they had used during task performance by choosing the most appropriate definition from a list of five alternatives (‘auditory rehearsal’, ‘verbal’, ‘visual imagery’, ‘somatosensory imagery’ and ‘no definite strategy’). Statistical analysis of the behavioral data (task performance accuracy and subjective difficulty level) was performed using the paired nonparametric Wilcoxon’s signed-ranks test. Reaction times were analyzed using a 2-way analysis of variance (ANOVA) for repeated measures with the factors being Task (location vs. pitch) and Probe type (match vs. nonmatch). If significant main effects were observed (P!0.05), post hoc analyses were performed using the Newman–Keuls test. 2.4. Neurophysiological data collection and analysis Electrophysiological data were recorded using simultaneous whole-head MEG (306-channel magnetometer VectorView, Elekta Neuromag, Finland) and EEG (60channel Ag/AgCl-electrode cap). The data were recorded in a magnetically shielded room (Euroshield, Finland). The reference electrode was placed on the nose and the ground electrode on the left cheek. In addition, vertical and horizontal electro-oculograms (EOG) were recorded. The analog recording passband was 0.03–100 Hz and the sampling rate 600 Hz. Epochs starting 100 ms before and ending 1500 ms after the auditory stimulus onset were averaged online. Epochs containing artifacts (EOG or EEG variation R150 mV) or incorrect responses were automatically excluded from the analysis. Signal amplitudes were defined with respect to the baseline, which was determined

1647

Fz

Cz

Pz

Fig. 2. The 15-electrode set for the analysis of the P3 and PSW.

as the average signal amplitude during the 100 ms period preceding stimulus onset. The ERP components were analyzed after digital filtering with a passband of 0.5–20 Hz separately in four experimental conditions: match and nonmatch trials in both location and pitch tasks. Their amplitudes were determined within a set of 15 electrodes centering on the parietal midline electrode (Pz). (Fig. 2). The amplitudes of the ERP components were determined as the mean amplitudes over a 50 ms time window around the peak latency at the Pz electrode site. The values were collected individually for each subject from each electrode site of the set. Statistical analysis of the peak latencies of ERP components was performed for the Pz electrode site. The P3 component was determined as the most positive peak within the 250–450 ms time window, and the PSW as the most positive peak within the 430–700 ms window, following the P3. The time windows for the P3 and PSW never overlapped for the same subject’s data set. For statistical comparison of the latencies of the two ERP components, a 2-way ANOVA with factors Task (location vs. pitch) and Probe type (match vs. nonmatch) was applied. The amplitudes of the ERP components were analyzed using a 4-way ANOVA with the factors being Task, Probe type, Component (P3 vs. PSW) and Electrode (15 sites). Source configurations underlying the MEG data sets were modeled using the minimum current estimate (MCE) algorithm (Elekta Neuromag OY, Finland) (Uutela et al., 1999). The MCE implements the minimum L1-norm estimate by minimizing the sum of the absolute values of the current amplitudes (Uutela et al., 1999). This method does not require any a priori assumption about either the number of sources or their spatial distribution. MCEs for all experimental conditions were calculated separately for each individual subject. Averaged responses were preliminarily filtered with a 20 Hz low-pass digital filter. Detrended baseline was set at an 800–1000 ms time interval in order to eliminate low-frequency noise. Computations were performed for each time sample starting from 100 ms before and up to 1000 ms after the stimulus onset using the spherically symmetric conductor model. The origin of

1648

I. Anurova et al. / Clinical Neurophysiology 116 (2005) 1644–1654

the spherical model was determined individually for each subject on the basis of his anatomical magnetic resonance image (MRI) by fitting a sphere to the curvature of the outer surface of the brain in temporal and centro-parietal cortical areas. Anatomical MRIs with 1 mm isotropic voxels were acquired with a Siemens Vision 1.5 T system (Erlangen, Germany) using a T1-weighted three-dimensional magnetization prepared rapid acquisition gradient-echo (MPRAGE) sequence (TRZ9.7 ms, TEZ4 ms, TIZ 20 ms flip angle 108, 180 sagittal slices with a thickness of 1 mm, no gap, field of view 256!256 mm, pixel size 1! 1 mm). For one subject, the anatomical scan was not obtained because of contraindications, and the MEG data of this subject was not analyzed. Source current distributions were compared across subjects; active areas common for at least five subjects from the group were considered for further analysis. The brain volumes with the highest current amplitudes within the region of interest were selected manually. The extent and coordinates of their center were adjusted to the maximal activity. The time courses of the activity within the selected areas were calculated as a spatially weighted average of the estimate with the maximal weight (1.0 in the sum) at the center of the volume. The weight extended to the neighboring locations with the form of a three-dimensional generalized normal distribution, and the points on the border of the region of interest had the weight 0.6 of that at the center. Two consecutive 150 ms integration windows were used for all subjects for the analysis of both late components (P3 and PSW) of the evoked fields; the limits of the timewindows were chosen individually based on the global field power plots obtained for each of the four experimental conditions. The same windows were always used for all conditions within each individual data set. For the statistical analysis a 4-way ANOVA was used: the averaged amplitudes across the 150 ms time-windows were compared between the Tasks (location vs. pitch), the Probe types (match vs. nonmatch), Hemispheres (left vs. right), and the two Components (P3 vs. PSW). 2.5. Transformation of source locations to the standard space The transformation between the subject’s anatomical MRI voxel coordinate space and MEG device coordinate space was determined by identifying the digitized anatomical landmarks (nasion, preauricular points) in the MRI. The source locations were transformed to MRI voxel coordinate space. Nonbrain structures were removed from the subject’s anatomical MRI by using FMRIB’s brain extraction software tool (Smith, 2002). The resulting image volume was co-registered to the ICBM152 T1-weighted brain template by using FMRIB’s Linear Image Registration Tool (Jenkinson et al., 2002). The resulting 12-parameter affine transformation was then used to map coordinates from the subject’s MRI to the ICBM152 standard coordinate space.

3. Results 3.1. Behavioral data Analysis of the behavioral data revealed no differences related to the type of task (location vs. pitch) either in the task performance or in the subjective evaluation of task difficulty, suggesting that the two tasks were well balanced in their cognitive demands. The mean percentage of incorrect responses was 9.6G1.7 (the meanGstandard error of mean, SEM) for the location task and 10.2G2.2 for the pitch task, the mean reaction times 803G47 and 769G41 ms, respectively. The respective subjective difficulty levels were 2.9G0.2 and 3.1G0.2, corresponding to the intermediate level. For a detailed report of the behavioral data, see Anurova et al. (2003). 3.2. EEG data The P3 and PSW in the responses to probes consistently appeared as separate peaks in 16 out of 19 subjects in all experimental conditions. In the three remaining subjects, these components were completely merged at least in one condition, which made it impossible to include their data in the group statistics. The main finding from the EEG data was a prominent and differential effect of the probe type on the amplitudes of the P3 and PSW (Component and Probe type interaction, F(1,15)Z50.5, P!0.001). The amplitude of the P3 was higher in the match than nonmatch condition (P!0.01), while the PSW was higher in the nonmatch than match condition (P!0.001) (Fig. 3A, C and E). However, the latencies of the P3 and PSW components did not depend on the Probe type and were not significantly different in the match and nonmatch conditions. The type of task (location or pitch) did not affect the amplitudes or latencies of the P3 and PSW in the evoked responses to probes. As expected, the ERP amplitudes were significantly affected by the electrode site (F(14,210)Z13.9 and F(14,210)Z20.4 respectively, P!0.001). There were slight differences in the scalp distributions of the P3 and PSW: the maximum values of the P3 amplitudes were obtained at the parietal electrodes while the amplitude maximum of the PSW was at the parieto-occipital electrodes. The late positive components were found to correlate with the behavioral data. The amplitudes of both the P3 and PSW correlated negatively with RTs, suggesting enhancement of the slow evoked potentials when behavioral responses were faster. The Pearson correlation coefficient was K0.67 (P! 0.001) for the P3 recorded at Pz site and K0.46 (P!0.001) for the PSW at POz site. The latency of the PSW correlated positively with RTs (Pearson correlation coefficient 0.39, P!0.01), whereas there was no correlation between the P3 latency and the efficiency of task performance.

I. Anurova et al. / Clinical Neurophysiology 116 (2005) 1644–1654

1649

Fig. 3. The effect of the probe type on the amplitude of the slow evoked responses. (A) Grand-averaged waveforms recorded at the Pz electrode during match and nonmatch conditions. (B) MEG global field power estimated for match and nonmatch conditions. (C) Spatial distribution of the mean amplitudes of the P3 (280–380 ms) and PSW (480–580 ms) recorded during match and nonmatch conditions. (D) Minimum current estimates for the match and nonmatch conditions integrated over the time interval of 250–500 ms. (E) The mean amplitudes of P3 and PSW within the analyzed electrode set. (F) Strength of magnetic field in the precuneal source. The vertical lines indicate standard errors of mean (SEM), *ZP!0.05, **ZP!0.01, ***ZP!0.001.

3.3. MEG data The minimum-norm current estimates suggested several areas as possible generators for the slow evoked responses: bilateral occipito-temporal (around the posterior part of the superior temporal sulcus (STS)), temporal (around the middle part of the STS) and parietal (around the junction of

postcentral and intraparietal sulci) cortices, and the precuneus (Table 1). 3.3.1. Interhemispheric differences A clear interhemispheric difference was observed in the parietal source, which was active mainly in the left hemisphere (F(1,12)Z16.6, P!0.01). The amplitude of

1650

I. Anurova et al. / Clinical Neurophysiology 116 (2005) 1644–1654

Table 1 Mean Talairach coordinates of the generators of slow evoked responses recorded during spatial and nonspatial working memory tasks Source

Component

Location task

Pitch task

Match

Temporal

P3 PSW

Occipito-temp.

P3 PSW

Parietal

P3 PSW

Precuneus

P3 PSW

L R L R L R L R L R L R

Nonmatch

Match

Nonmatch

x

y

z

x

y

z

x

y

z

x

y

z

K54 56 K55 54 K42 44 K44 47 K45 42 K45 35 2 2

K44 K25 K43 K25 K71 K54 K69 K55 K26 K23 K26 K25 K62 K61

K11 K6 K7 K7 10 7 10 5 43 48 47 55 44 47

K55 51 K53 53 K42 46 K44 47 K49 42 K45 36 1 1

K34 K22 K34 K23 K68 K52 K69 K57 K29 K26 K30 K26 K56 K55

K7 K1 K3 K4 7 13 6 14 40 49 46 53 46 46

K56 55 K56 56 K44 50 K40 54 K45 43 K46 41 1 4

K41 K28 K38 K24 K73 K54 K71 K54 K26 K22 K27 K19 K57 K60

K9 K1 K8 K4 5 8 10 4 45 50 47 47 46 46

K53 56 K53 55 K45 50 K44 52 K46 42 K45 37 3 2

K41 K27 K36 K26 K71 K54 K72 K58 K28 K25 K27 K23 K54 K61

K7 K3 K4 K5 6 9 4 10 44 49 48 50 49 46

the temporal source was higher in the right hemisphere (F(1,12)Z6.9, P!0.05) (Fig. 4A and B).

3.3.2. Match vs. nonmatch The strength of the MEG global field power was higher in the match than nonmatch condition (Fig. 3B). The Probe type significantly affected the amplitudes of evoked responses in the parietal (F(1,12)Z7.2, P!0.05) and precuneal (F(1,13)Z4.8, P!0.05) sources: both exhibited higher activity in the match than nonmatch condition (Fig. 3D). Furthermore, the activity of the precuneal source

was affected by the Probe type and Component interaction (F(1,13)Z4.6, PZ0.05): in the nonmatch condition the amplitude of the evoked field was higher during PSW than during P3 (Fig. 3F). 3.3.3. Differences between components Both the temporal (F(1,12)Z21.8, P!0.001) and occipito-temporal (F(1,8)Z11.2, P!0.05) sources were significantly affected by the component. While the occipitotemporal source demonstrated higher activity during the generation of the P3, the activity in the temporal source was higher during the PSW (Fig. 4A and B).

Fig. 4. Interhemispheric differences in the spatial distribution of the sources of the slow evoked responses. (A) Grand average minimum current estimate (MCE) source locations of the P3 (upper row) and PSW (lower row) in the left and right hemispheres. (B) Grand average activation time courses of the temporal (upper panel) and occipito-temporal (lower panel) sources.

I. Anurova et al. / Clinical Neurophysiology 116 (2005) 1644–1654

1651

Fig. 5. The effect of sound attribute on the spatial location of the occipito-temporal source. (A) Sources of P3 and PSW in match and nonmatch conditions of the location (blue circles) and pitch task performance (red circles). Data from an individual subject overlaid on his T1-weighted MRI. (B) Averaged Talairach coordinates of the occipito-temporal generator of slow evoked responses (projection on the axial plane). For interpretation of the reference to colour in this legend, the reader is referred to the web version of this article.

3.3.4. Location vs. pitch The occipito-temporal and temporal generators of the slow evoked responses were sensitive to the Type of task. The occipito-temporal source of the P3 demonstrated higher activity in the location than pitch task (Task and Component interaction, F(1,8)Z8.5, P!0.05). Since the occipitotemporal source was observed in the right hemisphere in six subjects, in the left hemisphere in seven subjects and bilaterally in four of these subjects, the statistical analysis of its coordinates was performed separately for the right and left hemispheres. This analysis revealed a structural segregation in the coordinates of the center of the active area in the medio-lateral direction. In the location task, the right-hemispheric occipito-temporal source was situated 5 mm more medially than in the pitch task (F(1,5)Z10.2, P!0.05) (Fig. 5A and B). There was some indication that activity in the temporal source also varied as a function of task type. In the analysis of the temporal source activity, the Hemisphere, Task and Component interaction was not, however, quite significant (F(1,12)Z4.0, PZ0.067). The activity in the left temporal generator of the PSW tended to be stronger during the pitch than location working memory task.

4. Discussion In the present study, MCE was applied to define the location and time course of the generators of the slow evoked responses, P3 and PSW elicited during the performance of spatial and nonspatial auditory working memory tasks. We show that the medial and posterior temporal generators of the P3 and PSW were sensitive to the sound attribute. This finding speaks for the segregation of spatial and nonspatial auditory information processing. The electric P3 and PSW differed from each other in their dependence on the type of probe stimulus but not the type of

task: the P3 was maximal in the match, while PSW in the nonmatch condition. As expected, several associative temporal and parietal cortical areas contributed to the generation of the slow evoked responses. Within the temporal lobe, activity was seen bilaterally around the posterior (here called the occipito-temporal source) and central parts of the STS (the temporal source), with right-hemispheric dominance for the temporal source. No activity was observed in the primary or secondary auditory cortex on the supratemporal plane within the analyzed time interval. In the parietal lobes, activity was found in the precuneus and around the junction of the postcentral and intraparietal sulci (the parietal source) mainly in the left hemisphere. Activation of the precuneus has been demonstrated in various neuroimaging studies employing auditory or visual working memory tasks (Maeder et al., 2001; Martinkauppi et al., 2000; Zurowski et al., 2002), or tasks requiring selective attention shifts (Nagahama et al., 1999) or mental calculations (Zago and Tzourio-Mazoyer, 2002), suggesting that this structure is part of a supramodal neuronal network engaged in such processes as allocation of attention, retrieval of information and updating of working memory buffer. The predominantly left-hemispheric activity that was detected within the parietal source is consistent with a recent fMRI study by Lewis et al. (2004), in which subjects performed a multiple-choice motor response task with the right hand during sound recognition. Activation in an area close to the left parietal source was observed also in another fMRI study (Culham et al., 2003) during precise grasping with the right hand. Thus, the left-sided activation of the parietal source in our study may reflect preparatory activity related to motor responses of the right hand. The present study revealed functional differences between the networks involved in the generation of the P3 and PSW. The activity within the temporal lobes during

1652

I. Anurova et al. / Clinical Neurophysiology 116 (2005) 1644–1654

the slow evoked responses was shown to increase with time in the postero-anterior direction: the occipito-temporal source was most active during the generation of the P3 component, whereas activity in the temporal source increased over time and reached its maximum during the PSW generation. The role of the posterior temporal areas in the generation of the P3 was emphasized in the combined electrophysiological and single photon emission tomography study by Ebmeier et al. (1995). The activation in the posterior temporal regions (an area close to the occipitotemporal source in the present study) was shown to correlate positively with the amplitude of the P3 component in an auditory target-detection task. The P3 and PSW recorded in the present study differed from each other with respect to match and nonmatch trials: the electrical P3 was strongest in the match and the PSW in the nonmatch condition (Fig. 3A). This result is in agreement with an earlier study employing the Sternberg paradigm (Pelosi et al., 1998) in which the P3 elicited in an auditory task was higher for positive than negative probes, whereas the PSW in the same task was higher for negative probes. In the present study, the activity in the precuneus was affected by the Probe type and Component interaction: in the nonmatch condition, in line with the ERP data, the amplitude of the evoked field increased during transition from the P3 to PSW (Fig. 3F). Furthermore, the electric P3 and PSW had different relationships with behavioral data: the latency of the PSW but not the P3 correlated positively with RTs. Taken together, the results of the present study suggest that P3 and PSW represent different neuronal events. The P3 elicited in the responses to probes during working memory task may reflect, in addition to other functions, the matching of the probe with the memory trace of the previously presented cue. The increase of the PSW amplitude in the nonmatch condition may be related to the engagement of additional retrieval mechanisms in order to ensure that the decision ‘different’ was correct. Another important result concerns the differences between spatial and nonspatial working memory processing in the auditory system: the occipito-temporal generator of the P3 was activated more strongly during the performance of the location task, while the activity of the left temporal generator of the PSW was enhanced during working memory processing of sound pitch, although the latter result was not statistically significant (PZ0.067). In the fMRI study by Lewis et al. (2004), the posterior portions of the middle temporal gyri (pMTG), close to the occipitotemporal area described in the present study, were shown to be activated bilaterally during recognition of environmental sounds produced by manipulated objects and objects that typically have strong visual motion associations. Since the activated pMTG areas in that study partially overlapped the cortical areas involved in high-level processing of visual motion, the pMTG foci were suggested to process multimodal or supramodal information about object-associated motion. Another fMRI study (Warren et al., 2002) provided

evidence of the involvement of the parieto-occipital junction in the processing of sound motion. Results of the above-mentioned studies and the present finding that activation in the occipito-temporal source is stronger during location than pitch task performance indicate that the processing of auditory spatial information recruits the posterior temporo-parietal pathway. Our results also suggest that auditory nonspatial information might be processed in more anterior temporal areas, which would be consistent with the result of an fMRI study where the right anterior STS region was shown to be selectively activated by auditory object feature variation contrasted to variation in stimulus location (Zatorre et al., 2004). In our earlier studies we found evidence that the segregation of auditory information processing to ‘what’ and ‘where’ functional networks takes place already at about 100 ms from the stimulus onset within the auditory cortex on the supratemporal plane (Anourova et al., 2001, 2003). The current study extends this finding by demonstrating that segregation also takes place at the time intervals of slow evoked responses in the occipito-temporal and possibly middle temporal cortical areas.

Acknowledgements We wish to thank Docent Ilkka Linnankoski for revising the language. This study was supported by The Academy of Finland, Sigrid Juselius Foundation and Helsinki University Central Hospital research funds.

References Alain C, Arnott SR, Hevenor S, Graham S, Grady CL. ‘What’ and ‘where’ in the human auditory system. Proc Natl Acad Sci USA 2001;98: 12301–6. Anourova I, Ra¨ma P, Alho K, Koivusalo S, Kalmari J, Carlson S. Selective interference reveals dissociation between auditory memory for location and pitch. Neuroreport 1999;10:3543–7. Anourova I, Nikouline VV, Ilmoniemi RJ, Hotta J, Aronen HJ, Carlson S. Evidence for dissociation of spatial and nonspatial auditory information processing. Neuroimage 2001;14:1268–77. Anurova I, Artchakov D, Korvenoja A, Ilmoniemi RJ, Aronen HJ, Carlson S. Differences between auditory evoked responses recorded during spatial and nonspatial working memory tasks. Neuroimage 2003;20:1181–92. Arnott SR, Binns MA, Grady CL, Alain C. Assessing the auditory dualpathway model in humans. Neuroimage 2004;22:401–8. Clarke S, Adriani M, Bellmann A. Distinct short-term memory systems for sound content and sound localization. Neuroreport 1998;9:3433–7. Clarke S, Bellmann A, Meuli RA, Assal G, Steck AJ. Auditory agnosia and auditory spatial deficits following left hemispheric lesions: evidence for distinct processing pathways. Neuropsychologia 2000;38:797–807. Clarke S, Bellmann Thiran A, Maeder P, Adriani M, Vernet O, Regli L, Cuisenaire O, Thiran JP. What and where in human audition: selective deficits following focal hemispheric lesions. Exp Brain Res 2002;147: 8–15.

I. Anurova et al. / Clinical Neurophysiology 116 (2005) 1644–1654 Culham JC, Danckert SL, DeSouza JF, Gati JS, Menon RS, Goodale MA. Visually guided grasping produces fMRI activation in dorsal but not ventral stream brain areas. Exp Brain Res 2003;153:180–9. Daruna JH, Nelson AV, Green JB. Unilateral temporal lobe lesions alter P300 scalp topography. Int J Neurosci 1989;46:243–7. Ebmeier KP, Steele JD, MacKenzie DM, O’Carroll RE, Kydd RR, Glabus MF, Blackwood DH, Rugg MD, Goodwin GM. Cognitive brain potentials and regional cerebral blood flow equivalents during two- and three-sound auditory ‘oddball tasks’. Electroencephalogr Clin Neurophysiol 1995;95:434–43. Garcia-Larrea L, Cezanne-Bert G. P3, positive slow wave and working memory load: a study on the functional correlates of slow wave activity. Electroencephalogr Clin Neurophysiol 1998;108:260–73. George JS, Aine CJ, Mosher JC, Schmidt DM, Ranken DM, Schlitt HA, Wood CC, Lewine JD, Sanders JA, Belliveau JW. Mapping function in the human brain with magnetoencephalography, anatomical magnetic resonance imaging, and functional magnetic resonance imaging. J Clin Neurophysiol 1995;12:406–31. Halgren E, Baudena P, Clarke JM, Heit G, Liegeois C, Chauvel P, Musolino A. Intracerebral potentials to rare target and distractor auditory and visual stimuli. I. Superior temporal plane and parietal lobe. Electroencephalogr Clin Neurophysiol 1995a;94:191–220. Halgren E, Baudena P, Clarke JM, Heit G, Marinkovic K, Devaux B, Vignal JP, Biraben A. Intracerebral potentials to rare target and distractor auditory and visual stimuli. II. Medial, lateral and posterior temporal lobe. Electroencephalogr Clin Neurophysiol 1995b;94: 229–50. Halgren E, Marinkovic K, Chauvel P. Generators of the late cognitive potentials in auditory and visual oddball tasks. Electroencephalogr Clin Neurophysiol 1998;106:156–64. Hegerl U, Frodl-Bauch T. Dipole source analysis of P300 component of the auditory evoked potential: a methodological advance? Psychiatry Res 1997;74:109–18. Horn H, Syed N, Lanfermann H, Maurer K, Dierks T. Cerebral networks linked to the event-related potential P300. Eur Arch Psychiatry Clin Neurosci 2003;253:154–9. Horovitz SG, Skudlarski P, Gore JC. Correlations and dissociations between BOLD signal and P300 amplitude in an auditory oddball task: a parametric approach to combining fMRI and ERP. Magn Reson Imaging 2002;20:319–25. Jenkinson M, Bannister P, Brady M, Smith S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 2002;17:825–41. Kaas JH, Hackett TA. Subdivisions of auditory cortex and levels of processing in primates. Audiol Neurootol 1998;3:73–85. Kaas JH, Hackett TA. Subdivisions of auditory cortex and processing streams in primates. Proc Natl Acad Sci USA 2000;97:11793–9. Kaas JH, Hackett TA, Tramo MJ. Auditory processing in primate cerebral cortex. Curr Opin Neurobiol 1999;9:164–70. Kanovsky P, Streitova H, Klajblova H, Bares M, Daniel P, Rektor I. The impact of motor activity on intracerebral ERPs: P3 latency variability in modified auditory odd-ball paradigms involving a motor task. Neurophysiol Clin 2003;33:159–68. Keil A, Bradley MM, Hauk O, Rockstroh B, Elbert T, Lang PJ. Large-scale neural correlates of affective picture processing. Psychophysiology 2002;39:641–9. Kiehl KA, Laurens KR, Duty TL, Forster BB, Liddle PF. Neural sources involved in auditory target detection and novelty processing: an eventrelated fMRI study. Psychophysiology 2001;38:133–42. Kirino E, Belger A, Goldman-Rakic P, McCarthy G. Prefrontal activation evoked by infrequent target and novel stimuli in a visual target detection task: an event-related functional magnetic resonance imaging study. J Neurosci 2000;20:6612–8. Kiss I, Dashieff RM, Lordeon P. A parieto-occipital generator for P300: evidence from human intracranial recordings. Int J Neurosci 1989;49: 133–9.

1653

Lewis JW, Wightman FL, Brefczynski JA, Phinney RE, Binder JR, DeYoe EA. Human brain regions involved in recognizing environmental sounds. Cereb Cortex 2004;14:1008–21. Linden DE, Prvulovic D, Formisano E, Vollinger M, Zanella FE, Goebel R, Dierks T. The functional neuroanatomy of target detection: an fMRI study of visual and auditory oddball tasks. Cereb Cortex 1999;9: 815–23. Maeder PP, Meuli RA, Adriani M, Bellmann A, Fornari E, Thiran JP, Pittet A, Clarke S. Distinct pathways involved in sound recognition and localization: a human fMRI study. Neuroimage 2001;14:802–16. Martinkauppi S, Ra¨ma P, Aronen HJ, Korvenoja A, Carlson S. Working memory of auditory localization. Cereb Cortex 2000;10:889–98. McCarthy G, Luby M, Gore J, Goldman-Rakic P. Infrequent events transiently activate human prefrontal and parietal cortex as measured by functional MRI. J Neurophysiol 1997;77:1630–4. Mecklinger A, Maess B, Opitz B, Pfeifer E, Cheyne D, Weinberg H. A MEG analysis of the P300 in visual discrimination tasks. Electroencephalogr Clin Neurophysiol 1998;108:45–56. Menon V, Ford JM, Lim KO, Glover GH, Pfefferbaum A. Combined eventrelated fMRI and EEG evidence for temporal-parietal cortex activation during target detection. Neuroreport 1997;8:3029–37. Moores KA, Clark CR, Hadfield JL, Brown GC, Taylor DJ, Fitzgibbon SP, Lewis AC, Weber DL, Greenblatt R. Investigating the generators of the scalp recorded visuo-verbal P300 using cortically constrained source localization. Hum Brain Mapp 2003;18:53–77. Nagahama Y, Okada T, Katsumi Y, Hayashi T, Yamauchi H, Sawamoto N, Toma K, Nakamura K, Hanakawa T, Konishi J, Fukuyama H, Shibasaki H. Transient neural activity in the medial superior frontal gyrus and precuneus time locked with attention shift between object features. Neuroimage 1999;10:193–9. Novitski N, Anourova I, Martinkauppi S, Aronen HJ, Na¨a¨ta¨nen R, Carlson S. Effects of noise from functional magnetic resonance imaging on auditory event-related potentials in working memory task. Neuroimage 2003;20:1320–8. Paller KA, McCarthy G, Roessler E, Allison T, Wood CC. Potentials evoked in human and monkey medial temporal lobe during auditory and visual oddball paradigms. Electroencephalogr Clin Neurophysiol 1992; 84:269–79. Pelosi L, Holly M, Slade T, Hayward M, Barrett G, Blumhardt LD. Wave form variations in auditory event-related potentials evoked by a memory-scanning task and their relationship with tests of intellectual function. Electroencephalogr Clin Neurophysiol 1992;84:344–52. Pelosi L, Hayward M, Blumhardt LD. Which event-related potentials reflect memory processing in a digit-probe identification task? Brain Res Cogn Brain Res 1998;6:205–18. Perrin F, Maquet P, Peigneux P, Ruby P, Degueldre C, Balteau E, Del Fiore G, Moonen G, Luxen A, Laureys S. Neural mechanisms involved in the detection of our first name: a combined ERPs and PET study. Neuropsychologia 2005;43:12–19. Raij T, McEvoy L, Ma¨kela¨ JP, Hari R. Human auditory cortex is activated by omissions of auditory stimuli. Brain Res 1997;745:134–43. Rauschecker JP, Tian B. Mechanisms and streams for processing of ‘what’ and ‘where’ in auditory cortex. Proc Natl Acad Sci USA 2000;97: 11800–6. Rauschecker JP, Tian B, Pons T, Mishkin M. Serial and parallel processing in rhesus monkey auditory cortex. J Comp Neurol 1997;382:89–103. Rogers RL, Baumann SB, Papanicolaou AC, Bourbon TW, Alagarsamy S, Eisenberg HM. Localization of the P3 sources using magnetoencephalography and magnetic resonance imaging. Electroencephalogr Clin Neurophysiol 1991;79:308–21. Romanski LM, Tian B, Fritz J, Mishkin M, Goldman-Rakic PS, Rauschecker JP. Dual streams of auditory afferents target multiple domains in the primate prefrontal cortex. Nat Neurosci 1999;2:1131–6. Roth WT, Ford JM, Kopell BS. Long-latency evoked potentials and reaction time. Psychophysiology 1978;15:17–23.

1654

I. Anurova et al. / Clinical Neurophysiology 116 (2005) 1644–1654

Ruchkin DS, Sutton S, Kietzman ML, Silver K. Slow wave and P300 in signal detection. Electroencephalogr Clin Neurophysiol 1980;50: 35–47. Ruchkin DS, Johnson Jr R, Mahaffey D, Sutton S. Toward a functional categorization of slow waves. Psychophysiology 1988; 25:339–53. Smith SM. Fast robust automated brain extraction. Hum Brain Mapp 2002; 17:143–55. Smith ME, Halgren E, Sokolik M, Baudena P, Musolino A, LiegeoisChauvel C, Chauvel P. The intracranial topography of the P3 eventrelated potential elicited during auditory oddball. Electroencephalogr Clin Neurophysiol 1990;76:235–48. Squires NK, Squires KC, Hillyard SA. Two varieties of long-latency positive waves evoked by unpredictable auditory stimuli in man. Electroencephalogr Clin Neurophysiol 1975;38:387–401. Tarkka IM, Stokic DS, Basile LF, Papanicolaou AC. Electric source localization of the auditory P300 agrees with magnetic source localization. Electroencephalogr Clin Neurophysiol 1995;96:538–45.

Uutela K, Ha¨ma¨la¨inen M, Somersalo E. Visualization of magnetoencephalographic data using minimum current estimates. Neuroimage 1999;10: 173–80. Warren JD, Griffiths TD. Distinct mechanisms for processing spatial sequences and pitch sequences in the human auditory brain. J Neurosci 2003;23:5799–804. Warren JD, Zielinski BA, Green GG, Rauschecker JP, Griffiths TD. Perception of sound-source motion by the human brain. Neuron 2002; 34:139–48. Zago L, Tzourio-Mazoyer N. Distinguishing visuospatial working memory and complex mental calculation areas within the parietal lobes. Neurosci Lett 2002;331:45–9. Zatorre RJ, Bouffard M, Belin P. Sensitivity to auditory object features in human temporal neocortex. J Neurosci 2004;24:3637–42. Zurowski B, Gostomzyk J, Gron G, Weller R, Schirrmeister H, Neumeier B, Spitzer M, Reske SN, Walter H. Dissociating a common working memory network from different neural substrates of phonological and spatial stimulus processing. Neuroimage 2002;15:45–57.