Shift in sound localization induced by rTMS of the posterior parietal lobe

Neuropsychologia 42 (2004) 1598–1607

Shift in sound localization induced by rTMS of the posterior parietal lobe Jörg Lewald a,b,∗ , Michael Wienemann c , Babak Boroojerdi c b

a Department of Cognitive and Environmental Psychology, Faculty for Psychology, Ruhr University Bochum, D-44780 Bochum, Germany Leibniz Research Centre for Working Environment and Human Factors, Institute for Occupational Physiology at the University of Dortmund, Ardeystr. 67, D-44139 Dortmund, Germany c Department of Neurology, University Hospital of Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany

Received 3 December 2003; accepted 23 April 2004

Abstract Neuroimaging studies in human subjects and single-unit recordings in monkeys have suggested the primate posterior parietal cortex (PPC) to be involved in auditory space perception. Here we tested this hypothesis by combining repetitive focal transcranial magnetic stimulation (rTMS) of the right PPC with a task of pointing to free-field-sound stimuli. After a period of 15 min rTMS at 1 Hz, subjects exhibited an overall signed error in pointing by 2.5◦ , directed to the left and downward, with reference to a baseline condition with “sham rTMS”. No effects of rTMS on the general precision of sound localization (unsigned errors) were found. Thus, low-frequency offline rTMS may have specifically affected neuronal circuits transforming auditory spatial coordinates in both azimuth and elevation. This is in accordance with the view that the PPC may represent a neural substrate of the perceptual stability in spatial hearing. © 2004 Elsevier Ltd. All rights reserved. Keywords: Auditory localization; Human; Psychophysics; Low-frequency offline repetitive transcranial magnetic stimulation; Space perception

1. Introduction A multitude of studies using neuroimaging in healthy human subjects, psychophysics in brain-damaged patients, or single-unit recordings in monkeys has suggested that the posterior parietal cortex (PPC) plays a decisive role in the processing of auditory spatial information (e.g., Alain, Arnott, Hevenor, Graham, & Grady, 2001; Bellmann, Meuli, & Clarke, 2001; Bisiach, Cornacchia, Sterzi, & Vallar, 1984; Bushara et al., 1999; Clarke et al., 2002; Griffiths et al., 1998; Mazzoni, Bracewell, Barash, & Andersen, 1996; Maeder et al., 2001; Pinek, Duhamel, Cavé, & Brouchon, 1989; Stricanne, Andersen, & Mazzoni, 1996; Tanaka, Hachisuka, & Ogata, 1999; Vallar, Guariglia, Nico, & Bisiach, 1995; Weeks et al., 1999; Zatorre, Bouffard, Ahad, & Belin, 2002). Recently, anatomical and physiological findings in monkeys as well as investigations using functional magnetic resonance imaging (fMRI) and event-related potentials in human subjects, have led to the hypothesis that the PPC is part of an auditory “where” stream, projecting from caudal superior temporal cortex to dorsolateral prefrontal cor∗ Corresponding author. Tel.: +49 234 32 22670; fax: +49 234 32 02074. E-mail address: [email protected] (J. Lewald).

0028-3932/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2004.04.012

tex (Alain et al., 2001; Maeder et al., 2001; Rauschecker, 1998; Rauschecker & Tian, 2000; Romanski et al., 1999). The dorsolateral pathway seems to be anatomically segregated from a ventrolateral “what” stream which processes non-spatial auditory information. This seems to be in analogy to the parietal “where” and temporal “what” processing streams that have long been established for the visual modality (Mishkin, Ungerleider, & Macko, 1983). The PPC is an area involved in crossmodal processing. In the monkey, neurons have been found to have a spatial selectivity for visual and for acoustic stimuli (Mazzoni et al., 1996). In order to maintain alignment of the auditory and visual reference frames with eye movements, sound locations may be transformed from the originally head-centered into eye-centered coordinates by using a signal of eye-in-head position (Stricanne et al., 1996). Moreover, proprioceptive and vestibular signals on head and body position might be used to generate a body- or world-referenced coding of external sensory space (Brotchie, Andersen, Snyder, & Goodman, 1995; Snyder, Grieve, Brotchie, & Andersen, 1998). In addition to this role in crossmodal spatial integration, the PPC seems, however, also to be part of the cortical network associated with binding of non-spatial auditory and visual information (Bushara, Grafman, & Hallett, 2001; Calvert, Campbell, & Brammer, 2000; for review, see Calvert, 2001).

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Thus far, the hypothesis of a functional significance of the human PPC in sound localization has received support mainly by neuroimaging studies (Alain et al., 2001; Bushara et al., 1999; Griffiths et al., 1998; Maeder et al., 2001; Weeks et al., 1999; Zatorre et al., 2002). With respect to the question of how a focal brain area is involved in spatial hearing functions, those techniques are, however, of restricted value. Neuroimaging data usually show networks composed of many segregated brain regions that are activated with a given psychophysical task, so that reliable conclusions on the specific contribution of one single area within this network are hardly to draw. Also, due to the position of the subject in the scanner, it is impossible to employ complex psychophysical tasks, that actually require the subject’s accurate localization of absolute sound position (i.e., by pointing to acoustic targets in a free sound field). Recently, low-frequency offline repetitive transcranial magnetic stimulation (rTMS) of the cortex has been introduced as a further method to investigate the neural substrates of sound localization in healthy human subjects (Lewald, Foltys, & Töpper, 2002; Lewald, Meister, Weidemann, & Töpper, 2004). During low-frequency rTMS over a long period, stimulation of the underlying cortical neurons induces alterations of the normal brain activity that persist for several minutes after application (Chen et al., 1997; Hallett, 2000; Lewald et al., 2002, 2004; Mottaghy et al., 1999; Pascual-Leone, Valls-Sole, Wassermann, & Hallett, 1994; Töpper, Foltys, Mottaghy, & Boroojerdi, 1999; Walsh & Cowey 2000). Consequently, application of magnetic stimuli does not directly interfere with the sound-localization tasks performed within this offline period. Due to the separation of rTMS and psychophysical measurement in time, there are practically no methodological restrictions with respect to the complexity of the task and the stimulus presentation. Thus, rTMS may represent a new powerful tool to investigate the role of focal brain areas, such as the PPC, in spatial hearing under the conditions of real free-field sound. In an earlier approach using dichotic sound stimuli presented via earphones (Lewald et al., 2002), it was shown that low-frequency offline rTMS of the PPC induced a systematic shift in the lateralization of interaural time differences (ITDs), whereas the acuity of ITD discrimination was unaffected. The direction of the perceptual shift of the sound image was opposite to the side of rTMS application. Since ITD is a main cue for auditory azimuth, these findings predict an azimuthal shift in localization in the same direction. An aim of the present study was to confirm this prediction with presentation of actual sound sources as the auditory stimuli. This is, however, not a mere replication. Under the conditions of a free sound field, interaural level differences and spectral pinna cues contribute to sound localization in addition to ITDs (cf. Blauert, 1997). Interaural level differences are (as ITDs) important for directional hearing in the azimuthal plane; spectral parameters are utilized as primary cues for sound elevation. An actual sound source provides the auditory system with all spatial cues in combination.

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The synthesis of these cues results in an auditory percept located in external space, while dichotic presentation of interaural differences in time or level usually evokes an intracranial percept located between the ears. Thus, one cannot completely exclude the possibility that effects of rTMS on lateralization of dichotic sound and free-field localization differ. The central goal of these experiments was to find out whether or not low-frequency offline rTMS of the PPC also influences sound localization in the vertical dimension. The present knowledge on potential neural substrates of the localization of sound elevation, which relies (unlike azimuthal localization) mainly on the utilization of spectral pinna cues, is only poor. Using neuromagnetic recordings, Fujiki, Riederer, Jousmäki, Mäkelä, and Hari (2002) suggested the processing of elevation cues to be located in the right superior temporal cortex. In an fMRI study, Pavani, Macaluso, Warren, Driver, and Griffiths (2002) argued for a common network for processing of sound motion in azimuth and elevation, including planum temporale, parietal cortex and prefrontal cortex. As was concluded by these authors, auditory information on both azimuth and elevation may be processed within the dorsolateral “where” stream. This hypothesis of Pavani et al. (2002) could be directly tested here. For, it predicts that in case rTMS of the PPC has any effect on azimuthal sound localization, a closely related effect must co-occur in the vertical dimension. In the present study, magnetic stimuli were applied over the PPC of the right hemisphere only. This restriction was made since previous magnetoencephalography, neuroimaging, and rTMS studies have concurrently suggested a general right-hemisphere dominance for the processing of auditory spatial cues in the human cortex (Bushara et al., 1999; Fujiki et al., 2002; Griffiths et al., 1998; Itoh, Yumoto, Uno, Kurauchi, & Kaga, 2000; Kaiser, Lutzenberger, Preissl, Ackermann, & Birbaumer, 2000; Lewald et al., 2002; Palomäki, Alku, Mäkinen, May, & Tiitinen, 2000; Weeks et al., 1999; Zatorre et al., 2002).

2. Materials and methods 2.1. Subjects Eleven right-handed male volunteers between the ages of 21 and 30 years participated in this study. All subjects exhibited normal auditory spatial abilities, as can be inferred from the data obtained without magnetic stimulation and after sham rTMS (cf. Fig. 3a and b). Experiments were performed in accordance with the ethical guidelines of the Declaration of Helsinki, and the safety guidelines for repetitive magnetic stimulation (Wassermann, 1998) were obeyed. Procedures were approved by the local ethical committee of the University of Bochum. All subjects tolerated the experiments without any complications.

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2.2. Magnetic stimulation The general methods employed for low-frequency offline rTMS were similar to those in a preceding study (Lewald et al., 2002). rTMS was applied using a magnetic stimulator (Magstim Rapid Stimulator, Magstim Co., UK) connected with a figure-of-eight coil (outer diameter 9 cm). The magnetic stimulator was triggered by an external device (Master 8 Trigger unit, AMPI, Israel) with a frequency of 1 Hz for 15 min (total number of stimuli 900). This frequency has been demonstrated to induce inhibitory effects on the underlying cortical structures in previous studies (e.g., Boroojerdi, Prager, Muellbacher, & Cohen, 2000; Chen et al., 1997). The intensity of magnetic stimulation was set to 60% of the stimulator output (maximum output 2.2 T). Low-frequency rTMS was delivered to the posterior parietal cortex of the right hemisphere. The stimulation site P4 was determined according to the 10–20 EEG system. The position of this stimulation site was over Brodmann area 40 of the inferior parietal lobule. The coil, oriented in posterior-anterior direction, was placed tangentially to the scalp, with its center (the intersection of the two windings) in contact with this site. During magnetic stimulation, subjects wore wax ear plugs (mean attenuation 27 dB; Ohropax, Germany) in combination with a supra-aural hearing protection (mean attenuation 27 dB; Bilsom 747, Bilsom, Sweden). Thus, the noise that accompanied the magnetic pulses was attenuated by more than 50 dB, and phenomena of auditory fatigue, such as a noise-induced temporary auditory threshold shift, were unlikely to occur (cf. Quaranta, Portalatini, & Henderson, 1998). Accordingly, any unspecific influences of the noise accompanying rTMS on sound lateralization were not demonstrable in our previous studies (Lewald et al., 2002, 2004). 2.3. Sound-localization task All experiments were conducted in a sound-proof and anechoic room (5.4 m × 4.4 m × 2.1 m; cf. Guski, 1990). Prior to the experiments, subjects were sufficiently familiarized with the sound-localization task and completed about 20–30 practice trials. During the psychophysical measurements, the room was absolutely dark, and subjects sat on a chair with their head fixed in a straight-ahead position by a custom-made restraint that consisted of stabilizing rests for the chin, forehead, and occiput. In each trial, high-frequency band-pass-filtered frozen noise (cutoff frequencies 1 and 16 kHz, sound pressure level 55 dB re 20 ␮Pa; duration 7.5 s; rise/fall time 0.1 s) was delivered via one of 21 broad-band loudspeakers (Visaton SC5.9). These 21 loudspeakers were part of an array of 121 loudspeakers that were arranged in the shape of a cross along the azimuthal and elevational planes such that the point of intersection (0◦ ) was in the subject’s median plane at eye level. The azimuthal array consisting of a total of 91 loudspeakers covered 180◦ (±90◦ to the left and right), but only the positions of ±6, ±12, ±18, ±24,

and ±30◦ were used in the present experiments, since only a restricted number of stimuli could be presented within the period of persistence of the effect of low-frequency rTMS. The elevational array of 31 loudspeaker positions was in the subject’s median plane and covered 62◦ (±31◦ to the top and bottom). Of these, only the elevations of ±7, ±13, ±19, ±25, and ±31◦ were used (negative azimuths are to the left and positive azimuths are to the right; negative elevations are to the bottom and positive elevations are to the top). All loudspeakers were arranged on the surface of a virtual sphere centered around the subject’s head (1.5 m distance). Sound localization was tested by using a pointing method similar to that employed previously (Lewald, Dörrscheidt, & Ehrenstein, 2000; Lewald, 2002a, 2004). A hand pointer was mounted in front of the subject. This swivel pointer consisted of a metal rod that the subject could rotate in both the azimuthal and elevational planes. One end of the rod was linked to the perpendicular axes of two potentiometers that were mounted on the front edge of the subject’s chair, with the pivot of the rod located at the level of the abdomen. These potentiometers recorded the azimuthal and elevational angles of the pointer. During the 7.5-s period of stimulus presentation, subjects had to adjust the pointer such that it pointed to the source of the sound as accurately as possible. We used this task of pointing to stimuli with long duration since we were specifically interested in the subjects’ direct (closed-loop) localization of actual sound sources, and aimed to exclude effects of rTMS on the spatial working memory, as may be relevant with delayed responses to remembered stimuli (cf. Lewald & Ehrenstein, 2001). After completion of the adjustment, a key had to be pressed that was mounted on the upper side of the rod. The position of the pointer at the moment of key-pressing was measured by the potentiometer, and azimuth and elevation were recorded automatically by the computer program. The next trial began 1.07 s after the end of the sound stimulus. Subjects were instructed to press the key before the sound stimulus ceased, but were explicitly informed that the accuracy of pointing, not speed, was important for the experiment, and that it was thus not necessary to press the key as fast as possible. Performing the pointing task usually took the subject 4–6 s. In case the subject failed to press the key within the 7.5-s period of presentation of the sound stimulus, the trial was repeated immediately. In most subjects such failures did not occur at all, and the maximum frequency of delayed and omitted responses obtained in individual subjects was about 5% of all trials. No instruction was given with respect to the position of the hands during adjustment of the pointer. However, subjects were explicitly instructed to keep constant the hand position in all experimental conditions. Compliance with the instruction was monitored on-line by the experimenter via an infrared video camera. Five subsequent blocks of the pointing task were conducted. Each block lasted 3 min and consisted of 21 trials (trial duration 8.57 s), with one presentation of the sound

J. Lewald et al. / Neuropsychologia 42 (2004) 1598–1607

stimulus at each position. Within blocks, sound positions changed following a fixed, quasi-random order. Changes in azimuth and elevation were presented intermixed within the same block. Thus, localization of each of the 21 sound positions was tested five times, resulting in a total number of 105 trials presented within 15 min. 2.4. Procedure During the whole experiment, subjects were seated in a comfortable chair inside the sound-proof room. The experiment began with the application of sham rTMS. All parameters and conditions were as described above for actual low-frequency offline rTMS, but the coil was held perpendicularly to the scalp surface. Immediately after sham rTMS, the coil and the hearing protections were removed, the subject’s head was fixed by the head restraint, and the room was darkened. This procedure took maximally 2 min. Then, the sound-localization task followed. After completion of the task, the head restraint was removed and the subject was allowed to rest for about 10 min. After this rest, actual rTMS and the subsequent psychophysical measurement were conducted in a corresponding manner as with sham rTMS, with the exception of the change in coil orientation (see above). After completion of the rTMS and the sham-rTMS conditions, subjects were tested in a third condition without magnetic stimulation. In this condition, subjects performed exclusively the sound-localization task as described above. These measurements were conducted on another day, without any other procedures that preceded or followed the task (except a few practice trials prior to experimentation). 2.5. Data analysis For the main analysis of the data, the signed azimuthal and elevational deviations of the subjects’ pointing responses from actual loudspeaker locations obtained with sham rTMS (which were used as the baseline data) and actual rTMS were computed for each trial and analysed by using a four-factor repeated-measures analysis of variance (ANOVA) with (1) experimental condition (sham rTMS versus rTMS), (2) dimension of the deviation in pointing (azimuth versus elevation), (3) number of the block, and (4) speaker position as factors. For further analyses, the azimuthal and elevational components of the pointing responses, plotted as a function of sound azimuth or elevation, respectively, were fitted to regression lines. Our aim was to differentiate between potential systematic (signed) errors induced by rTMS and changes in the subjects’ precision (i.e., in the subjects’ localization performance irrespective of systematic errors). For this purpose, the coefficients of determination (R2 ) resulting from the fit and the slopes of the regression lines were taken as measures (cf., e.g., Lewald, 2002a, 2004). The R2 value provides a measure for the deviations of the pointing responses from the regression line and is thus independent of system-

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atic errors. The slopes of the regression lines describe the subjects’ ability to judge the relative positions of the sound sources. Values obtained with sham rTMS and actual rTMS were compared using a two-factor repeated-measures ANOVA with (1) experimental condition (sham rTMS versus rTMS) and (2) dimension of pointing (azimuth versus elevation) as factors. All statistical comparisons were performed using the “General Linear Model” with repeated measurement in the Statistical Packages for Social Sciences (SPSS v10.0, SPSS Inc., Chicago, Ill., USA). For these computations, the ε-corrected F-value (Greenhouse-Geisser correction) was chosen. 3. Results 3.1. Systematic error in sound localization induced by low-frequency offline rTMS A four-factor repeated-measures ANOVA of the subjects’ deviations in pointing from actual sound sources revealed a significant main effect of the experimental condition (sham rTMS versus real rTMS) on sound localization (F[1,10] = 6.455, P = 0.029). The effect consisted of an overall angular difference between sound localization after sham rTMS and after actual rTMS of 2.50◦ , with a mean azimuthal component of −1.37◦ (S.E. ± 0.97) to the left and a mean elevational component of −2.09◦ (S.E. ± 2.03) downwards (Fig. 1). Even though there was a seeming trend of a stronger effect of rTMS on the elevational component than on the azimuthal component of this shift, the interaction of experimental condition and dimension of deviation (azimuth versus elevation) was non-significant (F[1,10] = 0.198, P = 0.666), thus rather suggesting equal effects on the two components. Also, the ANOVA did not reveal a significant interaction of experimental condition and block number (F[4,40] = 0.127, P = 0.873), which indicates approximately constant persistence of the effect of rTMS on sound localization over the whole 15-min period of the psychophysical measurements (Fig. 2). Furthermore, there was no significant interaction of experimental condition and sound position (F[20,200] = 0.696, P = 0.648), which gave support for the view that the position of the sound source was irrelevant for the magnitude of the post-rTMS shift in localization, that is, rTMS resulted in a consistent transformation of the auditory space within the range of azimuthal and elevational positions tested (Fig. 1). As was to be expected, the ANOVA also revealed significant main effects of the dimension of the pointing response (F[1,10] = 8.102, P = 0.017) as well as sound position (F[20,200] = 3.358, P = 0.027). These effects may reflect the well-known facts that sound localization is more accurate in azimuth than elevation and near the median plane compared to peripheral locations (cf., e.g., Blauert, 1997) and that there are characteristic systematic errors of localization depending on the angle of sound incidence with ref-

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Fig. 1. Shift in sound localization after rTMS of the right posterior parietal cortex. (a) Mean deviations of the subjects’ pointing responses from sound positions after rTMS. Data measured after actual rTMS (closed symbols) are normalized such that the pointing responses obtained after sham rTMS (open symbols) were assigned the real positions of the loudspeakers. (b) Post-rTMS shifts in elevation plotted as a function of sound elevation (sound positions at 0◦ azimuth). (c) Post-rTMS shifts in azimuth plotted as a function of sound azimuth (sound positions at 0◦ elevation). Insets (b and c) show the same data as in a. Negative shifts in azimuth are to the left and negative shifts in elevation are downwards; error bars, ±S.E.

erence to the subjects’ head (cf., e.g., Lewald et al., 2000). There was no significant main effect of the block number (F[4,40] = 2.481, P = 0.118), indicating only insignificant temporal variations in performance between blocks within one experimental condition.

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Fig. 2. Mean normalized post-rTMS shifts (±S.E.) in localization of sound elevation (a) and azimuth (b) plotted as a function of the block number. Each block lasted 3 min and included presentation of all sound locations.

Further comparisons between the pointing responses after sham rTMS and actual rTMS did not show any other differences. The R2 values for the fit of the azimuthal and elevational components of the pointing responses to regression lines were highly significant in each case (azimuth: range 0.864–0.982, P < 0.001; elevation: range 0.331–0.896; P < 0.001), indicating accurate general performance of sound localization. These values were used here as measures for the precision of pointing, regardless of systematic errors. A two-factor repeated-measures ANOVA did not reveal any significant differences between the R2 values for the two experimental conditions (ANOVA; F[1,10] = 0.566, P = 0.469; Fig. 3). Likewise, the slopes of the regression lines of these data were virtually identical for sham-rTMS and

J. Lewald et al. / Neuropsychologia 42 (2004) 1598–1607 (c)

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Fig. 3. Mean pointing responses in the azimuthal (a) and elevational dimension (b) obtained without magnetic stimulation (open triangles), after sham rTMS (open circles), and after actual rTMS (closed circles). The latter two sets of data are the same as shown in Fig. 1. Values obtained in each of the three conditions are fitted to a regression line. (c) Plot of the y-intercepts of the regression lines obtained for the elevational components in pointing (as shown in b) against the y-intercepts of the related azimuthal components (as shown in a). While mean pointing responses without rTMS and after sham rTMS only insignificantly differed, mean pointing positions measured after actual rTMS were to the left and lower with reference to both pointing without rTMS and sham rTMS.

rTMS conditions (F[1,10] = 0.893, P = 0.367; Fig. 3). Nor were significant interactions obtained between experimental condition and the dimension of pointing for both the analysis of R2 values (F[1,10] = 1.061, P = 0.327) and slopes of the regression line (F[1,10] = 1.382, P = 0.267). As was expected, there were, however, significant main effects of the dimension (R2 : F[1,10] = 17.781, P = 0.002; slope: F[1,10] = 17.306, P = 0.002), resulting from the generally higher precision for the azimuthal than the elevational component of pointing (see above). 3.3. Insignificant effects of sham rTMS A repeated-measures ANOVA of the subjects’ deviations in pointing from actual sound sources obtained without magnetic stimulation and after rTMS revealed a significant main effect of the experimental condition (F[1,10] = 11.960, P = 0.006), as was found for the comparison of the actualand sham-rTMS conditions. No main effect of the experimental condition was, on the other hand, demonstrable when the subjects’ pointing responses obtained without magnetic stimulation were compared with those obtained after sham rTMS (F[1,10] = 0.055, P = 0.819). Although there may be an insignificant trend that sounds were slightly mislocalized to the left after sham rTMS (cf. Fig. 3c), this statistical analysis indicates that potential effects of sham rTMS on sound localization were within the normal range of intraindividual variability in performance. 4. Discussion 4.1. Transformation of auditory spatial coordinates induced by low-frequency offline rTMS Magnetic stimulation of the right PPC induced a significant left-/downward shift in sound localization. There was

neither a general deterioration of localization precision, nor was the auditory space perceived in a distorted manner after rTMS. The effect rather represents a systematic error that was homogenous within the whole range of sound locations tested (cf. Fig. 1a). This post-rTMS shift thus can be geometrically described as either a translation of the auditory spatial coordinates parallel to the frontal plane or a rotation around the center of the head. On the one hand, the present result perfectly matches the prediction of an azimuthal shift, as was stated on the basis of the previous finding of a corresponding shift in the lateralization of ITDs (Lewald et al., 2002). On the other hand, the trajectory of the shift found here had obviously not only a horizontal, but also a vertical component of similar magnitude. Thus, rTMS of the PPC may have influenced neural processing of information on both absolute sound azimuth and elevation, suggesting that this area is involved in spatial hearing regardless of the dimension of auditory coordinates. This conclusion accords with recent fMRI findings: Pavani et al. (2002) showed that perception of sound motion in azimuth and elevation activated the same cortical areas, including the parietal lobe, while the contrast between sound movements in azimuth and elevation revealed no significant activation. The present findings are in agreement with the idea that a specific function of the PPC is the neural transformation of the coordinates of the extrapersonal sensory space in order to generate body- and world-referenced spatial coding, as has been suggested by recordings on visual neurons in the monkey parietal cortex (Andersen & Mountcastle, 1983; Andersen, Essick, & Siegel, 1985; Brotchie et al., 1995; Snyder et al., 1998). A portion of these visual neurons has been shown to respond also to auditory stimuli in a spatially selective manner, with the auditory aligned with the visual receptive fields (Mazzoni et al., 1996; Stricanne et al., 1996). It seems reasonable to assume that neural

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coordinate transformations, as shown for the visual domain, also occur in the auditory modality. That is, auditory spatial information may be integrated in the PPC with neck-proprioceptive information on head-to-trunk position and vestibular information on changes in the position of the head in space, in order to maintain perceptual stability of the auditory space during motion. This assumption predicts that any manipulation of the two latter types of afferent information must result in shifts of sound localization. In accordance with that, systematic shifts in sound lateralization or localization have been induced by neck-proprioceptive stimulation, using transcutaneous muscle vibration or eccentric head position (Lewald & Ehrenstein, 1998; Lewald, Karnath, & Ehrenstein, 1999; Lewald et al., 2000; Lewald, 2002b), cold-caloric stimulation of the semicircular-canal system, whole-body rotation, or stimulation of the otolith system by body tilt (DiZio, Held, Lackner, Shinn-Cunningham, & Durlach, 2001; Lewald & Karnath, 2000, 2001, 2002). Furthermore, neurophysiological recordings in the monkey parietal cortex have demonstrated auditory-visual bimodal neurons with eye-centered coding of auditory spatial information (Stricanne et al., 1996), and eccentric eye positions have been shown to induce perceptual shifts in sound localization or lateralization (Lewald & Ehrenstein, 1996; Lewald, 1998). This implies that an afferent signal on eye position is processed with the auditory spatial information. Thus, summing up, the present shift of the representation of auditory space can be explained by a modulating influence of low-frequency offline rTMS on the neural transmission of eye-position, neck-proprioceptive, and/or vestibular afferent information or on mechanisms utilizing this information for transformation of auditory coordinates during natural motion. On the basis of our data, one can, however, not differentiate between these possibilities, and any interpretation of the specific left-/downward direction of the auditory shift after rTMS of the right PPC would also be pure speculation. A further question that remains open is whether effects of rTMS of the left PPC could differ from those shown here for the right PPC. In this first approach, we confined ourselves to investigating only effects of rTMS over the right PPC, since most previous studies have indicated a more important role of the right hemisphere in sound localization (Bushara et al., 1999; Fujiki et al., 2002; Griffiths et al., 1998; Itoh et al., 2000; Kaiser et al., 2000; Palomäki et al., 2000; Weeks et al., 1999; Zatorre et al., 2002). In our preceding study (Lewald et al., 2002), we found a significant rightward shift in the lateralization of ITDs after rTMS of the left PPC. This shift was smaller in magnidude than the leftward shift obtained after stimulation of the right PPC, but the difference between the magnidudes of the effects of left and right rTMS was non-significant. Whether this applies also to the localization of actual sound sources has to be addressed by future studies.

4.2. Methodological considerations For an appropriate assessment of the present data, several methodological issues have to be addressed. Firstly, it has to be noted that the present pointing task involved not only an auditory, but also a motor component. One can, consequently, not completely exclude that rTMS affected motor, rather than sensory, representations. On the one hand, the areas of the motor cortex were in sufficient distance from the PPC stimulation site so that any direct effects of rTMS on these regions are unlikely. On the other hand, in the so-called “parietal reach region” of the monkey cortex (including the medial intraparietal area in the medial wall of the intraparietal sulcus and the dorsal aspect of the parieto-occipital area), neural activity has been shown to be associated with goal-directed planned as well as ongoing hand and arm movements, as could be relevant in the present pointing task (for reviews, see Cohen & Andersen, 2002; Snyder, 2000). Evidence for the representation of hand and arm movement in the human homologue of this region has been recently provided by an rTMS study (Glover, Miall, & Rushworth, 2003). Moreover, effects of rTMS over the right PPC in visual search tasks suggested a role of this area in the transformation between perception and action, that is, in forming spatially encoded stimulus response associations (Ellison, Rushworth, & Walsh, 2003). Thus, it is conceivable that representations of hand and arm movements or the transformation of the auditory spatial information into the appropriate motor response, rather than the representation of the auditory space, were modulated by rTMS in the present study. On the one hand, effects of rTMS on motor representations are unlikely to play a role in our experiment, since the pointing method used here did not require direct hand and arm movements in pointing to the sound, but the adjustment of a pointer apparatus. On the other hand, an influence of rTMS on auditory-motor transformations cannot completely be excluded. However, the clear-cut relation of the present results with those found previously using a task of left/right judgements on ITDs (Lewald et al., 2002), which did not involve any goal-directed motor responses, may argue against both these possibilities, at least for the azimuthal component of the effect. A second problem that is inherent in the present methodological approach is the potential effect of the disturbing noise produced by the magnetic pulses, although an efficient hearing protection was used. For this reason, sham rTMS producing identical acoustic emissions, but only minimal magnetic stimuli, was used as the baseline condition such that possible effects should be cancelled. Moreover, the comparison of sham rTMS and a reference measurement under ideal conditions without magnetic stimulation revealed only insignificant differences (Fig. 3). This is in line with several control measurements conducted in our earlier studies, that have not indicated any hints for such unspecific effects (Lewald et al., 2002, 2004). A third objection that may arise

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with respect to the elevation component of the post-rTMS shift is that rTMS may have influenced non-spatial hearing functions. Since vertical sound localization critically relies on monaural spectral cues, any frequency-specific impairment (and in particular a high-frequency loss) of hearing by rTMS must necessarily result in effects on perception of sound elevation. In that case, one may, however, expect a general deterioration in vertical localization ability, namely a flattening of the slope of the regression line when pointing elevation is plotted as a function of sound elevation. The fact that this could not be observed here (see Fig. 3b), but rather a relatively homogeneous systematic error (Fig. 1b), refutes this assumption.

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in the rodent auditory cortex, rTMS induces both long-term potentiation-like and long-term depression-like changes in evoked spike rate. The present effect of low-frequency offline rTMS thus could be interpreted in terms of subtle plastic changes of processing in the neural circuits performing transformations of auditory coordinates rather than general disturbances that are comparable with the consequences of cortical damage. In conclusion, the present method seems to be more appropriate to analyse specific functions of focal cortical areas in sound localization than investigations on brain-damaged patients.

Acknowledgements 4.3. Relation to studies on patients with parietal lesions Transcranial magnetic stimulation has often been supposed to induce transient “virtual lesions” of cortical areas. Thus, one may expect that patients with parietal lesions exhibit systematic errors as that found here after rTMS. Several studies have indeed demonstrated azimuthal shifts in free-field sound localization in patients suffering from temporoparietal lesions of the right hemisphere. The results were, however, inconsistent with respect to the directions of these shifts. In an investigation on eleven right-brain damaged patients with spatial neglect, Vallar et al. (1995) showed that the sound location that was perceived as being in the frontal median plane was shifted to the right compared to healthy subjects. This indicates a shift of azimuthal sound localization to the left, as was found here. By employing a task of hand-pointing, Pinek et al. (1989) obtained a systematic rightward error of azimuthal sound localization, but no deficits in vertical localization, in three patients with right parietal damage and spatial neglect (two of these had hemianopia in addition). Also studies that have tested sound lateralization in patients with right temporoparietal lesions using presentation of dichotic headphone stimuli reported either auditory shifts to the right or even complete inability to perform the task (Bellmann et al., 2001; Bisiach et al., 1984; Tanaka et al., 1999; Zimmer, Lewald, & Karnath, 2003). Thus, a clear-cut relation of our findings with deficits of brain-damaged patients cannot be established. The reason may be that ischemic lesions are usually not restricted to the PPC exclusively, but involve several cortical and subcortical brain regions. Furthermore, the effects of a cerebral ischemic lesion are always the product of the actual lesion and the consecutively occurring adaptive processes of the brain, whereas no such adaptive processes are thought to occur in response to the acute cerebral dysfunction induced by low-frequency offline rTMS. On the other hand, one has also to note that it is still unclear whether, under the specific conditions of the present experiment, rTMS at 1 Hz actually had an inhibiting or rather disinhibiting influence on PPC auditory spatial functions (cf. Lewald et al., 2002, 2004; Maeda, Keenan, Tormos, Topka, & Pascual-Leone, 2000). As shown by Wang et al. (1996), using recording of neural activity

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