Cortical representation of saccular vestibular stimulation: VEMPs in fMRI

www.elsevier.com/locate/ynimg NeuroImage 39 (2008) 19 – 31

Cortical representation of saccular vestibular stimulation: VEMPs in fMRI P. Schlindwein,a,⁎ M. Mueller,a T. Bauermann,b T. Brandt,c P. Stoeter,b and M. Dietericha a

Department of Neurology, Johannes Gutenberg University, Mainz, Germany Department of Neuroradiology, Johannes Gutenberg University, Mainz, Germany c Department of Neurology, Ludwig-Maximilians University, Munich, Germany b

Received 30 December 2006; revised 14 July 2007; accepted 17 August 2007 Available online 25 August 2007 Short tone bursts trigger a vestibular evoked myogenic potential (VEMP), an inhibitory potential which reflects a component of the vestibulocollic reflex (VCR). These potentials arise as a result of activation of the sacculus and are expressed through the vestibulo-collic reflex (VCR). Up to now, the ascending projections of the sacculus are unknown in humans, only the representation of the semicircular canals or the entire vestibular nerve has been demonstrated. The aim of this study was to determine whether a sacculus stimulus that evoked VEMPs could activate vestibular cortical areas in fMRI. To determine this, we studied the differential effects of unilateral VEMP stimulation in 21 healthy right-handers in a clinical 1.5 Tscanner while wearing piezo electric headphones. A unilateral VEMP stimulus and two auditory control stimuli were given in randomized order over the stimulated ear. A random effects statistical analysis was done with SPM2 (p b 0.05, corrected). After exclusion of the auditory effects, the major findings were as follows: (i) significant activations were located in the multisensory cortical vestibular network within both hemispheres, including the posterior insular cortex, the middle and superior temporal gyri, and the inferior parietal cortex. (ii) The activation pattern was elicited bilaterally with a predominance of the right hemisphere in righthanders. (iii) Saccular vestibular projection was predominantly ipsilateral, whereas (iv) pure acoustic stimuli were processed with a predominance of the respective contralateral and mainly in the left hemisphere. This is the first demonstration by means of fMRI of the cortical representation of the saccular input at cortical level. The activation pattern is similar to that known from the stimulation of the entire vestibular nerve or the horizontal semicircular canal. Our data give evidence of a task-dependent separation of the processing within the vestibular otolith and the auditory systems in the two hemispheres. © 2007 Elsevier Inc. All rights reserved.

⁎ Corresponding author. Neurologische Klinik, Johannes GutenbergUniversität, Langenbeckstrasse 1, D-55101 Mainz, Germany. Fax: +49 6131 175625. E-mail address: [email protected] (P. Schlindwein). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2007.08.016

Introduction Short tone bursts (STB) trigger vestibular evoked myogenic potentials (VEMPs) by saccular stimulation, i.e., inhibitory potentials recorded from the sternocleidomastoid muscle ipsi- and contralaterally which reflect a linear component of the vestibulocollic reflex (VCR) (Colebatch et al., 1994; de Waele, 2001). Its afference is the inferior vestibular nerve (Halmagyi et al., 2005). In this way the saccular otolith of one labyrinth reacts to loud click sounds of 85–130 dB sound pressure level (SPL). To date it is widely accepted that these sounds stimulate only the saccule and not the utricle or the semicircular canals (Halmagyi et al., 2005; McCue and Guinan, 1995; Murofushi and Curthoys, 1997). The VEMPs therefore reflect saccule activation. Up to now, the ascending projections of the sacculus are unknown in humans; only the representation of the semicircular canals or the entire vestibular nerve via the vestibulo-ocular reflex (VOR) had been worked up. Thus, the major goal of the present study was to determine whether a sacculus stimulation with tone bursts that evoked VEMPs could activate vestibular cortical areas via central otolith projections. The only imaging study in which VEMPs were used gave very preliminary data in single subjects, showing an apparent activation pattern in the human fronto-temporal cerebral cortex which was similar to only a small part of that during caloric irrigation (Miyamoto et al., 2005). Studies in monkeys have identified several separate multisensory areas of the temporo-insular and temporo-parietal cortex by means of multisensory neurons that responded to rotational vestibular as well as optokinetic, somatosensory, and in part visual stimuli (Baloh and Furman, 1989; Büttner and Buettner, 1978; Frederickson et al., 1974; Grüsser et al., 1990a; Ödkvist et al., 1974). However, none of these studies used otolith stimulation. Tracer studies in monkeys have shown that multisensory vestibular areas are closely connected to each other (Akbarian et al., 1994; Guldin and Grüsser, 1996). They include the parietoinsular vestibular cortex (PIVC) in the posterior insula, adjacent retroinsular areas, and the granular insular region (Grüsser et al., 1990b; Guldin and Grüsser, 1996), the visual temporal sylvian

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area posterior to the PIVC (Guldin and Grüsser, 1998), area 3aV in the central sulcus (Ödkvist et al., 1974), probably area 2v at the tip of the intraparietal sulcus (Frederickson et al., 1974), the periarcuate cortical area 6 pa (Ebata et al., 2004), area 7 in the inferior parietal lobule (Faugier-Grimaud and Ventre, 1989; Ventre and FaugierGrimaud, 1989), and the ventral intraparietal area (VIP) in the fundus of the intraparietal sulcus (Schlack et al., 2005). On the other hand, little is known on the central representation of linear vestibular stimulation of the vestibular system. Recent findings in non-human primates suggest that integration of visual and vestibular heading signals is achieved by the convergence of both modalities in a dorsal subdivision of the medial superior temporal area (MST) (Fetsch et al., 2007; Gu et al., 2007). MST was formerly thought to only process visual information (optic flow). During the last 10 years several functional imaging studies have revealed that the cortical network in both hemispheres is similar in humans (Bremmer et al., 2001; Fasold et al., 2002; Stephan et al., 2005). These studies used either galvanic stimulation of the entire vestibular nerve (i.e., semicircular canal and otolith fibers) or caloric irrigation of the external ear for vestibular stimulation. Caloric activation activates mainly the horizontal semicircular canal fibers. Areas activated during both types of vestibular stimulation were located in the posterior insula (first and second long insular gyri) and retroinsular regions (representing PIVC and the posterior adjacent visual temporal sylvian area VTS in the monkey (Guldin and Grüsser, 1998)), the superior temporal gyrus, parts of the inferior parietal lobule, the depth of the intraparietal sulcus, the postcentral and precentral gyrus, the anterior insula and adjacent inferior frontal gyrus, the anterior cingulate gyrus, the precuneus and the hippocampus, most often bilaterally. With respect to this vestibular cortical network the specific questions of the current study were whether short tone bursts that activated the sacculus can elicit activations of cortical areas in humans and, if so, which areas: (i) those of the extrapyramidal motor circuit with the basal ganglia due to involvement of head on trunk coordination in space, (ii) those of the multisensory vestibular cortical network, (iii) only those of the acoustic cortical system, or (iv) a specific combination of the abovementioned areas. If saccular stimulation activates the multisensory vestibular cortex, it would be interesting to determine if this activation is separate and distinct from the entire vestibular nerve stimulation as described above, i.e., if a specific saccular cortical area can be delineated as distinct from cortical areas activated by semicircular canal stimulation.

Vestibular stimulation by vestibular evoked myogenic potentials (VEMP)

Methods and materials

In a preceding experiment with six subjects (3 m, 3 f) the continuous tonic activation of the sternocleidomastoid muscle throughout the whole experiment did not influence the pattern of cortical activation induced by sacculus stimulation. This activation is only needed to enhance the amplitude of the response of the VCR (Akin et al., 2004). Thus, VEMPs in this study were performed without continuous tonic muscle activation. To define the optimal stimulation condition in the scanner all subjects were previously stimulated in a similar experimental setting outside the scanner in a darkened room in supine position with their eyes closed. 15 of 21 subjects reported that they felt tilted toward the stimulated ear during VEMP stimulation with 102 dB. After the MRI experiment each subject was debriefed. The differential effects of unilateral, right-sided and left-sided tone burst stimulation were examined while the contralateral ear was plugged. The tone burst signal used had a frequency of 500 Hz, a rise and fall time of 1 ms, and a plateau time of 8 ms to guarantee optimal saccule stimulation (Akin et al., 2003; Cheng and Murofushi, 2001a b). The stimulus was presented at a repetition rate of 3 Hz. No effects of habituation have been documented on the recorded potentials of the sternocleidomastoid muscle for longer periods of stimulation (Wu and Murofushi, 1999). The tone burst signal was created with the help of a digital audio editor (Goldwave Software Version 5.08, St. John’s, Canada). Individual sound level thresholds and the threshold for VEMPs were determined before the experiment while subjects lay in an identical supine position outside the scanner. All subjects showed reproducible VEMPs at 85 dB but none at the 65 dB sound pressure level (SPL) while in a supine position without head elevation or rotation. Subjects with a pathological hearing threshold, pathological shape of VEMPs, or a significant but not yet pathological side difference in VEMPs, e.g., more than 30% side difference in amplitude, were excluded. Each volunteer underwent one continuous session with three different stimulation conditions in a block design for each ear: 1. one trial with a 102 dB 500 Hz tone burst signal beforehand which induced VEMPs outside the scanner; 2. one trial as a control with an identical tone burst signal below threshold 65 dB SPL, which did not trigger VEMPs in the electrophysiological study beforehand outside the scanner; and 3. a third trial consisting of a continuous white noise signal at 102 dB as a control for the loudness of VEMP stimulation with the same sound pressure level. The order and sides of the unilateral stimulations were randomized for each subject.

Subjects

MRI acquisition

We examined a total of 21 healthy right-handed volunteers (ages 23 to 33 years; 10 males and 11 females). The modified laterality quotient of handedness according to the 10-item inventory of the Edinburgh test (Chapman and Chapman, 1987) was determined beforehand since differential effects due to hemispheric dominance had to be considered (Dieterich et al., 2003). Only completely righthanded subjects without a history of vestibular, hearing, or CNS disorders were included in the study. The participants did not report concurrent use of any medication. This study was carried out in accordance with the Helsinki Declaration and approved by the local ethics committee. Each subject gave his/her informed written consent.

The subjects were positioned in the circularly polarized head coil in a clinical 1.5 T scanner (Siemens Magnetom Vision, Erlangen) wearing MRI-suitable piezo-electric headphones (Jaencke, Zuerich). The sealed headphones measurably suppressed scanner noise for the subject to well below 45 dB SPL, thus overcoming the intrinsic acoustic fMRI problem of gradient noise. To reduce head movements and consequently artificial activation patterns during data acquisition (Friston et al., 1996), the subject’s forehead was taped to the coil. Subjects were asked to passively experience the stimuli and to lie in a relaxed position with their eyes closed for the whole experiment in an otherwise completely darkened scanner room. The protocol for each trial included 510 volumes, each

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consisting of 40 slices of a T2∗-weighted interleaved echo-planar imaging (EPI) sequence (TR = 4.2 s, TE = 60 ms, FOV = 192– 220 mm, image matrix = 642, slice thickness = 4 mm), covering the whole brain and the cerebellum in 13 alternating blocks of seven images at rest without any stimulation (time length 29.4 s) and six images (time length 25.2 s) during the different sound stimulations. We did not use a sparse sampling technique because the good suppression of the scanner noise by our modified head phones and the inevitably high repetition rate of our stimulus produced statistically better results in a continuous setup. All images were collected parallel to the AC–PC line. The first three volumes of each session were discarded for reasons of signal quality, e.g., spin saturation effects. During the whole experiment an infrared video-oculography unit (MREye Track LR SMI, Berlin, Germany) was used to monitor possible eyelid contractions and bulbus movements during all stimulations. Prior to the acquisition of the functional data, a highresolution sagittal T1-weighted image (MPRAGE sequence, 180 slices, slice thickness = 1 mm, image matrix = 2562, TR = 9.7 ms, TE = 4 ms) was made for each participant, on which results of the functional data were later superimposed as co-registered images on the individual anatomy.

tions are reported (Shmuel et al., 2002). Anatomical localizations of the results were determined using anatomical landmarks and the software and parcellation described by Tzourio-Mazoyer et al. (2002). The anatomical definition of insular and retroinsular territories is adopted from Bense et al. (2001), who divided the insular structures into five gyri, three in the anterior insula (I–III) and two in the posterior insula (IV, V). Cerebellar structures were named according to Schmahmann et al. (2000).

Data analysis

(A) Right-sided short tone burst 102 dB versus rest (VEMP versus rest t-contrast) We found bilateral activation of the superior, middle, and transverse temporal gyri (BA 21, 22, 29, 41, 42), the precentral gyrus, the middle and inferior frontal gyri (BA 10, 11, 44, 45, 47), the inferior parietal lobule (BA 40), and the insular gyri IV and V (Table 1; Fig. 1b). The clusters were larger in size and had higher t-values on the contralateral left side. The frontal eye fields (BA 8) were also activated bilaterally, again predominantly on the left side. A further activation was located in the right medial geniculate body touching the dorsolateral thalamus. At lower thresholds (p b 0.005 uncorrected) an activation was found in the left medial geniculate body. Within the cerebellum significant clusters were located in the right posterior lobe (uvula) and the right anterior lobe (culmen). Relevant deactivations were found in both hemispheres in the pre- and postcentral gyri (BA 1, 2, 3, 4, 6), the superior parietal lobule, the precuneus, and the pulvinar of the thalamus. The right superior occipital gyrus (BA 19) and the right superior temporal gyrus were also deactivated, as was a cluster covering parts of the left fusiform and the parahippocampal gyrus (BA 37).

fMRI data were processed using Pentium IV workstations running on Windows 2000 or XP®. The fMRI data sets were reconstructed offline and then converted into the file format that was analyzed using Statistical Parametric Mapping software (SPM2, Wellcome Department of Imaging Neuroscience, London 2005). The images were realigned to the first one of each scanning session to correct for subject movement and were then stereotactically normalized into the standard anatomical space defined by the Montreal Neurological Institute (MNI) template by means of linear and non-linear transformation (Friston et al., 1995a). Thus, all stereotactic coordinates given in this paper refer to the MNI coordinate system. During normalization, the image volumes were resampled to a resolution of 2 × 2 × 2 mm. Subsequently prior to statistical analysis, the normalized images were smoothed with a three-dimensional isotropic Gaussian filter using an 11-mm fullwidth half-maximum (FWHM) kernel. A high-pass filter 128 s long was integrated into the design matrix to eliminate low frequency noise. The effect of the different stimulation conditions on regional BOLD responses was estimated according to the general linear model (Friston et al., 1995c). Statistical parametric maps (SPMs) were generated on a voxel-by-voxel basis with a hemodynamic model of the stimulation periods present during the session (Friston et al., 1995b). Single subject t-contrasts were computed for the three stimulation conditions compared to the rest condition of the session: for unilateral VEMP stimulation, for unilateral tone burst with a SPL of 65 dB (tone burst), and for the stimulation with a 102 dB white noise signal (white noise). These condition images were entered into a second level statistical analysis to test for effects on a between subject basis. This approach corresponds to a random effects analysis, which extends the scope of inference to the population from which the subjects were initially recruited. Paired t-tests for the different sides of stimulation were performed using the linear t-contrasts. The resulting SPMs were thresholded at p b 0.05 false discovery rate (corrected) unless noted otherwise (Genovese et al., 2002; Nichols and Hayasaka, 2003). Only clusters with more than five voxels were considered significant. Activations and deactiva-

Results During debriefing after the experiment, the subjects reported that the 102 dB SPL tone bursts and the 102 dB SPL white noise stimulus were both equally more unpleasant than the 65 dB tone burst signal. All subjects reported that the three different stimuli were clearly distinguishable from the scanner noise during the whole experiment. In the testing for the VEMPs outside the scanner most subjects (15 of 21; 71%) reported that they felt tilted toward the stimulated ear during the tone bursts. For all of them, the ipsilateral perception of tilt inside the scanner was not different. Activations and deactivations

Left-sided short tone burst 102 dB versus rest (VEMP versus rest t-contrast) The stimulation of the left ear with the loud short tone bursts significantly activated the superior, middle, and transverse temporal gyri (BA 13, 21, 22, 29, 41) and the insular gyri IV and V bilaterally (Table 1; Fig. 1a). A cluster was also found in the right inferior parietal lobule (BA 40). The postcentral gyrus, the precuneus and cuneus, and the posterior cingulated gyrus were deactivated above threshold bilaterally. The left middle occipital gyrus (BA 19) ipsilateral to the stimulation was also deactivated. Thus, the monaural stimulus for each side combining otolith and auditory stimulation activated areas in the posterior insula and the temporal lobe as well as the inferior parietal lobe. Simultaneously, deactivations occurred in the occipital gyri, cuneus and precuneus, and postcentral gyri.

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Table 1 Results of the comparisons (t-contrasts) for all stimuli t-contrast

Brain area

Right-sided 102 dB short tone burst versus rest Activations of right hemisphere Superior, transverse, middle and inferior temporal gyrus Insula gyrus IV and V Precentral gyrus Inferior parietal lobule Frontal lobe Middle and inferior frontal gyrus Middle frontal gyrus Midbrain, medial geniculate body, thalamus Cerebellum posterior lobe, uvula Cerebellum anterior lobe, culmen/nucleus fastigii Activations of light hemisphere Superior, transverse, middle and inferior temporal gyrus Insula gyrus IV and V Anterior cingulum Precentral and middle frontal gyrus Inferior and middle frontal gyrus Inferior parietal lobule Deactivations of right hemisphere Medial frontal gyrus Middle frontal gyrus Precentral gyrus Postcentral gyrus Inferior and superior parietal lobe Precuneus Middle temporal gyrus Superior occipital and temporal gyrus Thalamus (pulvinar) Cerebellar posterior lobe and tonsil Deactivations of left hemisphere Angular gyrus Inferior and superior parietal lobe Precuneus Postcentral gyrus Precentral gyrus Thalamus (pulvinar) Fusiform gyrus, parahippocampal gyrus Right-sided 65 dB short tone burst versus rest Activations of right hemisphere Superior, middle and transverse temporal gyrus Insula gyrus V Precentral and inferior frontal gyrus Right brainstem, pons Activations of left hemisphere Superior, middle and transverse temporal gyrus Insula gyrus V Postcentral gyrus Middle cingulate gyrus Deactivations of right hemisphere None Deactivations of left hemisphere None

BA

x, y, z

Cluster size

t-value

13, 21, 22, 38, 41, 42

50, − 24, 4

2977

13, 1

50, 4, 50 14, − 24, − 6 8, − 74, − 24 4, − 50, − 28 − 50, −26, 2

671 162 33 48 237 95 53 6 20 3663

10, 85 13, 25 4, 55 8, 25 6, 77 5, 31 6, 34 3, 96 4, 05 14, 25

948 6 203 450 59 14 32 12 598 787 630 97 91 23 14 19 458 647 99 50 17 93

12, 32 3, 55 5, 22 5, 64 11, 32 4, 46 4, 08 4, 27 5, 4 7, 08 7, 17 6, 09 5, 35 4, 25 4, 61 3, 73 6, 57 5, 31 5, 12 5, 32 4, 89 4, 4

40, 43 29 10, 11, 44 45, 47 6, 8

13, 21, 22, 41, 42

4, 6 10, 11, 45, 46, 47 29, 40, 42, 43 10 8 6, 4 1, 2, 3 5, 40 39 19

39 40

− 18, − 2, 42 − 50, − 2, 48 − 38, 34, − 18 8, 54, 0 36, 20, 44 66, − 10, 32 54, − 20, 48 42, − 86, 20 18, − 36, 6 20, − 46, − 52 − 40, −80, 30

5, 7

37

−52, − 12, 30 − 16, − 36, 4 − 28, − 42, −14

13, 21, 22, 29, 38, 41, 42

58, − 26, 4

1983

6, 67

6, 9

48, 2, 38 4, − 28, − 42 − 46, − 24, 2

166 186 39 2776

4, 6 4, 32 9, 82

− 36, − 28, 44 − 12, − 16, 40

320 53 66

6, 19 5

1027

6, 36

140 22 87 72 9 115 20 20 12

6, 21 4, 76 7, 29 6, 98 3, 75 4, 86 4, 25 5, 73 4, 67

13, 21, 22, 29, 41, 42

2, 3

Right-sided 102 dB short tone burst versus rest – right-sided 65 dB short tone burst versus rest Activations of right hemisphere Superior, middle and transverse 13, 21, 22, 29, 41, 42 temporal gyrus Insula gyrus V Cerebellum anterior lobe, culmen, fastigium Activations of light hemisphere Superior and transverse temporal gyrus 13, 29, 41 Insula gyrus V Precentral gyrus Deactivations of right hemisphere Superior and middle frontal gyrus 8, 9 Middle and superior frontal gyrus 10 Anterior cingulate gyrus Middle frontal gyrus 6

42, − 34, 12 2, − 48, − 26 − 38, − 40, 12 − 48, − 14, 12 22, 38, 42 28, 50, 4 8, 12, 44 24, − 12, 60

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Table 1 (continued) t-contrast

Brain area

BA

Right-sided 102 dB short tone burst versus rest – right-sided 65 dB short tone burst versus rest Postcentral gyrus Cerebellum, anterior lobe, culmen Cerebellum, posterior lobe Deactivations of left hemisphere Parietal lobe, precuneus, postcentral gyrus 5, 7 Precentral and postcentral gyrus 4 Inferior parietal lobe, postcentral gyrus 40 Parietal lobe, precuneus, posterior cingulate gyrus Thalamus (pulvinar), parahippocampal gyrus Right-sided 102 dB short tone burst versus rest – right-sided 102 dB white noise signal versus rest Activations of right hemisphere Superior, transverse and middle 13, 21, 22, 41, 42 temporal gyrus Insula gyrus IV and V Precentral gyrus Inferior parietal lobule 40, 43 Inferior frontal gyrus 38 Middle frontal gyrus 6, 8 Inferior and middle frontal gyrus 47 Activations of light hemisphere Superior, transverse, middle and inferior 13, 21, 22, 41 temporal gyrus Insula gyrus IV and V Pre- and postcentral gyrus 6 Precentral gyrus 4, 6 Inferior frontal gyrus 45, 46, 47 Deactivations of right hemisphere Middle occipital and middle temporal gyrus 19 Deactivations of left hemisphere None Right-sided 102 dB short tone burst – right sided 65 dB STB – right-sided 102 dB white noise signal Activations of right hemisphere Superior, transverse and middle 13, 21, 22, 29, 41 temporal gyrus Insula gyrus V Activations of light hemisphere Inferior parietal lobe Deactivations of right hemisphere None Deactivations of left hemisphere None Left-sided 102 dB short tone burst versus rest Activations of right hemisphere Superior, transverse and middle temporal gyrus Insula gyrus V Inferior parietal lobe Activations of light hemisphere Superior, transverse and middle temporal gyrus Insula gyrus V Deactivations of right hemisphere Precuneus, postcentral gyrus Postcentral gyrus Posterior cingulate gyrus Cuneus Deactivations of left hemisphere Precuneus, postcentral gyrus Postcentral gyrus Posterior cingulate gyrus Cuneus Middle occipital gyrus Left-sided 65 dB short tone burst versus rest Activations of right hemisphere Superior, transverse and middle temporal gyrus Insula gyrus V Activations of light hemisphere Superior, transverse and middle temporal gyrus Insula gyrus V

13, 21, 22, 29, 41, 42

40 13, 21, 22, 29, 41

x, y, z

t-value

10, − 54, 60 34, − 46, − 32 18, − 50, − 54 − 10, − 54, 72 − 46, − 16, 30 − 40, − 34, 48 − 8, − 42, 44

13 57 7 895 196 52 25

3, 72 4, 27 4, 32 7, 39 4, 43 5, 8 4, 58

− 16, − 36, 4

91

5, 56

50, − 14, − 4

2065

11, 39

52, 2, 50 54, 40, −6 − 56, − 28, 6

712 219 43 30 94 15 2337

5, 14 3, 91 7, 62

− 46, − 8, 48 − 58, 32, − 2 46, − 82, 18

938 535 97 114 27

4, 21 5, 64 4

50, − 12, − 6

816

5, 23

− 44, − 36, 24

192 15

3, 74

52, − 12, − 4

1194

10, 06

− 50, − 24, − 2

353 20 1101

7, 78

5

5 3

Cluster size

− 18, − 62, 62

19

13, 21, 22, 29, 41, 42

56, − 26, 2

13, 21, 22, 29, 41, 42

− 46, − 34, 6

291 1417 718 444 69 1458 619 472 285 208

8, 3

8, 3

1173

14, 06

207 857

8, 15

74 (continued on next page)

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Table 1 (continued) t-contrast

Brain area

BA

x, y, z

Cluster size

t-value

Left-sided 65 dB short tone burst versus rest Deactivations of right hemisphere None Deactivations of left hemisphere None Left-sided 10 dB short tone burst versus rest – left-sided 65 dB short tone burst versus rest Activations of right hemisphere Superior and transverse temporal gyrus 13, 29, 41 Insula gyrus V Activations of light hemisphere Superior, transverse and middle temporal gyrus 13, 21, 22, 29, 41, 42 Insula gyrus V Deactivations of right hemisphere Posterior cingulate gyrus Cerebellum, posterior lobe, declive Deactivations of left hemisphere Medial and superior frontal gyrus 32 Anterior cingulate gyrus Left-sided 102 dB short tone burst versus rest – left-sided 102 dB white noise signal versus rest Activations of right hemisphere Superior, transverse and middle temporal gyrus 13, 21, 22, 29, 41, 42 Insula gyrus V Inferior parietal lobule 40 Activations of light hemisphere Superior, transverse and middle temporal gyrus 13, 21, 22, 29, 41, 42 Insula gyrus V Inferior parietal lobe 40 Deactivations of right hemisphere Middle and superior frontal gyrus 10 Precuneus Dorsomedial frontal cortex 8 Deactivations of left hemisphere Medial frontal gyrus 6 Left-sided 102 dB short tone burst – left sided 65 dB STB – left-sided 102 dB white noise signal Activations of right hemisphere None Activations of light hemisphere Superior, transverse and middle temporal gyrus 13, 21, 22, 29, 41 Insula gyrus V Deactivations of right hemisphere Superior and inferior parietal lobe 7, 40 Dorsomedial frontal cortex 8 Deactivations of left hemisphere Dorsomedial frontal cortex 8 Caudate body cerebellar tonsil Paired t-test right vs. left-sided 102 dB short tone burst versus rest Activations of right hemisphere Medial and superior frontal gyrus Cerebellum, vermis, inferior semilunar lobe Cerebellum, anterior lobe, dentate Activations of light hemisphere Inferior frontal gyrus Precentral gyrus Deactivations of right hemisphere None Deactivations of left hemisphere None Paired t-test right vs. left-sided 65 dB short tone burst versus rest Activations of right hemisphere Superior and medial frontal gyrus Inferior parietal lobe Activations of light hemisphere Brainstem, midbrain Middle and superior temporal gyrus Deactivations of right hemisphere Superior and middle temporal gyrus Deactivations of left hemisphere None

8

44 4, 6

10

21, 22 21, 22

38, − 32, 12 − 34, − 30, 8 2, − 40, 42 42, − 76, −28 − 10, 20, 42

46, − 28, 12 − 38, − 28, 12

40, 46, 24 36, − 76, 40 2, 26, 44 − 4, − 18, 76

− 34, − 26, 10

50 34 116 11 25 41 132 96

4, 5

1056 383 23 1450 528 52 97 14 68 37

7, 68

4, 68 4, 74 4, 44 5, 41

11, 76

4, 81 3, 91 4, 7 4, 67

40, − 68, 52 2, 22, 48 − 2, 22, 48 − 6, 6, 12 − 14, − 38, −48

400 238 42 29 30 15 8

5, 59 4, 06 4, 06 4, 51 4, 06

12, − 12, 60 4, − 80, − 34 18, − 52, −34 − 64, 12, 10 − 46, − 12, 54

448 43 53 113 133

5, 54 5, 09 4, 74 5, 9 4, 25

26, 44, 10 42, − 44, 28 − 8, − 22, − 12 − 58, − 12, − 6 52, − 28, 2

133 59 110 211 155

4, 45 5, 16 5, 17 4, 89 5, 22

283 52

5, 03 4, 87

50 35 119

4, 68 4, 61 4, 3

Paired t-test right vs. left-sided 102 dB short tone burst versus rest – ipsilateral 65 dB short tone burst versus rest Activations of right hemisphere Superior and middle temporal gyrus 21, 22 58, − 20, 0 Activations of light hemisphere Inferior frontal gyrus 45 − 58, 32, 8 Deactivations of right hemisphere None Deactivations of left hemisphere None Paired t-test right vs. left-sided 102 dB short tone burst versus rest – ipsilateral 102 dB short tone burst versus rest Activations of right hemisphere Cerebellum, posterior lobe, vermis 8, − 88, − 40 Middle cingulate gyrus 23 4, − 16, 28 Superior and medial frontal gyrus 6 12, − 10, 68

6, 83

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Table 1 (continued) t-contrast

Brain area

BA

x, y, z

Paired t-test right vs. left-sided 102 dB short tone burst versus rest – ipsilateral 102 dB short tone burst versus rest Activations of light hemisphere None Deactivations of right hemisphere Middle temporal gyrus 19 44, − 86, 18 Deactivations of left hemisphere None

Cluster size

6

t-value

3, 88

Listing of all activations and deactivations for all stimuli and calculated SPM (pb0.05 FDR corrected, 5 voxel minimum cluster size). In addition, we report the paired t-tests of the right ear stimulation for tone burst experiments. Bold coordinates represent the local maximum for a homogenous cluster with several actived brain areas.

(B) Right-sided short tone burst 65 dB versus rest (acoustic control stimulus versus rest) As expected, there was a bilateral activation of the superior, middle, and transverse temporal gyri (BA 13, 21, 22, 29, 38, 41, 42)

and the insular gyrus V (Table 1; Fig. 1d). The short tone bursts had a slightly stronger effect on the contralateral left hemisphere. Activations were further located in the right precentral and inferior gyrus, the right pontine brainstem, the left postcentral gyrus, and the

Fig. 1. Comparison of areas activated during left and right ear stimulation with 102 dB and 65 dB short tone bursts and after the t-contrast exclusion of all acoustic interference. Panels a and b give the activation patterns during combined saccular and acoustic stimulation, panels c and d the activation patterns during pure acoustic stimulation with click sounds at 65 dB SPL, and panels e and f the activation patterns during “pure” saccular stimulation. Note that the sacculus stimulation (e + f) is associated with an activation of the ipsilateral superior temporal gyri and insular gyri V.

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Table 2 Activations found in recent vestibular neuroimaging studieswith respect to the stimulated side Literature

Experimental setup

Stimulated side

Brain area

Imaging technique Suzuki et. al. [31]

Caloric irrigation with cold water fMRI

Left Right ear

Left ear

Fasold et. al. [30]

Caloric irrigation with nitrogen fMRI

Bilateral

Stephan et. al. [35]

AC-galvanic stimulation fMRI

Bilateral

Bense et. al. [29]s

DC-galvanic stimulation fMRI

Hemisphere

Bilateral

Paracentral lobulus Superior temporal gyrus Superior temporal gyrus Intraparietal gyrus Parahippocampal gyrus Hippocampus Cingulate gyrus Insular gyrus Intraparietal gyrus Thalamus Cingulate gyrus Parahippocampal gyrus Superior temporal gyrus Hippocampus Parahippocampal gyrus Inferior parietal lobulus Hippocampus Intraparietal gyrus Cingulate gyrus/paracentral lobule Insular gyrus Insular gyrus Parieto-insula Anterior insula Posterior superior temporal sulcus Posterior superior temporal gyrus Dorsolateral parietal area Occipital lateral gyrus Central sulcus Frontoparietal operculum Precentral gyrus Dorsolateral prefrontal Posterior cingular gyrus Anterior cingular gyrus Superior temporal gyrus Inferior frontal gyrus/superior temporal gyrus Insular gyri I–V Inferior/middle frontal gyrus Precentral gyrus, middle frontal gyrus Thalamus Superior temporal gyrus Inferior frontal gyrus/superior temporal gyru Insular gyri I–V Precentral gyrus, middle frontal gyrus Inferior/middle frontal gyrus Thalamus Inferior parietal lobule Vermal lobule VII Middle/inferior temporal gyrus Supplementary motor area Supplementary motor area Middle cingular gyrus Inferior parietal lobule Middle cingular gyrus Middle temporal gyrus Putamen Paramedian thalamus

× ×

× ×

BA

x, y, z

7 22 38

2, − 44, 62 − 56, 10, − 6 48, 10, − 16 38, − 56, 54 18, − 38, − 14 40, − 14, − 22 0, 12, 30 − 30, 10, − 8 42, − 58, 48 8, − 18, 0 8, 12, 32 − 16, −44, − 10 50, −16, 8 − 40, −12, − 14 − 22, −30, − 24 56, − 42, 44 34, − 12, − 24 − 30, −62, 46 4, − 6, 36 38, 2, −4 46, 14, −8

Right

× × × × ×

36

× × × × ×

36, 37 22, 42

× ×

36 40 36

× ×

× × × ×

24

× × ×

40/39 22

56, − 28, 24 54, 4, 4

× ×

45, 46, 47 6, 9

40, 2, − 6 42, 40, 0 52, 2, 44

× × ×

39, 40 22

− 16, −14, 6 − 58, − 22, 22 − 52, 2, 2

× ×

6, 9

− 36, 0, − 2 − 46, 4, 36

× × × ×

45, 46, 47 7, 40 × ×

× × × × × × ×

37 6 6 24 40 23 37

− 42, 36, 0 22, 2, 0 − 30, − 50, 50 − 18, − 70, −28 56, − 58, − 2 6, 6, 56 − 4, −2, 62 − 6, 6, 34 34, − 50, 46 12, − 26, 48 − 54, − 58, 2 − 18, 14, 4 − 8, −10, 6

P. Schlindwein et al. / NeuroImage 39 (2008) 19–31

27

Table 2 (continued) Literature

Experimental setup

Stimulated side

Brain area

Hemisphere

Right ear

Dorsolateral thalamus Dorsolateral thalamus Cerebellar hemisphere Cerebellar hemisphere Anterior cingulate gyrus Precentral gyrus Precentral gyrus Precentral/inferior frontal gyrus Middle frontal gyrus Middle frontal gyrus Inferior frontal gyrus Middle temporal gyrus Superior temporal gyrus Superior temporal gyrus Inferior parietal lobule Inferior parietal lobule Posterior/anterior insula Posterior/anterior insula Inferior frontal gyrus Postcentral gyrus Postcentral gyrus Postcentral gyrus Inferior parietale lobule Inferior parietale lobule Anterior cingulum Superior frontal gyrus Thalamus posterolateral Thalamus posterolateral Hippocampus Medial frontal gyrus Substantia nigra Precuneus Anterior/posterior insula

Imaging technique

Dieterich et. al. [33]

Caloric irrigation with warm water H2O-PET

Left

Left ear

Posterior Insula Posterior Insula Heschl's gyrus Putamen Inferior parietal lobule Anterior cingulum Anterior cingulum/corpus callosum Inferior frontal/precentral gyrus Superior frontal gyrus Thalamus posterolateral

BA

x, y, z

Right ×

× × × × × × ×

32 6 6 6, 44

× × × × × × × ×

46 47 37 22 22 40 40

× × × × × × × × × ×

46 40 42 40, 42 40 40 32 10

× × × ×

9

×

7

×

41 41

× ×

× × × × ×

40 32 32 24 6, 44 6

× × × ×

24, − 20, 12 − 22, −19, 12 − 18, −78, − 20 8, − 82, − 22 − 4, 34, 22 58, 12, 38 − 44, −2, 46 − 54, 12, 14 9, 46 42, 46, 26 −42, 38, 30 35, 25, −5 − 58, − 60, 2 56, 18, −8 − 50, 8, − 8 − 60, − 32, 28 58, − 32, 28 30, 2, − 8 −34, 0, − 4 38, 36, 6 48, − 26, 24 56, − 36, 20 − 66, −28, 22 64, − 36, 32 − 72, − 38, 36 − 12, 28, 28 − 18, 54, − 6 24, − 24, 6 − 24, −26, 14 28, − 42, − 2 28, − 42, − 2 − 10, −16, − 12 10, − 30, 48 − 50, 4, 0 − 36, − 2, 8 46, − 34, 16 − 38, 4, − 8 40, −30, 12 32, 2, 2 − 56, − 40, 24 6, 18, 36 14, 36, 22 14, 36, 22 − 46, 2, 24 − 20, 10, 72 22, − 26, 8

Brain areas in bold letters mark activations that are congruent with findings in our study.

medial cingulate gyrus. At lower thresholds (p b 0.005 uncorrected) only an activation in the left medial geniculate body was found. There were no relevant deactivations.

Left-sided short tone burst 65 dB versus rest (acoustic control stimulus versus rest) Again the experiment resulted in a significant bilateral signal increase in the superior, middle, and transverse temporal gyri (BA 13, 21, 22, 29, 38, 41, 42) and the insular gyrus V (Table 1; Fig. 1c). For this stimulation the effect was stronger (cluster size, t-values) in the left hemisphere.

There were no relevant deactivations. Thus, the auditory control stimulus for each ear resulted in a bilateral but mainly contralateral activation of the temporal gyri with a dominant response in the left hemisphere without concurrent deactivations.

(C) Right-sided stimulation, 102 dB–65 dB short tone burst versus rest (VEMP—acoustic control stimulus versus rest) Subtraction of the acoustic stimulus from the VEMP stimulus of the right ear revealed a strong activation of the right temporal lobe (superior, middle, and transverse temporal gyri; BA 13, 21,

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P. Schlindwein et al. / NeuroImage 39 (2008) 19–31

22, 29, 41, 42) and the right insular gyrus V. The same pattern was seen in the left hemisphere, but on a much smaller scale. There were other signal increases in the left precentral gyrus and the right cerebellar anterior lobe (culmen and fastigial nucleus) (Table 1). Deactivations included clusters in the right superior and middle frontal gyri (BA 9), the postcentral gyrus, the anterior cingulate gyrus, and the posterior and anterior cerebellar lobe (culmen) of the right hemisphere. In the left hemisphere areas in the parietal lobe, the precuneus (BA 5, 7), the pre- and postcentral gyrus (BA 4), the inferior parietal lobule (BA 40), the posterior cingulate gyrus and the pulvinar as well as a part of the parahippocampal gyrus were significantly deactivated. Left-sided stimulation, 102 dB–65 dB short tone burst versus rest (VEMP—acoustic control stimulus versus rest) This t-contrast revealed smaller activations compared to the right-sided stimulations in the right superior and transverse gyri (BA 13, 29, 41), the left superior, transverse, and middle temporal gyri (BA 13, 21, 22, 29, 41, 42), and the insular gyrus V of both hemispheres (Table 1). There were deactivations in the left posterior and the right anterior cingulate gyrus, in the medial and superior frontal gyri (BA 32), and the left posterior cerebellar lobe (declive). Thus, the subtraction of the acoustic control stimulus (tone bursts at 65 dB SPL) from the saccule stimulation with short tone bursts at 102 dB SPL, calculated separately for each side, resulted in an activation of the insular gyrus V and the transverse, superior, and middle temporal gyri predominantly in the right hemisphere. The results of the 102 dB short tone bursts vs. the acoustic loudness control stimulus (white noise at 102 dB SPL) contrast gave no additional information compared to the other t-contrast calculations. Nevertheless, the activated clusters are reported in Table 1. (D) Right-sided 102 dB short tone burst–65 dB short tone burst–102 dB white noise (VEMP—acoustic and loudness control stimulus versus rest) The t-contrast that excluded both acoustic control stimuli showed only ipsilateral activation of the right superior, transverse, and middle temporal gyrus (BA 13, 21, 22, 29, 41) and the right insular gyrus V (Table 1; Fig. 1f). In the contralateral left hemisphere only the inferior parietal lobule (BA 40, 43) showed a significant activation. There were no significant deactivations.

Discussion Cortical activation pattern during vestibular otolith stimulation of the saccule Otolith stimulation of the saccule by air-conducted tone bursts triggers inhibitory VEMPs recorded from the sternocleidomastoid muscles. To date, the ascending central projections of the saccule are unknown in humans; only the representation of the semicircular canal and the entire vestibular nerve has been examined during the last 7 years. Since it is widely accepted that the air-conducted sound of sufficient intensity activates receptors only in the saccule but not the utricle or the semicircular canals, the resulting cortical activations of a network of multisensory vestibular areas and the feeling of being tilted toward the stimulated ear, which was reported by 71% of the healthy subjects, both represent aspects of otolith processing at cortical level. The pattern of these cortical activations in the posterior insular gyri IV and V, the middle and superior temporal gyri (BA 13, 21, 22, 29, 41), and the inferior parietal cortex (BA 40) was very similar to that induced by galvanic stimulation of the entire vestibular nerve (Bense et al., 2001; Stephan et al., 2005) (Table 2). This fits the study of galvanic vestibular stimulation at different frequencies between 0.1 Hz and 5.0 Hz which found no mapping of different stimulation frequencies to different cortical locations (Stephan et al., 2005). This seems also to be true for the saccular otolith stimulation. The results of both studies are in agreement with the hypothesis that semicircular canal and otolith input may converge at brainstem level, e.g., within the vestibular nuclei, and reach vestibular cortex areas as integrated information. These mentioned areas are the most important within the typical complex network of multisensory areas predominantly in the temporo-insular and temporo-parietal cortex of both human hemispheres involved in the processing of vestibular information. They have been delineated during the last 7 years by functional imaging studies in humans (Bremmer et al., 2001; Emri et al., 2003; Fasold et al., 2002; Stephan et al., 2005). However, the activated clusters in our study appeared smaller in size than those found with unilateral galvanic stimulation, and there was no activation of the anterior insula and adjacent medial parts of the frontal gyrus and the dorsolateral thalamus. This absence might be explained by the ascending projection through the medial geniculate body, which we found activated on the ipsilateral side for the combined saccular and acoustic stimulus, but contralaterally for only the acoustic control stimulus. Deactivations during VEMP: interactions of multisensory neurons

Left-sided 102 dB short tone burst–65 dB short tone burst–102 dB white noise (VEMP—acoustic and loudness control stimulus versus rest) The t-contrast that excluded all acoustic stimuli for the leftsided stimuli also detected only ipsilateral activation of the left superior, transverse, and middle temporal gyri (BA 13, 21, 22, 29, 41) and the left insular gyrus V (Table 1; Fig. 1e). The dorsomedial frontal cortex (DMFC) was deactivated bilaterally, as was a cluster in the right superior (BA 7) and inferior parietal lobe (BA 40), the left cerebellar tonsil, and the left caudate body. Thus, subtraction of both auditory control stimuli from the 102 dB short tone bursts showed a remaining otolith activation in the superior, transverse, and middle temporal gyri and the insular gyrus V ipsilateral to the tested ear.

VEMP stimulation of the right ear induced simultaneous deactivations within the right hemisphere located in the superior and middle frontal gyri (BA 45), the postcentral and anterior cingulate gyrus, as well as the right posterior and anterior cerebellar lobes. The areas deactivated within the left hemisphere – the precuneus (BA 5, 7), the pre- and postcentral gyrus (BA 4), the pulvinar, the inferior parietal lobule (BA 40), the posterior cingulate gyrus, and the parahippocampal gyrus – represent somatosensory, visual, and vestibular areas of the multisensory cortical network. These deactivations of somatosensory or visual areas during vestibular stimulation can be attributed to the inhibitory interaction between the sensory systems (Brandt et al., 1998). They confirm earlier data observed during galvanic stimulation of the vestibular nerve (Bense et al., 2001).

P. Schlindwein et al. / NeuroImage 39 (2008) 19–31

It has been unclear up to now if ascending pathways to cortical level for saccular stimulation exist at all in humans and where their cortical integration centers might be located. Even animal studies on ascending otolith projections to multisensory cortical areas are rare (Newlands et al., 2003; Yingcharoen et al., 2003). The only studies in cats, monkeys, and guinea pigs using electrical otolith stimulation of the saccular and utricular nerves and concentrating on the sacculo- and utricular-ocular reflex described the projection from the peripheral nerve to the ocular motor areas in the brainstem and cerebellum (Burian et al., 1991; Yingcharoen et al., 2003), but no information is available about cortical areas such as the cortical eye fields. This study for the first time presents evidence by means of fMRI that saccular input is represented at cortical level within a temporo-parietal network that includes the FEF (BA 8). Based on a convergence of semicircular and otolith input at brainstem level within the vestibular nuclei and the ocular motor nuclei (Baker et al., 1973; Dickman and Angelaki, 2002) it is plausible that the FEF in humans may be part of a common cortical network not only activated by the vestibulo-ocular reflex but also solely by the sacculo-ocular reflex. The BOLD signal increases of the frontal eye fields, FEF (BA 8), in both hemispheres during tone burst stimulation of the right ear were not unexpected. FEF activations could be due to small torsional eye movements induced by the saccular-ocular reflex. An alternative explanation for this activation of the FEF could have been a constant stimulus that caused blinking of the eyes; this possibility was excluded with the help of infrared video-oculography during scanning. Activation of cortical areas was further expected because most of the subjects had described a perception of being tilted during VEMP stimulation, indicating an involvement of cortical function. Thus, not only caloric stimulation of the horizontal canals but also otolith stimulation appears to activate the same cortical multisensory network related to vestibular and ocular motor function. Hemispheric lateralization within the human cortex: right hemisphere dominance of the otolith vestibular system versus left hemisphere dominance of the acoustic system? Activations within the cortical network during vestibular stimulation of the horizontal semicircular canals and the entire vestibular nerve are not symmetrical in the two hemispheres. On the contrary, they depend on three determinants that were defined recently in a study investigating healthy right- and left-handers during caloric irrigation (Dieterich et al., 2003). These determinants were (1) the subject’s handedness, (2) the side of the stimulated ear, and (3) the direction of the induced vestibular symptoms. Activation was stronger in the right hemisphere in right-handers and in the left hemisphere in left-handers, in the hemisphere ipsilateral to the stimulated ear, and in the hemisphere ipsilateral to the fast phase of vestibular caloric nystagmus (Dieterich et al., 2003). Accounting for the acoustic control stimuli in our current study, we also found a dominance of the right hemisphere in our right-handed volunteers for the processing of exclusive saccular information during tone burst stimulation (Figs. 1e, f). This dominance of the vestibular otolith system within the right hemisphere in right-handers allowed us to differentiate between the vestibular and the acoustic systems. To the best of our knowledge, this is the first study in which a separation of both systems has succeeded. The laterality of the acoustic system at the cortical level seems to be dependent on the context. Single rapid tones, sounds within a context of speech, or of a phonetic quality elicited a predominant

29

activation of the left temporal cortex (Devlin et al., 2003; Zaehle et al., 2004). This activation pattern, moreover, showed a very strong contralaterality effect with monaural stimulation (Di Salle et al., 2003). Correspondingly, anatomical studies in humans showed that the temporal plane in the left hemisphere is larger than in the right hemisphere and that the connectivity of primary auditory cortex neurons via dendritic trees is greater in the left hemisphere (Seldon, 1981; Zaidel et al., 1990). In contrast to speech-related sounds, acoustic stimuli with a musical quality (pitch change) caused activations within the auditory cortex of the right hemisphere for binaural stimulations. Although there are bilateral acoustic pathways, activation level and side are thus determined by the semantic context and the given task (attention, sound profile, emotions), in which an auditory stimulus is presented (Brechmann and Scheich, 2005). An activation predominantly within the right acoustic cortex was also found during passive listening to different sound locations (Brunetti et al., 2005; Fujiki et al., 2002). Brunetti and co-workers concluded from this response pattern that information based on the auditory space (auditory “where” pathway) is mainly processed in the right hemisphere. However, the authors did not consider that their stimulus had a vestibular (otolith) component. In fact, their activation pattern was very similar to those elicited by different types of vestibular stimulation, as well as the pattern we saw in the current study during saccule stimulation. We were able to differentiate the processing of both systems, the acoustic and the vestibular, in our study by subtracting acoustic stimuli activations (by single rapid tones) from VEMP stimulus activations. This yielded for the saccular component a stronger activation within the ipsilateral hemisphere and within the right temporo-insular region during right- or left-sided stimulation (Figs. 1e, f). Thus, our results provide evidence that the processing of otolith information, which is important for the processes of head and body orientation in space, is located predominantly within the ipsilateral hemisphere and the right hemisphere in right-handers. This is in accordance with the activation of the FEF within both hemispheres, which was only found after saccular stimulation of the right ear, as were the right medial geniculate body and the cerebellar vermis. This underlines the dominance of the right afference. In contrast, our acoustic stimulus was mainly processed contralaterally during monaural stimulation, and there was a dominance of the left hemisphere in right-handers (Figs. 1c, d). Accordingly, activation of the medial geniculate body was also seen contralaterally. None of our stimuli (VEMPs, 65 dB tone burst, white noise) possessed any musical qualities. The results for the acoustic control stimulus (65 dB tone burst) confirmed an activation pattern with a strong contralateral preponderance, a finding well established for the auditory system (Di Salle et al., 2003). Several fMRI studies have demonstrated that monomorph tone signals without pitch change, such as rapid auditory stimuli, like the one we used, showed significantly larger BOLD responses in the contralateral transverse temporal gyrus (Devlin et al., 2003; Zaehle et al., 2004). In conclusion, our data give for the first time clear evidence of a task-dependent separation of the processing within the otolith vestibular and the auditory systems in the two hemispheres: a dominance of ipsilateral and right hemispheric processing for saccular information and a dominance of contralateral and left hemispheric processing for purely acoustic stimuli without a spatial or musical component in right-handers. Interestingly, this separation at the cortical level was still valid for the vestibular stimulus triggered by short, loud click sounds (VEMPs). This stimulus has several aspects in common with a simple acoustic stimulus, i.e., the

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