Brain Advance Access originally published online on May 21, 2003
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Brain, Vol. 126, No. 7, 1562-1578,
July 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg165
Cortical correlates of vestibulo-ocular reflex modulation: a PET study
1 Department of Otolaryngology – Head and Neck Surgery, 2 Nuclear Medicine and 3 Human Brain Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Correspondence to: Yasushi Naito, M.D. Department of Otolaryngology – Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan E-mail: naito{at}ent.kuhp.kyoto-u.ac.jp
Received July 18, 2002. Revised January 3, 2003. Accepted March 12, 2003.
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Summary |
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To elucidate cortical correlates of vestibulo-ocular reflex (VOR) modulation, we observed cortical activation during fixation suppression and habituation of caloric vestibular nystagmus in 12 normal subjects, using PET. Significant positive correlation between regional cerebral blood flow (rCBF) and slow phase eye velocity of caloric nystagmus was observed in the middle and posterior insula, inferior parietal lobule, temporal pole, right fusiform gyrus, lingual gyrus, and cerebellar vermis and hemisphere. The rCBF increase in the insular region and the inferior parietal lobule was lateralized depending on the direction of the nystagmus. Caloric nystagmus was suppressed as a result of visual fixation, during which time the area around the right frontal eye field, temporal pole, inferior temporal gyrus, a broad area in the visual cortex, including fusiform and lingual gyrus, cerebellar uvula/nodulus and flocculus, exhibited positive correlation with fixation suppression of caloric nystagmus, while vestibular cortices exhibited negative correlation. The caloric nystagmus habituated with repetition of stimulation. With habituation, we observed activation in the right anterior cingulate gyrus, left superior parietal lobule and right cuneus, and deactivation in the anterior insula, cingulate gyrus, inferior parietal lobule and occipito-temporal visual cortex. The region that showed significant co-activation with fixation suppression and habituation of caloric nystagmus was the right cuneus, and significant co-deactivation was observed in the anterior insula, cingulate gyrus, inferior parietal lobule and middle temporal visual cortex. The present results support previous observations that the parieto-insular cortex and inferior parietal lobule are involved in processing of vestibular information, and, in addition, suggest that activation may depend on the direction of nystagmus. Deactivation of vestibular cortices during visual fixation supports the concept of inhibitory visual–vestibular interaction in the cortex. Significant activation of the cingulate, superior parietal and visual cortices, and cerebellar vermis accompanying reduction of caloric response with repeated stimuli suggests possible involvement of these regions in vestibular habituation. Common activation of the cuneus in visual cortex and deactivation of vestibular and visuo-spatial association cortices by both visual suppression and habituation of VOR suggests that these two mechanisms are not completely independent but may share some cortical and subcortical regions.
Keywords: caloric nystagmus; fixation suppression; PET; vestibular habituation; visual–vestibular interaction
Abbreviations: MT = medial temporal area; MST = medial superior temporal area; rCBF = regional cerebral blood flow; SPV = slow phase eye velocity; VOR = vestibulo-ocular reflex
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Introduction |
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The vestibulo-ocular reflex (VOR) stabilizes the retinal image during head movement. The dynamic characteristics of the VOR are not rigidly fixed, but are modulated according to the movement and orientation of the head and the accompanying visual input. The VOR and visual input cooperate when fixating on a static earth-bound target during head movement, but fixating one’s gaze on a target that moves with the head requires suppression of the VOR. The striate cortex, the superior temporal sulcus and the posterior parietal cortex play important roles in such visual–vestibular interaction (Dow, 1974
; Robinson et al., 1978; Maunsell and Van Essen, 1983; Sakata et al., 1983; Albright, 1984; Tanaka et al., 1986), and these areas send efferent signals to the dorsolateral pontine nuclei (May and Anderson, 1986) and the cerebellum (Kato et al., 1988), which regulate eye movements.
Vestibular habituation also influences the VOR, with decrease in VOR response when vestibular stimuli are applied repeatedly. Unlike fixation suppression, habituation does not require visual input, and the time constant and gain of VOR are reduced (Leigh and Zee, 1999), which contributes to eliminating spontaneous nystagmus relieving vertigo of peripheral origins. With habituation, the brainstem velocity-storage integrator (Raphan et al., 1979), which improves the ability of the VOR to transduce the low-frequency components of head rotation, decreases its function (Baloh and Honrubia, 2001).
Vestibular signals are primarily processed in the brainstem in cooperation with the cerebellum. However, recent investigations using primates and functional imaging studies on humans have revealed the importance of vestibular information processing in the cortex, where it is integrated with other sensory information. Cortical processing of vestibular signals may contribute to establishing the internal representation of space, in which different sensory inputs are integrated and organized in ego-centered and object-centered coordinates (Karnath, 1994; Bottini et al., 2001). At the same time, cortical outputs to the vestibular nuclei regulate vestibular function for appropriate movement and posture in space (for a review see Fukushima, 1997). Normal humans can voluntarily modulate the gain of VOR without a visual target (Barr et al., 1976; Jones et al., 1984), and adaptive change of VOR can also be induced by mental effort (Jones and Berthoz, 1985). Although there are clinical studies on the effects of cortical deficits on VOR (Baloh et al., 1980; Estanol et al., 1980; Sharpe and Lo, 1981), the regions involved in modulation of VOR remain to be determined. Functional imaging can reveal cortical regions involved in a certain type of neuronal processing in the intact human brain, but imaging studies related to cortical control of the vestibular system are still very limited in number (Brandt et al., 1998; Galati et al., 1999).
One of the problems in assessing cortical vestibular processing by functional brain imaging has been the technical difficulty in monitoring vestibular function during experiments. In the present study, we used PET and an infrared eye camera system (Funabiki et al., 1997), which made it possible to monitor and quantitatively assess the VOR during regional cerebral blood flow (rCBF) measurement. The purposes of our study were to identify the cortical regions activated by caloric vestibular stimulation, and to locate the regions involved in the suppression of VOR with visual fixation. Another purpose of this study was to investigate whether there are cortical and/or subcortical regions related to VOR habituation, which modulate VOR independent of visual input, and, if there are, to investigate their relationship with the above-mentioned direct visual–vestibular interaction pathways. Observation of cortical and subcortical correlates of fixation suppression and habituation of VOR may contribute to understanding of vestibulo-cortical and cortico-vestibular interactions that yield suitable behaviour in space and maintenance of equilibrium.
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Subjects
Twelve male volunteers with no history of oto-neurological disorders were included in this study. The age of the subjects ranged from 22 to 44 years (mean ± SD, 28.7 ± 7.8). All subjects were right-handed.
Informed written consent was obtained from all subjects after a full explanation of the study. This study was performed in accordance with the guidelines of the Declaration of Helsinki, and was approved by the Committee of Medical Ethics, Graduate School of Medicine and Faculty of Medicine, Kyoto University.
Eye movement monitoring
Eye movement was monitored by an infrared CCD eye camera system (Funabiki et al., 1997), and video-recorded (GV-D900; Sony, Tokyo, Japan). The ocular movement induced by caloric stimulation consists of slow and saccadic components, and we developed software to analyse this eye movement (Funabiki et al., 1999). After removing saccades on the software, the mean slow phase eye velocity (SPV) during the 60 s of rCBF measurement was calculated. Viewing the subject’s eye using a video monitor monitored the alertness of the subject during measurement.
The subject could see the laser-illuminated point through a half mirror when the upper lid of the infra-red camera system was opened.
Stimuli and tasks
The subject lay supine on the PET scanner bed, and an air tube was inserted into the external auditory canal and fixed so that the tip of the tube was located at a depth of 2 cm from the tragus. The external end of the tube was connected to an air caloric stimulator (Varioair; Atmos, Lenzkirch, Germany). The rate of airflow was 5 l/min. The caloric stimulation produces an ocular response of low frequency characteristics (Baloh and Honrubia, 2001). This makes it possible to obtain efficient suppression of VOR, which is not possible with stimuli of higher frequencies.
rCBF was measured during four sets of tests under three different conditions: (1) body temperature (37°C) air irrigation; (2) cold (25°C) or hot (49°C) air irrigation in darkness; and (3) cold or hot air irrigation with gaze fixed on a laser-illuminated point. Cold-air irrigation was applied to the left ear in three subjects, and to the right ear in another three subjects. Hot-air irrigation was applied to the left ear in three subjects, and to the right ear in the remaining three subjects. During visual fixation, which started 30 s before rCBF measurement, the subjects were instructed to fixate on a laser-illuminated target at 20 cm in front of them.
The air irrigation continued for 3 min starting 2 min before rCBF measurement, with an intermission of 10 min between each session.
PET scanning
The PET scans were performed with a General Electric Advance tomograph (GE Medical Systems, Milwaukee, WI, USA) with the interslice septa retracted. This scanner acquires 35 slices with an interslice spacing of 4.25 mm. In 3D mode, the scanner acquires oblique sinograms with a maximum cross-coincidence of ±11 rings. A 10 min transmission scan using two rotating 68Ge sources was performed for attenuation correction. Images of rCBF were obtained by summing the activity during the 60 s period following the first detection of an increase in cerebral radioactivity after intravenous bolus injection of 10 mCi (370 MBq) of 15O-labelled water (Sadato et al., 1997). The images were reconstructed with the Kinahan–Rogers reconstruction algorithm (Kinahan and Rogers, 1989). Hanning filters were used, and yielded transaxial and axial resolutions of 6 and 10 mm (full-width half maximum), respectively. The field of view and pixel size of the reconstructed images were 256 and 2 x 2 x 2 mm, respectively. No arterial blood sampling was performed, and thus the images collected were those of tissue activity. Tissue activity recorded by this method is nearly linearly related to rCBF (Fox et al., 1984; Fox and Mintun, 1989). The rCBF measurements were adjusted to a global mean of 50 ml/100 g/min.
Data analysis
The data acquired were analysed with the Statistical Parametric Mapping (SPM99; Wellcome Department of Cognitive Neurology, London, UK) software implemented in MATLAB (Version 6.1 Release 12; The Mathworks, Inc., Matick, MA, USA). The scans of each subject were realigned to the first scanned image, and all images were transformed into a standard stereotaxic space (Talairach and Tournoux, 1988) using a Montreal Neurological Institute template of SPM to normalize image data. Each image was smoothed using a Gaussian filter of 15 mm (full-width half maximum) in the x, y and z axes to improve the signal-to-noise ratio. ANCOVA (analysis of covariance), using global activity as a confounding covariate, was performed on a pixel-to-pixel basis to adjust scan data.
Data were analysed based on the entire subject group (n = 12) or on the two subgroups divided by the direction of the caloric nystagmus: (group I) six subjects exhibiting right beating nystagmus (three subjects that received hot-air stimulation in the right ear and three subjects that received cold air stimulation in the left ear); and (group II) six subjects exhibiting left beating nystagmus (three subjects who received cold-air stimulation in the right ear and three subjects who received hot air stimulation in the left ear). The slow phase of the nystagmus in the right beating nystagmus group was directed toward the left, and that of the left beating nystagmus group was directed toward the right.
We analysed the data on a pixel-based SPM: (A) by covariates only to explore correlations between the SPV, which represents intensity of caloric response, and rCBF over the entire brain; and (B) by conditions to examine regions that may be related to habituation of caloric nystagmus (attenuation of caloric nystagmus by repeated stimulation) and their relationship to those involved in fixation suppression of caloric nystagmus.
In analysis (A), we used SPV and rCBF data obtained during conditions (1) and (2) to explore the regions in which rCBF exhibited a positive correlation with SPV of caloric nystagmus in group I and group II. Next, to reveal the effect of direction of nystagmus on rCBF, we performed correlation analysis for each subject, and compared the results for six subjects in group I with those for six subjects in group II using the two-sample t-test in random effects analysis as implemented in SPM99, thus taking into account the response variance from subject to subject.
Since the mean SPV of caloric nystagmus in condition (3) was significantly lower than that in condition (2) due to visual fixation (see Results), cortical regions the rCBF of which negatively or positively correlated to SPV were explored to reveal areas in which rCBF positively or negatively, respectively, correlated with fixation suppression of caloric nystagmus. Data obtained during conditions (2) and (3) were used. The level of significance in analysis (A) was set at P < 0.001 (uncorrected for multiple comparisons).
Caloric nystagmus habituated with repetition of caloric vestibular stimulation (see Results). Since the decrease of SPV did not reach the level of significance when the subjects were divided into subgroups by the direction of nystagmus, analysis (B) was performed on the entire subject group, including those exhibiting both right and left beating nystagmus.
In analysis (B), we compared rCBF change during the fourth caloric stimulation condition relative to the fourth control (body temperature stimulation) condition with that during the first caloric irrigation relative to the first control condition (P < 0.05) to identify the cortical regions related to attenuation of caloric nystagmus by repeated stimulation (vestibular habituation). To explore the regions within the areas that were activated by caloric vestibular stimulation, we inclusively masked the above-described contrast by overall contrast between caloric stimulation conditions and control conditions; [(no. 4 condition 2 – no. 4 condition 1) versus (no. 1 condition 2 – no. 1 condition 1)] inclusively masked by (all condition 2 – all condition 1) at P = 0.05.
To identify the regions co-activated or co-deactivated with fixation suppression and habituation of caloric nystagmus, we used inclusive masking in an entire subject group [n = 12, activated or deactivated with attenuation of caloric nystagmus by repetition (P < 0.05) inclusively masked by fixation suppression contrast (all condition 3 – all condition 2 or all condition 2 – all condition 3) at P = 0.05].
Significant activations were reported for cluster sizes >10 voxels in the present study.
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Results |
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SPV of nystagmus
Body-temperature air irrigation induced no or very weak nystagmus, and the SPV of the subjects in each group during four body-temperature irrigations averaged 0.3 ± 0.7 deg/s (mean ± SD) in group I, and 0.3 ± 0.4 deg/s in group II. Caloric stimulation in darkness evoked nystagmus, the mean SPV of which was 4.8 ± 4.1 deg/s in group I, and 6.4 ± 3.4 deg/s in group II. Visual fixation attenuated the SPV of caloric nystagmus to 0.8 ± 1.2 deg/s in group I, and 0.3 ± 0.5 deg/s in group II. In each group, the SPV during caloric stimulation was significantly higher than under the other two conditions [F = 26.87 for group I (n = 6) and F = 81.34 for group II (n = 6), P < 0.01, repeated-measures ANOVA (analysis of variance)] (Fig. 1A).
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The SPV of caloric nystagmus decreased with repetition of caloric stimulation. In the entire subject group (n = 12), the mean SPV (absolute value irrespective of their directions) decreased significantly with repeated irrigations (F = 5.46, P < 0.01, repeated-measures ANOVA): first irrigation 7.4 ± 4.3 deg/s; second irrigation 6.2 ± 4.2 deg/s; third irrigation 4.5 ± 3.0 deg/s; and fourth irrigation 4.3 ± 3.2 deg/s (Fig. 1B). When the subjects were divided into groups I (n = 6) and II (n = 6) according to the direction of nystagmus, the change of SPV did not reach the level of significance (group I, F = 4.04, P > 0.05; group II, F = 3.45, P > 0.05).
Cortical activations
Regions in which rCBF exhibited positive correlation with SPV of caloric nystagmus
In group I, significant positive correlation was observed in the right middle frontal gyrus [Brodmann area (BA) 6], right posterior insula, right inferior parietal lobule (BA 40), left superior temporal gyrus (temporal pole: BA 38), right inferior temporal gyrus (BA 20), pyramis of the cerebellar vermis, and left cerebellar hemisphere.
In group II, significant positive correlation was observed in the left middle and posterior insula, left inferior parietal lobule (BA 40), right and left superior temporal gyri (temporal pole: BA 38), right inferior temporal gyrus (temporal pole: BA 20), right fusiform gyrus (BA 37) and right lingual gyrus (BA 18) (Fig. 2; Table 1).
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Comparison of right (group I) and left (group II) beating nystagmus groups
Regions that exhibited stronger positive rCBF–SPV correlation in group I than in group II. The right posterior insula, right postcentral gyrus (BA 3/1/2), right inferior parietal lobule (BA 40), left cuneus (BA 19), right fusiform gyrus (BA 18/19), left parahippocampal gyrus (BA 28) and bilateral cerebellar hemispheres exhibited stronger positive rCBF–SPV correlation in group I than in group II (Fig. 3; Table 2).
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Regions that exhibited stronger positive rCBF–SPV correlation in group II than in group I. The left insula, left inferior parietal lobule (BA 40), bilateral precuneus (BA 7), left inferior temporal gyrus (BA 20) and left hippocampus exhibited stronger positive rCBF–SPV correlation in group II than in group I (Fig. 3; Table 2).
Regions in which rCBF correlated positively with fixation suppression of caloric nystagmus. In group I, significant positive correlation was observed in the right superior temporal gyrus (temporal pole: BA 38), right inferior occipital gyrus (BA 18), bilateral fusiform gyri (BA 19) and right cerebellar flocculus. In group II, bilateral middle frontal gyri (BA 6/8/9), right inferior temporal gyrus (BA 20), right fusiform gyrus (BA 18), left lingual gyrus (BA 18) and uvula/nodulus of the cerebellar vermis exhibited significant positive correlation (Fig. 4; Table 3).
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Regions in which rCBF correlated negatively with fixation suppression of caloric nystagmus. In group I, significant negative correlation was observed in the right middle frontal gyrus (BA 11), right supplementary motor area (BA 6), right middle and posterior insula, left superior temporal gyrus (BA 22), right hippocampus and hippocampal gyrus, right pons, culmen of the cerebellar vermis, and bilateral cerebellar hemispheres. In group II, the right middle frontal gyrus (BA 11), left postcentral gyrus (BA 3/1/2), left cingulate gyri (BA 24/32), left middle and posterior insula, and right caudate nucleus exhibited significant negative correlation (Fig. 5; Table 3).
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Regions in which caloric activation increased with repeated stimulation. The cortical regions in which caloric activation increased with repeated stimulation were the right anterior cingulate gyrus (BA 32), left superior parietal lobule (BA 7), right cuneus (BA 19) and uvula/pyramis of the cerebellar vermis (Fig. 6; Table 4).
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Regions in which caloric activation decreased with repeated stimulation. Significant decrease of activation with repeated caloric stimulation was observed in the left middle frontal gyrus (BA 11), bilateral anterior insulae, bilateral cingulate gyri (BA 23), bilateral inferior parietal lobules (BA 40), right middle temporal gyrus (BA 21), right middle occipital gyrus (BA 19/37), left fusiform gyrus (BA 19), right pons and right cerebellar hemisphere (Fig. 6; Table 4).
Regions co-activated with fixation suppression of caloric nystagmus and attenuation of caloric nystagmus by repetition. The right cuneus (BA 19) exhibited significant co-activation with fixation suppression of caloric nystagmus and attenuation of caloric nystagmus by repetition (Fig. 7; Table 5).
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Regions deactivated with fixation suppression of caloric nystagmus and attenuation of caloric nystagmus by repitition. The regions that exhibited significant co-deactivation with fixation suppression of caloric nystagmus and attenuation of caloric nystagmus by repetition were the left middle frontal gyrus (BA 11), bilateral anterior insulae, bilateral inferior parietal lobules (BA 40), right middle temporal gyrus (BA 21) and right pons (Fig. 7; Table 5).
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Discussion |
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Caloric vestibular stimulation
The caloric stimulation used in the present study activates the horizontal semicircular canal crista, the reflex responses of which involve eye movements in the horizontal plane. Thus, the results observed here are not necessarily comparable to those obtained by other methods of vestibular stimulation, for example galvanic stimulation (Bense et al., 2001
), used in previous studies.
During physiological rotatory stimulation of the horizontal semicircular canals, the brainstem secondary vestibular neurons on one side receive ampullopetal signals (increased firing of primary afferent neurons), while the neurons on the opposite side receive ampullofugal signals (decreased firing). However, since excitatory type I neurons are connected to inhibitory type II neurons of the opposite side, excitatory type I neurons receive a combination of stimulation from the two ears, corresponding to the sum of the ampullopetal (excitatory) signals from the ipsilateral side and the inverted ampullofugal (disinhibitory) signals mediated by the type II (inhibitory) neurons (Baloh and Honrubia, 2001).
During caloric stimulation, hot air stimulation activates the vestibular afferent neurons innervating the horizontal semicircular canals, and cold air stimulation in the opposite ear deactivates the horizontal semicircular canal afferents of this side. Although hot stimulation in one ear and cold stimulation in the other ear have different effects on the primary vestibular afferent neurons, the direction of the nystagmus induced by cold stimulation in one ear is the same as that induced by hot stimulation in the opposite ear, since inhibitory type II neurons in the vestibular nuclei mediate inverted input signals from the opposite side. However, when interpreting the present results, it is necessary to recognize that caloric vestibular stimulation, which stimulates only one ear, is not a physiological one, and that the activities of vestibular neurons involved in this phenomenon are not identical to those activated during head rotation.
Vestibular cortex
Parietal and insular regions
Although the vestibular sense is not prominent in human consciousness, vestibular signals are essential for various cortical activities including control of active movement in three-dimensional space (Wilson and Melvill Jones, 1979; Fukushima, 1997), perception of self-motion (Büttner and Henn, 1981), spatial perception and memory (Berthoz et al., 1995), and perception of visual object motion (Mergner et al., 1992). We found rCBF increase in the inferior parietal lobule during caloric vestibular stimulation. This result was consistent with previous findings in humans (Bottini et al., 1994; Blanke et al., 2000; Bense et al., 2001; Suzuki et al., 2001), as well as in animal experiments (Faugier-Grimaud and Ventre, 1989), which revealed the involvement of this region in processing of vestibular signals. This region is also engaged in somatosensory processing (Hodge et al., 1998; Ruben et al., 2001), visual motion perception (Corbetta et al., 1991) and visuo-motor control (Squatrito et al., 1996), and is generally regarded as a site of higher-order processing of sensory information and sensorimotor integration. The present discovery of activation of the inferior parietal cortex by caloric vestibular stimulation is consistent with the expectation that vestibular information may be used in combination with other sensory and sensori-motor information.
rCBF increase correlated with SPV of caloric nystagmus in the insular regions was expected, since this region has been shown to be activated by vestibular stimulation both in humans (Friberg et al., 1985; Bottini et al., 1994, 2001) and in monkeys (Akbarian et al., 1988; Grüsser et al., 1990a, b). This region, located adjacent to the posterior insula in the depth of the lateral sulcus, is termed the parieto-insular vestibular cortex (PIVC), in which more than 50% of the neurons are vestibular driven (Guldin and Grüsser, 1998). The neurons in this area are multisensory (Grüsser et al., 1990a, b), and activation of the region is demonstrable in humans not only through vestibular stimulation, but also as a result of optokinetic stimulation (Dieterich et al., 1998).
To control movement and posture, vestibular information must be integrated with other information, including somatosensory and visual signals, and the present finding of activation of the parietal and insular regions reflects the multi-modal nature of the vestibular cortical network. In addition, the inferior parietal and insular activation occurred in the hemisphere ipsilateral to the direction of caloric nystagmus, which was further confirmed by direct comparison of groups I and II using random effects analysis (Fig. 3; Table 2). Neuronal activities in the inferior parietal and insular regions may thus be lateralized depending on the lateralization of afferent vestibular signals. Although the relationship between the direction of nystagmus and the side of hemispheric activation in our results was not as expected, since lateral head tilts and rotations predominantly activate ipsilateral vestibular organ and the contralateral cortex (Previc, 1991; Gresty et al., 1992), it is nevertheless in line with the observation that counterclockwise visual field rotation predominantly activates the right hemisphere and clockwise visual field rotation results in greater left-hemispheric activity (Previc et al., 2000). The present results also accord with the previous PET findings that revealed cold water caloric stimulation induced significant contralateral parieto-insular vestibular cortex activation (Bottini et al., 1994).
Visual cortex
It is interesting to note that rCBF of several regions in visual cortex exhibited positive correlation with SPV of caloric nystagmus, despite the fact that the rCBF measurement was performed in complete darkness. We found significant correlation in the right inferior temporal/fusiform gyrus and the right lingual gyrus during caloric vestibular stimulation. Although this region is known to exhibit stable responses to the viewing of faces (Sergent et al., 1992; Puce et al., 1995; Kanwisher et al., 1997), it is also activated during processing of visual orientation (Orban et al., 1998; de Jong et al., 1999), judging the speed of a moving random dot pattern (Orban et al., 1998) and discriminating the direction of motion of a random dot pattern (Cornette et al., 1998). Since caloric vestibular stimulation induces sensations of self- and space-rotation, the present finding of increased activity in the ventral occipital area may be related to the processing of orientation, speed and direction of such motion sensations.
Suppression of VOR with visual fixation
Visual–vestibular interaction
The VOR and visual system cooperate when fixating on an earth-bound target and stabilize gaze in space, while the VOR must be suppressed when the head is rotated to fixate on a moving target, in which situation the direction of gaze moves in space. Interaction between the visual and vestibular systems was first demonstrated in the vestibular nuclei in goldfish (Dichgans et al., 1973), and then under various experimental conditions using a variety of animals, including monkeys (Waespe and Henn, 1978). In afoveate animals, the subcortical accessory optic system is the predominant pathway of visual–vestibular interaction, while cortical pathways become progressively more important with development of the fovea (Baloh and Honrubia, 2001).
In primates, the retinal motion information for a moving target reaches the pontine nuclei via the striate cortex, medial temporal area (MT) and medial superior temporal area (MST). It is then sent to the vestibular nuclei via the flocculus and the vermis of the cerebellum, and reaches the brainstem oculomotor nuclei (Leigh and Zee, 1999). Lesions in this pathway impair fixation suppression of vestibular nystagmus with a foveal target (Baloh and Honrubia, 2001).
Regions positively correlated with fixation suppression of caloric nystagmus
The areas of visual cortex positively correlated to fixation suppression of caloric nystagmus in the present study included the striate cortices, MT and MST, but we could not distinguish the boundaries of these areas due to intense activation of the entire visual cortex in this condition. The focus of correlation in the left middle frontal gyrus was close to that of the frontal eye field (Fox et al., 1985), which is located at a depth of 
10 mm from the surface, on the anterior lip of the precentral sulcus. Activation of this region during suppression of VOR with visual fixation was expected, since frontal eye field contributes to voluntary control of gaze, and becomes active during fixation on a stationary target (Petit et al., 1995) and during smooth pursuit (Petit et al., 1997).
As discussed in the previous section, the fusiform gyrus is known to be involved in perception of speed and orientation of motion. rCBF increase in this region may be due to rotatory signals induced by vestibular stimulation, rather than by visual fixation on a target.
The temporal pole regions exhibited rCBF increase both during caloric stimulation and its fixation suppression. These regions are involved in various types of mental processes such as recognition, memory and emotion (Zatorre et al., 1991; Nakamura and Kubota, 1996; Royet et al., 2000). Since vertiginous sensation induced by vestibular stimulation is frequently uncomfortable and can cause some anxiety, the present discovery of the activation of the temporal pole may relate to such emotional responses to this stimulus. However, there is also a report that visual memory and visual imagery of large-field patterns can activate this region as well as bilateral frontal and anterior cingulate cortex (Roland and Gulyas, 1995). Thus, there is also a possibility that the temporal pole is involved in visual–vestibular interaction per se through processing of higher-order visual information.
Cerebellar vermis (nodulus, VI, VII and VIII), the flocculus, and the fastigial and dentate nuclei are closely linked with ocular movements. Retinal sensory information reaches the cerebellar vermis via the deep layers of the superior colliculus and the dorsal pontine nucleus (Kawamura and Brodal, 1973; Hoddevik et al., 1977). The dorsal pontine nucleus also receives projections from the striate (Brodal, 1972) and extrastriate cortices (Glickstein et al., 1980). A part of the inferior olive that projects to the flocculus and the nodulus receives afferents from the terminal region of the mesencephalon and from the terminal nucleus of the accessory optic tract (Hoddevik and Brodal, 1977). Outflow from the cerebellar Purkinje cells terminates at secondary vestibular neurons and neurons in the adjacent reticular substance. The cerebellar input to the vestibular nuclei can modify the gain at the synapses between some primary and secondary vestibular neurons and thus modify the gain of VOR, and lesions of the flocculus impair fixation suppression of vestibular nystagmus with a foveal target (Takemori and Cohen, 1974; Zee et al., 1981). The significant rCBF increase in the flocculus correlated with visual suppression of vestibular nystagmus observed in the present study provides another piece of evidence for the involvement of this structure in visual–vestibular interaction (Ito, 1982; Lisberger et al., 1984). Lesions in the nodulus are reported to cause transient loss of visual suppression of caloric nystagmus (Takemori, 1975), and the increased activity in the nodulus and uvula that we observed during fixation suppression of caloric nystagmus suggests that these structures may also play a role in visuo-motor control.
Regions negatively correlated with fixation suppression of caloric nystagmus
Decrease of rCBF in insular regions correlated with fixation suppression of caloric nystagmus was as expected in view of inhibitory visual–vestibular interaction (Brandt et al., 1998). Decreased activity in these regions was greater in the right hemisphere in the right beating nystagmus group, and in the left hemisphere in the left beating nystagmus group (Fig. 5, insets), which may be due to lateralized caloric activation being suppressed.
The hippocampus and the hippocampal gyrus were also deactivated. In the rat, the hippocampus is activated by multi-sensory cues in spatial tasks, and firing of the cells of the hippocampus is modulated by vestibular stimulation (Wiener et al., 1995). The hippocampus has been shown to use information from the vestibular inner ear to build up maps of space that can be used in the development of spatial memory during learning tasks (Zheng et al., 2001). A previous study revealed significant activation of the hippocampus by vestibular stimulation in humans (Vitte et al., 1996). Decrease of rCBF in hippocampal regions during fixation suppression of vestibular nystagmus observed in the present study suggests an inhibitory influence of a stable target image on vestibular driven spatial information processing in this region.
The putamen is a common site among the basal ganglia for activation by vestibular stimulation (Bottini et al., 1994; Vitte et al., 1996; Bense et al., 2001; Bottini et al., 2001). We observed decreased rCBF in the caudate nucleus, which is another major component of the basal ganglia. The putamen and the caudate nucleus form the striatum and are thought to participate in various neuronal activities, including control of posture and movement. The caudate nucleus is also activated by optokinetic simulation (Dieterich et al., 1998), suggesting that this nucleus may play a role in visual–vestibular interaction.
In the present fixation suppression condition, vestibular organs send signals of head rotation while visual input reports that the head is not rotating. Decreased rCBF in the vestibular related regions by visual fixation indicates that visual influence predominates over vestibular information processing in these regions when visual and vestibular signals are not in accordance.
Habituation of VOR
Vestibular habituation becomes evident after repeated constant-velocity rotations or low-frequency continuous oscillations, which are outside the frequency range of most natural head movements (Blair and Gavin, 1979; Baloh et al., 1982). Vestibular nucleus neurons respond to sustained rotational stimuli with an initial increment in discharge rate that declines exponentially with the same time constant as the VOR (15 s), which is longer than the cupula or vestibular nerve time constant (6 s). The neuronal mechanism that improves the ability of the VOR to transduce the low-frequency components of head rotation is called the velocity-storage integrator (Raphan et al., 1979), and it is presumed that, with habituation, there is a gradual decrease in velocity storage, shifting the low-frequency VOR response toward that of primary afferent signals (Baloh and Honrubia, 2001). Although it is known that neuronal networks of vestibular habituation are located in the brainstem and cerebellum, voluntary modulation of VOR gain and its adaptive process (Barr, 1976; Jones et al., 1984; Jones and Berthoz, 1985) suggest that the cortex may also influence vestibular habituation. In the present study, caloric nystagmus habituated by repeated caloric stimulation, and we explored cortical regions that exhibit significant increase or decrease of caloric activation with repeated stimulation, in search of cortical correlates of vestibular habituation.
Regions in which caloric activation increased with repeated stimulation
We observed that rCBF in the anterior cingulate gyrus, cuneus, superior parietal lobule and cerebellar vermis (uvula/pyramis) increased with the repetition of caloric stimuli, and thus with decrease in SPV.
Akbarian and colleagues reported that the anterior cingulate gyrus projects directly to the vestibular nuclei (Akbarian et al., 1993), and imaging studies in humans have revealed significant activation of the anterior cingulate gyrus by caloric (Bottini et al., 1994) and galvanic (Bense et al., 2001) vestibular stimulation. An anatomical study in the macaque monkey also revealed projections to the vestibular nuclei from the anterior cingulate gyrus (Akbarian et al., 1994). The anterior cingulate gyrus, together with the inferior parietal lobule, has intimate connections with the posterior insular vestibular cortex (Guldin and Grüsser, 1996), and may be considered an important component of the cortical vestibular circuit.
The anterior cingulate gyrus is activated during fixation suppression of optokinetic nystagmus (Dieterich et al., 1998). In addition, since the anterior cingulate gyrus has efferent anatomical connections to the vestibular nuclei as described above, it may be that this region inhibits the VOR during its habituation. On the other hand, tasks requiring special attention and motivation (Corbetta et al., 1991) also activate the anterior cingulate gyrus. Therefore, the fact that repeated vestibular stimuli and rotational sensation command high levels of attention could also explain our findings.
There are two main processing pathways in visual perception: a dorsal route, which is important for detection of spatial relations between objects; and a ventral route, which is specialized for processing of information about physical qualities of visual objects (Roland, 1993). The dorsal pathway may be further subdivided into two major substreams (Graziano and Gross, 1995; Vaina et al., 2001). One such substream, specialized for spatial and visuo-spatial functions, consists of areas V2, V3A and parieto-occipital junction, and then areas 7 and adjacent intraparietal areas. Another substream, specialized for the analysis of complex motions, includes MT and MST, and terminates in the superior temporal polysensory area (Vaina et al., 2001).
The activity in the cuneus revealed by the present vestibular habituation contrast was centered on an area corresponding to human cortical area V3/V3A (DeYoe et al., 1996), which is in the visuo-spatial processing pathway. These areas are reported to be activated by direction discrimination (Cornette et al., 1998) or by continuous expanding or contracting movement of a ring (Tootell et al., 1997). Another area activated by this contrast was the superior parietal lobule (BA 7). The superior parietal lobule is activated by visuo-spatial information processing such as direction discrimination (Cornette et al., 1998), by oculomotor control during horizontal and vertical optokinetic stimulation (Dieterich et al., 1998), and during sequences of saccades that are unfamiliar to the subjects (Grosbras et al., 2001). Thus, activities in occipital and parietal regions involved in processing visuo-spatial and oculomotor information processing might be related to habituation of caloric vestibular nystagmus, which may provide another example of inhibitory visual–vestibular interaction.
Activation of the uvula of the cerebellar vermis that accompanied habituation of caloric nystagmus was as expected, since the uvula, together with the nodulus, is known to play a key role in VOR adaptation. The ventral uvula and the nodulus receive afferents from the vestibular nuclei, nucleus prepositus hypoglossi, inferior olivary nucleus and vestibular nerve. They send efferents to the vestibular nuclei and control the velocity-storage mechanism of the VOR (Waespe et al., 1985). In monkeys, lesions of the nodulus and uvula cause prompt and permanent loss of vestibular habituation (Cohen et al., 1992), and transient loss of fixation suppression of vestibular nystagmus (Takemori, 1975). Activation of the uvula along with habituation of caloric nystagmus observed in the present study is consistent with the result of studies on monkeys.
Regions in which caloric activation decreased with repeated stimulation
Activation of the bilateral anterior insula decreased with repeated caloric stimulation. The anterior insula has been reported to be activated during optokinetic stimulation (Dieterich et al., 1998), remembered saccades as opposed to reflexive saccades (Anderson et al., 1994), and self-paced saccades in the dark (Petit et al., 1993), and is suggested to be part of the neural network for spatially oriented eye movements (Dieterich et al., 1998). Thus, decreased activation of this region may result from decreased saccadic eye movements due to habituation of caloric vestibular nystagmus. We also observed decreased activation of the bilateral inferior parietal lobules. This region is known to be involved in vestibular and visuo-spatial information processing, and its deactivation may reflect decreased vestibular input to this area as a result of habituation.
Decreased activation of the anterior middle occipital and posterior middle temporal gyrus also accompanied vestibular habituation. This region corresponds to the MT, which is involved in the analysis of visual motion and encodes speed and direction of visual stimuli (Leigh and Zee, 1999). Significant changes in its activation accompanying vestibular habituation indicate that its activity does not necessarily require overt visual stimuli, since all rCBF measurements involved in this contrast were performed in complete darkness. In addition, deactivation of this region accompanying decreased vestibular responses indicates that visual–vestibular interaction may not always be inhibitory.
Possible common pathways of fixation suppression and habituation of VOR
Masking analysis allowed us to check for jointly activated or deactivated areas under two stimulus conditions. The neuronal mechanisms of fixation suppression and habituation of VOR differ in that the former is dependent on retinal input, while the latter can occur in complete darkness. However, common activation of the visual cortex under these two conditions suggests that these two mechanisms that modulate VOR are not completely independent, but may share some cortical and subcortical regions.
The right cuneus was co-activated by fixation suppression and habituation. Activation of this region with vestibular habituation is impressive, since the habituation process occurred in darkness. Activation of visual cortex without overt visual stimuli was reported in the experiment which explored self-generated eye movements in darkness (Dejardin et al., 1998; Law et al., 1998), and was interpreted as the result of neural activity related to the reception of efferent copies of motor commands or activation of neurons coding for eye position. In the study of adaptive control of VOR by mental effort (Jones, 1984), the subjects reported that ‘irregular mosaics of light or light clouds’ emerged in darkness to aid VOR suppression, which demonstrated that a slipping retinal image is not a necessary condition, and enhancement of adaptive suppression of the VOR by mental effort might be based on an ‘internally generated visual signal’. A possible interpretation may be that activation of visual cortex during vestibular habituation also results from such ‘internal visual signal’. However, it is not possible to confirm whether such ‘internal visual images’ influenced our results, since distinct instruction concerning visual imagery was not given to the subjects. An alternative, but not mutually exclusive, possibility to explain the deactivation of visual cortex is suppression of visual cortex by vestibular stimulation. According to a concept of inhibitory visual–vestibular interaction (Brandt et al., 1998), decrease in vestibular response might decrease inhibition on the visual system, which may result in relative increase in rCBF in visual cortices. Further studies are necessary to determine whether the activation of the visual cortex reflects its primary role in vestibular habituation or whether it is a response secondary to decreased activity of VOR.
Deactivation of the bilateral inferior parietal lobule by both visual suppression and habituation may result from reduced VOR activity. The inferior parietal lobule is considered a site of multi-sensory integration, and the present results suggest that its activity can be modified by changes in vestibular signals both with and without participation of visual sensory input.
In conclusion, our findings support observations drawn from studies of monkeys and humans that the cortical regions activated by vestibular stimulation are involved in integration of multiple sensory inputs relating to perception of motion and orientation in space. Activities of the visual cortex, frontal eye field, temporal pole and cerebellar vermis were positively correlated with fixation suppression of caloric nystagmus, and activation of the anterior cingulate gyrus, superior parietal lobule, cuneus and cerebellar vermis increased with repetition of caloric stimulation. Among these regions, the cuneus exhibited significant activation during both fixation suppression and habituation of caloric nystagmus, which suggests that this region in the visual cortex may be shared by these two different neuronal systems that modulate VOR.
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The authors wish to thank Professor Manabi Hinoki for his encouragement and valuable comments and two anonymous reviewers for helpful suggestions. This study was supported by Grant-in-Aid for Scientific Research (B2) 12470355 and 14370542 from the Japan Ministry of Education, Science, Sports, and Culture, a Health Scientific Research Grant for Research on Eye and Ear Sciences, Immunology, Allergy and Organ Transplantation from the Japan Ministry of Health and Welfare, and a grant from the Japan Space Forum. This work was presented, in part, at the Symposium ‘Brain Science and otolaryngology’ at the 103rd Annual Meeting of the Oto-Rhino-Laryngological Society of Japan.
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M. Dieterich and T. Brandt Functional brain imaging of peripheral and central vestibular disorders Brain, October 1, 2008; 131(10): 2538 - 2552. [Abstract] [Full Text] [PDF]
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