1Department of Neurology and 2Department of Neuroradiology, Klinikum Grosshadern, Ludwig-Maximilians University, 81377 Munich, Germany
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ABSTRACT |
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Bense, Sandra, Thomas Stephan, Tarek A. Yousry, Thomas Brandt, and Marianne Dieterich. Multisensory Cortical Signal Increases and Decreases During Vestibular Galvanic Stimulation (fMRI). J. Neurophysiol. 85: 886-899, 2001. Functional magnetic resonance imaging blood-oxygenation-level-dependent (BOLD) signal increases (activations) and BOLD signal decreases ("deactivations") were compared in six healthy volunteers during galvanic vestibular (mastoid) and galvanic cutaneous (neck) stimulation in order to differentiate vestibular from ocular motor and nociceptive functions. By calculating the contrast for vestibular activation minus cutaneous activation for the group, we found activations in the anterior parts of the insula, the paramedian and dorsolateral thalamus, the putamen, the inferior parietal lobule [Brodmann area (BA) 40], the precentral gyrus (frontal eye field, BA 6), the middle frontal gyrus (prefrontal cortex, BA 46/9), the middle temporal gyrus (BA 37), the superior temporal gyrus (BA 22), and the anterior cingulate gyrus (BA 32) as well as in both cerebellar hemispheres. These activations can be attributed to multisensory vestibular and ocular motor functions. Single-subject analysis in addition showed distinctly nonoverlapping activations in the posterior insula, which corresponds to the parieto-insular vestibular cortex in the monkey. During vestibular stimulation, there was also a significant signal decrease in the visual cortex (BA 18, 19), which spared BA 17. A different "deactivation" was found during cutaneous stimulation; it included upper parieto-occipital areas in the middle temporal and occipital gyri (BA 19/39/18). Under both stimulation conditions, there were signal decreases in the somatosensory cortex (BA 2/3/4). Stimulus-dependent, inhibitory vestibular-visual, and nociceptive-somatosensory interactions may be functionally significant for processing perception and sensorimotor control.
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INTRODUCTION |
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Galvanic vestibular stimulation
(GVS) at the mastoid level acts on the eighth nerve (Goldberg et
al. 1984) and elicits postural imbalance (Inglis et al.
1996
), a rotational or tilt sensation, and tonic ocular torsion
with superimposed nystagmus (Watson and Colebach 1998
;
Zink et al. 1998
). GVS can be used to identify vestibular cortex structures provided that the differential effects of
the associated auditory and somatosensory systems can be separated clearly enough. An experimental vestibular stimulus that selectively excites only the vestibular system is not currently available.
A previous fMRI study using fast low-angle shot (FLASH) sequences of
the insular-thalamic region showed that GVS induced significant activations of the parieto-insular vestibular cortex (PIVC) and the
posterior median thalamus (Bucher et al. 1998).
According to monkey studies, both of these areas are involved in the
processing of vestibular function (Grüsser et al.
1990a
,b
). However, the simultaneous activation of the
transverse temporal (Heschl's) gyrus indicates that the auditory
systems are also involved. Likewise the bilateral activation of the
medial part of the insula and the anterior-median thalamus indicates
that the nociceptive system is involved too. Cutaneous galvanic pain
stimulation (GPS) at the neck C5 level as a
control (Bucher et al. 1998
) also activated these
nociceptive areas. Due to technical limitations, this FLASH study was
limited to three sections in the insular-thalamic region and did not
allow differentiation between signal increases and decreases. The only
available study on whole-brain imaging during GVS ascribed multiple
cortical areas to vestibular function (Lobel et al.
1998
). Some of these areas probably reflect nonvestibular auditory and nociceptive functions since no control stimuli were used
for both sensory stimuli.
On the basis of these previous works, we addressed two major questions
in the present whole-brain functional magnetic resonance imaging (fMRI)
study on GVS in normal subjects: what are the differential activation
patterns during galvanic (nonvestibular) cutaneous, galvanic vestibular
and cutaneous, and purely auditory stimulation and is not only
"activation" [blood-oxygenation-level-dependent (BOLD) signal
increase] but also simultaneous BOLD signal decrease ("deactivation") evident under these conditions? "Deactivation" is of particular interest, since in an earlier positron emission tomography (PET) study on vestibular caloric irrigation, we found an
increase in regional cerebral blood flow (rCBF) of the posterior insula
(e.g., PIVC) with a simultaneous, significant, bilateral decrease in
rCBF of the visual cortex covering Brodmann areas 17-19 (Wenzel
et al. 1996).
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METHODS |
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We examined six healthy, right-handed volunteers (3 females, 3 males; ages 25-43 yr, mean age, 33.3 yr) without any history of cochlear, vestibular, or CNS disorders. The study was approved by the local Ethics Committee of the Ludwig-Maximilians University, and all subjects gave their informed written consent.
MRI acquisition
Functional images were acquired on a standard clinical scanner (Siemens Vision, Erlangen, Germany) at a magnetic field strength of 1.5 T using a circularly polarized head coil and echo-planar imaging (EPI) with a T2*-weighted gradient-echo multislice sequence (TE = 66 ms, TR = 5,500 ms, voxel size 1.88 × 1.88 × 5 mm3). Twenty-four transversal slices with a matrix size of 128 × 128 pixels covered the whole brain and the upper parts of the cerebellum. Each scanning session comprised two successive time series consisting of 110 and 60 images, respectively, due to technical limitations of the scanner software. In both runs, a block design of five images at rest and five images during stimulation was used; the first 5 volumes of each run were discarded because of spin-saturation effects. In the first series, GVS at the mastoid and GPS at the neck C5/6 level were interchangeably applied in blocks; in the second series acoustic stimulation (AS) alternated with the rest condition (a total of 25 volumes per each stimulation condition). For anatomical comparisons an additional set of T1-weighted images was acquired with the slice orientation adjusted to the functional images (matrix 256 × 256 × 24, voxel size 0.94 × 0.94 × 5 mm). During acquisition, the subjects lay supine with eyes closed and wore MRI suitable earphones. To reduce movement artifacts, the forehead was also taped to the coil.
Galvanic stimulation
Animal studies have shown that externally applied galvanic
currents modulate the tonic firing rate of vestibular afferents by
acting directly on the vestibular afferents close to their postsynaptic
trigger site (Goldberg et al. 1984). This broad-based stimulation is believed to act primarily on the fibers of the vestibular nerve. Galvanic vestibular stimulation in humans
was performed in two runs by placing adhesive carbon electrodes over both mastoid processes: cathode always on the left side
(n = 2), cathode always on the right side
(n = 2), or cathode once on the left and once on the
right side (n = 2). Galvanic pain
stimulation (GPS) was used as a control by placing an additional
pair paravertebrally at the neck C5/6 level,
which is far enough away from the upper cervical segments to ensure
that no major muscle spindle afferents to the vestibular nuclei were
stimulated. A battery-powered generator outside the Faraday cage
produced rectangular electric DC (rise time of 2 mA/s) for periods of
27.5 s. To prevent radio frequency pickup and propagation by the
wires, small LC filters tuned for resonance at 64 MHz and resistors (1 k
) were placed between the electrodes and connection cable to the
stimulus generator. For safety reasons, subjects held a switch in their
hand during the whole acquisition time, with which they could
immediately interrupt the conduction to the electrodes. The individual
electric current threshold to elicit vestibular effects and cutaneous
pain varies considerably (1-4 mA), depending on the exact position of
the electrode, the body position (upright or supine), and the skin resistance. Therefore we adjusted the current level of GVS for each
subject according to the vestibular effects (perceived tilt) elicited,
just before MRI acquisition, while the subject was already positioned
on the scanner table. The current level of GPS was individually
adjusted to match the intensity of pain during GVS.
Auditory stimulation
For auditory stimulation a special MR-safe headset (Resonance Technology, Northridge, CA) was connected to a conventional audio CD player. Repeated notes of ascending pitch (frequency 150 Hz to 6.3 kHz) were used as stimulus at a rate of six notes per second. They were presented without special instructions to the volunteers (nondirected listening). The headset largely attenuated the scanner background noise level (approximately 85 dB sound pressure level), which was the same under all test conditions.
In an earlier study, GVS at the mastoid level activated an area in the
auditory cortex (Heschl's gyrus), although it caused no auditory
sensations in the subjects (Bucher et al. 1998). Because auditory sensations were absent, it was not possible to calibrate auditory stimulation. The DC GVS used in our study does not represent a
localized physiological stimulation; it can spread into the inner ear
and neighboring tissues and affect acoustic nerve fibers. Moreover this
type of stimulation can activate not only areas in the primary auditory
receiving cortex but also areas involved in integrative or associative
auditory functions. For this reason, we chose repeated notes of
ascending pitch to provide a broad base on which the activated areas
could overlap during GVS.
Data analysis
Data processing was done on an UltraSPARC workstation (Sun
Microsystems) using statistical parametric mapping (SPM96)
(Friston et al. 1995b) implemented in MATLAB (Mathworks,
Sherborn, MA). All volumes were realigned to the first one of each
scanning session to correct for subject motion, and spatially
normalized (Friston et al. 1995a
) into the standard
space of Talairach and Tournoux (1988)
. Prior to
statistical analysis, each image was smoothed with a 6-mm (single
subject) or 10-mm (group) isotropic Gaussian kernel to compensate for
intersubject gyral variability and to attenuate high-frequency noise,
thus increasing the signal to noise ratio. Statistical parametric maps
were calculated on a voxel-by-voxel basis using the general linear
model (Friston et al. 1995b
) and the theory of Gaussian
fields (Worsley and Friston 1995
). SPM96 calculated the
relative contributions of a delayed-box-car reference waveform as well
as confounding variables (whole brain activity and low frequency
variations) to the measured data. The delayed box car serves as a model
of the expected hemodynamic response to the stimulus.
BOLD signal increases
Each scanning session consisted of four different conditions:
GVS at the mastoid level, cutaneous GPS at the neck
C5/6 level, AS, and the rest condition without
any stimulation. Statistical analysis was performed individually for
the six subjects and group-wise (P 0.01, corresponding to Z
2.33). In an appropriate design matrix the following contrasts were specified: GVS-rest, GPS-rest, AS-rest, and GVS-GPS, to isolate vestibular from extravestibular nociceptive effects. Furthermore, conjunction analysis was performed both between GVS-rest and GPS-rest and between GVS-rest and
AS-rest. The results from a conjunction analysis between two contrasts show only voxels that are common to the used contrasts and are not
significantly different in these contrasts (Price and Friston 1997
); conjunction analysis therefore makes it possible to
check for jointly activated areas under two different stimulus
conditions. The results reported are based on an anatomically
constrained hypothesis because the aim of the study was to separate the
known areas reported in previous studies from the areas of nociceptive and auditory side effects due to GVS. Therefore uncorrected
P-values were used for the contrasts mentioned in the
preceding text and the conjunction analysis (P
0.001, corresponding to Z
3.09).
BOLD signal decreases
Task-induced BOLD MRI signal decreases were also measured, but
their significance is still not clearly understood. In a comparative fMRI and PET study on visual optokinetic stimulation, we found a very
similar activation pattern for signal increases and decreases in both
techniques (Bense et al. 2000). This consistency
supports the view that signal decreases with fMRI correlate with
regional cerebral blood flow decreases in PET and may reflect
functional deactivation (Fransson et al. 1999
;
Rauch et al. 1998
). However, this correlation does not
yet allow a conclusive statement about the neuronal activity in these
areas. Consequently we analyzed the contrasts rest-GVS and rest-GPS
without an a priori hypothesis and considered only P values
corrected for multiple comparisons as significant (P
0.001, corresponding to Z
3.09).
Aguirre et al. (1998) recently demonstrated that the use
of global scaling may lead to detection of false-negative signal changes if the signal in a voxel is less correlated with the task than
the global brain signal itself. Therefore we also analyzed the data
without the use of global scaling for comparison. Furthermore, the
degrees of correlation of the global signal with the reference waveforms were computed.
For simplicity, we will use the term "deactivations" in quotation marks when referring to BOLD signal decreases.
Anatomical localization
To define the anatomical sites of activation and
"deactivation" clusters derived by the different statistical
approaches, we used the Talairach coordinates (Stephan et al.
1997; Talairach and Tournoux 1988
) as well as
defined anatomic landmarks (Naidich and Brightbill
1996a
,b
; Naidich et al. 1995
; Yousry et
al. 1997a
,b
). The anatomic-functional correlation was performed
by a neuroradiologist experienced in the identification of cortical landmarks.
To the best of our knowledge, there is still no internationally agreed upon definition of insular and retroinsular regions available in the literature. The insula is anatomically divided into five gyri; three short (I-III) and two long insular gyri (IV and V) (Fig. 1). We define the region frontal to the central insular sulcus as the anterior insula; it includes the short insular gyri (I-III). The region posterior to the central insular sulcus is defined as the posterior insula; it includes the first (IV) and second (V) long insular gyrus. The retroinsular territory is defined as the area posterior to the second long insular gyrus.
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RESULTS |
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Anodal stimulation, at the right (left) mastoid level led in all
subjects to an apparent counterclockwise (clockwise) self-rotation of
90 to 360° around the nasal-occipital axis (from the viewpoint of the
subject) and mild to moderate cutaneous pain sensations on the order of
a pin-prick. Three subjects reported a slightly metallic taste. There
were no recognizable postural reactions, no acoustic sensations, and no
nausea during either GVS or GPS. The subjects denied substantial
anxiety or stress. Mode, build-up, and intensity of pain could
not be distinguished by the subjects under either stimulation
condition. During control pain stimulation at
C5/C6 level, subjects did
not mention any contraction of neck muscles, vestibular sensations, or
head movements. Therefore we did not expect these neck muscles to
contribute to the results. Even if the sacculo-cervical reflex
(Halmagyi et al. 1995) was elicited by rapidly rising
galvanic stimulation (which we did not use), the main muscle response
would be expected in the sternocleidomastoideus muscle. However, such a
short-lived effect would be negligible in the average over one stimulus
period (27.5 s). Moreover, no stimulus-correlated head movements were
detected during data preprocessing. In the realignment process of
statistical parametric mapping (SPM), the overall head movement across
all scanning sessions was below 1.5 mm in translation and 1.5° in
rotation for all individual subjects.
Activations during vestibular stimulation
Since GVS at the mastoid level not only activates vestibular but also nociceptive cortex areas, we concentrated on the contrast GVS-GPS. In the group analysis, this contrast included bilateral activation of the dorsolateral thalamus, anterior parts of the insula, the superior temporal gyrus (BA 22), the inferior parietal lobule (BA 40), the precentral gyrus (BA 6), and the middle frontal gyrus (BA 46/9) as well as both cerebellar hemispheres (Fig. 2). Activation in the putamen, paramedian thalamus, the middle temporal gyrus (BA 37), the precentral gyrus/inferior frontal gyrus/(BA 6/44), and the anterior cingulate gyrus (BA 32) was significant for one hemisphere only. The polarity of stimulation (either cathode left or right) did not influence the unilateral or bilateral activation patterns. For coordinates and Z-scores see Table 1.
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Individual analysis indicated that all subjects showed an increased signal in the posterior insula or retroinsular region. Along the z-axis the individually circumscribed activations of the posterior insula, which had in the majority of cases a cluster size smaller than 20 voxels, ranged from 10 mm below to 10 mm above the AC-PC line. However, because of the considerable interindividual anatomical variation (Fig. 3), the vestibular area in the posterior insula (corresponding to the PIVC in monkeys) failed to show statistical significance in the group analysis (Fig. 2).
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Activations during auditory stimulation
Although the subjects reported no auditory sensations with GVS, cochlear nerve stimulation might induce activation of auditory areas via the auditory portion of the eighth nerve. Nongalvanic AS caused broad bilateral activation not only in the primary auditory receptive cortex (transverse temporal gyrus of Heschl, BA 41) but also in its association and integration areas in the superior and medial temporal gyri (maxima BA 42/22/21), including parts of the inferior parietal lobule (BA 40). Additional activation foci were found in the posterior cingulate gyrus (BA 29), the superior temporal gyrus (BA 38), the anterior/paramedian thalamus, and the precentral gyrus (BA 6/4/8) (Table 2, Fig. 4, AS-rest).
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Conjunction analysis of GVS and pure auditory stimulation
(P 0.001, uncorrected, Fig. 4, GVS-rest vs.
AS-rest) showed common activations of the following areas bilaterally:
superior temporal gyrus (BA 38/22), precentral gyrus (BA 6), inferior
parietal lobule (BA 40), paramedian and dorsolateral thalamus, and both
cerebellar hemispheres. The middle frontal gyrus (BA 46/9), the
putamen, the anterior cingulate gyrus (BA 8/32), and the middle
temporal gyrus (BA 37) were significantly activated unilaterally. The
areas activated in common represent in part visual and ocular motor functions. The broad activation of the primary auditory cortex, its
association and integration areas, overlap with the vestibularly activated areas in only a small part of the superior temporal gyrus (BA
42/22; 14 voxels) and in the depths of the transverse temporal
(Heschl's) gyrus adjacent to the posterior insula (BA 41; 23 voxels,
Fig. 4, GVS-rest and AS-rest).
Activations during pain stimulation
GPS activates the anterior (BA 32) and posterior cingulate (BA 29) gyrus, anterior insula (short insular gyri I/II), middle/inferior frontal gyrus (BA 10/46/9), precentral gyrus (BA 6/44), inferior/superior parietal gyrus (BA 40/7), paramedian thalamus, pulvinar, and both cerebellar hemispheres. In addition, there was an unusual bilateral activation of the white matter between the anterior insula and the middle frontal gyrus (Table 3, Fig. 4, GPS-rest). Although BOLD signal changes should not occur in the white matter, the activation was statistically significant in the group analysis.
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Conjunction analysis of GVS and GPS (Fig. 4, GVS-rest vs. GPS-rest) showed joint activations bilaterally in the cerebellar hemispheres, widespread in the frontal lobe [inferior/superior frontal gyrus, anterior insula (short insular gyri I/II), middle frontal gyrus (BA 9/46)], precentral gyrus (BA 6), the anterior and posterior cingulate gyrus, the putamen, the anterior/paramedian and dorsolateral thalamus as well as in the left inferior parietal lobule (BA 40). Subtraction analysis of GVS-GPS was described in the preceding text.
FMRI signal decreases ("deactivations")
Negative BOLD MRI responses were calculated for GVS and GPS
(P 0.001, corrected for multiple comparisons).
Comparison of the negative signal changes with and without the use of
global scaling revealed that there were no additional clusters with
global scaling. We also did not find a significant degree of
correlation between the global signal and the reference waveforms used.
However, the Z scores of the results were slightly
different. We conclude that the global signal in our study does not
behave as a confound, and therefore global scaling can be used in the
statistical analysis.
Both contrasts, rest-GVS and rest-GPS, showed significant signal decreases in the central sulcus region, predominantly in the postcentral gyrus analogously to the primary somatosensory cortex (BA 2/3/4 left, BA 3/4/6 right). During GVS, further signal decreases were found in the visual cortex bilaterally (fusiform/inferior occipital gyrus, BA 18/19), sparing Brodmann area 17, and in the right precuneus near the interhemispheric fissure (BA 7). In contrast, GPS led to an additional signal decrease in the middle temporal/occipital gyrus (BA 19/39/18; Table 4, Fig. 5).
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DISCUSSION |
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There is no natural or noninvasive experimental stimulus available
that selectively excites the vestibular system. The advantage of GVS
over caloric vestibular stimulation is its short buildup and offset.
Thus it is possible to alternate short periods of GVS with the rest
condition in fMRI. GVS at the mastoid level not only induces a
rotational or tilt sensation with tonic ocular torsion but also a mild
cutaneous pain sensation (Watson and Colebach 1998;
Zink et al. 1998
). Interpretation of the complex
activation pattern during GVS must also take into account that there is
no primary vestibular cortex comparable to the striate visual cortex or
Heschl's auditory cortex. The vestibular cortex is part of a
multisensory cortex, which involves other sensory modalities for
spatial orientation, self-motion perception, and control of eye
movements (Guldin and Grüsser 1998
).
In the following, we attempt to attribute particular activated areas to multisensory vestibular or ocular motor functions. Therefore the analytic procedure comprises detailed comparisons between GVS and the rest condition and also between GVS and the auditory and nociceptive control stimuli. By this means we were able to separate areas involved in the processing of vestibular and ocular motor, auditory, and nociceptive functions. The second part of the DISCUSSION deals with a newly observed phenomenon: an inhibitory reciprocal vestibular-visual interaction.
Activations related to ocular motor function
The activations revealed by the group contrast GVS-GPS, which reduced the nociceptive part of GVS activation pattern as far as possible, can be attributed to multisensory vestibular and ocular motor functions (Fig. 2; Table 1).
In detail, the two separate activations in the precentral
gyrus of the frontal lobe (BA 6) represent the frontal eye fields (FEF) (Paus 1996) and an area anterior to the FEF (BA
44/6). Activation of the FEF can be related to torsional eye movements
induced by the vestibular stimulation. Other types of eye movements,
such as optokinetic nystagmus (Dieterich et al. 1998
),
saccades (Anderson et al. 1994
; Sweeney et al.
1996
), and smooth pursuit eye movements (Petit et al.
1997
, 1998
) also activate this area. The second area anterior
to this region might represent a second part of the FEF (Paus
1996
) and correspond to a portion of the premotor cortex. This
area was also activated by eye movements during spatial attention tasks
(Gitelman et al. 1999
) or memory-guided saccades (W. Heide, personal communication). Fujii et al. (1998)
reported that intracortical microstimulation of the FEF in the anterior wall of the arcuate sulcus in monkeys fixating a visual target elicited
contraversive saccades. The posterior arcuate area in monkeys (area
6pa) is part of the premotor area 6, which sends efferent axons to the
vestibular nuclei as well as to the multisensory vestibular cortices
(e.g., to PIVC). For this reason, Guldin and Grüsser attributed
premotor area 6 to the "inner vestibular circuit" (Guldin
and Grüsser 1996
).
Additional activations were located bilaterally in the middle
frontal gyrus of the frontal lobe (BA 46, BA 9/46), which in part
represents the prefrontal cortex (PFC) and is known to be involved in
several ocular motor tasks, such as prosaccades and antisaccades (fMRI:
Müri et al. 1998; PET: Sweeny et al.
1996
), remembered or memory-guided saccades (PET:
O'Sullivan et al. 1995
; Sweeney et al.
1996
), as well as visually guided saccades and fixation tasks
(PET: Sweeney et al. 1996
).
The activations of the anterior insula, thalamus, and
putamen may be related to an efference copy of ocular motor
signals. In particular, the activations of the thalamus and putamen fit the concept of an efferent basal ganglia-thalamo-cortical (ocular) motor loop proposed by Alexander et al. (1986).
Moreover, the thalamus is considered a complex relay station for
efferent ocular motor pathways in the paramedian thalamus (subnuclei
ventralis lateralis, dorsomedialis, pulvinaris) (Bucher et al.
1997
) and for vestibular afferents conveyed to vestibular
cortex areas via the ventroposterior subnucleus (Akbarian et al.
1992
). The activation pattern here (anterior insula, basal
ganglia, thalamus) corresponds to that of activations during
optokinetic stimulation [optokinetic nystagmus (OKN)] (Bucher
et al. 1997
) and voluntary saccades (Petit et al.
1993
). The fact that the anterior part of the insula was activated during OKN, but not when OKN was suppressed by fixation of a
stationary target indicates its attribution to ocular motor function
(Dieterich et al. 1998
). On the one hand, this view is also supported by earlier studies in monkeys, which showed an extensive
efferent pathway from the anterior insula directly across the external
capsules into the putamen and the globus pallidus (Showers and
Lauer 1961
). On the other, these areas were found to be
activated in several experimental and clinical pain studies using PET
and fMRI in humans (Bucher et al. 1998
; Coghill
et al. 1994
; Davis et al. 1998
;
Derbyshire and Jones 1998
; Hsieh et al. 1995
; Tölle et al. 1999
).
Dostrovsky and Craig (1996)
were able to characterize
electrophysiologically nociceptive neurons in the ventral medial
nucleus of the thalamus of monkeys, emphasizing the multisensory
function of these neurons. Thus, despite the subtraction analysis used
(GVS-GPS), we cannot completely exclude the possibility of additional
pain-related activations.
The activations that can be related to the ocular motor system were the
two cortical structures, the prefrontal (FEF) and the middle frontal
gyrus (PFC), as well as the anterior-median insula, thalamus, and
putamen, which are elements of the descending pathways to the brain
stem. However, some of these areas are activated by a variety of
sensory stimuli and motor tasks. Therefore registration of activation
in these areas must not necessarily reflect the actual execution of eye
movements. They could simply reflect the stimulus-induced readiness of
the ocular motor system to execute eye movements. A number of imaging
and electrophysiological studies show that imagination of sensory motor
tasks causes activations similar to that caused by the actual
performance (Bodis-Wollner et al. 1997; Hollinger
et al. 1999
; Lang et al. 1994
; Law et al. 1997
).
Activations related to multisensory vestibular function
Experimental studies in monkeys (Grüsser et al.
1990a,b
) and cats (Jijiwa et al. 1991
), clinical
lesion studies in patients (Brandt and Dieterich 1999
;
Brandt et al. 1994
, 1995
), and activation studies in
healthy subjects (Bottini et al. 1994
; Bucher et
al. 1997
, 1998
; Dieterich et al. 1998
,
1999
)
all indicate that the posterior insula and the
retroinsular regions are the human homologue of the PIVC in monkeys. In
the current study, the small individual activations regularly found in
posterior insular and retroinsular areas varied in their
location. These activations did not reach the level of significance in
the group analysis obviously because of the considerable
anatomical variation between the individual subjects (Figs. 2 and 3).
The neurons of PIVC in the monkey brain are multisensory and respond
not only to vestibular but also to various kinds of visual and
somatosensory stimulations (Grüsser et al.
1990a
,b
). This was further demonstrated in earlier human studies using optokinetic (fMRI: Bucher et al. 1997
;
Dieterich et al. 1998
), caloric (PET: Bottini et
al. 1994
; Dieterich et al. 1999
), or galvanic
vestibular stimulation (fMRI: Bucher et al. 1998
). All
these studies localized PIVC around the bicommissural line of Talairach
(AC-PC) level (e.g., Talairach coordinates between
5 and +5 mm along
the z-axis). The only other study on GVS using EPI sequences
attributed the PIVC to an activation area in the temporo-parietal
junction 20 mm above the AC-PC level
(x/y/z =
64/
36/+20)
(Lobel et al. 1998
). These coordinates, however, correspond better to lower parts of BA 40, which we attribute to monkey
area 7 and not to PIVC. Lobel and co-workers did not describe
activation of the posterior or anterior parts of the insula, which we
found in both individual (posterior) and group analyses (anterior).
We did not find any activation in areas corresponding to areas 2v and 3a, which are also parts of the inner vestibular circuit in monkeys. To the best of our knowledge, no human brain activation study so far was able to unequivocally show activations of the multisensory vestibular cortex areas 2v and 3a.
Activations in the inferior parietal lobule (BA 40) and the
anterior cingulate gyrus were also seen during caloric
vestibular stimulation in PET studies (Bottini et al.
1994; Dieterich et al. 1999
). Both areas have
intimate connections to the PIVC and belong to the inner vestibular
circuit (Guldin and Grüsser 1996
). After injection
of tracer substances into different parts of the brain stem vestibular
nuclear complex of monkeys, labeled cells were observed not only in the
PFC, area 6pa, and dorsal to the prearcuate gyrus but also in the
ventral bank of the anterior cingulate gyrus (Akbarian et al.
1994
). Monkey studies revealed two multisensory areas in the
parietal lobe, visual and vestibular, named visual temporal sylvian
area (Guldin and Grüsser 1996
) and area 7b
(Faugier-Grimaud and Ventre 1989
). The location is comparable to parts of our activation in BA 40. To complicate matters,
the inferior parietal lobule and the anterior cingulate cortex are also
involved in human pain [Casey et al. 1996
;
Derbyshire et al. 1997
, 1998
; Hsieh et al.
1995
; current study (GPS-rest)], in auditory (in the current
study the inferior parietal lobule is part of the bilateral big
activation clusters with their maxima in the temporal lobe) and ocular
motor processing (Dieterich et al. 1998
; Paus et
al. 1993
) as well as in manual and speech responses (Paus et al. 1993
). The involvement of these areas in
several sensory functions might indicate that they also play a role in orientation in space (BA 40) (Griffiths et al. 1998
;
Weeks et al. 1999
) and in the motivational-affective
system (cingulum, BA 40) (Bushnell et al. 1995
).
The activation of the middle temporal gyrus (BA 37)
corresponds best with the human homologue of the motion-sensitive area MT/MST in the monkey (Desimone and Ungerleider 1986;
Dubner and Zeki 1971
; Lagae et al. 1994
;
Wurtz and Newsome 1985
). It also receives vestibular
input (Thier and Erickson 1992
) and is the origin of
direct fibers to the vestibular nuclei (Faugier-Grimaud and
Ventre 1989
; Jeannerod 1996
). In humans, this
structure is also known to play an important role in eye movement and
visuomotor processing such as object motion perception (Barton
et al. 1996
; Brandt et al. 1998a
;
Dupont et al. 1994
; Zeki et al. 1991
) and self-motion perception (Brandt et al. 1998
; Cheng
et al. 1995
; de Jong et al. 1994
).
Bilateral activation in the cerebellar hemispheres was found
during all stimuli used and can be related to attention (Allen et al. 1997; Kim et al. 1999
), timing
(Jueptner et al. 1995
; Penhune et al.
1998
), learning (Raymond et al. 1996
), and
ocular motor processing (Dieterich et al. 1999
;
Heide et al. 1999
; Nitschke et al. 1996
,
1999
).
The conjunction analysis allowed us to check for jointly activated areas under two stimulus conditions. The results showed for the conjunction between the contrasts GVS-rest and AS-rest, only two small overlaps in the insular area in the depths of the transverse temporal and in the superior temporal gyrus. There was no jointly activated area in the short or long insular gyri. This supports the view that GVS only represents a weak stimulus for the auditory system. In contrast, significant activations in the frontal eye field, prefrontal cortex, inferior parietal lobule (BA 40), the paramedian thalamus, and the cerebellar hemispheres also appeared not only in the conjunction analysis between GVS and AS but also between GVS and GPS (Fig. 4). Activations of these ocular motor centers might represent a basic network involved in orientation in space which is activated by different sensory stimuli.
Despite the obvious difficulties of selectively attributing one specific function to one specific area, we identified the posterior and retroinsular regions, parts of the inferior parietal lobule (BA 40), and premotor area 6 as areas mainly involved in processing of multisensory vestibular function.
Concurrent "deactivations" of the visual and the somatosensory cortex areas
It is becoming increasingly apparent that relative deactivations
may be as important for brain function as are activations. A PET study
using caloric stimulation demonstrated not only an activation of the
PIVC but also a highly significant decrease in rCBF of the visual
cortex (Wenzel et al. 1996). Brandt et al. (1998)
were able to add to this example of an inhibitory
vestibular-visual interaction in their recent demonstration of a
visual-vestibular interaction using large-field motion patterns that
induce apparent self-motion perception. They found that during
activation of parieto-occipital areas in the visual cortex, there was a
simultaneous rCBF decrease of the posterior insula (PIVC) bilaterally.
This mechanism of a reciprocal inhibitory interaction theoretically
allows the dominant sensorial weight to be shifted from one modality to
the other, depending on which mode of stimulation prevails
(Brandt and Dieterich 1999
).
The first evidence of stimulus-dependent circumscribed
"deactivations" came from PET studies (Shulman et al.
1997; Wenzel et al. 1996
). Such
"deactivations" are detected on fMRI when calculating negative BOLD
signal changes (Allison et al. 2000
; Fransson et al. 1999
; Rauch et al. 1998
). Despite the
considerable disparities in earlier reports comparing PET and fMRI data
(Sadato et al. 1998
; Schlösser et al.
1998
), recent studies draw attention to similarities
(Votaw et al. 1999
). In our study using global scaling, we found negative BOLD responses during GVS in the form of a bilateral "deactivation" in the visual cortex (fusiform gyrus/inferior
occipital gyrus, BA 18/19), sparing BA 17. These responses occurred
independently of whether global scaling was applied or not. The finding
of "deactivations" in the visual cortex agrees well with findings
of an earlier PET study on caloric irrigation (Wenzel et al.
1996
). While Wenzel and co-workers used the extreme stimulus of
ice water stimulation and found a "deactivation" of BA 17-19, we
used the comparatively weak galvanic stimulus and found that the
striate visual cortex, BA 17, was spared. This difference may also be
related to the relatively poor spatial resolution of PET.
On analogy with the inhibitory vestibular-visual interaction, we found
an inhibitory nociceptive-somatosensory interaction during both kinds
of stimulation, GVS and GPS. The "deactivated" areas involved the
somatosensory cortex bilaterally (BA 2/3/4 left, BA 3/4/6 right) and
occurred simultaneously with activations of nociceptive areas in the
frontal lobe and the anterior insula (short insular gyri I/II
bilaterally). In agreement with our findings, Apkarian et al.
(1992) in an earlier Tc99m-HMPAO study observed a decrease in
rCBF in the contralateral somatosensory cortex during persistent pain
stimulation that they interpreted to be cortical inhibition. While
using nonvestibular neck stimulation (GPS), we saw additional
"deactivations" in the precuneus (BA 7) and upper parieto-occipital
areas in the middle temporal and occipital gyrus (BA 19/39/18, Fig. 5,
Table 4). This was seen also during GVS, if a lower level of
significance was used.
In conclusion, GVS not only elicits a complex pattern of activations that can be related to ocular motor and vestibular function, but it also interacts with other sensory systems by means of circumscribed "deactivations" within the visual or somatosensory cortex (Fig. 6). Intersensory inhibitions may provide a basic mechanism for spatial orientation and self-motion perception. In case of inappropriate or misleading input from two afferent sensory systems, visual-vestibular or nociceptive-somatosensory, a perceptual mismatch can be avoided by suppressing the input from one sensory system.
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ACKNOWLEDGMENTS |
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We are grateful to J. Benson for critically reading the manuscript.
This work was supported by the Deutsche Forschungsgemeinschaft (Clinical Research Group, BR 639/5-3), Stifter Verband, and the Wilhelm-Sander-Stiftung.
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FOOTNOTES |
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Address for reprint requests: S. Bense, Dept. of Neurology, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany (E-mail: sbense{at}nefo.med.uni-muenchen.de).
Received 11 April 2000; accepted in final form 10 October 2000.
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REFERENCES |
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