INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The vestibular, visual, and somatosensory systems jointly perceive the spatial orientation of the human body and coordinate the processes that play a role in bringing about this orientation. Egocentric coordination and exocentric coordination are distinguished on the basis of whether the individual or the surrounding world is referred to (Bottini et al. 2001; Brandt 1999; Brandt and Dieterich 1999; Brandt et al. 2002). It is generally accepted that the above function can be ascribed to a complex network of cortical and subcortical regions that continuously process afferent impulses, with one or another element of the network possibly predominating in this process (Guldin and Grüsser 1998).

A number of animal experiments have been performed to identify the elements of the network. As a result, areas with vestibular afferentation have been found in the parietal and temporal regions of primates. These areas comprise area 2v, located at the ventral tip of the intraparietal sulcus, area 3a, situated along the central sulcus, the parietoinsular vestibular cortex (PIVC), at the posterior pole of the insula, and area 7, in the inferior parietal lobe (Faugier-Grimaud and Ventre 1989; Grüsser and Guldin 1995; Ödkvist et al. 1974; Pandya and Sanides 1973; Schwarz and Fredrickson 1971).

Parts of the network responsible for spatial orientation have been identified in patients with lesions of one cerebral hemisphere and suffering from the contralateral spatial neglect syndrome. Elements have been located in the inferior parietal lobe, the area of the temporoparietal junction, the lateral region of the premotor cortex, and certain subcortical regions such as the thalamus and basal ganglia (Husain and Kennard 1996; Vallar and Perani 1986; Vallar et al. 1993).

The most widely used examination techniques in which stimulation is applied involve optokinetic, galvanic, and caloric vestibular stimulation (CVS) and the neck vibration (NV) test (Bense et al. 2001; Bottini et al. 1994 2001; Bucher et al. 1998; Kisely et al. 2001; Lobel et al. 1998 1999; Paulesu et al. 1997). The various authors agree that any technique of stimulation will affect more than one modality. Accordingly, the cerebral activation patterns obtained by using different techniques may be discordant. An attempt has been made to circumvent this problem (Bottini et al. 2001) by measuring the brain activation in healthy volunteers on the use of CVS and mechanical vibration stimulation of the cervical muscles and by identifying the anatomical structures responsible for the representation of egocentric space as the overlap between the activation patterns obtained with the two techniques. Bottini et al. (2001) suggested that the vestibularly driven human cortical system comprises four areas, in contrast with the findings in primate experiments, which supported a core region hypothesis in the vestibular cortical system.

In an attempt to supplement the capabilities of single-unit recording experiments and tracer studies, in the present investigation we applied a different approach. In addition to including healthy volunteers in the brain activation studies, we also examined patients following the removal of tumors from the right cerebello pontine angle (CPA). All of these patients had suffered a complete loss of peripheral vestibular input on that side. Accordingly comparison of the CVS-induced regional cerebral blood flow (rCBF) changes in populations with or without this input seemed a promising way to delineate the cortical area most sensitive to pure vestibular signaling. The cerebral area responsible for vestibular signal processing was identified by statistical comparison of the perfusion changes detected in the two populations.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Study populations

Six healthy volunteers (3 males and 3 females, aged 35.5 ± 9 yr) and six patients (4 males and 2 females, aged 49.2 ± 16 yr), all of them right-handed, were examined. Each of the patients had undergone tumor removal from the right CPA. Histologically, the tumors were schwannomas in five cases and meningeoma in one case. PET investigations were performed 6-18 mo postoperatively. This period of time was sufficient for complete central vestibular compensation to develop. Chronic otitis media, previous ear surgery, disorders of the inner ear, and neurological diseases involving other than the cerebello pontine process were exclusion criteria in the operated patients.

Postoperative anacusis and complete lesion of the right-sided facial nerve developed in all of the patients in addition to a complete loss of the vestibular function. Pure-tone audiometric tests confirmed that the contralateral hearing was intact and appropriate for age. No complaint of dizziness was mentioned at the time of the examinations. Thorough electronystagmographic vestibular investigations (examination of spontaneous signs, calorimetric excitation with cold and warm water, and the rotational stimulus response) demonstrated a complete peripheral vestibular lesion on the operated side in all of the patients and normal responses to the stimuli on the intact side. Moreover the vestibular clinical signs in patients with left-sided CVS were very similar to those observed in the healthy volunteers. Identical investigations did not reveal any deviation from physiological conditions in the healthy volunteers, who were selected as the best responders to CVS on the basis of the frequency and amplitude of nystagmus.

The individuals taking part in the investigations were all provided with fully detailed information concerning the procedure and the possible complications. Perfusion measurements were carried out only after the permission of the Ethical Committee of the University of Debrecen and the written consent of the individuals involved in the tests had been obtained.

Caloric stimulation

CVS was performed by the injection of 30 ml of water (0°C) in 60 s into the external acoustic meatus (Bottini et al. 1994, 2001; Kisely et al. 2001). To ensure standard conditions, the injection was always performed with a Braun perfusion pump. Nystagmus was observed during each PET scan with CVS (except in patients with right-sided CVS), proving the efficacy of the stimulation, but it was not recorded by electronystagmograph.

PET investigations

Perfusion investigations were performed with a GE 4096 Plus PET camera. Special attention was paid to the sensory deprivation to ensure the correspondence of the activation pattern to the specific stimulation applied. To achieve this, complete silence and near-complete darkness were provided in the examination room. The individuals were asked to relax completely and regular checks were made that they were awake between stimulations. During the screening session of the patients and volunteers, three conditions, i.e., rest (A), left-sided CVS (B), and right-sided CVS (C), were repeated alternately three times (sequence: ABCABCABC).

The reconstructed images contained 15 tomographic slices within the 10.5-cm field of view of the camera. The sections were made in planes parallel to that determined by the temporal canthus of the eye and the tragus on both sides. To decrease errors caused by motion, the head of each individual was kept in the same position by a fixation method, using a plastic mesh. The correction for tissue attenuation was based on the data of 25-min transmission measurements, performed with a ⁶⁸Ge source of 8 mCi activity. [¹⁵O]-butanol (45 mCi) was injected 55 s after the start of vestibular stimulation in a 5-s iv bolus. Dynamic data acquisition (36 × 5 s) was started simultaneously with the administration of the tracer. Prior to reconstruction, sinograms were summed up for 90 s data collection, starting from the moment when the butanol reached the brain tissue. This happened with a 10- to 20-s delay relative to the start of the bolus injection. Thus the data used for the image reconstruction were acquired 5 s following the end of the CVS or later. The PET images of the individual measurements were reconstructed by applying a 4.2-mm Hanning filter (image matrix size: 128 × 128 × 15; image voxel size: 2 × 2 × 6.5 mm) after completion of the necessary corrections for random coincidence, scattering, dead time, and tissue attenuation.

A T1-weighted, 3D MPRAGE sagittal plane MR investigation (Siemens MAGNETOM Harmony 1.0 T Whole Body MR, slice thickness 1.5 mm, repetition time (TR) = 11.1 ms, echo delay time (TE) = 4.3 ms) was carried out in each case. MR images were transformed into Talairach's system of coordinates (Collins et al. 1995; Evans et al. 1994; Talairach and Tournoux 1988). The PET images were realigned into the same anatomical position as the relevant MR images (Woods et al. 1993) and stereotaxially normalized perfusion images were prepared by applying transformations determined during the spatial standardization of the MR images. Gaussian-weighted, isotropic spatial smoothing with a half-width of 16 mm was applied to these spatially normalized perfusion images to improve the signal-to-noise ratio and to decrease perfusion differences arising from individual variations in gyral anatomy. Because of the limitation of the axial field of view of the scanner, the searching volume of the statistical analysis after the spatial normalization was limited from below by the z = 28 mm plane, with the highest values of the z coordinate being 34 mm (occipitally) and 58 mm (frontally).

Statistical analysis

Statistical analysis was performed on a voxel by voxel basis, using SPM99 software. Global differences in CBF were covaried out for all voxels. Comparisons of the means across CVS and control tasks in the populations, and comparisons of the responses of the populations, were made by using t statistics with appropriate linear contrasts (Friston et al. 1995, 1996). The statistical parametric maps (SPMs) of both populations were generated first with standard subtraction contrasts (B  A and C  A). The distribution of the differences between the responses of the populations (i.e., the activations in the controls exceeding those in the patients) during the given stimulation was examined by fixed-effect analysis. The appropriate SPMs were evaluated via the contrasts [B  A]_c  [B  A]_p and [C  A]_c - [C  A]_p (with subscripts c and p referring to the control and patient populations, respectively). A probability threshold of P < 0.05 corrected for multiple comparisons (corresponding to Z > 4.36) and an activation cluster-size minimum (k > 20) were chosen to highlight the differences in the SPMs (Poline et al. 1997).

The activation foci were superimposed on the averaged, T1-weighted MR images of the populations (Evans et al. 1994), which allowed a precise anatomical description.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Left-sided and right-sided CVS were applied for both the healthy volunteers and the patient population. All the subjects complained of earache, lasting on average for 30 s, and a sensation of cold following stimulation. Nevertheless, dizziness and vegetative symptoms (sweating and nausea) predominated both in the healthy control group and in the patients during left-sided CVS. There was no difference between the nystagmus evoked in the patients and that in the healthy subjects during left-sided CVS, whereas stimulation on the right side elicited no eye movements in the former group, but a strong response in the latter group.

The results of the group analyses are reported in Tables 1-4 ([B  A]_c, [B  A]_p, [C  A]_c, and [C  A]_p, respectively). Large activations induced by left-sided CVS were seen bilaterally in the SPMs of both populations. Activations were observed in the precentral and postcentral gyrus, the insula, the area SII, and the retroinsular (Ri) cortex (Tables 1 and 2). Nevertheless, the statistical magnitudes of activations of the right hemisphere were higher (contralateral dominance) in both SPMs. Activations with limited spatial extent and low magnitude were observed in the cingulate cortex of both populations, the putamen of healthy volunteers, and the thalamus of the patient group.

Large activations induced by right-sided CVS were seen bilaterally in the SPM of healthy volunteers as well. Activations were observed in the precentral and postcentral gyrus, the insula, the area SII, and the Ri cortex and activations with limited spatial extent were observed only in the cingulate cortex of this populations (Table 3). The statistical magnitudes of activations of the left hemisphere were higher (contralateral dominance) in this SPM.

Activations induced by right-sided CVS were seen only ipsilaterally in the SPM of the patient group (precentral gyrus, postcentral gyrus, and insula), while activations with limited spatial extent and low magnitude were observed in the left hemisphere (precentral and postcentral gyrus). The statistical magnitudes of the activations induced by right-sided CVS in the left insula of the patient group were less than the P_uncorrected < 0.001 (corresponding to Z > 3.09) statistical threshold (Table 4).

Statistical analysis of the group comparison did not reveal any cerebral region for which there was a significant difference in the CVS-induced response with the data obtained following left-sided CVS (the contrast [B  A]_c - [B  A]_p was used) when the statistical criteria were P_corrected < 0.05 and k > 20. In the case of right-sided CVS with the same statistical thresholds, however, a large cluster was found within which CVS induced a significantly higher rCBF increase ([C  A]_c - [C  A]_p) in the control group than in the patient group (coordinates of the cluster maximum: x = 40, y = 28 mm, z = 24 mm, maximum Z score = 4.89; P_corrected < 0.006, size of the cluster = 1,360 mm³). Repeated analysis with a lower statistical threshold, P_uncorrected < 0.001 (corresponding to Z > 3.09), resulted in a larger (8,880 mm³) single cluster covering the contralateral inferior parietal lobe, the transverse and superior temporal gyri, and the area of the temporoparietal junction, corresponding to the posterior region of the insula (Figs. 1 and 2; Table 5). A lower statistical threshold (P_uncorrected < 0.01) resulted an extra cluster with small spatial extent and low statistical magnitude in the insula (Fig. 2; Table 5).

View larger version (61K): [in this window] [in a new window]   Fig. 1. Activated clusters indicated by the right-sided caloric vestibular stimulation (left and middle) and the activation pattern revealed by the response difference approach (right), superimposed on the spatially standardized, averaged T1-weighted MR data of the populations.

View larger version (57K): [in this window] [in a new window]   Fig. 2. Statistical parametric map of response difference (thresholded by Puncorrected < 0.01) superimposed on the spatially standardized, averaged T1-weighted MR data of the populations. The numbers indicate the stereotactic coordinates of slices relative to the intercommissural line in vertical (z) direction.

The statistical comparison of the right-sided CVS response of the individuals in the two groups, which differed from each other exclusively as concerns the presence or absence of the peripheral vestibular (and acoustic) input, demarcated a cortical area corresponding to part of the particular cortical region observed by Bottini et al. (2001) that can be activated by both CVS and NV stimulation. This part is anatomically identical to the sum of somatosensory area SII and the region identified in primates as the Ri cortex. The displayed data (Table 5) show that, in contrast with that of Bottini and coworkers, our experimental approach did not demonstrate a significant rCBF difference between the healthy volunteers and the operated patients within the insula. At the same time, the CVS-induced activation patterns of the two populations included a rCBF increase in these areas relative to the rest state, though the statistical comparison of these activations did not indicate a significant difference between the groups. In a similar way, we were able to demonstrate right-sided CVS-induced activation in both populations in the splenium of the corpus callosum and the ipsilateral superior temporal gyrus, but again statistical comparison of the population responses did not reveal any significant difference between the activation patterns.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The introduction of functional imaging into research relating to the processing of signals of the vestibular system proved to be a breakthrough (Bense et al. 2001; Bottini et al. 1994 1995, 2001; Brandt et al. 1998, 2002; Brandt 1999; Brandt and Dieterich 1999; Kisely et al. 2001; Lobel et al. 1998 1999; Ödkvist et al. 1974; Paulesu et al. 1997; Penfield 1957; Takeda et al. 1996). These techniques are suitable for studies of the regional blood flow in the CNS, which are effective in the localization of different cerebral functions. As an increased rCBF ensures the extra glucose required by the increased neuronal cerebral activity, the rCBF and the neuronal activity undergo change in close correlation with each other (Ganong 1999). With the ¹³³Xe inhalation technique, a significant activation due to vestibular stimulation was demonstrated in regions behind the primary auditory cortex (Friberg et al. 1985; Penfield 1957). The data obtained in consequence of the developing technologies, the ever-increasing sensitivity, and the improved resolution have documented that, together with the insular and retroinsular regions, the inferior parietal lobe, certain temporal areas, and other regions also take part in the processing of vestibular signals received from the periphery. These areas are situated in both hemispheres, with a contralateral predominance over the stimulated side. Additionally, increased activity has been registered in the postcentral gyrus, claustrum, putamen, precentral gyrus, and gyrus cinguli (Bottini et al. 1994, 1995, 2001; Brandt 1999).

The considerable discordance of the published data may be explained by the differences in the experimental conditions. The effects of several modalities are usually involved in brain activation studies of the cerebral projection of the egocentric coordination. The optokinetic technique stimulates both the visual cortex and the oculomotor system. Changes resulting from galvanic stimulation have been described in the activities of the nociceptive and auditory parts of the cortex (Bense et al. 2001; Bucher et al. 1998). The rCBF increase induced by galvanic stimulation was corrected for the rCBF increase resulting from the pain caused by the stimulus, but the activation caused by pain still could not be completely excluded from the response (Bense et al. 2001). In the stimulation of subjects by NV, an attempt was made to prevent acoustic stimulation from the vibrator by keeping the turned-on device near the patients (without skin contact) even in investigations at rest, but exclusion of the tactile component was unsuccessful (Bottini et al. 2001). Which nonvestibular elements contribute to those changes in rCBF caused by CVS must be clarified.

CVS cannot ensure pure vestibular stimulation either. Scientists relying on this technique have made efforts to guarantee experimental conditions under which the tactile, nociceptive, and possibly auditory components of CVS do not influence the results of the measurements, i.e., waiting for 10 s after the injection of cold water prior to the start of PET data acquisition (Bottini et al. 1994, 2001) or delaying the start of PET investigations by an average of 145 and 25 s following stimulation with cold water or warm air, respectively, in an effort ensure that the effect of fast-quenching activation due to mechanical and CVS is decreased (Wenzel et al. 1996). In earlier experiments (Kisely et al. 2001), we applied the technique of stimulation with icy water and found that this resulted in an expressed and prolonged sensation of cold and pain, which persisted during data acquisition. These observations immediately led to the question as to which of the components of the changes in rCBF induced by CVS stimulation could be attributed to the processing of vestibular signals and which were related to the pain or cold sensation.

To separate the vestibular and nonvestibular components in our brain activation studies with CVS, PET investigations were performed on two populations. All of the patients included in the present study had suffered a complete loss of right-sided hearing and a right-sided peripheral lesion of the facial nerve. Consequently, the activation obtained through the CVS of the operated side was certainly free of vestibular and acoustic components. Joint evaluation of the perfusion results obtained using right-sided CVS in the healthy and the operated patient populations made it possible to distinguish the effects of the stimuli on the rCBF via the trigeminal, glossopharyngeal, and vagus nerves, as it may be assumed that the vestibular component is the only difference between the activation in the healthy subjects and that in the operated patients. This assumption is supported by the fact that the acoustic stimulation-induced effects faded out completely during the 5-s or more delay of the acquisition of the data used for the image reconstruction relative to the end of CVS.

Our statistical comparison of the CVS-related responses by these two populations of subjects, who differed only in the existence of the vestibular input, resulted in a single contralateral area with vestibular activation. This cortical area corresponds to part of the cortical region described by Bottini et al. (2001), which can be activated by both CVS and NV. This subregion appears to be anatomically identical to the aggregate of the somatosensory area SII and the Ri cortex identified in primates. Other investigators have identified this region as an analog of the PIVC described in primates (Brandt and Dieterich 1999). Bottini et al. (1994, 1995, 2001) reported on six (four contralateral and two ipsilateral) maxima in the CVS-NV shared activation pattern. We made a detailed study of the Gaussianized t (Z) values in our SPMs, at the locations corresponding to the maxima in the activation pattern reported by Bottini et al. (2001), within the overlap of the areas relating to CVS and NV (Table 5). The evaluated results for the three insular maxima indicate a small difference of subthreshold significance between the CVS-induced rCBF responses of the control and the operated subjects. The extents of the activation in the healthy and operated groups were similar. Accordingly, within these regions we did not succeed in proving a systematic difference by means of the statistical comparison (Table 5). As a probable explanation of the difference between our results and those of Bottini et al., we suggest that the activation within these insular areas is related to the stimulation modalities, which differ from the vestibular component and which are also present during NV stimulation. It should be noted, however, that the small number of subjects in our study may also contribute to the different results observed by ourselves and by Bottini et al. (2001) and an increase in the number of scans might result in the appearance of additional areas in our SPMs.

In a very similar way, use of our protocol led to the detection of a significantly elevated rCBF ipsilaterally in the area of the superior temporal gyrus in both the healthy volunteers and the patient population. However, differential statistical analysis did not indicate a difference in this localization between the perfusion changes detected in the two groups. Here again, it can be presumed that these activations were brought about by the nonvestibular components of the applied stimulation. Our measurements further disclosed low Z scores within the area of the splenium of the corpus callosum. This is explained by the similarly low-level perfusion increase of this area as a result of CVS in both the voluntary group and the operated subjects.

In almost all of the previous studies, the resting state served as the reference state in the stimulation protocols and paradigms applied to explore the cortical structures participating in the adjustment and control of the spatial orientation. Consequently, the investigated state was characterized by multimodality signal processing, resulting in a complex multicomponent activation pattern whose interpretation was rather difficult. Bottini and coworkers followed a more efficient strategy, applying two different paradigms, both stimulating the vestibular system. Thus the overlap of the two activation maps definitely contained all regions participating in the processing of the signals from the vestibular periphery. Moreover, the effects of nonvestibular stimulation present in only one of the two paradigms will not appear in the common part of the involved activation patterns. It is theoretically possible, however, that regions excited by nonvestibular modalities, but otherwise present in both stimulation protocols, will also appear in the overlap of the two individual activation patterns. In our experimental approach, the cortical area representing the projection of the vestibular signaling is defined as the difference of two activation patterns relating to two different groups of subjects but obtained through use of exactly the same experimental protocol. Consequently, all activations resulting from the same modality of the applied paradigm will be canceled unless special excitation appears in the activation pattern of one of the populations, due to some special feature in that group. We consider that this experimental protocol (if it can be applied) may be more instrumental in certain cases, as it allows exclusion of the effects of unwanted stimulations.

Our differential method resulted in a single continuous area being activated by the vestibular input signals. For the reasons detailed above, it is quite unlikely that this area embodies subregions excited by nonvestibular components of the CVS applied. The population of healthy volunteers and that of operated patients differed only in the peripheral and acoustic vestibular input, which had been lost completely due to the surgical intervention in the patient group who received right-sided CVS. The specifically tailored stimulation protocol (the data acquisition started with a 5-s delay relative to the end of the injection of cold water) excluded the disturbing effect of any auditory response. Thus the complete lesion of the acoustic nerve did not disturb the analysis of the population differences. This was supported by the fact that no activation of the primary auditory cortex was observed in either of the populations. This condition resulted in an advantageous arrangement, with only a single modality differing in the brain activation of the two experimental populations: the signals from the semicircular canals of the inner ear.

The significant difference in regional response of the two populations to CVS, localized in the Ri/SII areas, can be unequivocally ascribed to the cortical representation of the sensory input provided by the vestibular nerve. Thus our result provides further evidence via functional imaging concerning the hypothesis that this region is the human analog of the PIVC ascribed in primates (Bottini et al. 2001; Guldin and Grüsser 1998). Earlier results achieved with electrophysiological, histological, and functional imaging techniques suggested that specific areas of the CNS participating in the adjustment of the spatial orientation of the body comprise the elements of a network with a multimodal sensorium (cortical vestibular system). It seems quite feasible that the area with the most significant perfusional change induced by pure vestibular stimulation, and whose perfusion increases significantly in response to either CVS or NV excitation, can be regarded as the "core region" (Guldin and Grüsser 1998), i.e., the common constituent of all neural systems contributing to the spatial recognition. This accords well with the finding of Brandt and Dieterich (1999) and Brandt et al. (2002) that the PIVC is the dominant cortical vestibular area.

Although we have also found activations related to right-sided CVS in brain regions different from the PIVC, these areas were present in both populations. Statistical comparison revealed population differences, but these were below the set significance threshold. The difference between the groups was statistically acceptable only in the PIVC region; the other cortical and subcortical differences could be regarded as mere chance, related to the small number of subjects in each group. These regions include two insular gray matter fields and one in the left frontal lobe, as well as subcortical regions in the left putamen and thalamus. All the clusters of elevated rCBF demarcated by group comparison statistics possibly belong in the vestibular cortical system described by Guldin and Grüsser (1998). The elements of this system are connected to the vestibular nuclei through the thalamus and also to each other (Akbarian et al. 1993 1994; Guldin et al. 1993; Guldin and Grüsser 1998). Single-unit recording studies (Guldin and Grüsser 1998, Grüsser et al. 1990a,b) documented that they differ from each other in the fraction of neurons responding mainly to vestibular, somatosensory, or visual stimuli. Moreover, simultaneous activation and inhibition to specific modalities can be demonstrated in these areas. Thus it is not surprising that the activation pattern in the healthy volunteers was dominated by the highly significant rCBF increase in the Ri/SII (PIVC) region, since more than 50% of the neurons in this area are primarily responsive to the vestibular stimulus. On the other hand, it is reasonable that some of the elements of this network with a smaller fraction of vestibularly driven units (e.g., the vestibular cingulate area) were not found in our study, given the small number of subjects. Activations of this kind in clusters of the vestibular cortical system could be attributed in part to the vestibular input, but the contribution of proprioceptive and visual stimuli due to involuntary muscle responses to cold and pain cannot be excluded. In view of the missing vestibular nerve, it seems quite obvious that the clusters activated in the patient group with right-sided CVS represent areas responsive to nonvestibular modality of the stimulation scenario. The relatively subtle dissimilarity of the activation patterns of the groups with respect to the clusters distinct from the PIVC may be related to the multimodal feature of these areas. At the same time, it is quite feasible that the inherent properties of the imaging method used are responsible for the enhancement of the PIVC region on comparison of the activation patterns of the populations. With the pure vestibular input as the major difference between the groups, the integrated effect of the stimulation on the rCBF is manifested in a dramatic perfusion change if this input reaches the specific cortical areas. Since this integrated response in the PIVC region is so much more pronounced and different from those observed at other sites of the cortical vestibular system, the role of this area in the processing of vestibular input seems in a way to be unique. This finding is in full agreement with the observation that the PIVC is the only vestibular cortex in the squirrel monkey model that is connected with all other areas suggested to belong to the vestibular cortical system. In consequence, this area of the human brain may be regarded as the core region of this system, though further investigations of larger populations are needed to provide stronger support of this.