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The aim of this 15O-labelled H2O bolus positron emission tomography (PET) study was to analyse the hemispheric dominance of the vestibular cortical system. Therefore, the differential effects of caloric vestibular stimulation (right or left ear irrigation with warm water at 44°C) on cortical and subcortical activation were studied in 12 right-handed and 12 left-handed healthy volunteers. Caloric irrigation induces a direction-specific sensation of rotation and nystagmus. Significant regional cerebral blood flow increases were found in a network within both hemispheres, including the superior frontal gyrus/sulcus, the precentral gyrus and the inferior parietal lobule with the supramarginal gyrus. These areas correspond best to the cortical ocular motor centres, namely the prefrontal cortex, the frontal eye field and the parietal eye field, known to be involved in the processing of caloric nystagmus. Furthermore, distinct temporo-parietal activations could be separated in the posterior part of the insula with the adjacent superior temporal gyrus, the inferior parietal lobule and precuneus. These areas fit best to the human homologues of multisensory vestibular cortex areas identified in the monkey and correspond to the parieto-insular vestibular cortex (PIVC), the visual temporal sylvian area (VTS) and areas 7 and 6. Further cortical activations were seen in the anterior insula, the inferior frontal gyrus and anterior cingulum. The subcortical activation pattern in the putamen, thalamus and midbrain is consistent with the organization of efferent ocular motor pathways. Cortical and subcortical activation of the described areas was bilateral during monaural stimulation, but predominant in the hemisphere ipsilateral to the stimulated ear and exhibited a significant right hemispheric dominance for vestibular and ocular motor structures in right-handed volunteers. Similarly, a significant left hemispheric dominance was found in the 12 left-handed volunteers. Thus, this PET study showed for the first time that cortical and subcortical activation by vestibular caloric stimulation depends (i) on the handedness of the subjects and (ii) on the side of the stimulated ear. Maximum activation was therefore found when the non-dominant hemisphere was ipsilateral to the stimulated ear, i.e. in the right hemisphere of right-handed subjects during caloric irrigation of the right ear and in the left hemisphere of left-handed subjects during caloric irrigation of the left ear. The localization of handedness and vestibular dominance in opposite hemispheres might conceivably indicate that the vestibular system and its hemispheric dominance, which matures earlier during ontogenesis, determine right- or left-handedness.