To accurately localize a visual target in space despite eye movement-induced shifts of its retinal image, the brain must take into account both its retinal location and information about current eye position or at least the preceding eye displacement. We examined this ability with respect to saccadic eye movements by applying "double-step" stimuli, where the locations of two sequentially flashed target lights have to be fixated by two successive saccades performed after their disappearance. As the 2nd saccade will not start at the spatial location from which the 2nd target was seen, a dissonance arises between its retinal coordinates and the motor coordinates of the required 2nd saccade. Nevertheless, these saccades were performed quite accurately by 32 healthy human adults. To investigate the contribution of the cerebral cortex, we recorded horizontal double-step saccades in 35 patients with focal unilateral hemispheric lesions. Whereas frontal lesions impaired temporal properties, posterior parietal lesions caused spatial dysmetria or failure of even ipsiversive 2nd saccades following contraversive 1st saccades. This reflects an inability to compensate for retinospatial dissonance by using nonretinal information (corollary discharge) about eye displacement associated with a previous saccade into the contralesional hemifield. In conclusion, the parietal cortex is crucial for spatial constancy across saccades.

To determine the cortical areas controlling memory-guided sequences of saccadic eye movements, we performed functional magnetic resonance imaging (fMRI) in six healthy adults. Subjects had to perform a memorized sequence of three saccades in darkness, after a triple-step stimulus of successively flashed laser targets. To assess the differential contribution of saccadic subfunctions, we applied several control conditions, such as central fixation with or without triple-step visual stimulation, self-paced saccades in darkness, visually guided saccades and single memory-guided saccades. Triple-step saccades strongly activated the regions of the frontal eye fields, the adjacent ventral premotor cortex, the supplementary eye fields, the anterior cingulate cortex and several posterior parietal foci in the superior parietal lobule, the precuneus, and the middle and posterior portion of the intraparietal sulcus, the probable location of the human parietal eye field. Comparison with the control conditions showed that the right intraparietal sulcus and parts of the frontal and supplementary eye fields are more involved in the execution of triple-step saccades than in the other saccade tasks. In accordance with evidence from clinical lesion studies, we propose that the supplementary eye field essentially controls the triggering of memorized saccadic sequences, whereas activation near the middle portion of the right intraparietal sulcus appears to reflect the necessary spatial computations, including the use of extraretinal information (efference copy) about a saccadic eye displacement for updating the spatial representation of the second or third target of the triple-step sequence.

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We report the clinical features of the original Chilean family with Kufor-Rakeb syndrome (KRS) that led to the discovery of the ATP13A2 gene at the PARK9 locus. KRS is a rare juvenile-onset autosomal recessive disease characterized by progressive Parkinsonism, pyramidal signs, and cognitive decline in addition to vertical gaze palsy and facial-faucial-finger minimyoclonus. Neurological and neuropsychological examination during a 10-year period, videotaping, neuroimaging, and measurement of DNA methylation of the ATP13A2 promoter region were performed. The youngest 5 of 17 children of nonconsanguineous parents, carrying compound-heterozygous ATP13A2 mutations, had normal development until ages ∼10 to 12 years, when school performance deteriorated and slowness, rigidity, and frequent falls developed. Examination revealed bradykinesia, subtle postural/action tremor, cogwheel rigidity, spasticity, upward gaze palsy, smooth pursuit with saccadic intrusions, and dementia. Additional signs included facial-faucial-finger minimyoclonus, absent postural reflexes, visual/auditory hallucinations, and insomnia. Levodopa response could not be fully judged in this family. T2* magnetic resonance imaging sequences revealed marked diffuse hypointensity of the caudate (head and body) and lenticular nucleus bilaterally. Disease progression was slow including epilepsy, cachexia, and anarthria. Four affected members died after 28.5 ± 5.5 (mean ± SD) years of disease. Two heterozygous carriers, the mother and eldest sibling, showed jerky perioral muscle contractions and clumsiness of hand movements. There was no significant correlation between DNA methylation of the ATP13A2 promoter region and disease progression. The marked caudate and lenticular nucleus T2*-hypointensity suggests that KRS might belong to the family of neurodegenerative diseases associated with brain iron accumulation.

Functionally, saccadic eye movements are closely linked to visuo-spatial orientation. Anatomically, the network of cortical areas controlling saccades also seems to be involved in spatial attention and orientation. Consequently, lesions should cause deficits in both categories. We investigated this in 34 patients with focal unilateral lesions of the posterior parietal cortex (PPC), the frontal eye fields (FEF), the supplementary motor area (SMA), or the dorsolateral prefrontal cortex (PFC). Saccadic eye movements were recorded using infrared reflection oculography. Visual hemineglect or other visuo-spatial disorders were investigated by a series of standardized paper-pencil tests. Further, the internal spatial coordinates (subjective visual vertical and subjective straight ahead) were assessed psychophysically. Depending on the site of the lesion, different patterns of deficits were identified: lesions of the PPC impaired reflexive exploration of visual space in terms of delayed and hypometric visually triggered saccades into the contralesional hemifield, related to the severity of visual hemineglect. Further, PPC lesions specifically affected basic functions of the perceptual analysis of space, such as the internal spatial coordinates and spatial constancy across saccades. The latter was tested by applying visual double-step stimuli, where saccade-related extraretinal information had to be taken into account for achieving spatial accuracy. Frontal lesions left these functions intact. FEF lesions, however, impaired systematic intentional exploration of space, thus causing an exploratory-motor type of visual hemineglect. Prefrontal (PFC) lesions impaired the working memory for saccade-related spatial information, and SMA lesions affected temporal properties such as the timing of saccadic sequences, but did not cause specific visuo-spatial deficits. In conclusion, patients with frontal or parietal cortical lesions often exhibit combined saccadic and visuo-spatial disorders, most of which are topically specific.