Oculomotor Impairments in Developmental Dyspraxia.

Children with developmental dyspraxia (DD) express impairments in the acquisition of various motor skills and in the development of their social cognition abilities. Although the neural bases of this condition are not fully understood, they are thought to involve frontal cortical areas, subcortical structures, and the cerebellum. Although cerebellar dysfunction is typically difficult to assess and quantify using traditional neurophysiological methods, oculomotor analysis may provide insight into specific cerebellar patterns. The aim of the present study was to investigate, in dyspraxic and typically developing subjects, various oculomotor saccade tasks specifically designed to reveal frontal and cerebellar dysfunction. In addition to evidence supporting prefrontal dysfunction, our results revealed increased variability of saccade accuracy consistent with cerebellar impairments. Furthermore, we found that dyspraxic patients showed decreased velocities of non-visually guided saccades. A closer analysis revealed significant differences in saccade velocity profiles with slightly decreased maximum saccade velocities but markedly prolonged deceleration phases. We show that this pattern was not related to a decreased state of alertness but was suggestive of cerebellar dysfunction. However, the clear predominance of this pattern in non-visually guided saccades warrants alternative hypotheses. In light of previous experimental and anatomical studies, we propose that this unusual pattern may be a consequence of impaired connections between frontal areas and cerebellar oculomotor structures.

Functional consequences of oculomotor disorders in hereditary cerebellar ataxias.

Saccadic eye movements are traditionally cited as an especially successful combination of accuracy and velocity, such high level of performances being believed to be crucial for optimal vision. Although the structures subtending these properties are now well recognized, very little is known about the functional consequences on visually guided behaviors of reduced saccade performances, i.e., slowness and/or inaccuracy. We therefore investigated the impact of such impairments in patients with spino-cerebellar and Friedreich ataxia, i.e., diseases known to affect both saccade parameters. Subjects performed a classical eye movement task, in order to quantify saccade inaccuracy and/or slowness, a visually search task and a reading task and completed a questionnaire designed to evaluate their perceived visual discomfort in daily activities. The first main result was that saccade impairments did have an impact on visually guided behaviors, resulting in an increased time for target detection, especially when accurate foveation was needed, and in an increased reading time. The main responsible oculomotor factor was increased variability of saccade accuracy, and the least responsible factor was reduced saccade velocity. The second main result was that saccade disorders did not induce significant subjective discomfort, since no correlations were found between the results of the questionnaire and saccade parameters. These results emphasize the functional impact of increased variable error of saccade accuracy and question the rationale of high saccade velocities. The discrepancy between objective and subjective measures underlines the largely unconscious aspect of saccade control and leads us to consider the need for an adapted therapy.

Effects of structural and functional cerebellar lesions on sensorimotor adaptation of saccades.

The cerebellum is critically involved in the adaptation mechanisms that maintain the accuracy of goal-directed acts such as saccadic eye movements. Two categories of saccades, each relying on different adaptation mechanisms, are defined: reactive (externally triggered) saccades and voluntary (internally triggered) saccades. The contribution of the medio-posterior part of the cerebellum to reactive saccades adaptation has been clearly demonstrated, but the evidence that other parts of the cerebellum are also involved is limited. Moreover, the cerebellar substrates of voluntary saccades adaptation have only been marginally investigated. Here, we addressed these two questions by investigating the adaptive capabilities of patients with cerebellar or pre-cerebellar stroke. We recruited three groups of patients presenting focal lesions located, respectively, in the supero-anterior cerebellum, the infero-posterior cerebellum and the lateral medulla (leading to a Wallenberg syndrome including motor dysfunctions similar to those resulting from lesion of the medio-posterior cerebellum). Adaptations of reactive saccades and of voluntary saccades were tested during separate sessions in all patients and in a group of healthy participants. The functional lesion of the medio-posterior cerebellum in Wallenberg syndrome strongly impaired the adaptation of both reactive and voluntary saccades. In contrast, patients with lesion in the supero-anterior part of the cerebellum presented a specific adaptation deficit of voluntary saccades. Finally, patients with an infero-posterior cerebellar lesion showed mild adaptation deficits. We conclude that the medio-posterior cerebellum is critical for the adaptation of both saccade categories, whereas the supero-anterior cerebellum is specifically involved in the adaptation of voluntary saccades.

Cortical and sub-cortical control of saccades and clinical application.

Saccades allow object of interest that are perceived by the peripheral retina to be displayed on the fovea, a small central retinal area of maximum visual accuracy. Saccades may be generated under a large variety of circumstances, from reflexive like saccades (e.g. towards a threatening visual cue) to highly volitional saccades (e.g. towards the memorized location of a no longer present visual cue). These different contexts correspond to different complexities of decision-making processes and, on a behavioral aspect, to saccades with different latencies, and to the involvement of different cortical areas. However, whatever their type, saccades need to be fast, in order to avoid any persaccadic visual blur, and accurate since the fovea represents less than 1° of visual angle. This combination of accuracy and velocity is achieved thanks to a collaboration of brainstem and cerebellar oculomotor structures. The basic neural structures involved in these processes are reviewed, a special emphasis being given to clinically relevant mechanisms.

Mixing pro- and antisaccades in patients with parkinsonian syndromes.

Prosaccades and antisaccades were investigated in three groups of patients with parkinsonian syndromes, Parkinson's disease, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), and in a control group. Saccade tasks were performed in single-task blocks (i.e. either blocks of prosaccades or blocks of antisaccades) and in mixed-task blocks (i.e. in blocks of randomly interleaved pro- and antisaccades). Saccade latencies and directional errors (misdirected saccades) were analysed in each subject, and we concentrated more specifically on the comparison of error rates in single tasks and in repeated trials of mixed tasks (i.e. mixing costs). The performance of each group in single tasks was largely consistent with previous studies, with normal antisaccade error rates in Parkinson's disease and CBD patients and increased antisaccade error rates in PSP patients. In contrast, a double dissociation was observed in mixed tasks. Parkinson's disease and CBD patients showed a marked increase in prosaccade and antisaccade error rates in repeated trials of mixed tasks, illustrated by increased mixing costs, whereas PSP patients showed similar error rates in single and repeated trials of mixed tasks, i.e. normal mixing costs. These results demonstrate that: (i) antisaccade performances may be differentially affected in mixed tasks and single tasks; (ii) the region of the dorsolateral prefrontal cortex which is crucial for reflexive saccade inhibition does not seem to be involved in the additional processes required in mixed-task conditions; (iii) the study of interleaved pro- and antisaccades may increase the accuracy of the differential diagnosis between these parkinsonian syndromes.

Unidirectional ocular flutter.

Ocular flutter is a rare abnormal eye movement consisting of irregular bursts of to-and-fro bidirectional horizontal saccades and is frequently encountered in association with cerebellar symptoms. We present a patient with a probable post-infectious ocular flutter that exhibited characteristics not previously reported in the literature. Bursts of ocular flutter consisted almost exclusively of initial rightward saccades and were clearly influenced by orbital eye position and the presence of a visual stimulus. The most recent models of saccadic oscillations do not provide an explanation for such atypical features, especially for the systematic directional bias. Based on existing experimental data, we propose that dysfunction of vermal pause neurons in an unstable saccade network could account for such atypical characteristics.

Effect of gabapentin on oculomotor control and parkinsonism in patients with progressive supranuclear palsy.

The efficacy of gabapentin on motor, oculomotor and frontal lobe symptoms was evaluated in patients with progressive supranuclear palsy (PSP) in a pilot study. Fourteen patients were included and seven of them received gabapentin. Clinical evaluation and horizontal eye movement recordings were performed at inclusion and 5-weeks later. Motor score and saccade latency in the visually guided saccade (VGS) task were identical in the two groups. However, the error rate in the antisaccade task was significantly decreased in the gabapentin group. This preliminary study shows that gabapentin improves reflexive saccade inhibition in patients with PSP but does not improve the latency of VGSs.

Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein.

Whether the recessive ataxias, Ataxia with oculomotor apraxia type 1 (AOA1) and 2 (AOA2) and Ataxia telangiectasia (AT), can be distinguished by video-oculography and alpha-fetoprotein level remains unknown. We compared 40 patients with AOA1, AOA2 and AT, consecutively referred between 2008 and 2015 with 17 healthy subjects. Video-oculography revealed constant impairments in patients such as cerebellar signs, altered fixation, impaired pursuit, hypometric saccades and abnormal antisaccades. Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in one third of patients. Specific distinctive alpha-fetoprotein thresholds were determined for AOA1 (7-15 µg/L), AOA2 (15-65 µg/L) and AT (>65 µg/L). Early age onset, severe walking disability, movement disorders, sensori-motor neuropathy and cerebellar atrophy were all shared. In conclusion, alpha-fetoprotein level seems to permit a distinction while video-oculography does not and therefore is not mandatory, even if an appropriate oculomotor examination remains crucial. Our findings are that AOA1, AOA2 and AT form a particular group characterized by ataxia with complex oculomotor disturbances and elevated AFP for which the final diagnosis is relying on genetic analysis. These findings could guide genetic analysis, assist reverse-phenotyping and provide background for the interpretation of the numerous variants of unknown significance provided by next-generation sequencing.

Perisaccadic mislocalization without saccadic eye movements.

Despite frequent saccadic gaze shifts we perceive the surrounding visual world as stable. It has been proposed that the brain uses extraretinal eye position signals to cancel out saccade-induced retinal image motion. Nevertheless, stimuli flashed briefly around the onset of a saccade are grossly mislocalized, resulting in a shift and, under certain conditions, an additional compression of visual space. Perisaccadic mislocalization has been related to a spatio-temporal misalignment of an extraretinal eye position signal with the corresponding saccade. Here, we investigated perceptual mislocalization of human observers both in saccade and fixation conditions. In the latter conditions, the retinal stimulation during saccadic eye movements was simulated by a fast saccade-like shift of the stimulus display. We show that the spatio-temporal pattern of both the shift and compression components of perceptual mislocalization can be surprisingly similar before real and simulated saccades. Our findings suggest that the full pattern of perisaccadic mislocalization can also occur in conditions which are unlikely to involve changes of an extraretinal eye position signal. Instead, we suggest that, under the conditions of our experiments, the arising difficulty to establish a stable percept of a briefly flashed stimulus within a given visual reference frame yields mislocalizations before fast retinal image motion. The availability of visual references appears to exert a major influence on the relative contributions of shift and compression components to mislocalization across the visual field.

Reproduction of self-rotation duration.

The vestibular system detects the velocity of the head even in complete darkness, and thus contributes to spatial orientation. However, during vestibular estimation of linear passive self-motion distance in darkness, healthy human subjects mainly rely on time, and they replicate also stimulus duration when required to reproduce previous self-rotation. We then made the hypothesis that the perception of vestibular-sensed motion duration is embedded within encoding of motion kinetics. The ability to estimate time during passive self-motion in darkness was examined with a self-rotation reproduction paradigm. Subjects were required to replicate through self-driven transport the plateau velocity (30, 60 and 90 degrees /s) and duration (2, 3 and 4s) of the previously imposed whole-body rotation (trapezoid velocity profile) in complete darkness; the rotating chair position was recorded (500 Hz) during the whole trials. The results showed that the peak velocity, but not duration, of the plateau phase of the imposed rotation was accurately reproduced. Suspecting that the velocity instruction had impaired the duration reproduction, we added a control experiment requiring subjects to reproduce two successive identical rotations separated by a momentary motion interruption (MMI). The MMI was of identical duration to the previous plateau phase. MMI duration was fidelitously reproduced whereas that of the plateau phase was hypometric (i.e. lesser reproduced duration than plateau) suggesting that subjective time is shorter during vestibular stimulation. Furthermore, the accurate reproduction of the whole motion duration, that was not required, indicates an automatic process and confirms that vestibular duration perception is embedded within motion kinetics.

Longitudinal ocular motor study in corticobasal degeneration and progressive supranuclear palsy.

OBJECTIVE: To evaluate the usefulness of ocular motor information in the early diagnosis of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). METHODS: Seven PSP patients, six CBD patients, and three atypical CBD patients were followed longitudinally with repeated electrooculographic (EOG) recordings, at 6-month intervals, to search for features that could confirm or modify the diagnosis. Visually guided saccades and antisaccades were studied. Data from clinical evaluations were independently collected. RESULTS: PSP patients had decreased saccade velocity throughout the disease course. Patients with probable CBD showed preserved saccade velocity but important increased saccade latency ipsilateral to the apraxia side. Similar to patients with PSP, those with atypical CBD features exhibited clinically evident abnormalities of vertical saccades and early slowing of horizontal saccade velocity, but no increase in saccade latency or early square-wave jerks. When clinical "telltale signs" appeared and the clinical diagnosis was reviewed independent of EOG recording, the three patients with atypical CBD features were diagnosed as having PSP although new or overlapping syndromes cannot be excluded. CONCLUSIONS: Consecutive EOG recordings help diagnose atypical CBD and PSP disorders earlier.

Role of pontine nuclei damage in smooth pursuit impairment of progressive supranuclear palsy: a clinical-pathologic study.

We performed a quantitative study of the pontine nuclei in the basis pontis and a semiquantitative study of extrapontine structures involved in smooth pursuit in four patients with severe impairment of horizontal smooth pursuit and histopathologically confirmed diagnosis of progressive supranuclear palsy (PSP). There were only slight changes in the extrapontine structures involved in smooth pursuit, but there was a significant neuronal loss--massive in three patients and mild in one patient--in all nuclei of the basis pontis. Our results suggest that degenerative lesions affecting the pontine nuclei are largely responsible for the horizontal smooth pursuit impairment in PSP.

Hemispheric asymmetry in cortical control of memory-guided saccades. A transcranial magnetic stimulation study.

To study the temporal organisation of memory-guided saccade control we used single-pulse transcranial magnetic stimulation (TMS) over the left posterior parietal (PPC) and prefrontal cortex (PFC) in eight healthy subjects. TMS was applied either following presentation of a visual target, i.e. 160, 260, and 360 ms after the flashed point, or during the period of memorisation, i.e. between 700 and 1500 ms, or finally 100 ms after extinguishing of the central fixation point (i.e. 2100 ms after the target presentation). Latency of memory-guided saccades and the percentage of error in amplitude (PEA) was measured and compared with results without stimulation.TMS over the left PPC 100 ms after the extinguishing of the central fixation point significantly increased memory-guided saccade latency bilaterally. Furthermore, stimulation over the left PFC had a significant effect on the PEA of contralateral memory-guided saccades when applied during the period of memorisation, i.e. between 700 and 1500 ms.In a previous study using identical methodology [13: Müri RM, Vermersch SI, Rivaud S, Gaymard B, Pierrot-Deseilligny C. Effects of single-pulse transcranial magnetic stimulation over the prefrontal and posterior parietal cortices during memory-guided saccades in humans. Journal of Neurophysiology 1996;76:2102-2106], we found that TMS over the right PPC increased the contralateral PEA when applied 260 ms after the flash, the effects on saccade latency after right PPC stimulation or on the PEA after right PFC stimulation being similar to those observed here. Taken together, these results show that (1) a hemispheric asymmetry in the preparation of memory-guided saccade amplitude during the early phase of sensorimotor integration exists, (2) memory-guided saccade triggering is controlled by PPC on both sides, and (3) PFC on both sides are involved in spatial working memory performance.

Role of the prefrontal cortex in the control of express saccades. A transcranial magnetic stimulation study.

Single pulse transcranial magnet stimulation (TMS) was applied in five subjects during a saccadic gap task, i.e. with a temporal gap of 200 ms between the extinguishing of the central fixation point and the appearance of the lateral target. In all subjects, a significant increase of contralateral express saccades was found when TMS was applied over the dorsolateral prefrontal cortex (DPFC) at the end of the gap of 200 ms. Earlier stimulation over the DPFC during the gap had no significant effect. Furthermore, stimulation over the posterior parietal cortex with the same time intervals, and stimulation during a no gap task had no significant influence on express saccades. These results suggest that TMS is capable of interfering specifically with the functioning of the DPFC, probably by inhibition of this region. Possibly such stimulation of the DPFC reduces the inhibition by this region onto the superior colliculus, which results in a facilitation of express saccades.

Cortical control of ocular saccades in humans: a model for motricity.

Our knowledge of the cortical control of saccadic eye movements (saccades) in humans has recently progressed mainly thanks to lesion and transcranial magnetic stimulation (TMS) studies, but also to functional imaging. It is now well-known that the frontal eye field is involved in the triggering of intentional saccades, the parietal eye field in that of reflexive saccades, the supplementary eye field (SEF) in the initiation of motor programs comprising saccades, the pre-SEF in learning of these programs, and the dorsolateral prefrontal cortex (DLPFC) in saccade inhibition, prediction and spatial working memory. Saccades may also be used as a convenient model of motricity to study general cognitive processes preparing movements, such as attention, spatial memory and motivation. Visuo-spatial attention appears to be controlled by a bilateral parieto-frontal network comprising different parts of the posterior parietal cortex and the frontal areas involved in saccade control, suggesting that visual attentional shifts and saccades are closely linked. Recently, our understanding of the cortical control of spatial memory has noticeably progressed by using the simple visuo-oculomotor model represented by the memory-guided saccade paradigm, in which a single saccade is made to the remembered position of a unique visual item presented a while before. TMS studies have determined that, after a brief stage of spatial integration in the posterior parietal cortex (inferior to 300 ms), short-term spatial memory (i.e. up to 15-20 s) is controlled by the DLPFC. Behavioral and lesion studies have shown that medium-term spatial memory (between 15-20 s and a few minutes) is specifically controlled by the parahippocampal cortex, before long-term memorization (i.e. after a few minutes) in the hippocampal formation. Lastly, it has been shown that the posterior part of the anterior cingulate cortex, called the cingulate eye field, is involved in motivation and the preparation of all intentional saccades, but not in reflexive saccades. These different but complementary study methods used in humans have thus contributed to a better understanding of both eye movement physiology and general cognitive processes preparing motricity as whole.

Effects of cortical lesions on saccadic: eye movements in humans.

Our knowledge of the cortical control of saccadic eye movements (saccades) in humans has recently progressed mainly because of lesion and transcranial magnetic stimulation (TMS) studies, but also because of functional imaging. It is now well known that the frontal eye field is involved in the control of intentional saccades, the parietal eye field in that of reflexive saccades, the supplementary eye field (SEF) in the initiation of motor programs comprising saccades, the pre-SEF in the learning of these programs, and the dorsolateral prefrontal cortex (DLPFC) in saccade inhibition, prediction and spatial working memory. Saccades may also be used as a convenient model of motricity to study general cognitive processes such as motivation and spatial memory. Thus, it has been shown that the posterior part of the anterior cingulate cortex, called the cingulate eye field, is involved in motivation and the preparation of all intentional saccades, but not in reflexive saccades. Recently, our understanding of the cortical control of spatial memory has noticeably progressed by using the simple visuo-oculomotor model represented by the memory-guide saccade paradigm, in which a single saccade is made to the remembered position of a unique visual item presented a while before. Transcranial magnetic stimulation studies have determined that after a brief stage of spatial integration in the posterior parietal cortex (inferior to 300 ms), short-term spatial memory (i.e., up to 15-20 seconds) is controlled by the DLPFC. Behavioral and lesion studies have shown that medium-term spatial memory (between 15 and 20 seconds and a few minutes) is specifically controlled by the parahippocampal cortex, before long-term memorization (i.e., after a few minutes) in the hippocampal formation. These different but complementary study methods used in humans have thus contributed to a better understanding of both eye movement physiology and general cognitive processes preparing motricity as whole.

Cerebral ocular motor signs.

Eye movement disturbances resulting from cerebral lesions are reviewed and the specific roles of the different ocular motor areas are summarized. Three cortical areas may trigger saccades: the frontal eye field (FEF), the supplementary eye field (SEF) and the parietal eye field (PEF). The FEF could be involved mainly in intentional visual exploration (intentional saccades), the PEF mainly in reflexive visual exploration (reflexive saccades) and the SEF in the preparation of motor programs (sequences of saccades). Only bilateral lesions affecting these areas result in visible saccade disturbances (at bedside examination), as manifested in Balint's syndrome after parietal lesions, and ocular motor apraxia after fronto-parietal lesions. Other cortical areas prepare saccades: the posterior parietal cortex (near the PEF) controls visuomotor integration; the prefrontal cortex (i.e. area 46 of Brodmann) is involved in inhibition of unwanted reflexive saccades, prediction (predictive saccades) and spatial memory. Smooth pursuit is controlled by the FEF and the medial superior temporal area, located in the posterior part of the cerebral hemisphere. Eye movement disorders resulting from basal ganglia lesions are also reviewed. Lastly, the contribution of eye movement recordings in early diagnosis of some cerebral degenerative diseases (such as progressive supranuclear palsy or corticobasal degeneration) is emphasized.

Progressive necrosis of the conus medullaris: magnetic resonance imaging and surgical findings.

A 67-year-old man with non-insulin-dependent diabetes mellitus progressively developed, over a 2-year period, lower extremity sensory and motor defects associated with impaired bladder function and perineal and perianal sensation related to a disease of the conus medullaris extending from T12 to S5. The magnetic resonance imaging scan suggested myelomalacia and the diagnosis of progressive necrotic myelopathy was confirmed by surgical intervention.

[Electrophysiologic study in a patient presenting with expanding cerebral lacunae]. / Etude électrophysiologique chez un patient présentant des lacunes cérébrales expansives.

A 42-year-old man was affected with multiple cerebral lesions suggesting expanding lacunae. He had suffered for about 15 years of headaches and blurred vision. Neurological examination showed a Parinaud syndrome and a skew deviation. Magnetic resonance imaging showed an enlargement of the third and lateral ventricles and multiple intraparenchymatous lesions with a signal similar to that of the cerebrospinal fluid. These lesions were located in the mesencephalon and right thalamic region. Important discrepancies between the topography of the lesion and the clinical data were observed. Neurological examination, ocular movements during wake and neuropsychological testing suggested sub-cortical dysfunction. These results suggest functional rather than lesional repercussion of expansive lacunae.

Cerebellar hemangioblastoma and primary hyperparathyroidism.

The authors report the case of a 52-year-old woman presenting with cerebellar hemangioblastoma and primary hyperparathyroidism. It is the second reported case involving this new association. The relationship between these two tumors is discussed.