Step-By-Step Standardization of the Bottom-Up Semi-Automated Nanocrystallization of Pharmaceuticals: A Quality By Design and Design of Experiments Joint Approach.

Nanosized drug crystals have been reported with enhanced apparent solubility, bioavailability, and therapeutic efficacy compared to microcrystal materials, which are not suitable for parenteral administration. However, nanocrystal design and development by bottom-up approaches are challenging, especially considering the non-standardized process parameters in the injection step. This work aims to present a systematic step-by-step approach through Quality-by-Design (QbD) and Design of Experiments (DoE) for synthesizing drug nanocrystals by a semi-automated nanoprecipitation method. Curcumin is used as a drug model due to its well-known poor water solubility (0.6 µg mL-1, 25 °C). Formal and informal risk assessment tools allow identifying the critical factors. A fractional factorial 24-1 screening design evaluates their impact on the average size and polydispersity of nanocrystals. The optimization of significant factors is done by a Central Composite Design. This response surface methodology supports the rational design of the nanocrystals, identifying and exploring the design space. The proposed joint approach leads to a reproducible, robust, and stable nanocrystalline preparation of 316 nm with a PdI of 0.217 in compliance with the quality profile. An orthogonal approach for particle size and polydispersity characterization allows discarding the formation of aggregates. Overall, the synergy between advanced data analysis and semi-automated standardized nanocrystallization of drugs is highlighted.

Cortico-cerebellar network involved in saccade adaptation.

Saccade adaptation is the learning process that ensures that vision and saccades remain calibrated. The central nervous system network involved in these adaptive processes remains unclear because of difficulties in isolating the learning process from the correlated visual and motor processes. Here we imaged the human brain during a novel saccade adaptation paradigm that allowed us to isolate neural signals involved in learning independent of the changes in the amplitude of corrective saccades usually correlated with adaptation. We show that the changes in activation in the ipsiversive cerebellar vermis that track adaptation are not driven by the changes in corrective saccades and thus provide critical supporting evidence for previous findings. Similarly, we find that activation in the dorsomedial wall of the contraversive precuneus mirrors the pattern found in the cerebellum. Finally, we identify dorsolateral and dorsomedial cortical areas in the frontal and parietal lobes that encode the retinal errors following inaccurate saccades used to drive recalibration. Together, these data identify a distributed network of cerebellar and cortical areas and their specific roles in oculomotor learning. NEW & NOTEWORTHY The central nervous system constantly learns from errors and adapts to keep visual targets and saccades in registration. We imaged the human brain while the gain of saccades adapted to a visual target that was displaced while the eye was in motion, inducing retinal error. Activity in the cerebellum and precuneus tracked learning, whereas parts of the dorsolateral and dorsomedial frontal and parietal cortex encoded the retinal error used to drive learning.

Neural correlates for task-relevant facilitation of visual inputs during visually-guided hand movements.

Vision is a powerful source of information for controlling movements, especially fine actions produced by the hand that require a great deal of accuracy. However, the neural processes that enable vision to enhance movement accuracy are not well understood. In the present study, we tested the hypothesis that the cortical sensitivity to visual inputs increases during a spatially-constrained hand movement compared to a situation where visual information is irrelevant to the task. Specifically, we compared the cortical visual-evoked potentials (VEPs) in response to flashes (right visual hemifield) recorded while participants followed the outline of an irregular polygon with a pen (i.e., tracing), with VEPs recorded when participants simply kept the pen still. This tracing task was chosen specifically because it requires many different visual processes (e.g., detection of line orientation, motion perception, visuomotor transformation) to be completed successfully. The tracing and resting tasks were performed with normal vision and also with mirror-reversed vision, thereby increasing task difficulty when tracing. We predicted that the sensitivity to visual inputs would be enhanced (i.e. greater VEPs) during tracing and that this increase in response sensitivity would be greater when tracing was performed with mirror-reversed vision. In addition, in order to investigate the existence of a link between the sensitivity to visual inputs and the accuracy with which participants traced the shape, we assigned participants to high performer (HP) or low performer (LP) groups according to their tracing performance in the condition with mirror-reversed visual feedback. Source analyses revealed that, for both groups, the sensitivity to visual inputs of the left occipital and MT/MST regions increased when participants traced the shape as compared to when they were resting. Also, for both groups of participants, the mirror-reversed vision did not affect the amplitude of the cortical response to visual inputs but increased the latencies of the responses in the occipital, temporal, and parietal regions. However, the HP group showed cortical responses that largely differed from those displayed by the LP group. Specifically, the HP group demonstrated movement-related increases of visual sensitivity in regions of the visual cortex that were not observed in the LP group. These increased responses to visual inputs were evidenced in the posterior inferior parietal, temporal-occipital, and inferior-temporal regions. Overall, our results are in line with the assertion that increasing the sensitivity to visual inputs serves to promote relevant visual information for the different processes involved during visually-guided hand movements. Our results also suggest that maintaining accurate hand tracing movements in the presence of discrepant visual and somatosensory feedback requires additional perceptual and spatial information processing that is tightly linked to visual inputs.

Opposed optimal strategies of weighting somatosensory inputs for planning reaching movements toward visual and proprioceptive targets.

Behavioral studies have suggested that the brain uses a visual estimate of the hand to plan reaching movements toward visual targets and somatosensory inputs in the case of somatosensory targets. However, neural correlates for distinct coding of the hand according to the sensory modality of the target have not yet been identified. Here we tested the twofold hypothesis that the somatosensory input from the reaching hand is facilitated and inhibited, respectively, when planning movements toward somatosensory (unseen fingers) or visual targets. The weight of the somatosensory inputs was assessed by measuring the amplitude of the somatosensory evoked potential (SEP) resulting from vibration of the reaching finger during movement planning. The target sensory modality had no significant effect on SEP amplitude. However, Spearman's analyses showed significant correlations between the SEPs and reaching errors. When planning movements toward proprioceptive targets without visual feedback of the reaching hand, participants showing the greater SEPs were those who produced the smaller directional errors. Inversely, participants showing the smaller SEPs when planning movements toward visual targets with visual feedback of the reaching hand were those who produced the smaller directional errors. No significant correlation was found between the SEPs and radial or amplitude errors. Our results indicate that the sensory strategy for planning movements is highly flexible among individuals and also for a given sensory context. Most importantly, they provide neural bases for the suggestion that optimization of movement planning requires the target and the reaching hand to both be represented in the same sensory modality.

Saccadic inhibition is accompanied by large and complex amplitude modulations when induced by visual backward masking.

Saccadic inhibition refers to the strong temporary decrease in saccadic initiation observed when a visual distractor appears shortly after the onset of a saccadic target. Here, to gain a better understanding of this phenomenon, we assessed whether saccade amplitude changes could accompany these modulations of latency distributions. As previous studies on the saccadic system using visual backward masking--a protocol in which the mask appears shortly after the target--showed latency increases and amplitude changes, we suspected that this could be a condition in which amplitude changes would accompany saccadic inhibition. We show here that visual backward masking produces a strong saccadic inhibition. In addition, this saccadic inhibition was accompanied by large and complex amplitude changes: a first phase of gain decrease occurred before the saccadic inhibition; when saccades reappeared after the inhibition, they were accurate before rapidly entering into a second phase of gain decrease. We observed changes in saccade kinematics that were consistent with the possibility of saccades being interrupted during these two phases of gain decrease. These results show that the onset of a large stimulus shortly after a first one induces the previously reported saccadic inhibition, but also induces a complex pattern of amplitude changes resulting from a dual amplitude perturbation mechanism with fast and slow components.

Distractor-induced saccade trajectory curvature reveals visual contralateral bias with respect to the dominant eye.

The functional consequences of the visual system lateralization referred to as "eye dominance" remain poorly understood. We previously reported shorter hand reaction times for targets appearing in the contralateral visual hemifield with respect to the dominant eye (DE). Here, we further explore this contralateral bias by studying the influence of laterally placed visual distractors on vertical saccade trajectories, a sensitive method to assess visual processing. In binocular conditions, saccade trajectory curvature was larger toward a distractor placed in the contralateral hemifield with respect to the DE (e.g., in the left visual hemifield for a participant with a right dominant eye) than toward one presented in the ipsilateral hemifield (in the right visual hemifield in our example). When two distractors were present at the same time, the vertical saccade showed curvature toward the contralateral side. In monocular conditions, when one distractor was presented, a similar larger influence of the contralateral distractor was observed only when the viewing eye was the DE. When the non dominant eye (NDE) was viewing, curvature was symmetric for both distractor sides. Interestingly, this curvature was as large as the one obtained for the contralateral distractor when the DE was viewing, suggesting that eye dominance consequences rely on inhibition mechanisms present when the DE is viewing. Overall, these results demonstrate that DE influences visual integration occurring around saccade production and support a DE-based contralateral visual bias.

Wound healing and catheter thrombosis after implantable venous access device placement in 266 breast cancers treated with bevacizumab therapy.

The aim of this study was to determine, in a population with metastatic breast cancer treated with bevacizumab therapy, the incidence of wound dehiscence after placement of an implantable venous access device (VAD) and to study the risk of catheter thrombosis. This study enrolled all VADs placed by 14 anesthetists between 1 January 2007 and 31 December 2009: 273 VADs in patients treated with bevacizumab therapy and 4196 VADs in patients not treated with bevacizumab therapy. In the bevacizumab therapy group, 13 cases of wound dehiscence occurred in 12 patients requiring removal of the VAD (4.76%). All cases of dehiscence occurred when bevacizumab therapy was initiated less than 7 days after VAD placement. Bevacizumab therapy was initiated less than 7 days after VAD placement in 150 cases (13 of 150: 8.6%). The risk of dehiscence was the same from 0 to 7 days. In parallel, the VAD wound dehiscence rate in patients not receiving bevacizumab therapy was eight of 4197 cases (0.19%) (Fisher's test significant, P<0.001). No risk factors of dehiscence were identified: anesthetists, learning curves, and irradiated patients. VAD thrombosis occurred in four patients (1.5%). In parallel, VAD thrombosis occurred in 51 of 4197 patients (1.2%) not receiving bevacizumab therapy (Fisher's test not significant; P=0.43). Bevacizumab therapy was permanently discontinued in five patients related to wound dehiscence and in one patient due to extensive skin necrosis. These data suggest the need to observe an interval of at least 7 days between VAD placement and initiation of bevacizumab therapy to avoid the risk of a wound dehiscence requiring chest wall port explant. The risk of VAD thrombosis does not require any particular primary prevention.

Adaptation of reactive and voluntary saccades: different patterns of adaptation revealed in the antisaccade task.

Sensorimotor adaptation restores and maintains the accuracy of goal-directed movements. It remains unclear whether these adaptive mechanisms modify actions by controlling peripheral premotor stages that send commands to the effectors and/or earlier processing stages involved in registration of target location. Here, we studied the effect of adaptation of saccadic eye movements, a well-established model of sensorimotor adaptation, in an antisaccade task. This task introduces a clear spatial dissociation between the actual target direction and the requested saccade direction because the correct movement direction is in the opposite direction from the target location. We used this requirement of a vector inversion to assess the level(s) of saccadic adaptation for two different types of adapted saccades. In two different experiments, we tested the transfer to antisaccades of the adaptation in one direction of reactive saccades to jumping targets and of scanning voluntary saccades within a target array. In the first experiment, we found that adaptation of reactive saccades transferred only to antisaccades in the adapted direction. In contrast, in the second experiment, adaptation of scanning voluntary saccades transferred to antisaccades in both the adapted and non-adapted directions. We conclude that adaptation of reactive saccades acts only downstream of the vector inversion required in the antisaccade task, whereas adaptation of voluntary saccades has a distributed influence, acting both upstream and downstream of vector inversion.

Nutritional risk factors in planned oncologic surgery: what clinical and biological parameters should be routinely used?

BACKGROUND: Screening for malnutrition is recommended in hospitalized and planned surgical patients. The aim of this study was to analyze the feasibility and routine prognostic value of using the principal recommended nutritional screening and evaluation tools for cancer patients undergoing major surgery. METHODS: This study is a prospective, 3-month, multicenter observational trial recording weight loss, body mass index, albumin, transthyretin, and PG-SGA. The morbidity rate was assessed on the basis of major complications (MC), whether of an infectious (MIC) or noninfectious (MNIC) nature. RESULTS: Two hundred seventy-five patients were recruited at nine centers. The following percentages were recorded with respect to morbidity: 28.4% MC, 12.7% MIC, and 22.2% MNIC. Univariate analysis revealed a statistical association only between weight loss greater than 10% and MIC and hospital stay. A weight loss of 15% is required to demonstrate an association with either MC, MIC, or MNIC. Body mass index (BMI) was associated only with MNIC, PG-SGA with MC, and albumin <30 g/l was strongly associated with all types of morbidity (MC, MIC, MNIC). Multivariate analysis indicated that only albumin <30 g/l and an operating time of more than 4 h are significantly associated with morbidity. CONCLUSIONS: In this study, the best nutritional factor for detecting the risk of MC is albumin levels below 30 g/l. A weight loss greater than 15% is required to obtain a statistically significant correlation with the existence of MC.

Interhemispheric Transfer Time Asymmetry of Visual Information Depends on Eye Dominance: An Electrophysiological Study.

The interhemispheric transfer of information is a fundamental process in the human brain. When a visual stimulus appears eccentrically in one visual-hemifield, it will first activate the contralateral hemisphere but also the ipsilateral one with a slight delay due to the interhemispheric transfer. This interhemispheric transfer of visual information is believed to be faster from the right to the left hemisphere in right-handers. Such an asymmetry is considered as a relevant fact in the context of the lateralization of the human brain. We show here using current source density (CSD) analyses of visually evoked potential (VEP) that, in right-handers and, to a lesser extent in left-handers, this asymmetry is in fact dependent on the sighting eye dominance, the tendency we have to prefer one eye for monocular tasks. Indeed, in right-handers, a faster interhemispheric transfer of visual information from the right to left hemisphere was observed only in participants with a right dominant eye (DE). Right-handers with a left DE showed the opposite pattern, with a faster transfer from the left to the right hemisphere. In left-handers, albeit a smaller number of participants has been tested and hence confirmation is required, only those with a right DE showed an asymmetrical interhemispheric transfer with a faster transfer from the right to the left hemisphere. As a whole these results demonstrate that eye dominance is a fundamental determinant of asymmetries in interhemispheric transfer of visual information and suggest that it is an important factor of brain lateralization.

Oculomotor plasticity: are mechanisms of adaptation for reactive and voluntary saccades separate?

Saccadic eye movements are permanently controlled and their accuracy maintained by adaptive mechanisms that compensate for physiological or pathological perturbations. In contrast to the adaptation of reactive saccades (RS) which are automatically triggered by the sudden appearance of a single target, little is known about the adaptation of voluntary saccades which allow us to intentionally scan our environment in nearly all our daily activities. In this study, we addressed this issue in human subjects by determining the properties of adaptation of scanning voluntary saccades (SVS) and comparing these features to those of RS. We also tested the reciprocal transfers of adaptation between the two saccade types. Our results revealed that SVS and RS adaptations disclosed similar adaptation fields, time course and recovery levels, with only a slightly lower after-effect for SVS. Moreover, RS and SVS main sequences both remained unaffected after adaptation. Finally and quite unexpectedly, the pattern of adaptation transfers was asymmetrical, with a much stronger transfer from SVS to RS (79%) than in the reverse direction (22%). These data demonstrate that adaptations of RS and SVS share several behavioural properties but at the same time rely on partially distinct processes. Based on these findings, it is proposed that adaptations of RS and SVS may involve a neural network including both a common site and two separate sites specifically recruited for each saccade type.

Asymmetry in visual information processing depends on the strength of eye dominance.

Unlike handedness, sighting eye dominance, defined as the eye unconsciously chosen when performing monocular tasks, is very rarely considered in studies investigating cerebral asymmetries. We previously showed that sighting eye dominance has an influence on visually triggered manual action with shorter reaction time (RT) when the stimulus appears in the contralateral visual hemifield with respect to the dominant eye (Chaumillon et al. 2014). We also suggested that eye dominance may be more or less pronounced depending on individuals and that this eye dominance strength could be evaluated through saccadic peak velocity analysis in binocular recordings (Vergilino-Perez et al. 2012). Based on these two previous studies, we further examine here whether the strength of the eye dominance can modulate the influence of this lateralization on manual reaction time. Results revealed that participants categorized as having a strong eye dominance, but not those categorized as having a weak eye dominance, exhibited the difference in RT between the two visual hemifields. This present study reinforces that the analysis of saccade peak velocity in binocular recordings provides an effective tool to better categorize the eye dominance. It also shows that the influence of eye dominance in visuo-motor tasks depends on its strength. Our study also highlights the importance of considering the strength of eye dominance in future studies dealing with brain lateralization.

Limitations of short range Mexican hat connection for driving target selection in a 2D neural field: activity suppression and deviation from input stimuli.

Dynamic Neural Field models (DNF) often use a kernel of connection with short range excitation and long range inhibition. This organization has been suggested as a model for brain structures or for artificial systems involved in winner-take-all processes such as saliency localization, perceptual decision or target/action selection. A good example of such a DNF is the superior colliculus (SC), a key structure for eye movements. Recent results suggest that the superficial layers of the SC (SCs) exhibit relatively short range inhibition with a longer time constant than excitation. The aim of the present study was to further examine the properties of a DNF with such an inhibition pattern in the context of target selection. First we tested the effects of stimulus size and shape on when and where self-maintained clusters of firing neurons appeared, using three variants of the model. In each model variant, small stimuli led to rapid formation of a spiking cluster, a range of medium sizes led to the suppression of any activity on the network and hence to no target selection, while larger sizes led to delayed selection of multiple loci. Second, we tested the model with two stimuli separated by a varying distance. Again single, none, or multiple spiking clusters could occur, depending on distance and relative stimulus strength. For short distances, activity attracted toward the strongest stimulus, reminiscent of well-known behavioral data for saccadic eye movements, while for larger distances repulsion away from the second stimulus occurred. All these properties predicted by the model suggest that the SCs, or any other neural structure thought to implement a short range MH, is an imperfect winner-take-all system. Although, those properties call for systematic testing, the discussion gathers neurophysiological and behavioral data suggesting that such properties are indeed present in target selection for saccadic eye movements.

Control of saccadic eye movements and combined eye/head gaze shifts by the medio-posterior cerebellum.

The cerebellar areas involved in the control of saccades have recently been identified in the medio-posterior cerebellum (MPC). Unit activity recordings, experimental lesions and electrical microstimulation of this region in cats and monkeys have provided a considerable amount of data and allowed the development of new computational models. In this paper, we review these data and concepts about cerebellar function, discuss their importance and limitations and suggest future directions for research. The anatomical data indicate that the MPC has more than one site of action in the visuo-oculomotor system. In contrast, most models emphasize the role of cerebellar connections with immediate pre-oculomotor circuits in the reticular formation, and only one recent model also incorporates the ascending projections of the MPC to the superior colliculus. A major challenge for future studies, in continuation with this initial attempt, is to determine whether the various cerebellar output pathways correspond to distinct contributions to the control of saccadic eye movements. Also, a series of recent studies in the cat have indicated a more general role of the MPC in the control of orienting movements in space, calling for an increasing effort to the study of the MPC in the production of head-unrestrained saccadic gaze shifts.

Eye dominance influences triggering action: the Poffenberger paradigm revisited.

Our dominant eye (DE) is the one we unconsciously choose when performing a monocular task. Although it has been recognized for centuries, eye dominance and its behavioral consequences remain poorly understood. Here we used the simple and well-known Poffenberger paradigm (1912) in which participants press a button with the right or left index finger, in reaction to the appearance of a lateralized visual stimulus. By selecting participants according to their DE and handedness, we were able to decipher the impact of eye dominance on visuomotor transformation speed. We show, for the first time, that in right-handers simple reaction times (RT) in response to a lateralized visual target are shorter when it appears in the contralateral visual hemifield with respect to the DE. In left-handers, only those with a right DE exhibit a shorter RT with the left hand and they show no hemifield difference. Additionally, the Poffenberger paradigm has been used to estimate the interhemispheric transfer time (IHTT) in both directions, from the right to the left hemisphere or the reverse, by comparing hand RTs following stimulation of each visual hemifield. The present study demonstrates that this paradigm leads to biased estimations of these directionally considered IHTT and provides an explanation to the often reported IHTT negative values that otherwise appear implausible. These new findings highlight the need to consider eye dominance in studies investigating the neural processes underlying visually-guided actions. More generally, they demonstrate a substantial impact of eye dominance on the neural mechanisms involved in converting visual inputs into motor commands.

Apical sorting of lysoGPI-anchored proteins occurs independent of association with detergent-resistant membranes but dependent on their N-glycosylation.

Most glycosylphosphatidylinositol-anchored proteins (GPI-APs) are located at the apical surface of epithelial cells. The apical delivery of GPI-APs is believed to result from their association with lipid rafts. We find that overexpression of C-terminally tagged PGAP3 caused predominant production of lysoGPI-APs, an intermediate precursor in the GPI lipid remodeling process in Madin-Darby canine kidney cells. In these cells, produced lysoGPI-APs are not incorporated into detergent-resistant membranes (DRMs) but still are delivered apically, suggesting that GPI-AP association with DRMs is not necessary for apical targeting. In contrast, apical transport of both fully remodeled and lyso forms of GPI-APs is dependent on N-glycosylation, confirming a general role of N-glycans in apical protein transport. We also find that depletion of cholesterol causes apical-to-basolateral retargeting not only of fully remodeled GPI-APs, but also of lysoGPI-APs, as well as endogenous soluble and transmembrane proteins that would normally be targeted to the apical membrane. These findings confirm the essential role for cholesterol in the apical protein targeting and further demonstrate that the mechanism of cholesterol-dependent apical sorting is not related to DRM association of GPI-APs.

Hand-eye coordination relies on extra-retinal signals: evidence from reactive saccade adaptation.

Execution of a saccadic eye movement towards the goal of a hand pointing movement improves the accuracy of this hand movement. Still controversial is the role of extra-retinal signals, i.e. efference copy of the saccadic command and/or ocular proprioception, in the definition of the hand pointing target. We report here that hand pointing movements produced without visual feedback, with accompanying saccades and towards a target extinguished at saccade onset, were modified after gain change of reactive saccades through saccadic adaptation. As we have previously shown that the adaptation of reactive saccades does not influence the target representations that are common to the eye and the hand motor sub-systems (Cotti J, Guillaume A, Alahyane N, Pelisson D, Vercher JL. Adaptation of voluntary saccades, but not of reactive saccades. Transfers to hand pointing movements. J Neurophysiol 2007;98:602-12), the results of the present study demonstrate that extra-retinal signals participate in defining the target of hand pointing movements.

Adaptation of voluntary saccades, but not of reactive saccades, transfers to hand pointing movements.

Studying the transfer of visuomotor adaptation from a given effector (e.g., the eye) to another (e.g., the hand) allows us to question whether sensorimotor processes influenced by adaptation are common to both effector control systems and thus to address the level where adaptation takes place. Previous studies have shown only very weak transfer of the amplitude adaptation of reactive saccades--i.e., produced automatically in response to the sudden appearance of visual targets--to hand pointing movements. Here we compared the amplitude of hand pointing movements recorded before and after adaptation of either reactive or voluntary saccades, produced either in a saccade sequence task or in a single saccade task. No transfer to hand pointing movements was found after adaptation of reactive saccades. In contrast, a substantial transfer to the hand was obtained following adaptation of voluntary saccades produced in sequence. Large amounts of transfer between the two saccade types were also found. These results demonstrate that the visuomotor processes influenced by saccadic adaptation depend on the type of saccades and that, in the case of voluntary saccades, they are shared by hand pointing movements. Implications for the neurophysiological substrates of the adaptation of reactive and voluntary saccades are discussed.

Kinematics and eye-head coordination of gaze shifts evoked from different sites in the superior colliculus of the cat.

Shifting gaze requires precise coordination of eye and head movements. It is clear that the superior colliculus (SC) is involved with saccadic gaze shifts. Here we investigate its role in controlling both eye and head movements during gaze shifts. Gaze shifts of the same amplitude can be evoked from different SC sites by controlled electrical microstimulation. To describe how the SC coordinates the eye and the head, we compare the characteristics of these amplitude-matched gaze shifts evoked from different SC sites. We show that matched amplitude gaze shifts elicited from progressively more caudal sites are progressively slower and associated with a greater head contribution. Stimulation at more caudal SC sites decreased the peak velocity of the eye but not of the head, suggesting that the lower peak gaze velocity for the caudal sites is due to the increased contribution of the slower-moving head. Eye-head coordination across the SC motor map is also indicated by the relative latencies of the eye and head movements. For some amplitudes of gaze shift, rostral stimulation evoked eye movement before head movement, whereas this reversed with caudal stimulation, which caused the head to move before the eyes. These results show that gaze shifts of similar amplitude evoked from different SC sites are produced with different kinematics and coordination of eye and head movements. In other words, gaze shifts evoked from different SC sites follow different amplitude-velocity curves, with different eye-head contributions. These findings shed light on mechanisms used by the central nervous system to translate a high-level motor representation (a desired gaze displacement on the SC map) into motor commands appropriate for the involved body segments (the eye and the head).

Visuo-motor deficits induced by fastigial nucleus inactivation.

The contribution of the cerebellar vermal lobules Vic/VII and of the caudal part of the fastigial nucleus (cFN) to the control of saccadic eye movements has been established by converging neurophysiological approaches. The precise delineation of these saccade-related territories in the medio-posterior cerebellum (MPC) has stimulated the development of detailed investigations of its output nucleus, the cFN. In the present paper, we review recent studies that describe the deficits of the saccadic displacement of the line of sight (gaze) induced by a reversible cFN inactivation under different experimental situations (head restrained, head-unrestrained or body-unrestrained). These data first indicate that the MPC does not solely influence the generation of saccadic eye movements but also the accompanying head movements during saccadic shifts of gaze in the head-unrestrained animal. They also support, in agreement with anatomical data, a distributed influence of the MPC on several levels of the sensory-motor system for orienting gaze, rather than a limited control of the immediate pre-motor structures.