How does Parkinson's disease and aging affect temporal expectation and the implicit timing of eye movements?

Anticipatory eye movements are often evoked by the temporal expectation of an upcoming event. Temporal expectation is based on implicit timing about when a future event could occur. Implicit timing emerges from observed temporal regularities in a changing stimulus without any voluntary estimate of elapsed time, unlike explicit timing. The neural bases of explicit and implicit timing are likely different. It has been shown that the basal ganglia (BG) play a central role in explicit timing. In order to determine the influence of BG in implicit timing, we investigated the influence of early Parkinson's disease (PD) and aging on the latency of anticipatory eye movements. We hypothesized that a deficit of implicit timing should yield inadequate temporal expectations, and consequently abnormally timed anticipatory eye movements compared with age-matched controls. To test this hypothesis, we used an oculomotor paradigm where anticipation of a salient target event plays a central role. Participants pursued a visual target that moved along a circular path at a constant velocity. After a randomly short (1200 ms) or long (2400 ms) forward path, the target reversed direction, returned to its starting position and stopped. Target motion reversal caused an abrupt 'slip' of the pursued target image on the retina and was a particularly salient event evoking anticipatory eye movements. Anticipatory eye movements were less frequent in PD patients. However, the timing of anticipation of target motion reversal was statistically similar in PD patients and control subjects. Other eye movements showed statistically significant differences between PD and controls, but these differences could be attributed to other factors. We conclude that all anticipatory eye movements are not similarly impaired in PD and that implicit timing of salient events seems largely unaffected by this disease. The results support the hypothesis that implicit and explicit timing are differently affected by BG dysfunction.

Influence of previous target motion on anticipatory pursuit deceleration.

During visual pursuit of a moving target, expected changes in its trajectory often evoke anticipatory smooth pursuit responses. In the present study, we investigated characteristics of anticipatory smooth pursuit decelerations before a change or the end of a target trajectory. Healthy humans had to pursue with the eyes a target moving along a circular path that predictably or unpredictably reversed direction and then retraced its movement back to the starting position. We found that anticipatory eye decelerations were often evoked in temporal expectation of target reversal and of the end of the trajectory. The latency of anticipatory decelerations initiated before target reversal was variable, had poor temporal accuracy and depended on the history of previous trials. Anticipations of the end of the trajectory were more accurate, more precise and were not influenced by previous trials. In this case, subjects probably based their estimate of the end of the trajectory on the duration just experienced before target motion reversal. These results suggest that anticipatory eye decelerations are based on the characteristics of the current or preceding trials depending on the most reliable information available.

Influence of cognitive expectation on the initiation of anticipatory and visual pursuit eye movements in the rhesus monkey.

A classic paradigm to study anticipatory pursuit consists in training monkeys to look at a target that appears in the center of a visual display, disappears during a short "gap" period, then reappears and immediately starts to move. To determine the role of prior directional information on anticipatory pursuit eye movements, we trained rhesus monkeys to associate the color of a centrally presented visual cue with the direction of an upcoming target motion. In a first experiment, a gap period occurred randomly in 50% of the trials. Consequently, two possible choices of timing of target motion onset were given to subjects to guide their anticipatory responses. In a second experiment, a gap period occurred during each trial and only a single choice of timing of target motion onset was given to subjects. We found that monkeys used the learned association between the color of the cue and the direction of future target motion to voluntarily initiate anticipatory pursuit movements in the appropriate direction. Anticipatory movements could be classified in two distinct populations: early and late movements. Early movements were most frequent when prior directional information was provided and when two choices of timing of target motion onset were given. The latency of visual pursuit was shortened and its velocity was larger when prior directional information was provided. We conclude that cognitive expectation of future target motion plays a dominant role in determining characteristics of anticipatory pursuit in the monkey.

Supplementary eye fields stimulation facilitates anticipatory pursuit.

Anticipatory movements are motor responses occurring before likely sensory events in contrast to reflexive actions. Anticipatory movements are necessary to compensate for delays present in sensory and motor systems. Smooth pursuit eye movements are often used as a paradigmatic example for the study of anticipation. However, the neural control of anticipatory pursuit is unknown. A previous study suggested that the supplementary eye fields (SEFs) could play a role in the guidance of smooth pursuit to predictable target motion. In this study, we favored anticipatory responses in monkeys by making the parameters of target motion highly predictable and electrically stimulated the SEF before and during this behavior. Stimulation sites were restricted to regions of the SEF where saccades could not be evoked at the same low currents. We found that electrical microstimulation in the SEF increased the velocity of anticipatory pursuit movements and decreased their latency. These effects will be referred to as anticipatory pursuit facilitation. The degree of facilitation was the largest if the stimulation train was delivered near the end of the fixation period, before the moment when anticipatory pursuit usually begins. No anticipatory smooth eye movements could be evoked during fixation without an expectation of target motion. These results suggest that the SEF pursuit area might be involved in the process of guiding anticipatory pursuit.

Further evidence that a shared efferent collicular pathway drives separate circuits for smooth eye movements and saccades.

The aim of the present study was to find out whether smooth eye movements (SEMs) evoked by superior colliculus (SC) stimulation are, as suggested by Breznen et al. (1996), artefactual eye movements resulting from a non-physiological response of the saccadic generator. This question was reinvestigated in head-restrained cats. Long-lasting SC stimulation was found to evoke, in a comparable proportion, either a single saccade followed by an uninterrupted SEM or a staircase of two or three saccades interleaved with SEMs. These two different patterns of eye movements could be elicited at a near-threshold current and at low stimulation frequencies. In most cases, SEM direction clearly differed from that of the preceding saccade. This difference between SEM and saccade directions varied in a systematic way as a function of the initial saccade direction. As demonstrated by computer simulation, this observation can be explained if the neural circuit controlling SEMs reaches a saturation level earlier than the saccadic burst-generator. Our results in cats were reminiscent of those reported by Breznen et al. (1996) in the monkey only in some instances, when high frequency stimulation (400-600 Hz) was applied. Indeed, in the case of near-threshold stimulation-elicited staircase saccades, increasing the stimulation frequency led to a progressive disappearance of the smaller subsequent saccades that were substituted by uninterrupted SEM-like movements. Altogether, the present results confirm the view that SEMs are genuine eye movements. These results rule out the hypothesis that SEMs result from a saturation of the saccadic generator and strengthen the hypothesis that SEMs and saccades are distinct movements. We suggest that the same collicular efferent cells carry out the motor command to saccadic and SEM circuits and that the position error originating from the SC may be distributed amongst separate downstream motor systems.

Common inhibitory mechanism for saccades and smooth-pursuit eye movements.

The premotor pathways subserving saccades and smooth-pursuit eye movements are usually thought to be different. Indeed, saccade and smooth-pursuit eye movements have different dynamics and functions. In particular, a group of midline cells in the pons called omnipause neurons (OPNs) are considered to be part of the saccadic system only. It has been established that OPNs keep premotor neurons for saccades under constant inhibition during fixation periods. Saccades occur only when the activity of OPNs has completely stopped or paused. Accordingly, electrical stimulation in the region of OPNs inhibits premotor neurons and interrupts saccades. The premotor relay for smooth pursuit is thought to be organized differently and omnipause neurons are not supposed to be involved in smooth-pursuit eye movements. To investigate this supposition, OPNs were recorded during saccades and during smooth pursuit in the monkey (Macaca mulatta). Unexpectedly, we found that neuronal activity of OPNs decreased during smooth pursuit. The resulting activity reduction reached statistical significance in approximately 50% of OPNs recorded during pursuit of a target moving at 40 degrees /s. On average, activity was reduced by 34% but never completely stopped or paused. The onset of activity reduction coincided with the onset of smooth pursuit. The duration of activity reduction was correlated with pursuit duration and its intensity was correlated with eye velocity. Activity reduction was observed even in the absence of catch-up saccades that frequently occur during pursuit. Electrical microstimulation in the OPNs' area induced a strong deceleration of the eye during smooth pursuit. These results suggest that OPNs form an inhibitory mechanism that could control the time course of smooth pursuit. This inhibitory mechanism is part of the fixation system and is probably needed to avoid reflexive eye movements toward targets that are not purposefully selected. This study shows that saccades and smooth pursuit, although they are different kinds of eye movements, are controlled by the same inhibitory system.

A quantitative analysis of the correlations between eye movements and neural activity in the pretectum.

The study of the saccadic system has focused mainly on neurons active before the beginning of saccades, in order to determine their contribution in movement planning and execution. However, most oculomotor structures contain also neurons whose activity starts only after the onset of saccades, the maximum of their activity sometimes occurring near saccade end. Their characteristics are still largely unknown. We investigated pretectal neurons with saccade-related activity in the alert cat during eye movements towards a moving target. They emitted a high-frequency burst of action potentials after the onset of saccades, irrespective of their direction, and will be referred to as "pretectal saccade-related neurons". The delay between saccade onset and cell activity varied from 17 to 66 ms on average. We found that burst parameters were correlated with the parameters of saccades; the peak eye velocity was correlated with the peak of the spike density function, the saccade amplitude with the number of spikes in the burst, and burst duration increased with saccade duration. The activity of six pretectal saccade-related neurons was studied during smooth pursuit at different velocities. A correlation was found between smooth pursuit velocity and mean firing rate. A minority of these neurons (2/6) were also visually responsive. Their visual activity was proportional to the difference between eye and target velocity during smooth pursuit (retinal slip). These results indicate that the activity of pretectal saccade-related neurons is correlated with the characteristics of eye movements. This finding is in agreement with the known anatomical projections from premotor regions of the saccadic system to the pretectum.

Facilitation of smooth pursuit initiation by electrical stimulation in the supplementary eye fields.

The role of the supplementary eye fields (SEF) during smooth pursuit was investigated with electrical microstimulation. We found that stimulation in the SEF increased the acceleration and velocity of the eyes in the direction of target motion during smooth pursuit initiation but not during sustained pursuit. The increase in eye velocity during initiation will be referred to as pursuit facilitation and was observed at sites where saccades could not be evoked with the same stimulation parameters. On average, electrical stimulation increased eye velocity by approximately 20%. At most sites, the threshold for a significant facilitation was 50 microA with a stimulation frequency of 300 Hz. Facilitation of pursuit initiation depended on the timing of stimulation trains. The effect was most pronounced if the stimulation was delivered before smooth pursuit initiation. On average, eye velocity in stimulation trials increased linearly as a function of eye velocity in control trials, and this function had a slope greater than one, suggesting a multiplicative influence of the stimulation. Stimulation during a fixation task did not evoke smooth eye movements. The latency of catch-up saccades was increased during facilitation, but their accuracy was not affected. Saccades toward stationary targets were not affected by the stimulation. The results are further evidence that the SEF plays a role in smooth pursuit in addition to its known role in saccade planning and suggest that this role may be to control the gain of smooth pursuit during initiation. The covariance between pursuit facilitation and the timing of the catch-up saccade as a result of stimulation suggests that these different eye movements systems are coordinated to achieve a common goal.

Role of retinal slip in the prediction of target motion during smooth and saccadic pursuit.

Visual tracking of moving targets requires the combination of smooth pursuit eye movements with catch-up saccades. In primates, catch-up saccades usually take place only during pursuit initiation because pursuit gain is close to unity. This contrasts with the lower and more variable gain of smooth pursuit in cats, where smooth eye movements are intermingled with catch-up saccades during steady-state pursuit. In this paper, we studied in detail the role of retinal slip in the prediction of target motion during smooth and saccadic pursuit in the cat. We found that the typical pattern of pursuit in the cat was a combination of smooth eye movements with saccades. During smooth pursuit initiation, there was a correlation between peak eye acceleration and target velocity. During pursuit maintenance, eye velocity oscillated at approximately 3 Hz around a steady-state value. The average gain of smooth pursuit was approximately 0.5. Trained cats were able to continue pursuing in the absence of a visible target, suggesting a role of the prediction of future target motion in this species. The analysis of catch-up saccades showed that the smooth-pursuit motor command is added to the saccadic command during catch-up saccades and that both position error and retinal slip are taken into account in their programming. The influence of retinal slip on catch-up saccades showed that prediction about future target motion is used in the programming of catch-up saccades. Altogether, these results suggest that pursuit systems in primates and cats are qualitatively similar, with a lower average gain in the cat and that prediction affects both saccades and smooth eye movements during pursuit.

Activity of mesencephalic vertical burst neurons during saccades and smooth pursuit.

The activity of vertical burst neurons (BNs) was recorded in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF-BNs) and in the interstitial nucleus of Cajal (NIC-BNs) in head-restrained cats while performing saccades or smooth pursuit. BNs emitted a high-frequency burst of action potentials before and during vertical saccades. On average, these bursts led saccade onset by 14 +/- 4 ms (mean +/- SD, n = 23), and this value was in the range of latencies ( approximately 5-15 ms) of medium-lead burst neurons (MLBNs). All NIC-BNs (n = 15) had a downward preferred direction, whereas riMLF-BNs showed either a downward (n = 3) or an upward (n = 5) preferred direction. We found significant correlations between saccade and burst parameters in all BNs: vertical amplitude was correlated with the number of spikes, maximum vertical velocity with maximum of the spike density, and saccade duration with burst duration. A correlation was also found between instantaneous vertical velocity and neuronal activity during saccades. During fixation, all riMLF-BNs and approximately 50% of NIC-BNs (7/15) were silent. Among NIC-BNs active during fixation (8/15), only two cells had an activity correlated with the eye position in the orbit. During smooth pursuit, most riMLF-BNs were silent (7/8), but all NIC-BNs showed an activity that was significantly correlated with the eye velocity. This activity was unaltered during temporary disappearance of the visual target, demonstrating that it was not visual in origin. For a given neuron, its ON-direction during smooth pursuit and saccades remained identical. The activity of NIC-BNs during both saccades and smooth pursuit can be described by a nonlinear exponential function using the velocity of the eye as independent variable. We suggest that riMLF-BNs, which were not active during smooth pursuit, are vertical MLBNs responsible for the generation of vertical saccades. Because NIC-BNs discharged during both saccades and pursuit, they cannot be regarded as MLBNs as usually defined. NIC-BNs could, however, be the site of convergence of both the saccadic and smooth pursuit signals at the premotoneuronal level. Alternatively, NIC-BNs could participate in the integration of eye velocity to eye position signals and represent input neurons to a common integrator.

Difference between visually and electrically evoked gaze saccades disclosed by altering the head moment of inertia.

Differences between gaze shifts evoked by collicular electrical stimulation and those triggered by the presentation of a visual stimulus were studied in head-free cats by increasing the head moment of inertia. This maneuver modified the dynamics of these two types of gaze shifts by slowing down head movements. Such an increase in the head moment of inertia did not affect the metrics of visually evoked gaze saccades because their duration was precisely adjusted to compensate for these changes in movement dynamics. In contrast, the duration of electrically evoked gaze shifts remained constant irrespective of the head moment of inertia, and therefore their amplitude was significantly reduced. These results suggest that visually and electrically evoked gaze saccades are controlled by different mechanisms. Whereas the accuracy of visually evoked saccades is likely to be assured by on-line feedback information, the absence of duration adjustment in electrically evoked gaze shifts suggests that feedback information necessary to maintain their metrics is not accessible or is corrupted during collicular stimulation. This is of great importance when these two types of movements are compared to infer the role of the superior colliculus in the control of orienting gaze shifts.

Shape interactions in macaque inferior temporal neurons.

Missal et al. observed that the responses of inferior temporal (IT) neurons to a shape were reduced markedly when this shape partially overlapped a larger second shape, suggesting that shape interactions determine IT responses. In the present study, we compared the responses of IT neurons with combinations of two shapes which did or did not overlap and studied the effect of the relative and absolute positions of the two shapes. In a first test, a preferred shape (figure) was presented at the fixation point while a second, nonpreferred, shape was displayed either in the background of the figure (overlap) or at one of four peripheral positions (nonoverlap). Controls consisted of presentations of either shape in isolation at each of the five positions. The stimuli were presented during a fixation task. The responses to these combinations of two shapes were, on average, reduced compared with those elicited by the preferred shape presented in isolation. This suppression occurred whether or not the two shapes overlapped, but the degree of suppression in the overlap and nonoverlap conditions did not correlate. These interactions were stronger when the interacting stimulus was located in the contralateral compared with the ipsilateral hemifield. The position of the interacting stimulus within a hemifield significantly affected the suppression associated with combined shapes in some neurons. The strength of the interactions of the two nonoverlapping shapes depended on the shape of the interacting stimulus in half of the neurons. In a second test, the preferred shape and interacting stimulus could appear either at the fixation point or at one eccentric position. Here we found that the suppression was, on average, strongest when the interacting stimulus, rather than the preferred shape, was presented at the fixation position. Also, in 40% of the neurons, the response reduction was similar in overlap and nonoverlap conditions if effects of stimulus position were taken into account. In both tests, we also measured the responses to combinations of a nonpreferred shape and the interacting stimulus and showed that the response to a combination of two nonpreferred shapes was, in general, smaller than the response to a combination of the preferred and nonpreferred shape. Overall the results indicate that stimulus interactions in the receptive fields of IT neurons can be position and shape selective; this can contribute to the coding for the relationships between object parts.

Responses of macaque inferior temporal neurons to overlapping shapes.

We tested whether macaque inferior temporal neurons can signal the presence of their preferred shape independently of other shapes simultaneously present, by comparing the responses and selectivity of TE neurons to shapes (figures), either presented in isolation or overlapping another shape (background). The two overlapping shapes differed in color or texture and thus were easily segmentable. We found that the response and selectivity of TE neurons to the figure can be dramatically altered, most commonly reduced, when the figure is overlapping the background. This reduction in response was also present when the monkey was required to actively discriminate the figures from varying backgrounds during recording. The level of suppression depended on the shape of the background and on whether or not figure and background can be discriminated. These results indicate that responses of TE cells are not only determined by the properties of the figures but also are influenced by the properties of stimuli in the background.

Smooth eye movements evoked by electrical stimulation of the cat's superior colliculus.

Head-fixed gaze shifts were evoked by electrical stimulation of the deeper layers of the cat superior colliculus (SC). After a short latency, saccades were triggered with kinematics similar to those of visually guided saccades. When electrical stimulation was maintained for more than 150-200 ms, postsaccadic smooth eye movements (SEMs) were observed. These movements were characterized by a period of approximately constant velocity following the evoked saccade. Depending on electrode position, a single saccade followed by a slow displacement or a "staircase" of saccades interspersed by SEMs were evoked. Mean velocity decreased with increasing deviation of the eye in the orbit in the direction of the movement. In the situation where a single evoked saccade was followed by a smooth movement, the duration of the latter depended on the duration of the stimulation train. In the situation where evoked saccades converged towards a restricted region of the visual field ("goal"-directed or craniocentric saccades), the SEMs were directed towards the centre of this region and their mean velocity decreased as the eye approached the goal. The direction of induced SEMs depended on the site of stimulation, as is the case for saccadic eye movements, and was not modified by stimulation parameters ("place" code). On the other hand, mean velocity of the movements depended on the site of stimulation and on the frequency and intensity of the current ("rate" code), as reported for saccades in the cat. The kinematics of these postsaccadic SEMs are similar to the kinematics of slow, postsaccadic correction observed during visually triggered gaze shifts of the alert cat. These results support the hypothesis that the SC is not exclusively implicated in the control of fast refixation of gaze but also in controlling postsaccadic conjugate slow eye movements in the cat.

Evidence for high-velocity smooth pursuit in the trained cat.

It is generally accepted that in cats smooth pursuit velocity of the eye never exceeds a few degrees per second. This is in contrast with observations in primates, where smooth pursuit velocity can reach values as high as 100 degrees/s. Cats were trained to fixate and pursue spots of light appearing on a translucent screen. Spots were moved in the horizontal and vertical planes at different constant velocities up to 80%. Eye position was recorded with the scleral search coil technique. Naive cats did not pursue moving targets with high efficiency. Smooth eye movement velocity saturated at 5 degrees/s. After a few days of training, smooth-pursuit eye velocity increased with target velocity and saturated at 25 degrees/s on average. However, velocities twice as high have been observed frequently. When the target was unexpectedly extinguished, smooth eye movement velocity dropped to values close to 0 degree/s in approximately 350 ms. After a short training period (usually 5 times the same target presentation), the eye continued to move smoothly until the target reappeared. These data suggest that smooth pursuit eye movements of the cat are qualitatively similar to those of primates, but reach lower velocities and are more variable in their characteristics.

Modeling slow correcting gaze movements.

Recent experimental results show evidence for the corrective role of postsaccadic drifts. This paper addresses the modeling of these slow correcting gaze movements (SCMs). Classical arguments to explain drifts are presented, both in the head fixed condition (pulse-step mismatch) and in the head free condition (vestibulo-ocular reflex (VOR)). The most significant behavioral and electrophysiological experimental data related to SCMs are then briefly reported, with the conclusion that SCMs have a clear corrective role, incompatible with classical explanations of drifts. Based on these experimental data, existing models of the saccadic system are then compared. A theoretical comparison of the classical Robinson model with an alternative model is proposed. Two possible (slow and fast) pathways involved in the control of SCMs are examined, and simulation results are presented. Finally, the discussion addresses the observed species differences in SCMs. The link between natural SCMs and electrical SC stimulations, and the interactions between saccades, VOR, and SCMs are also discussed.

Slow correcting eye movements of head-fixed, trained cats toward stationary targets.

Inspection of eye saccades made by head-fixed, trained cats revealed the existence of many eye shifts at an approximately constant velocity during the deceleratory phase of the saccade or at the end of it. Slow eye movements occurring at the end of a saccade are usually referred to as "postsaccadic drifts". It is shown that the duration and mean velocity of these "drifts" are related to the amplitude of the movement. The kinematics of these slow eye movements are nevertheless different from those of saccades. Slow movements at the end of the gaze shift have longer durations than those occurring during the intersaccadic interval between a saccade and a reacceleration of the eye. A closer study of the drifts of three trained cats showed that they play an important corrective role in reducing the residual error at the end of a saccade or during an intersaccadic interval. This functional corrective role was demonstrated by relating the amplitude of the slow movement to the amplitude of the residual error when the slow velocity eye shift began. It is therefore proposed to name these eye shifts "slow correcting movements".