Saccades normally place the eye on target with one smooth movement. In late-onset Tay—Sachs (LOTS), intrasaccadic transient decelerations occur that may result from (1) premature omnipause neuron (OPN) re-activation due to malfunction of the latch circuit that inhibits OPNs for the duration of the saccade or (2) premature inhibitory burst neuron (IBN) activation due to fastigial nucleus (FN) dysregulation by the dorsal cerebellar vermis. Neuroanatomic analysis of a LOTS brain was performed. Purkinje cells were absent and gliosis of the granular cell layer was present in the dorsal cerebellar vermis. Deep cerebellar nuclei contained large inclusions. IBNs were present with small inclusions. The sample did not contain the complete OPN region; however, neurons in the OPN region contained massive inclusions. Pathologic findings suggest that premature OPN re-activation and/or inappropriate firing of IBNs may be responsible for interrupted saccades in LOTS. Cerebellar clinical dysfunction, lack of saccadic slowing, and significant loss of cerebellar cells suggest that the second cause is more likely.
fastigial nucleus; omnipause neurons; burst neurons; latch circuit; brainstem
Saccadic eye movements rapidly orient the line of sight towards the object of interest. Pre-motor burst neurons (BNs) controlling saccades receive excitation from superior colliculus and cerebellum, but inhibition by omnipause neurons (OPNs) prevents saccades. When the OPNs pause, BNs begin to fire. It has been presumed that part of the BN burst comes from post-inhibitory rebound (PIR). We hypothesized that in the absence of prior inhibition from OPNs there would be no PIR, and thus the increase in initial firing rate of BNs would be reduced. Consequently, saccade acceleration would be reduced. We measured eye movements and showed that sustained eye closure, which inhibits the activity of OPNs and thus hypothetically should weaken PIR, reduced the peak velocity, acceleration, and deceleration of saccades in healthy human subjects. Saccades under closed eyelids also had irregular trajectories; the frequency of the oscillations underlying this irregularity was similar to that of high-frequency ocular flutter (back-to-back saccades) often seen in normal subjects during attempted fixation at straight ahead while eyes are closed. Saccades and quick phases of nystagmus are generated by the same pre-motor neurons, and we found that the quick-phase velocity of nystagmus was also reduced by lid closure. These changes were not due to a mechanical hindrance to the eyes, because lid closure did not affect the peak velocities or accelerations of the eyes in the “slow-phase” response to rapid head movements of comparable speeds to those of saccades. These results indicate a role for OPNs in generating the abrupt onset and high velocities of saccades. We hypothesize that the mechanism involved is PIR in pre-motor burst neurons.
Omnipause neurons; Burst neurons; Oscillations; Ballistic movement; Post-inhibitory rebound
Saccade accuracy is maintained by adaptive mechanisms that continually modify saccade amplitude to reduce dysmetria. Previous studies suggest that adaptation occurs upstream of the caudal fastigial nucleus (CFN), the output of the oculomotor cerebellar vermis but downstream from the superior colliculus (SC). The nucleus reticularis tegmenti pontis (NRTP) is a major source of afferents to both the oculomotor vermis and the CFN and in turn receives direct input from the SC. Here we examine the activity of NRTP neurons in four rhesus monkeys during behaviorally induced changes in saccade amplitude to assess whether their discharge might reveal adaptation mechanisms that mediate changes in saccade amplitude. During amplitude decrease adaptation (average, 22%), the gradual reduction of saccade amplitude was accompanied by an increase in the number of spikes in the burst of 19/34 neurons (56%) and no change for 15 neurons (44%). For the neurons that increased their discharge, the additional spikes were added at the beginning of the saccadic burst and adaptation also delayed the peak-firing rate in some neurons. Moreover, after amplitude reduction, the movement fields changed shape in all 15 open field neurons tested. Our data show that saccadic amplitude reduction affects the number of spikes in the burst of more than half of NRTP neurons tested, primarily by increasing burst duration not frequency. Therefore adaptive changes in saccade amplitude are reflected already at a major input to the oculomotor cerebellum.
Rapid shifts of the point of visual fixation between equidistant targets require equal-sized saccades of each eye. The brainstem medial longitudinal fasciculus (MLF) plays a cardinal role in ensuring that horizontal saccades between equidistant targets are tightly yoked. Lesions of the MLF—internuclear ophthalmoparesis (INO)—cause horizontal saccades to become disjunctive: adducting saccades are slow, small, or absent. However, in INO, convergence movements may remain intact. We studied horizontal gaze shifts between equidistant targets and between far and near targets aligned on the visual axis of one eye (Müller test paradigm) in five cases of INO and five control subjects. We estimated the saccadic component of each movement by measuring peak velocity and peak acceleration. We tested whether the ratio of the saccadic component of the adducting/abducting eyes stayed constant or changed for the two types of saccades. For saccades made by control subjects between equidistant targets, the group mean ratio (±SD) of adducting/abducting peak velocity was 0.96 ± 0.07 and adducting/abducting peak acceleration was 0.94 ± 0.09. Corresponding ratios for INO cases were 0.45 ± 0.10 for peak velocity and 0.27 ± 0.11 for peak acceleration, reflecting reduced saccadic pulses for adduction. For control subjects, during the Müller paradigm, the adducting/abducting ratio was 1.25 ± 0.14 for peak velocity and 1.03 ± 0.12 for peak acceleration. Corresponding ratios for INO cases were 0.82 ± 0.18 for peak velocity and 0.48 ± 0.13 for peak acceleration. When adducting/abducting ratios during Müller versus equidistant targets paradigms were compared, INO cases showed larger relative increases for both peak velocity and peak acceleration compared with control subjects. Comparison of similar-sized movements during the two test paradigms indicated that whereas INO patients could decrease peak velocity of their abducting eye during the Müller paradigm, they were unable to modulate adducting velocity in response to viewing conditions. However, the initial component of each eye’s movement was similar in both cases, possibly reflecting activation of saccadic burst neurons. These findings support the hypothesis that horizontal saccades are governed by disjunctive signals, preceded by an initial, high-acceleration conjugate transient and followed by a slower vergence component.
Eye movements; Saccades; Vergence; Medial longitudinal fasciculus; Hering’s law; Multiple sclerosis; Internuclear ophthalmoplegia
The superior colliculus (SC) provides signals for the generation of
saccades via a direct pathway to the brain stem burst generator (BG). In
addition, it sends saccade-related activity to the BG indirectly through the
cerebellum via a relay in the nucleus reticularis tegmenti pontis (NRTP).
Lesions of the oculomotor vermis, lobules VIc and VII, and inactivation of the
caudal fastigial nucleus, the cerebellar output nucleus to which it projects,
produce saccade dysmetria but have little effect on saccade peak velocity and
duration. We expected similar deficits from inactivation of the NRTP. Instead,
injections as small as 80 nl into the NRTP first slowed ipsiversive saccades and
then gradually reduced their amplitudes. Postinjection saccades had slower peak
velocities and longer durations than preinjection saccades with similar
amplitudes. Contraversive saccades retained their normal kinematics. When the
gains of ipsiversive saccades to 10° target steps had fallen to
their lowest values (0.28 ± 0.19; mean ± SD;
n = 10 experiments), the gains of contraversive
saccades to 10° target steps had decreased very little (0.82
± 0.11). Eventually, ipsiversive saccades did not exceed
5°, even to 20° target steps. Moreover, these small
remaining saccades apparently were made with considerable difficulty because
their latencies increased substantially. When ipsiversive saccade gain was at
its lowest, the gain and kinematics of vertical saccades to 10°
target steps exhibited inconsistent changes. We argue that our injections did
not compromise the direct SC pathway. Therefore these data suggest that the
cerebellar saccade pathway does not simply modulate BG activity but is required
for horizontal saccades to occur at all.
Omnipause neurons (OPNs) within the nucleus raphe interpositus (RIP) help gate the transition between fixation and saccadic eye movements by monosynaptically suppressing activity in premotor burst neurons during fixation, and releasing them during saccades. Premotor neuron activity is initiated by excitatory input from the superior colliculus (SC), but how the tectum's saccade-related activity turns off OPNs is not known. Since the central mesencephalic reticular formation (cMRF) is a major SC target, we explored whether this nucleus has the appropriate connections to support tectal gating of OPN activity. In dual-tracer experiments undertaken in macaque monkeys (Macaca fascicularis), cMRF neurons labeled retrogradely from injections into RIP had numerous anterogradely labeled terminals closely associated with them following SC injections. This suggested the presence of an SC–cMRF–RIP pathway. Furthermore, anterograde tracers injected into the cMRF of other macaques labeled axonal terminals in RIP, confirming this cMRF projection. To determine whether the cMRF projections gate OPN activity, postembedding electron microscopic immunochemistry was performed on anterogradely labeled cMRF terminals with antibody to GABA or glycine. Of the terminals analyzed, 51.4% were GABA positive, 35.5% were GABA negative, and most contacted glycinergic cells. In summary, a trans-cMRF pathway connecting the SC to the RIP is present. This pathway contains inhibitory elements that could help gate omnipause activity and allow other tectal drives to induce the bursts of firing in premotor neurons that are necessary for saccades. The non-GABAergic cMRF terminals may derive from fixation units in the cMRF.
Current knowledge of saccade-blink interactions suggests that blinks have paradoxical effects on saccade generation. Blinks suppress saccade generation by attenuating the oculomotor drive command in structures like the superior colliculus (SC), but they also disinhibit the saccadic system by removing the potent inhibition of pontine omnipause neurons (OPNs). To better characterize these effects, we evoked the trigeminal blink reflex by delivering an air puff to one eye as saccades were evoked by sub-optimal stimulation of the SC. For every stimulation site, the peak and average velocities of stimulation with blink movements (SwBMs) were lower than stimulation-only saccades (SoMs), supporting the notion that the oculomotor drive is weakened in the presence of a blink. In contrast, the duration of the SwBMs was longer, consistent with the hypothesis that the blink-induced inhibition of the OPNs could prolong the window of time available for oculomotor commands to drive an eye movement. The amplitude of the SwBM could also be larger than the SoM amplitude obtained from the same site, particularly for cases in which blink-associated eye movements exhibited the slowest kinematics. The results are interpreted in terms of neural signatures of saccade-blink interactions.
A major challenge in computational neurobiology is to understand how populations of noisy, broadly-tuned neurons produce accurate goal-directed actions such as saccades. Saccades are high-velocity eye movements that have stereotyped, nonlinear kinematics; their duration increases with amplitude, while peak eye-velocity saturates for large saccades. Recent theories suggest that these characteristics reflect a deliberate strategy that optimizes a speed-accuracy tradeoff in the presence of signal-dependent noise in the neural control signals. Here we argue that the midbrain superior colliculus (SC), a key sensorimotor interface that contains a topographically-organized map of saccade vectors, is in an ideal position to implement such an optimization principle. Most models attribute the nonlinear saccade kinematics to saturation in the brainstem pulse generator downstream from the SC. However, there is little data to support this assumption. We now present new neurophysiological evidence for an alternative scheme, which proposes that these properties reside in the spatial-temporal dynamics of SC activity. As predicted by this scheme, we found a remarkably systematic organization in the burst properties of saccade-related neurons along the rostral-to-caudal (i.e., amplitude-coding) dimension of the SC motor map: peak firing-rates systematically decrease for cells encoding larger saccades, while burst durations and skewness increase, suggesting that this spatial gradient underlies the increase in duration and skewness of the eye velocity profiles with amplitude. We also show that all neurons in the recruited population synchronize their burst profiles, indicating that the burst-timing of each cell is determined by the planned saccade vector in which it participates, rather than by its anatomical location. Together with the observation that saccade-related SC cells indeed show signal-dependent noise, this precisely tuned organization of SC burst activity strongly supports the notion of an optimal motor-control principle embedded in the SC motor map as it fully accounts for the straight trajectories and kinematic nonlinearity of saccades.
As the fovea is the only spot on the retina with high spatial resolution, primates need to move their eyes to peripheral targets for detailed inspection. Saccades are the fastest movements of the body, and theoretical studies suggest that their trajectories are optimized to bring the fovea as fast and accurately as possible on target. Speed-accuracy optimization principles explain the stereotyped nonlinear ‘main-sequence’ relationship between saccade amplitude, duration, and peak velocity. Earlier models attributed these kinematic properties to nonlinear neural circuitry in the brainstem but this creates problems for oblique saccades. Here, we demonstrate how the brainstem can be linear, and how instead the midbrain superior colliculus (SC) could optimize saccadic speed-accuracy tradeoff. Each saccade involves the recruitment of a large population of SC neurons. We show that peak firing-rate and burst shape of the recruited cells systematically vary with their location in the SC, and that burst shapes nicely match the eye-velocity profiles. This organization of burst properties fully explains the main-sequence. Moreover, all cells synchronize their bursts, thus maximizing the total instantaneous input to the brainstem, and ensuring that oblique saccades have straight trajectories. We thus discovered a sophisticated neural mechanism underlying optimal motor control in the brain.
Individuals with autism spectrum disorder (ASD) show atypical scan paths during social interaction and when viewing faces, and recent evidence suggests that they also show abnormal saccadic eye movement dynamics and accuracy when viewing less complex and non-social stimuli. Eye movements are a uniquely promising target for studies of ASD as their spatial and temporal characteristics can be measured precisely and the brain circuits supporting them are well-defined. Control of saccade metrics is supported by discrete circuits within the cerebellum and brainstem - two brain regions implicated in magnetic resonance (MR) morphometry and histopathological studies of ASD. The functional integrity of these distinct brain systems can be examined by evaluating different parameters of visually-guided saccades.
A total of 65 participants with ASD and 43 healthy controls, matched on age (between 6 and 44-years-old), gender and nonverbal IQ made saccades to peripheral targets. To examine the influence of attentional processes, blocked gap and overlap trials were presented. We examined saccade latency, accuracy and dynamics, as well as the trial-to-trial variability of participants’ performance.
Saccades of individuals with ASD were characterized by reduced accuracy, elevated variability in accuracy across trials, and reduced peak velocity and prolonged duration. In addition, their saccades took longer to accelerate to peak velocity, with no alteration in the duration of saccade deceleration. Gap/overlap effects on saccade latencies were similar across groups, suggesting that visual orienting and attention systems are relatively spared in ASD. Age-related changes did not differ across groups.
Deficits precisely and consistently directing eye movements suggest impairment in the error-reducing function of the cerebellum in ASD. Atypical increases in the duration of movement acceleration combined with lower peak saccade velocities implicate pontine nuclei, specifically suggesting reduced excitatory activity in burst cells that drive saccades relative to inhibitory activity in omnipause cells that maintain stable fixation. Thus, our findings suggest that both cerebellar and brainstem abnormalities contribute to altered sensorimotor control in ASD.
Electronic supplementary material
The online version of this article (doi:10.1186/2040-2392-5-47) contains supplementary material, which is available to authorized users.
Autism spectrum disorder (ASD); Sensorimotor; Eye movement; Saccade; Cerebellum; Brainstem
The caudal part of the cerebellar fastigial nucleus (CFN) influences the horizontal component of saccades. Previous reports show that activity in the CFN contralateral to saccade direction aids saccade acceleration and that activity in the ipsilateral CFN aids saccade deceleration. Here we refine this description by characterizing how blocking CFN activity changes the distance that the eye rotates during each of 4 phases of saccades, the increasing and decreasing saccade acceleration (phases 1 & 2) and deceleration (3 and 4). We found that unilateral CFN inactivation increases total eye rotation to ~1.8X normal. This resulted from rotation increases in all four phases of ipsiversive saccades. Rotation during phases 1 and 2 increases slightly, more during phase 3, and most during phase 4, to ~4.4X normal. Thus, the ipsilateral CFN normally reduces eye rotation throughout a saccade but reduces it the most near saccade end. After unilateral CFN inactivation, rotation during contraversive saccades was ~0.8X normal. This resulted from decreased rotation during phases 1–3, to ~0.7X normal, and then normal rotation during phase 4. Thus the CFN contraversive to saccade direction normally increases eye rotation during acceleration and the first phase of deceleration. These data indicate that the influences of the CFNs on saccades overlap extensively and that there is a smooth shift from predominance of the contralateral CFN early in a saccade to the ipsilateral CFN later. The pathway from the CFN to contralateral IBNs and then to the abducens nucleus can account for these effects.
saccades; caudal fastigial nucleus; muscimol; monkey; fastigial oculomotor region
The anatomy and neurophysiology of the saccadic eye movement system have been well studied, but the roles of certain key neurons in this system are not fully appreciated. Important clues about the functional interactions in the saccadic system can be gleaned from the histochemistry of different saccadic neurons. The most prominent inhibitory neurons in the circuit are the omnidirectional pause neurons (OPN), which inhibit the premotor burst neurons that drive the eye. Most inhibitory neurons in the brain transmit γ-aminobutyric acid (GABA), but OPN transmit glycine (Gly). It is interesting to ask whether the saccadic system would work any differently if OPN were GABA-ergic. Gly and GABA receptors both provide a channel for a hyperpolarizing Cl- current that inhibits its target neuron. Depolarizing currents that excite the neurons come through several channels, including the NMDA receptor (NMDAR). The NMDAR is unique among receptors in that it has active sites for two different neurotransmitters, glutamate (Glu) and Gly. Gly is a co-agonist that acts to amplify the current produced by Glu. We have proposed a model of the saccadic brain stem circuitry that exploits this dual role of Gly to produce both inhibition of the saccadic circuit during fixation, and to increase its responsiveness, or gain, during movements. This suggests that OPNs act more as a regulator of the saccadic circuit’s gain, rather than as a gate for allowing saccades. We propose a new hypothesis: the OPNs play a general role as a modulator of arousal in orienting subsystems, such as saccades, pursuit, head movements, etc.
glycine; burst neurons; brainstem; saccades
A neural network model of biophysical neurons in the midbrain is presented to drive a muscle fiber oculomotor plant during horizontal monkey saccades. Neural circuitry, including omnipause neuron, premotor excitatory and inhibitory burst neurons, long lead burst neuron, tonic neuron, interneuron, abducens nucleus, and oculomotor nucleus, is developed to examine saccade dynamics. The time-optimal control strategy by realization of agonist and antagonist controller models is investigated. In consequence, each agonist muscle fiber is stimulated by an agonist neuron, while an antagonist muscle fiber is unstimulated by a pause and step from the antagonist neuron. It is concluded that the neural network is constrained by a minimum duration of the agonist pulse and that the most dominant factor in determining the saccade magnitude is the number of active neurons for the small saccades. For the large saccades, however, the duration of agonist burst firing significantly affects the control of saccades. The proposed saccadic circuitry establishes a complete model of saccade generation since it not only includes the neural circuits at both the premotor and motor stages of the saccade generator, but also uses a time-optimal controller to yield the desired saccade magnitude.
Prefrontal neurons exhibit saccade-related activity and pre-saccadic memory-related activity often encodes the directions of forthcoming eye movements, in line with demonstrated prefrontal contribution to flexible control of voluntary eye movements. However, many prefrontal neurons exhibit post-saccadic activity that is initiated well after the initiation of eye movement. Although post-saccadic activity has been observed in the frontal eye field, this activity is thought to be a corollary discharge from oculomotor centers, because this activity shows no directional tuning and is observed whenever the monkeys perform eye movements regardless of goal-directed or not. However, prefrontal post-saccadic activities exhibit directional tunings similar as pre-saccadic activities and show context dependency, such that post-saccadic activity is observed only when monkeys perform goal-directed saccades. Context-dependency of prefrontal post-saccadic activity suggests that this activity is not a result of corollary signals from oculomotor centers, but contributes to other functions of the prefrontal cortex. One function might be the termination of memory-related activity after a behavioral response is done. This is supported by the observation that the termination of memory-related activity coincides with the initiation of post-saccadic activity in population analyses of prefrontal activities. The termination of memory-related activity at the end of the trial ensures that the subjects can prepare to receive new and updated information. Another function might be the monitoring of behavioral performance, since the termination of memory-related activity by post-saccadic activity could be associated with informing the correctness of the response and the termination of the trial. However, further studies are needed to examine the characteristics of saccade-related activities in the prefrontal cortex and their functions in eye movement control and a variety of cognitive functions.
prefrontal cortex; saccadic eye movement; post-saccadic activity; context dependency; directional selectivity; frontal eye field
The ocular motor system provides several advantages for studying the brain, including well-defined populations of neurons that contribute to specific eye movements. Generation of rapid eye movements (saccades) depends on excitatory burst neurons (EBNs) and omnipause neurons (OPNs) within the brain stem; both types of cell are highly active. Experimental lesions of EBNs and OPNs cause slowing or complete loss of saccades. We report a patient who developed a permanent, selective saccadic palsy following cardiac surgery. When she died several years later, surprisingly, autopsy showed preservation of EBNs and OPNs. We therefore considered other mechanisms that could explain her saccadic palsy. Recent work has shown that both EBNs and OPNs are ensheathed by perineuronal nets (PNs), which are specialized extracellular matrix structures that may help stabilize synaptic contacts, promote local ion homeostasis, or play a protective role in certain highly active neurons. Here, we review the possibility that damage to PNs, rather than to the neurons they support, could lead to neuronal dysfunction—such as saccadic palsy. We also suggest how future studies could test this hypothesis, which may provide insights into the vulnerability of other active neurons in the nervous system that depend on PNs.
supranuclear gaze palsy; omnipause neurons; burst neurons; PPRF; RIMLF; eye movements
Perception of our visual environment strongly depends on saccadic eye movements, which in turn are calibrated by saccadic adaptation mechanisms elicited by systematic movement errors. Current models of saccadic adaptation assume that visual error signals are acquired only after saccade completion, because the high speed of saccade execution disturbs visual processing (saccadic “suppression” and “mislocalization”). Complementing a previous study from our group, here we report that visual information presented during saccades can drive adaptation mechanisms and we further determine the critical time window of such error processing. In 15 healthy volunteers, shortening adaptation of reactive saccades toward a ±8° visual target was induced by flashing the target for 2 ms less eccentrically than its initial location either near saccade peak velocity (“PV” condition) or peak deceleration (“PD”) or saccade termination (“END”). Results showed that, as compared to the “CONTROL” condition (target flashed at its initial location upon saccade termination), saccade amplitude decreased all throughout the “PD” and “END” conditions, reaching significant levels in the second adaptation and post-adaptation blocks. The results of nine other subjects tested in a saccade lengthening adaptation paradigm with the target flashing near peak deceleration (“PD” and “CONTROL” conditions) revealed no significant change of gain, confirming that saccade shortening adaptation is easier to elicit. Also, together with this last result, the stable gain observed in the “CONTROL” conditions of both experiments suggests that mislocalization of the target flash is not responsible for the saccade shortening adaptation demonstrated in the first group. Altogether, these findings reveal that the visual “suppression” and “mislocalization” phenomena related to saccade execution do not prevent brief visual information delivered “in-flight” from being processed to elicit oculomotor adaptation.
eye movements; sensorimotor integration; adaptation; error processing; mislocalization; saccadic suppression
When normal subjects fix their eyes upon a stationary target, their gaze is not perfectly still, due to small movements that prevent visual fading. Visual loss is known to cause greater instability of gaze, but reported comparisons with normal subjects using reliable measurement techniques are few. We measured binocular gaze using the magnetic search coil technique during attempted fixation (monocular or binocular viewing) of 4 individuals with childhood-onset of monocular visual loss, 2 individuals with late-onset monocular visual loss due to age-related macular degeneration, 2 individuals with bilateral visual loss, and 20 healthy control subjects. We also measured saccades to visual or somatosensory cues. We tested the hypothesis that gaze instability following visual impairment is caused by loss of inputs that normally optimize the performance of the neural network (integrator), which ensures both monocular and conjugate gaze stability. During binocular viewing, patients with early-onset monocular loss of vision showed greater instability of vertical gaze in the eye with visual loss and, to a lesser extent, in the normal eye, compared with control subjects. These vertical eye drifts were much more disjunctive than upward saccades. In individuals with late monocular visual loss, gaze stability was more similar to control subjects. Bilateral visual loss caused eye drifts that were larger than following monocular visual loss or in control subjects. Accurate saccades could be made to somatosensory cues by an individual with acquired blindness, but voluntary saccades were absent in an individual with congenital blindness. We conclude that the neural gaze-stabilizing network, which contains neurons with both binocular and monocular discharge preferences, is under adaptive visual control. Whereas monocular visual loss causes disjunctive gaze instability, binocular blindness causes both disjunctive and conjugate gaze instability (drifts and nystagmus). Inputs that bypass this neural network, such as projections to motoneurons for upward saccades, remain conjugate.
Perineuronal nets (PN) form a specialized extracellular matrix around certain highly active neurons within the central nervous system and may help to stabilize synaptic contacts, promote local ion homeostasis, or play a protective role. Within the ocular motor system, excitatory burst neurons and omnipause neurons are highly active cells that generate rapid eye movements – saccades; both groups of neurons contain the calcium-binding protein parvalbumin and are ensheathed by PN. Experimental lesions of excitatory burst neurons and omnipause neurons cause slowing or complete loss of saccades. Selective palsy of saccades in humans is reported following cardiac surgery, but such cases have shown normal brainstem neuroimaging, with only one clinicopathological study that demonstrated paramedian pontine infarction. Our objective was to test the hypothesis that lesions of PN surrounding these brainstem saccade-related neurons may cause saccadic palsy.
Together with four controls we studied the brain of a patient who had developed a permanent selective saccadic palsy following cardiac surgery and died several years later. Sections of formalin-fixed paraffin-embedded brainstem blocks were applied to double-immunoperoxidase staining of parvalbumin and three different components of PN. Triple immunofluorescence labeling for all PN components served as internal controls. Combined immunostaining of parvalbumin and synaptophysin revealed the presence of synapses.
Excitatory burst neurons and omnipause neurons were preserved and still received synaptic input, but their surrounding PN showed severe loss or fragmentation.
Our findings support current models and experimental studies of the brainstem saccade-generating neurons and indicate that damage to PN may permanently impair the function of these neurons that the PN ensheathe. How a postulated hypoxic mechanism could selectively damage the PN remains unclear. We propose that the well-studied saccadic eye movement system provides an accessible model to evaluate the role of PN in health and disease.
The cerebellum plays an important role in programming accurate saccades. Cerebellar lesions affecting the ocular motor region of the fastigial nucleus (FOR) cause saccadic hypermetria; however, if a second target is presented before a saccade can be initiated (double-step paradigm), saccade hypermetria may be decreased. We tested the hypothesis that the cerebellum, especially FOR, plays a pivotal role in programming sequences of saccades. We studied patients with saccadic hypermetria due either to genetic cerebellar ataxia or surgical lesions affecting FOR and confirmed that the gain of initial saccades made to double-step stimuli was reduced compared with the gain of saccades to single target jumps. Based on measurements of the intersaccadic interval, we found that the ability to perform parallel processing of saccades was reduced or absent in all of our patients with cerebellar disease. Our results support the crucial role of the cerebellum, especially FOR, in programming sequences of saccades.
fastigial nucleus; double-step; saccade; latency; spinocerebellar ataxia; hypermetria; parallel processing
Eye movements create an ever-changing image of the world on the retina. In
particular, frequent saccades call for a compensatory mechanism to transform the
changing visual information into a stable percept. To this end, the brain
presumably uses internal copies of motor commands. Electrophysiological
recordings of visual neurons in the primate lateral intraparietal cortex, the
frontal eye fields, and the superior colliculus suggest that the receptive
fields (RFs) of special neurons shift towards their post-saccadic positions
before the onset of a saccade. However, the perceptual consequences of these
shifts remain controversial. We wanted to test in humans whether a remapping of
motion adaptation occurs in visual perception.
The motion aftereffect (MAE) occurs after viewing of a moving stimulus as an
apparent movement to the opposite direction. We designed a saccade paradigm
suitable for revealing pre-saccadic remapping of the MAE. Indeed, a transfer of
motion adaptation from pre-saccadic to post-saccadic position could be observed
when subjects prepared saccades. In the remapping condition, the strength of the
MAE was comparable to the effect measured in a control condition
(33±7% vs. 27±4%). Contrary, after a saccade or
without saccade planning, the MAE was weak or absent when adaptation and test
stimulus were located at different retinal locations, i.e. the effect was
Regarding visual cognition, our study reveals for the first time predictive
remapping of the MAE but no spatiotopic transfer across saccades. Since the
cortical sites involved in motion adaptation in primates are most likely the
primary visual cortex and the middle temporal area (MT/V5) corresponding to
human MT, our results suggest that pre-saccadic remapping extends to these
areas, which have been associated with strict retinotopy and therefore with
classical RF organization. The pre-saccadic transfer of visual features
demonstrated here may be a crucial determinant for a stable percept despite
When we applied a single pulse of transcranial magnetic stimulation (TMS) to any part of the human head during a saccadic eye movement, the ongoing eye velocity was reduced starting as early as 45ms after the TMS, and lasted around 32ms. The perturbation to the saccade trajectory was not due to a mechanical effect of the lid on the eye (e.g., from blinks). When the saccade involved coordinated movements of both the eyes and the lids, e.g., in vertical saccades, TMS produced a synchronized inhibition of the motor commands to both eye and lid muscles. The TMS induced perturbation of the eye trajectory did not show habituation with repetition, and was present in both pro- and anti-saccades. Despite the perturbation, the eye trajectory was corrected within the same saccade with compensatory motor commands that guided the eyes to the target. This within-saccade correction did not rely on visual input, suggesting that the brain monitored the oculomotor commands as the saccade unfolded, maintained a real time estimate of the position of the eyes, and corrected for the perturbation. TMS disrupted saccades regardless of the location of the coil on the head, suggesting that the coil discharge engages a non-habituating startle-like reflex system. This system affects ongoing motor commands upstream of the oculomotor neurons, possibly at the level of the superior colliculus or omnipause neurons. Therefore, a TMS pulse centrally perturbs saccadic motor commands, which are monitored possibly via efference copy, and are corrected via internal feedback.
saccade accuracy; pause; TMS; startle; omnipause neuron; forward model
Neurons in the brainstem nucleus locus ceruleus (LC) often exhibit phasic activation in the context of simple sensory-motor tasks. The functional role of this activation, which leads to the release of norepinephrine throughout the brain, is not yet understood in part because the conditions under which it occurs remain in question. Early studies focused on the relationship of LC phasic activation to salient sensory events, whereas more recent work has emphasized its timing relative to goal-directed behavioral responses, possibly representing the end of a sensory-motor decision process. To better understand the relationship between LC phasic activation and sensory, motor, and decision processing, we recorded spiking activity of neurons in the LC+ (LC and the adjacent, norepinephrine-containing subceruleus nucleus) of monkeys performing a countermanding task. The task required the monkeys to occasionally withhold planned, saccadic eye movements to a visual target. We found that many well isolated LC+ units responded to both the onset of the visual cue instructing the monkey to initiate the saccade and again after saccade onset, even when it was initiated erroneously in the presence of a stop signal. Many of these neurons did not respond to saccades made outside of the task context. In contrast, neither the appearance of the stop signal nor the successful withholding of the saccade elicited an LC+ response. Therefore, LC+ phasic activation encodes sensory and motor events related to decisions to execute, but not withhold, movements, implying a functional role in goal-directed actions, but not necessarily more covert forms of processing.
countermanding; norepinephrine; saccade
When goal-directed movements are inaccurate, two responses are generated by the brain: a fast motor correction toward the target and an adaptive motor recalibration developing progressively across subsequent trials. For the saccadic system, there is a clear dissociation between the fast motor correction (corrective saccade production) and the adaptive motor recalibration (primary saccade modification). Error signals used to trigger corrective saccades and to induce adaptation are based on post-saccadic visual feedback. The goal of this study was to determine if similar or different error signals are involved in saccadic adaptation and in corrective saccade generation. Saccadic accuracy was experimentally altered by systematically displacing the visual target during motor execution. Post-saccadic error signals were studied by manipulating visual information in two ways. First, the duration of the displaced target after primary saccade termination was set at 15, 50, 100 or 800 ms in different adaptation sessions. Second, in some sessions, the displaced target was followed by a visual mask that interfered with visual processing. Because they rely on different mechanisms, the adaptation of reactive saccades and the adaptation of voluntary saccades were both evaluated. We found that saccadic adaptation and corrective saccade production were both affected by the manipulations of post-saccadic visual information, but in different ways. This first finding suggests that different types of error signal processing are involved in the induction of these two motor corrections. Interestingly, voluntary saccades required a longer duration of post-saccadic target presentation to reach the same amount of adaptation as reactive saccades. Finally, the visual mask interfered with the production of corrective saccades only during the voluntary saccades adaptation task. These last observations suggest that post-saccadic perception depends on the previously performed action and that the differences between saccade categories of motor correction and adaptation occur at an early level of visual processing.
Frequent oulomotricity problems with orthoptic testing were reported in patients with tinnitus. This study examines with objective recordings vergence eye movements in patients with somatic tinnitus patients with ability to modify their subjective tinnitus percept by various movements, such as jaw, neck, eye movements or skin pressure.
Vergence eye movements were recorded with the Eyelink II video system in 15 (23–63 years) control adults and 19 (36–62 years) subjects with somatic tinnitus.
1) Accuracy of divergence but not of convergence was lower in subjects with somatic tinnitus than in control subjects. 2) Vergence duration was longer and peak velocity was lower in subjects with somatic tinnitus than in control subjects. 3) The number of embedded saccades and the amplitude of saccades coinciding with the peak velocity of vergence were higher for tinnitus subjects. Yet, saccades did not increase peak velocity of vergence for tinnitus subjects, but they did so for controls. 4) In contrast, there was no significant difference of vergence latency between these two groups.
The results suggest dysfunction of vergence areas involving cortical-brainstem-cerebellar circuits. We hypothesize that central auditory dysfunction related to tinnitus percept could trigger mild cerebellar-brainstem dysfunction or that tinnitus and vergence dysfunction could both be manifestations of mild cortical-brainstem-cerebellar syndrome reflecting abnormal cross-modality interactions between vergence eye movements and auditory signals.
To describe an unusual form of acquired ocular motor apraxia.
Case reports with electronic eye movement recordings.
Three patients had surgery to repair aortic root or arch dissections or aneurysms. A few days after surgery, all had ophthalmoplegia. Neuro-ophthalmic examination found complete absence of horizontal and vertical volitional and reflex saccades in 1 patient and slow, hypometric saccades in 2 others. However, smooth pursuit, slow phases of optokinetic nystagmus, and the vestibulo-ocular response (VOR) were intact. Fast phases of the VOR were absent in 2 patients but were intact in the other. Video and electronic eye movement recordings documented the findings. Magnetic resonance imaging (MRI) in 1 patient showed small infarcts in a cerebellar hemisphere, pons, and cerebral hemispheres. The other patients’ MRIs showed no significant lesions.
Acquired ocular motor apraxia with profoundly impaired volitional saccades after aortic surgery is a distinctive syndrome, but its pathophysiology is unclear. Studies of neurologic damage in animals and patients undergoing similar surgical procedures provide conflicting data. However, knowledge about the complex neural pathways generating saccades from animal and human studies, and detailed clinical observations, as in the patients described here, can help to determine the location of lesions. Based on the 3 cases reported here, we propose that this syndrome might be due to damage to excitatory burst and/or omnipause neurons in the brainstem or by damage to pathways from the frontal eye fields to the brainstem.
The paramedian pontine reticular formation contains the premotoneuronal cell groups that constitute the saccadic burst generator and control saccadic eye movements. Despite years of study and numerous investigations, the rostral portion of this area has received comparatively little attention, particularly the cell type known as long-lead burst neurons (LLBNs). Several hypotheses about the functional role of LLBNs in saccade generation have been proposed, although there is little information with which to assess them. To address this issue, I mapped and recorded LLBNs in the rostral pons to measure their discharge characteristics and correlate those characteristics with the metrics of the concurrent saccades. On the basis of their discharge and location, I identified three types of LLBNs in the rostral pons: excitatory (eLLBN), dorsal (dLLBN), and nucleus reticularis tegmenti pontis (nrtp) LLBNs. The eLLBNs, encountered throughout the pons, discharge for ipsilateral saccades in proportion to saccade amplitude, velocity, and duration. The dLLBNs, found at the pontomesencephalic junction, discharge maximally for ipsilateral saccades of a particular amplitude, usually <10°, and are not associated with a particular anatomical nucleus. The nrtp LLBNs, previously described as vector LLBNs, discharge for saccades of a particular direction and sometimes a particular amplitude. The discharge of the eLLBNs suggests they drive motor neurons. The anatomical projections of the nrtp LLBNs suggest that their involvement in saccade production is less direct. The discharge of dLLBNs is consistent with a role in providing the “trigger” signal that initiates saccades.