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1.  Distinctive Features of Saccadic Intrusions and Microsaccades in Progressive Supranuclear Palsy 
The eyes do not stay perfectly still during attempted fixation; fixational eye movements and saccadic intrusions (SIs) continuously change the position of gaze. The most common type of SI, square-wave jerk (SWJ), consists of saccade pairs that appear purely horizontal on clinical inspection: the first saccade moves the eye away from the fixation target and, after a short interval, the second saccade brings it back towards the target. SWJs are prevalent in certain neurological disorders, including progressive supranuclear palsy (PSP). Here we developed an objective method to identify SWJs. We found that SWJs are more frequent, larger and more markedly horizontal in PSP patients than in healthy human subjects. Further, the loss of a vertical component in fixational saccades and SWJs was the eye movement feature that best distinguished PSP patients from controls. We moreover determined that in PSP patients and controls, the larger the saccade the more likely it was part of a SWJ. Further, saccades produced by PSP patients had equivalent properties whether they were part of a SWJ or not, suggesting that normal fixational saccades (microsaccades) are rare in PSP. We propose that fixational saccades and SIs are generated by the same neural circuit, and that, both in PSP patients and in controls, SWJs result from a coupling mechanism that generates a second corrective saccade shortly after a large fixation saccade. Due to brainstem and/or cerebellum impairment, fixational saccades in PSP are abnormally large, and thus more likely to trigger a corrective saccade, giving rise to SWJs.
doi:10.1523/JNEUROSCI.2600-10.2011
PMCID: PMC3111217  PMID: 21430139
Fixational eye movements; microsaccades; saccadic palsy; square wave jerks; parkinsonian disorders
2.  The Disturbance of Gaze in Progressive Supranuclear Palsy: Implications for Pathogenesis 
Progressive supranuclear palsy (PSP) is a disease of later life that is currently regarded as a form of neurodegenerative tauopathy. Disturbance of gaze is a cardinal clinical feature of PSP that often helps clinicians to establish the diagnosis. Since the neurobiology of gaze control is now well understood, it is possible to use eye movements as investigational tools to understand aspects of the pathogenesis of PSP. In this review, we summarize each disorder of gaze control that occurs in PSP, drawing on our studies of 50 patients, and on reports from other laboratories that have measured the disturbances of eye movements. When these gaze disorders are approached by considering each functional class of eye movements and its neurobiological basis, a distinct pattern of eye movement deficits emerges that provides insight into the pathogenesis of PSP. Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free. Taken with the prominent early feature of falls, these findings suggest that PSP tauopathy impairs a recently evolved neural system concerned with bipedal locomotion in an erect posture and frequent gaze shifts between the distant environment and proximate hands. This approach provides a conceptual framework that can be used to address the nosological challenge posed by overlapping clinical and neuropathological features of neurodegenerative tauopathies.
doi:10.3389/fneur.2010.00147
PMCID: PMC3008928  PMID: 21188269
saccades; vergence; vestibular; parkinsonian disorders; tauopathy
3.  Validation of mobile eye-tracking as novel and efficient means for differentiating progressive supranuclear palsy from Parkinson's disease 
Background: The decreased ability to carry out vertical saccades is a key symptom of Progressive Supranuclear Palsy (PSP). Objective measurement devices can help to reliably detect subtle eye movement disturbances to improve sensitivity and specificity of the clinical diagnosis. The present study aims at transferring findings from restricted stationary video-oculography (VOG) to a wearable head-mounted device, which can be readily applied in clinical practice. Methods: We investigated the eye movements in 10 possible or probable PSP patients, 11 Parkinson's disease (PD) patients, and 10 age-matched healthy controls (HCs) using a mobile, gaze-driven video camera setup (EyeSeeCam). Ocular movements were analyzed during a standardized fixation protocol and in an unrestricted real-life scenario while walking along a corridor. Results: The EyeSeeCam detected prominent impairment of both saccade velocity and amplitude in PSP patients, differentiating them from PD and HCs. Differences were particularly evident for saccades in the vertical plane, and stronger for saccades than for other eye movements. Differences were more pronounced during the standardized protocol than in the real-life scenario. Conclusions: Combined analysis of saccade velocity and saccade amplitude during the fixation protocol with the EyeSeeCam provides a simple, rapid (<20 s), and reliable tool to differentiate clinically established PSP patients from PD and HCs. As such, our findings prepare the ground for using wearable eye-tracking in patients with uncertain diagnoses.
doi:10.3389/fnbeh.2012.00088
PMCID: PMC3521127  PMID: 23248593
progressive supranuclear palsy; mobile eye-tracking; eye movements; Parkinson's disease; video-oculography
4.  Whipple's disease mimicking progressive supranuclear palsy: the diagnostic value of eye movement recording 
Treatable causes of parkinsonian syndromes are rare; Whipple's disease is one of them. A patient is described who presented with a parkinsonian syndrome and abnormal vertical gaze. Measurement of eye movements showed marked slowing of upward saccades, moderate slowing of downward saccades, a full range of voluntary vertical eye movements, curved trajectories of oblique saccades, and absence of square wave jerks. These features, atypical of progressive supranuclear palsy, suggested the diagnosis of Whipple's disease, which was subsequently confirmed by polymerase chain reaction analysis of intestinal biopsy material. Precise measurement of the dynamic properties of saccadic eye movements in parkinsonian patients may provide a means of identifying treatable disorders.


PMCID: PMC1736291  PMID: 10201431
5.  Oblique Gaze Shifts: Head Movements Reveal New Aspects of Component Coupling 
Progress in brain research  2008;171:323-330.
When the head is prevented from moving, it has been clearly demonstrated that the horizontal and vertical components of oblique saccades are not independently produced. The duration of the smaller of the two components is stretched in time to match the duration of the larger component. Several hypotheses have been proposed and each can account for the observed interaction between horizontal and vertical saccade components. When the head is free to move, gaze shifts can be accomplished by combining eye and head movements. During repeated gaze shifts of the same amplitude, as head contribution increases, saccade amplitude declines but saccade duration increases. Thus, the expected relationship between duration and amplitude of saccadic eye movements can be reversed. We have used this altered relationship to determine whether the duration of the vertical saccade component is affected by the amplitude or the duration of the horizontal component. We find that the relative amplitudes of horizontal and vertical saccades cannot account for the observed temporal stretching: vertical component duration increases despite a decrease in the amplitude of the horizontal component. These results are likely inconsistent with models that rely on calculating the vector or relative component amplitudes to account for component stretching.
doi:10.1016/S0079-6123(08)00647-X
PMCID: PMC2605951  PMID: 18718321
6.  Abnormalities of optokinetic nystagmus in progressive supranuclear palsy 
Objectives: To measure vertical and horizontal responses to optokinetic (OK) stimulation and investigate directional abnormalities of quick phases in progressive supranuclear palsy (PSP).
Methods: Saccades and OK nystagmus were studied in six PSP patients, five with Parkinson's disease (PD), and 10 controls. The OK stimulus subtended 72° horizontally, 60° vertically, consisted of black and white stripes, and moved at 10–50°/s.
Results: All PSP patients showed slowed voluntary vertical saccades and nystagmus quick phases compared with PD or controls. Small, paired, horizontal saccadic intrusions (SWJ) were more frequent and larger in PSP during fixation. Vertical saccades were transiently faster at the time of SWJ and horizontal saccades in PSP. During vertical OK nystagmus, small quick phases were often combined with horizontal SWJ in all subjects; in PSP the vector was closer to horizontal. Vertical OK slow phase gain was reduced in PSP but, in most PD patients, was similar to normals. The average position of gaze shifted in the direction of vertical OK stimulus in PSP patients with preserved slow phase responses but impaired quick phases.
Conclusions: Vertical OK responses in PSP show impaired slow phase responses, and quick phases that are slowed and combined with SWJ to produce an oblique vector. SWJ facilitate vertical saccades and quick phases in PSP, but it is unclear whether this is an adaptive process or a result of the disease. A large OK stimulus is useful to induce responses that can be quantitatively analysed in patients with limited voluntary range of vertical gaze.
doi:10.1136/jnnp.2003.027367
PMCID: PMC1738726  PMID: 15377682
7.  Three-dimensional kinematics of saccadic and pursuit eye movements in humans: relationship between Donders’ and Listing’s laws 
Vision Research  2012;60:7-15.
For Listing’s law to be obeyed during eye movements, the “half-angle rule” must be satisfied: the eye velocity axis must tilt away from Listing’s plane by half the angle of eye position eccentricity from primary position. We aimed to determine if this rule is satisfied during horizontal and vertical pursuit compared with saccades. Three-dimensional (3-d) eye rotation data were acquired from five normal head-fixed humans using the search coil technique. Saccades were recorded in response to 40° horizontal or vertical steps in target position, at different elevations and azimuths. Pursuit was recorded while tracking a target moving horizontally or vertically at 20°/s, with peak-to-peak amplitude of 40°, at the same elevations and azimuths. First- and second-order surfaces were fitted to 3-d eye position data from periods of fixation. In all subjects, eye positions did not lie on a planar surface, but on a twisted surface in 3-d space. The tilt-angle coefficient (TAC) during saccades and pursuit was calculated as the ratio of the angle of eye velocity axis tilt to the angle of eye position eccentricity. During horizontal saccades and pursuit, mean TACs were 0.58 and 0.64, respectively. During vertical saccades and pursuit, mean TACs were 0.35 and 0.43, respectively, and lower than their horizontal counterparts (p<0.05). These findings suggest that Listing’s law is not perfectly satisfied during saccades or pursuit. On the basis of model simulations, we propose that the discrepancy in horizontal and vertical TACs causes eye positions to lie on a twisted rather than a planar surface.
doi:10.1016/j.visres.2012.02.012
PMCID: PMC3345270  PMID: 22406307
Saccades; Smooth Pursuit; Kinematics; Listing’s Law; Donders’ Law
8.  The Saccadic and Neurological Deficits in Type 3 Gaucher Disease 
PLoS ONE  2011;6(7):e22410.
Our objective was to characterize the saccadic eye movements in patients with type 3 Gaucher disease (chronic neuronopathic) in relationship to neurological and neurophysiological abnormalities. For approximately 4 years, we prospectively followed a cohort of 15 patients with Gaucher type 3, ages 8–28 years, by measuring saccadic eye movements using the scleral search coil method. We found that patients with type 3 Gaucher disease had a significantly higher regression slope of duration vs amplitude and peak duration vs amplitude compared to healthy controls for both horizontal and vertical saccades. Saccadic latency was significantly increased for horizontal saccades only. Downward saccades were more affected than upward saccades. Saccade abnormalities increased over time in some patients reflecting the slowly progressive nature of the disease. Phase plane plots showed individually characteristic patterns of abnormal saccade trajectories. Oculo-manual dexterity scores on the Purdue Pegboard test were low in virtually all patients, even in those with normal cognitive function. Vertical saccade peak duration vs amplitude slope significantly correlated with IQ and with the performance on the Purdue Pegboard but not with the brainstem and somatosensory evoked potentials. We conclude that, in patients with Gaucher disease type 3, saccadic eye movements and oculo-manual dexterity are representative neurological functions for longitudinal studies and can probably be used as endpoints for therapeutic clinical trials.
Trial Registration
ClinicalTrials.gov NCT00001289
doi:10.1371/journal.pone.0022410
PMCID: PMC3140522  PMID: 21799847
9.  Dissociated effects of botulinum toxin chemodenervation on ocular deviation and saccade dynamics in chronic lateral rectus palsy 
AIM—Changes in saccade velocity/amplitude characteristics (main sequence) and attenuation of distance esotropia in response to botulinum toxin (BTX-A) chemodenervation of the antagonist medial rectus were studied in a group of nine patients with chronic lateral rectus palsy.
METHODS—Serial measurements of ocular deviation and infrared oculograms of saccadic eye movements to targets at 5°-20° of lateral gaze were made before injection and at 2, 4, 8, 16, and 20 weeks after injection.
RESULTS—At 2 weeks after injection, the ocular deviation changed by a mean of 34.5 prism dioptres and the 5° and 10° adduction saccades were significantly slowed (p<0.02 Wilcoxon signed rank test). By the second examination, however, the adducting saccade peak velocity had returned to normal while the mean ocular deviation remained significantly changed (p=0.01 Wilcoxon matched pairs). By 20 weeks the mean ocular deviation was not significantly different from that before injection (p=0.14 matched pairs).
CONCLUSIONS—The ocular realignment caused by BTX-A may persist after saccadic function has been restored. This may be because toxin may have a more profound and long lasting effect on the orbital singly innervated fibres which are active tonically at rest to hold gaze whereas there is relative sparing of the additional motor units recruited during fast eye movements.

 Keywords: lateral rectus palsy; botulinum toxin; saccades
PMCID: PMC1722334  PMID: 9536885
10.  Oculomotor function in frontotemporal lobar degeneration, related disorders and Alzheimer's disease 
Brain  2008;131(5):1268-1281.
Frontotemporal lobar degeneration (FTLD) often overlaps clinically with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), both of which have prominent eye movement abnormalities. To investigate the ability of oculomotor performance to differentiate between FTLD, Alzheimer's disease, CBS and PSP, saccades and smooth pursuit were measured in three FTLD subtypes, including 24 individuals with frontotemporal dementia (FTD), 19 with semantic dementia (SD) and six with progressive non-fluent aphasia (PA), as compared to 28 individuals with Alzheimer's disease, 15 with CBS, 10 with PSP and 27 control subjects. Different combinations of oculomotor abnormalities were identified in all clinical syndromes except for SD, which had oculomotor performance that was indistinguishable from age-matched controls. Only PSP patients displayed abnormalities in saccade velocity, whereas abnormalities in saccade gain were observed in PSP > CBS > Alzheimer's disease subjects. All patient groups except those with SD were impaired on the anti-saccade task, however only the FTLD subjects and not Alzheimer's disease, CBS or PSP groups, were able to spontaneously self-correct anti-saccade errors as well as controls. Receiver operating characteristic statistics demonstrated that oculomotor findings were superior to neuropsychological tests in differentiating PSP from other disorders, and comparable to neuropsychological tests in differentiating the other patient groups. These data suggest that oculomotor assessment may aid in the diagnosis of FTLD and related disorders.
doi:10.1093/brain/awn047
PMCID: PMC2367697  PMID: 18362099
oculomotor; frontotemporal lobar degeneration; corticobasal syndrome; progressive supranuclear palsy; Alzheimer's disease
11.  Eccentric head positions reveal disorders of conjugate eye movement. 
The effect of head position on conjugate horizontal gaze was studied in healthy adults, in patients with multiple sclerosis without eye movement signs, and in patients with downbeat nystagmus indicative of low brain stem lesions. Displacements of gaze from primary position to 30 degrees left and right were recorded using the electro-oculogram, with the head in the primary position, and turned voluntarily to the left and right (in yaw). The quality of eye movements was noted and peak velocities of saccades were measured. The head turning test trebled the incidence of abnormal eye movements found in the multiple sclerosis patients and increased it by tenfold in the patients with downbeat nystagmus. Disorders of eye movement were also found in approximately 20--30% of healthy subjects tested. Weakness of abduction was the most common eye movement defect and appeared to be posterior internuclear ophthalmoplegia. A hypothesis is made which unifies the theoretical explanations of anterior and posterior internuclear ophthalmoplegia. The most likely cause of the disorders of eye movement observed is vertebrobasilar ischaemia induced by stretching and compression of the vertebral arteries during eccentric head posture.
Images
PMCID: PMC492883  PMID: 591979
12.  Saccadic velocity measurements in strabismus. 
Traditional evaluation of strabismus has included cover test measurements, evaluation of the range of ocular rotations, and an array of subjective sensory tests. These studies could not always differentiate paresis of an extraocular muscle from restrictions and from various neuro-ophthalmic motility disorders. The measurement of horizontal and vertical saccadic movements can provide an objective test of rectus muscle function. Using EOG, saccades can be recorded easily, inexpensively, and repeatably at any age. In ocular muscle paresis or paralysis, saccadic speed is reduced mildly to markedly and can be used to monitor recovery. Assessment of saccadic velocity does not appear useful in evaluating superior oblique palsy, although it is valuable in sixth nerve palsy, Duane's syndrome, and third nerve palsy. When restrictions are the major cause of limited rotation, as in thyroid ophthalmopathy and orbital floor fracture, saccadic speed is unaffected. The induction of OKN or vestibular nystagmus is helpful in the study of children too young to perform voluntary saccadic movements. In patients with limitation of elevation or depression, this technique can separate innervational from mechanical causes of diminished rotation. The specific saccadic velocity pattern in myasthenia gravis, progressive external ophthalmoplegia, internuclear ophthalmoplegia, and Möbius' syndrome is helpful in differentiating these disorders from other neuroophthalmic motility problems. Transposition surgery of the rectus muscle is effective because of an increase in force, seen as an improvement in saccadic velocity and resulting from the change of insertion of the muscles. Saccadic velocities can also be of assistance in diagnosing a lost or disinserted muscle following surgery for strabismus. Although analysis of saccadic velocity is not required for the proper evaluation of all problems in strabismus and motility, it can be of inestimable value in the diagnosis of many complex and confusing disorders. Together with forced duction testing, a clinical profile can be obtained concerning muscle force and muscle and orbital restrictions, which are required information for appropriate surgical planning.
Images
PMCID: PMC1312465  PMID: 6676980
13.  The Saccadic Re-Centering Bias is Associated with Activity Changes in the Human Superior Colliculus 
Being able to effectively explore our visual world is of fundamental importance, and it has been suggested that the straight-ahead gaze (primary position) might play a special role in this context. We employed fMRI in humans to investigate how neural activity might be modulated for saccades relative to this putative default position. Using an endogenous cueing paradigm, saccade direction and orbital starting position were systematically manipulated, resulting in saccades toward primary position (centripetal) and away from primary position (centrifugal) that were matched in amplitude, directional predictability, as well as orbital starting position. In accord with earlier research, we found that fMRI activity in the superior colliculus (SC), as well as in the frontal eye fields and the intraparietal sulcus, was enhanced contralateral to saccade direction across all saccade conditions. Furthermore, the SC exhibited a relative activity decrease during re-centering relative to centrifugal saccades, a pattern that was paralleled by faster saccadic reaction times. In contrast, activity within the cortical eye fields was not significantly modulated during re-centering saccades as compared to other saccade types, suggesting that the re-centering bias is predominantly implemented at a subcortical rather than cortical processing stage. Such a modulation might reflect a special coding bias facilitating the return of gaze to a default position in the gaze space in which retinotopic and egocentric reference frames are aligned and from which the visual world can be effectively explored.
doi:10.3389/fnhum.2010.00193
PMCID: PMC2987555  PMID: 21103010
superior colliculus; fMRI; eye movement; re-centering bias; cortical eye fields
14.  TMS perturbs saccade trajectories and unmasks an internal feedback controller for saccades 
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.
doi:10.1523/JNEUROSCI.1584-11.2011
PMCID: PMC3167087  PMID: 21832184
saccade accuracy; pause; TMS; startle; omnipause neuron; forward model
15.  Interactions between gaze-evoked blinks and gaze shifts in monkeys 
Rapid eyelid closure, or a blink, often accompanies head-restrained and head-unrestrained gaze shifts. This study examines the interactions between such gaze-evoked blinks and gaze shifts in monkeys. Blink probability increased with gaze amplitude and at a faster rate for head-unrestrained movements. Across animals, blink likelihood was inversely correlated with the average gaze velocity of large amplitude control movements. Gaze-evoked blinks induce robust perturbations in eye velocity. Peak and average velocities are reduced, duration is increased, but accuracy is preserved. The temporal features of the perturbation depend on factors such as the time of blink relative to gaze onset, inherent velocity kinematics of control movements, and perhaps initial eye-in-head positions. Although variable across animals, the initial effect is a reduction in eye velocity, followed by a reacceleration that yields two or more peaks in its waveform. Interestingly, head velocity is not attenuated; instead, it peaks slightly later and with a larger magnitude. Gaze latency is slightly reduced on trials with gaze-evoked blinks, although the effect was more variable during head-unrestrained movements, and no reduction in head latency was observed. Preliminary data also demonstrated a similar perturbation of gaze-evoked blinks during vertical saccades. The results are compared with previously reported effects of reflexive blinks (evoked by air-puff delivered to one eye or supra-orbital ridge stimulation) and discussed in terms of effects of blinks on saccadic suppression, neural correlates of the altered eye velocity signals, and implications on the hypothesis that the attenuation in eye velocity is produced by a head movement command.
doi:10.1007/s00221-011-2937-z
PMCID: PMC3262917  PMID: 22083094
16.  Selective Defects of Visual Tracking in Progressive Supranuclear Palsy (PSP): Implications for mechanisms of motion vision 
Vision research  2010;50(8):761-771.
Smooth ocular tracking of a moving visual stimulus comprises a range of responses that encompass the ocular following response (OFR), a pre-attentive, short-latency mechanism, and smooth pursuit, which directs the retinal fovea at the moving stimulus. In order to determine how interdependent these two forms of ocular tracking are, we studied vertical OFR in progressive supranuclear palsy (PSP), a parkinsonian disorder in which vertical smooth pursuit is known to be impaired. We measured eye movements of 9 patients with PSP and 12 healthy control subjects. Subjects viewed vertically moving sine-wave gratings that had a temporal frequency of 16.7 Hz, contrast of 32%, and spatial frequencies of 0.17, 0.27 or 0.44 cycles/°. We measured OFR amplitude as change in eye position in the 70 – 150 ms, open-loop interval following stimulus onset. Vertical smooth pursuit was studied as subjects attempted to track a 0.27 cycles/° grating moving sinusoidally through several cycles at frequencies between 0.1 – 2.5 Hz. We found that OFR amplitude, and its dependence on spatial frequency, was similar in PSP patients (group mean 0.10°) and control subjects (0.11°), but the latency to onset of OFR was greater for PSP patients (group mean 99 ms) than control subjects (90 ms). When OFR amplitude was re-measured, taking into account the increased latency in PSP patients, there was still no difference from control subjects. We confirmed that smooth pursuit was consistently impaired in PSP; group mean tracking gain at 0.7 Hz was 0.29 for PSP patients and 0.63 for controls. Neither PSP patients nor control subjects showed any correlation between OFR amplitude and smooth-pursuit gain. We propose that OFR is spared because it is generated by low-level motion processing that is dependent on posterior cerebral cortex, which is less affected in PSP. Conversely, smooth pursuit depends more on projections from frontal cortex to the pontine nuclei, both of which are involved in PSP. The accessory optic pathway, which is heavily involved in PSP, seems unlikely to contribute to the OFR in humans.
doi:10.1016/j.visres.2010.01.017
PMCID: PMC2846391  PMID: 20123108
Smooth pursuit; ocular following response; pontine nuclei; tau protein
17.  The role of the medial longitudinal fasciculus in horizontal gaze: tests of current hypotheses for saccade-vergence interactions 
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.
doi:10.1007/s00221-010-2485-y
PMCID: PMC3039121  PMID: 21082311
Eye movements; Saccades; Vergence; Medial longitudinal fasciculus; Hering’s law; Multiple sclerosis; Internuclear ophthalmoplegia
18.  Saccadic Adaptation to Moving Targets 
PLoS ONE  2012;7(6):e39708.
Saccades are so called ballistic movements which are executed without online visual feedback. After each saccade the saccadic motor plan is modified in response to post-saccadic feedback with the mechanism of saccadic adaptation. The post-saccadic feedback is provided by the retinal position of the target after the saccade. If the target moves after the saccade, gaze may follow the moving target. In that case, the eyes are controlled by the pursuit system, a system that controls smooth eye movements. Although these two systems have in the past been considered as mostly independent, recent lines of research point towards many interactions between them. We were interested in the question if saccade amplitude adaptation is induced when the target moves smoothly after the saccade. Prior studies of saccadic adaptation have considered intra-saccadic target steps as learning signals. In the present study, the intra-saccadic target step of the McLaughlin paradigm of saccadic adaptation was replaced by target movement, and a post-saccadic pursuit of the target. We found that saccadic adaptation occurred in this situation, a further indication of an interaction of the saccadic system and the pursuit system with the aim of optimized eye movements.
doi:10.1371/journal.pone.0039708
PMCID: PMC3387193  PMID: 22768109
19.  Learning the Optimal Control of Coordinated Eye and Head Movements 
PLoS Computational Biology  2011;7(11):e1002253.
Various optimality principles have been proposed to explain the characteristics of coordinated eye and head movements during visual orienting behavior. At the same time, researchers have suggested several neural models to underly the generation of saccades, but these do not include online learning as a mechanism of optimization. Here, we suggest an open-loop neural controller with a local adaptation mechanism that minimizes a proposed cost function. Simulations show that the characteristics of coordinated eye and head movements generated by this model match the experimental data in many aspects, including the relationship between amplitude, duration and peak velocity in head-restrained and the relative contribution of eye and head to the total gaze shift in head-free conditions. Our model is a first step towards bringing together an optimality principle and an incremental local learning mechanism into a unified control scheme for coordinated eye and head movements.
Author Summary
Human beings and many other species redirect their gaze towards targets of interest through rapid gaze shifts known as saccades. These are made approximately three to four times every second, and larger saccades result from fast and concurrent movement of the animal's eyes and head. Experimental studies have revealed that during saccades, the motor system follows certain principles such as respecting a specific relationship between the relative contribution of eye and head motor systems to total gaze shift. Various researchers have hypothesized that these principles are implications of some optimality criteria in the brain, but it remains unclear how the brain can learn such an optimal behavior. We propose a new model that uses a plausible learning mechanism to satisfy an optimality criterion. We show that after learning, the model is able to reproduce motor behavior with biologically plausible properties. In addition, it predicts the nature of the learning signals. Further experimental research is necessary to test the validity of our model.
doi:10.1371/journal.pcbi.1002253
PMCID: PMC3207939  PMID: 22072953
20.  Pathological torsional eye deviation during voluntary saccades: a violation of Listing's law. 
BACKGROUND: Under normal conditions, there are no torsional eye movements during voluntary saccades when the head is stationary (Listing's law). METHODS AND RESULTS: Using dual search coils for three dimensional eye movement recordings, a patient is reported who had direction specific rapid deviations of torsional eye position (up to 10.5 degrees) during voluntary saccades followed by a slow exponential torsional drift after the end of the saccade ("blip") towards the initial torsional eye position. In the absence of spontaneous nystagmus, this transient torsion means a violation of Listing's law for voluntary saccades and was associated with a lesion involving the cerebellar vermis, its deep nuclei, and the dorsolateral medulla. Amplitudes of the blip were larger for ipsilesional (hypermetric) than contralesional (hypometric) horizontal saccades. For comparison transient torsion during and after saccades was also examined in six normal subjects. Using the same in vivo calibration, there were no blips larger than 1.2 degrees in any of them. CONCLUSION: Transient torsion with large amplitudes can be clinically seen on bedside examination and might thus be a new clinical sign in the diagnosis of saccadic disorders.
Images
PMCID: PMC1064154  PMID: 9069480
21.  CONTRIBUTION OF THE FRONTAL EYE FIELD TO GAZE SHIFTS IN THE HEAD-UNRESTRAINED RHESUS MONKEY: NEURONAL ACTIVITY 
Neuroscience  2012;225:213-236.
The frontal eye field (FEF) has a strong influence on saccadic eye movements with the head restrained. With the head unrestrained, eye saccades combine with head movements to produce large gaze shifts, and microstimulation of the FEF evokes both eye and head movements. To test whether the dorsomedial FEF provides commands for the entire gaze shift or its separate eye and head components, we recorded extracellular single-unit activity in monkeys trained to make large head-unrestrained gaze shifts. We recorded 80 units active during gaze shifts, and closely examined 26 of these that discharged a burst of action potentials that preceded horizontal gaze movements. These units were movement or visuomovement related and most exhibited open movement fields with respect to amplitude. To reveal the relations of burst parameters to gaze, eye, and/or head movement metrics, we used behavioral dissociations of gaze, eye, and head movements and linear regression analyses. The burst number of spikes (NOS) was strongly correlated with movement amplitude and burst temporal parameters were strongly correlated with movement temporal metrics for eight gaze-related burst neurons (GBNs) and five saccade-related burst neurons (SBNs). For the remaining 13 neurons, the NOS was strongly correlated with the head movement amplitude, but burst temporal parameters were most strongly correlated with eye movement temporal metrics (head-eye-related burst neurons, HEBNs). These results suggest that FEF units do not encode a command for the unified gaze shift only; instead, different units may carry signals related to the overall gaze shift or its eye and/or head components. Moreover, the HEBNs exhibit bursts whose magnitude and timing may encode a head displacement signal and a signal that influences the timing of the eye saccade, thereby serving as a mechanism for coordinating the eye and head movements of a gaze shift.
doi:10.1016/j.neuroscience.2012.08.050
PMCID: PMC3482142  PMID: 22944386
Frontal eye field; gaze shift; unit activity; eye-head coordination; monkey
22.  Optimal Control of Saccades by Spatial-Temporal Activity Patterns in the Monkey Superior Colliculus 
PLoS Computational Biology  2012;8(5):e1002508.
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.
Author Summary
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.
doi:10.1371/journal.pcbi.1002508
PMCID: PMC3355059  PMID: 22615548
23.  Diagnosing disconjugate eye movements 
Neurology  2008;71(15):1167-1175.
Background:
Saccades are fast eye movements that conjugately shift the point of fixation between distant features of interest in the visual environment. Several disorders, affecting sites from brainstem to extraocular muscle, may cause horizontal saccades to become disconjugate. Prior techniques for detection of saccadic disconjugacy, especially in internuclear ophthalmoparesis (INO), have compared only one point in abducting vs adducting saccades, such as peak velocity.
Methods:
We applied a phase-plane technique that compared each eye’s velocity as a function of change in position (normalized displacement) in 22 patients with disease variously affecting the brainstem reticular formation, the abducens nucleus, the medial longitudinal fasciculus, the oculomotor nerve, the abducens nerve, the neuromuscular junction, or the extraocular muscles; 10 age-matched subjects served as controls.
Results:
We found three different patterns of disconjugacy throughout the course of horizontal saccades: early abnormal velocity disconjugacy during the first 10% of the displacement in patients with INO, oculomotor or abducens nerve palsy, and advanced extraocular muscle disease; late disconjugacy in patients with disease affecting the neuromuscular junction; and variable middle-course disconjugacy in patients with pontine lesions. When normal subjects made disconjugate saccades between two targets aligned on one eye, the initial part of the movement remained conjugate.
Conclusions:
Along with conventional measures of saccades, such as peak velocity, phase planes provide a useful tool to determine the site, extent, and pathogenesis of disconjugacy. We hypothesize that the pale global extraocular muscle fibers, which drive the high-acceleration component of saccades, receive a neural command that ensures initial ocular conjugacy.
GLOSSARY
= abducens;
= cranial nerve;
= chronic progressive external ophthalmoplegia;
= eye movement;
= horizontal;
= internuclear ophthalmoparesis;
= myasthenia gravis;
= medial longitudinal fasciculus;
= multiple sclerosis;
= patient;
= prediction interval;
= paramedian pontine reticular formation;
= raphe interpositus;
= vertical.
doi:10.1212/01.wnl.0000327525.72168.57
PMCID: PMC2586990  PMID: 18838664
24.  Dysphagia as a risk factor for mortality in Niemann-Pick disease type C: systematic literature review and evidence from studies with miglustat 
Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological deterioration and premature death, and has an estimated birth incidence of 1:120,000. Mutations in the NPC1 gene (in 95% of cases) and the NPC2 gene (in approximately 4% of cases) give rise to impaired intracellular lipid metabolism in a number of tissues, including the brain. Typical neurological manifestations include vertical supranuclear gaze palsy, saccadic eye movement abnormalities, cerebellar ataxia, dystonia, dysmetria, dysphagia and dysarthria. Oropharyngeal dysphagia can be particularly problematic as it can often lead to food or fluid aspiration and subsequent pneumonia. Epidemiological data suggest that bronchopneumonia subsequent to food or fluid aspiration is a major cause of mortality in NP-C and other neurodegenerative disorders. These findings indicate that a therapy capable of improving or stabilising swallowing function might reduce the risk of aspiration pneumonia, and could have a positive impact on patient survival. Miglustat, currently the only approved disease-specific therapy for NP-C in children and adults, has been shown to stabilise key neurological manifestations in NP-C, including dysphagia. In this article we present findings from a systematic literature review of published data on bronchopneumonia/aspiration pneumonia as a cause of death, and on the occurrence of dysphagia in NP-C and other neurodegenerative diseases. We then examine the potential links between dysphagia, aspiration, pneumonia and mortality with a view to assessing the possible effect of miglustat on patient lifespan.
doi:10.1186/1750-1172-7-76
PMCID: PMC3552828  PMID: 23039766
Niemann-Pick disease type C; Dysphagia; Mortality; Swallowing; Pneumonia; Aspiration; Miglustat.
25.  A Small Dorsal Pontine Infarction Presenting with Total Gaze Palsy Including Vertical Saccades and Pursuit 
A small localized infarction in the dorsal pontine area can cause various eye-movement disturbances, such as abducens palsy, horizontal conjugate gaze palsy, internuclear ophthalmoplegia, and one-and-a-half syndrome. However, complete loss of vertical saccades and pursuit with horizontal gaze palsy has not been reported previously in a patient with a small pontine lesion. We report a 67-year-old man with a small dorsal caudal pontine infarct who exhibited total horizontal gaze palsy as well as loss of vertical saccades and pursuit.
doi:10.3988/jcn.2007.3.4.208
PMCID: PMC2686940  PMID: 19513135
Ophthalmoplegia; Pontine infarction; Omnipause neurons

Results 1-25 (238417)