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1.  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
2.  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
3.  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
4.  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
5.  Kinematics of Vertical Saccades during the Yaw Vestibulo-ocular Reflex in Humans 
Purpose
Listing’s law (LL) constrains the rotational axes of saccades and pursuit eye movements to Listing’s plane (LP). In the velocity domain, LL is ordinarily equivalent to a tilt in the ocular velocity axis equal to half the change in eye position, giving a tilt angle ratio (TAR) of 0.5. This study was undertaken to investigate vertical saccade behavior after the yaw vestibulo-ocular reflex (VOR) had driven eye torsion out of LP, an initial condition causing the position and velocity domain formulations of LL to differ.
Methods
Binocular eye and head motions were recorded with magnetic search coils in eight humans. With the head immobile, LP was determined for each eye, and mean TAR was 0.50 ± 0.07 (mean ± SD) for horizontal and 0.45 ± 0.11 for vertical saccades. The VOR was evoked by transient, whole-body yaw at 2800 deg/s2 peak acceleration, capable of evoking large, uninterrupted VOR slow phases. Before rotation, subjects viewed a target at eye level, 20° up, or 20° down. In two thirds of the trials, the target moved upward or downward at systematically varying times, triggering a vertical saccade during the horizontal VOR slow phase.
Results
Because the head rotation axis was generally misaligned with LP, the eye averaged 3.6° out of LP at vertical saccade onset. During the saccade, eye position continued to depart LP by an average 0.8°. The horizontal TAR at saccade onset was 0.29 ± 0.07. At peak saccade velocity 35 ± 3 ms later, the vertical TAR was 0.45 ± 0.07, statistically similar to that of head fixed saccades. Saccades did not return to LP.
Conclusions
Although they did not observe the position domain formulation of LL, vertical saccades, during the VOR, observed the half-angle velocity domain formulation of LL.
doi:10.1167/iovs.05-0147
PMCID: PMC1876708  PMID: 16043853
6.  Central ocular motor disorders, including gaze palsy and nystagmus 
Journal of Neurology  2014;261(Suppl 2):542-558.
An impairment of eye movements, or nystagmus, is seen in many diseases of the central nervous system, in particular those affecting the brainstem and cerebellum, as well as in those of the vestibular system. The key to diagnosis is a systematic clinical examination of the different types of eye movements, including: eye position, range of eye movements, smooth pursuit, saccades, gaze-holding function and optokinetic nystagmus, as well as testing for the different types of nystagmus (e.g., central fixation nystagmus or peripheral vestibular nystagmus). Depending on the time course of the signs and symptoms, eye movements often indicate a specific underlying cause (e.g., stroke or neurodegenerative or metabolic disorders). A detailed knowledge of the anatomy and physiology of eye movements enables the physician to localize the disturbance to a specific area in the brainstem (midbrain, pons or medulla) or cerebellum (in particular the flocculus). For example, isolated dysfunction of vertical eye movements is due to a midbrain lesion affecting the rostral interstitial nucleus of the medial longitudinal fascicle, with impaired vertical saccades only, the interstitial nucleus of Cajal or the posterior commissure; common causes with an acute onset are an infarction or bleeding in the upper midbrain or in patients with chronic progressive supranuclear palsy (PSP) and Niemann–Pick type C (NP-C). Isolated dysfunction of horizontal saccades is due to a pontine lesion affecting the paramedian pontine reticular formation due, for instance, to brainstem bleeding, glioma or Gaucher disease type 3; an impairment of horizontal and vertical saccades is found in later stages of PSP, NP-C and Gaucher disease type 3. Gaze-evoked nystagmus (GEN) in all directions indicates a cerebellar dysfunction and can have multiple causes such as drugs, in particular antiepileptics, chronic alcohol abuse, neurodegenerative cerebellar disorders or cerebellar ataxias; purely vertical GEN is due to a midbrain lesion, while purely horizontal GEN is due to a pontomedullary lesion. The pathognomonic clinical sign of internuclear ophthalmoplegia is an impaired adduction while testing horizontal saccades on the side of the lesion in the ipsilateral medial longitudinal fascicule. The most common pathological types of central nystagmus are downbeat nystagmus (DBN) and upbeat nystagmus (UBN). DBN is generally due to cerebellar dysfunction affecting the flocculus bilaterally (e.g., due to a neurodegenerative disease). Treatment options exist for a few disorders: miglustat for NP-C and aminopyridines for DBN and UBN. It is therefore particularly important to identify treatable cases with these conditions.
doi:10.1007/s00415-014-7385-9
PMCID: PMC4141156  PMID: 25145891
Ocular motor; Examination; Neurodegenerative disorder; Diagnosis; Treatment
7.  Coordination of the Eyes and Head during Visual Orienting 
Changing the direction of the line of sight is essential for the visual exploration of our environment. When the head does not move, re-orientation of the visual axis is accomplished with high velocity, conjugate movements of the eyes known as saccades. Our understanding of the neural mechanisms that control saccadic eye movements has advanced rapidly as specific hypotheses have been developed, evaluated and sometimes rejected on the basis of new observations. Constraints on new hypotheses and new tests of existing models have often arisen from the careful assessment of behavioral observations. The definition of the set of features (or rules) of saccadic eye movements was critical in the development of hypotheses of their neural control.
When the head is free to move, changes in the direction of the line of sight can involve simultaneous saccadic eye movements and movements of the head. When the head moves in conjunction with the eyes to accomplish these shifts in gaze direction, the rules that helped define head-restrained saccadic eye movements are altered. For example, the slope relationship between duration and amplitude for saccadic eye movements is reversed (the slope is negative) during gaze shifts of similar amplitude initiated with the eyes in different orbital positions. Modifications to the hypotheses developed in head-restrained subjects may be needed to account for these new observations. This review briefly recounts features of head-restrained saccadic eye movements, and then describes some of the characteristics of coordinated eye-head movements that have led to development of new hypotheses describing the mechanisms of gaze shift control.
doi:10.1007/s00221-008-1504-8
PMCID: PMC2605952  PMID: 18704387
8.  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
9.  Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer’s disease 
Archives of neurology  2012;69(4):509-517.
Objective
Deficits in the generation and control of saccades have been described in clinically-defined frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses, we sought to determine the saccade abnormalities associated with autopsy-defined cases of FTLD and AD.
Participants and design
An infrared eye tracker was used to record visually guided saccades to ten degree targets and antisaccades in 28 autopsy-confirmed FTD and 10 AD subjects, an average of 35.6 ± 10 months prior to death and 27 age-matched normal controls (NC). 12 FTD subjects had FTLD-TDP pathology, 15 had FTLD-tau pathology and one showed FTLD-FUS pathology. Receiver operating curve (ROC) statistics were used to determine diagnostic value of oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry (VBM).
Results
All FTD and AD subjects were impaired relative to NC on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually-guided saccade abnormalities. AD cases displayed prominent increases in horizontal saccade latency that differentiated them from FTD cases. Impairments in velocity and gain were most severe in individuals with Progressive Supranuclear Palsy (PSP) but were also present in other tauopathies. Vertical and horizontal saccade velocity and gain were able to differentiate PSP cases from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume.
Conclusion
Decreased visually-guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of PSP.
doi:10.1001/archneurol.2011.1021
PMCID: PMC3423186  PMID: 22491196
Frontotemporal Dementia; Corticobasal Degeneration; Progressive Supranuclear Palsy; Ocular Motility
10.  Visual Exploration during Locomotion Limited by Fear of Heights 
PLoS ONE  2014;9(8):e105906.
Background
Visual exploration of the surroundings during locomotion at heights has not yet been investigated in subjects suffering from fear of heights.
Methods
Eye and head movements were recorded separately in 16 subjects susceptible to fear of heights and in 16 non-susceptible controls while walking on an emergency escape balcony 20 meters above ground level. Participants wore mobile infrared eye-tracking goggles with a head-fixed scene camera and integrated 6-degrees-of-freedom inertial sensors for recording head movements. Video recordings of the subjects were simultaneously made to correlate gaze and gait behavior.
Results
Susceptibles exhibited a limited visual exploration of the surroundings, particularly the depth. Head movements were significantly reduced in all three planes (yaw, pitch, and roll) with less vertical head oscillations, whereas total eye movements (saccade amplitudes, frequencies, fixation durations) did not differ from those of controls. However, there was an anisotropy, with a preference for the vertical as opposed to the horizontal direction of saccades. Comparison of eye and head movement histograms and the resulting gaze-in-space revealed a smaller total area of visual exploration, which was mainly directed straight ahead and covered vertically an area from the horizon to the ground in front of the feet. This gaze behavior was associated with a slow, cautious gait.
Conclusions
The visual exploration of the surroundings by susceptibles to fear of heights differs during locomotion at heights from the earlier investigated behavior of standing still and looking from a balcony. During locomotion, anisotropy of gaze-in-space shows a preference for the vertical as opposed to the horizontal direction during stance. Avoiding looking into the abyss may reduce anxiety in both conditions; exploration of the “vertical strip” in the heading direction is beneficial for visual control of balance and avoidance of obstacles during locomotion.
doi:10.1371/journal.pone.0105906
PMCID: PMC4148313  PMID: 25165822
11.  Axis of Eye Rotation Changes with Head-Pitch Orientation during Head Impulses about Earth-Vertical 
The goal of this study was to assess how the axis of head rotation, Listing's law, and eye position influence the axis of eye rotation during brief, rapid head rotations. We specifically asked how the axis of eye rotation during the initial angular vestibuloocular reflex (VOR) changed when the pitch orientation of the head relative to Earth-vertical was varied, but the initial position of the eye in the orbit and the orientation of Listing's plane with respect to the head were fixed. We measured three-dimensional eye and head rotation axes in eight normal humans using the search coil technique during head-and-trunk (whole-body) and head-on-trunk (head-only) “impulses” about an Earth-vertical axis. The head was initially oriented at one of five pitch angles (30° nose down, 15° nose down, 0°, 15° nose up, 30° nose up). The fixation target was always aligned with the nasooccipital axis. Whole-body impulses were passive, unpredictable, manual, rotations with peak-amplitude of ∼20°, peak-velocity of ∼80°/s, and peak-acceleration of ∼1000°/s2. Head-only impulses were also passive, unpredictable, manual, rotations with peak-amplitude of ∼20°, peak-velocity of ∼150°/s, and peak-acceleration of ∼3000°/s2. During whole-body impulses, the axis of eye rotation tilted in the same direction, and by an amount proportional (0.51 ± 0.09), to the starting pitch head orientation (P < 0.05). This proportionality constant decreased slightly to 0.39 ± 0.08 (P < 0.05) during head-only impulses. Using the head-only impulse data, with the head pitched up, we showed that only 50% of the tilt in the axis of eye rotation could be predicted from vectorial summation of the gains (eye velocity/head velocity) obtained for rotations about the pure yaw and roll head axes. Thus, even when the orientation of Listing's plane and eye position in the orbit are fixed, the axis of eye rotation during the VOR reflects a compromise between the requirements of Listing's law and a perfectly compensatory VOR.
doi:10.1007/s10162-006-0029-8
PMCID: PMC2504578  PMID: 16552499
vestibuloocular reflex; axis of eye rotation; axis of head rotation; torsion; Listing's law
12.  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
13.  Horizontal Saccade Disconjugacy in Strabismic Monkeys 
Purpose
Previous studies have shown that binocular coordination during saccadic eye movement is affected in humans with large strabismus. The purpose of this study was to examine the conjugacy of saccadic eye movements in monkeys with sensory strabismus.
Methods
The authors recorded binocular eye movements in four strabismic monkeys and one unaffected monkey. Strabismus was induced by first occluding one eye for 24 hours, switching the occluder to the fellow eye for the next 24 hours, and repeating this pattern of daily alternating monocular occlusion for the first 4 to 6 months of life. Horizontal saccades were measured during monocular viewing when the animals were 2 to 3 years of age.
Results
Horizontal saccade testing during monocular viewing showed that the amplitude of saccades in the nonviewing eye was usually different from that in the viewing eye (saccade disconjugacy). The amount of saccade disconjugacy varied among animals as a function of the degree of ocular misalignment as measured in primary gaze. Saccade disconjugacy also increased with eccentric orbital positions of the nonviewing eye. If the saccade disconjugacy was large, there was an immediate postsaccadic drift for less than 200 ms. The control animal showed none of these effects.
Conclusions
As do humans with large strabismus, strabismic monkey display disconjugate saccadic eye movements. Saccade disconjugacy varies with orbital position and increases as a function of ocular misalignment as measured in primary gaze. This type of sensory-induced strabismus serves as a useful animal model to investigate the neural or mechanical factors responsible for saccade disconjugacy observed in humans with strabismus.
doi:10.1167/iovs.06-0955
PMCID: PMC2562538  PMID: 17591880
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  Alternating Fixation and Saccade Behavior in Nonhuman Primates with Alternating Occlusion–Induced Exotropia 
Purpose
Nonhuman primates reared with daily alternating monocular occlusion (AMO) during their first few months of life develop large horizontal strabismus, A/V patterns and dissociated vertical deviation (DVD). In addition, these animals often alternate or switch the fixating eye during binocular viewing. The purpose of this study was to characterize the alternating fixation behavior of these animals during visually guided saccade tasks.
Methods
Binocular eye movements were measured in two monkeys with AMO-induced exotropia as they performed a visually guided saccade task (random target presentation over a ±15° grid horizontally and vertically) during either monocular or binocular viewing.
Results
During binocular viewing, large target steps into the temporal hemifield of the nonfixating eye (nasal retina of the nonfixating eye) produced fixation switches. Target steps into the nasal hemifield of the nonfixating eye (temporal retina of the nonfixating eye) tended not to produce a fixation switch. There were no significant differences in the amplitude–peak velocity or amplitude– duration main sequence relationships between alternating (binocular viewing) and nonalternating saccades (monocular or binocular viewing). Saccade latency tended to be greater during binocular viewing than during monocular viewing.
Conclusions
This study shows that the AMO model for strabismus may be used for studying neural circuits involved in generating alternating fixation and alternating saccade behavior. Since patterns of alternating fixation are likely to be influenced by patterns of visual suppression, alternating saccade behavior may also be used as a probe to study mechanisms of visual suppression in strabismus.
doi:10.1167/iovs.08-2772
PMCID: PMC2837805  PMID: 19279316
22.  Temporal Dynamics of Ocular Position Dependence of the Initial Human Vestibulo-ocular Reflex 
Purpose
While an ideal vestibulo-ocular reflex (VOR) generates ocular rotations compensatory for head motion, during visually guided movements, Listing’s Law (LL) constrains the eye to rotational axes lying in Listing’s Plane (LP). The present study was conducted to explore the recent proposal that the VOR’s rotational axis is not collinear with the head’s, but rather follows a time-dependent strategy intermediate between LL and an ideal VOR.
Methods
Binocular LPs were defined during visual fixation in eight normal humans. The VOR was evoked by a highly repeatable transient whole-body yaw rotation in darkness at a peak acceleration of 2800 deg/s2. Immediately before rotation, subjects regarded targets 15 or 500 cm distant located at eye level, 20° up, or 20° down. Eye and head responses were compared with LL predictions in the position and velocity domains.
Results
LP orientation varied both among subjects and between individual subject’s eyes, and rotated temporally with convergence by 5 ± 5° (±SEM). In the position domain, the eye compensated for head displacement even when the head rotated out of LP. Even within the first 20 ms from onset of head rotation, the ocular velocity axis tilted relative to the head axis by 30% ± 8% of vertical gaze position. Saccades increased this tilt. Regardless of vertical gaze position, the ocular rotation axis tilted backward 4° farther in abduction than in adduction. There was also a binocular vertical eye velocity transient and lateral tilt of the ocular axis.
Conclusions
These disconjugate, short-latency axis perturbations appear intrinsic to the VOR and may have neural or mechanical origins.
doi:10.1167/iovs.05-0172
PMCID: PMC1866306  PMID: 16565376
23.  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
24.  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
25.  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

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