Ocular Motor System Research Articles

Ocular Myasthenia

Although myasthenia gravis (MG) is often considered the best-understood autoimmune disorder and effective treatments have controlled life-threatening complications, the pathogenesis of ocular myasthenia (OM) remains enigmatic, and its clinical consequences offer therapeutic challenges. About half of patients with MG present with visual complaints of droopy eyelids or double vision, and many will remain with purely ocular muscle weakness without generalized weakness, defined as OM. OM may be confused with disorders of the brainstem, ocular motor nerves, and eye muscles. Frustrating for the clinician, confirmatory tests such as the edrophonium test, serum acetylcholine receptor antibodies, and standard electrodiagnostic evaluations may fail to positively identify the clinical suspicion of OM. Patients may derive relief from nonpharmacologic interventions and cholinesterase inhibitors, but most will desire better symptom control with corticosteroids or need other immunosuppression. Early corticosteroid therapy may reduce the probability of generalization of the disease. The reasons for ocular muscle involvement by OM include physiologic and cellular properties of the ocular motor system and the unique immunology of OM, which, when better understood, will lead to novel treatments. OM is a challenging disorder for the clinician and scientist, with both learning from the other for the betterment of the patient. The future requires answers to why the ocular muscles are so frequently involved by MG, whether the generalization of the disease may be limited by early corticosteroid treatment, and what treatment options may be developed which will improve symptoms without long-term complications.

Eye Movement Recordings as an Effectiveness Indicator of Gene Therapy inRPE65-Deficient Canines: Implications for the Ocular Motor System

To perform ocular motility recordings of infantile nystagmus (IN) in RPE65-deficient canines and determine whether they can be used as a motor indicator of restored retinal function to investigate the effects of gene therapy. Treated and untreated canines were comfortably suspended in a custom-built sling and encouraged to fixate on distant targets at gaze angles varying between +/-15 degrees horizontally and +/-10 degrees vertically. Ocular motility recordings were made, using two distinct methods-infrared reflection and high-speed video. The resultant recordings from three untreated, four treated, and three pre- and post-treatment dogs were analyzed for using the eXpanded Nystagmus Acuity Function (NAFX), which yields an objective assessment of best potential visual acuity, based on the duration and repeatable accuracy of foveation and centralisation. During fixation, the untreated dogs exhibited large-amplitude, classic IN waveforms, including pendular and jerk in both the horizontal and vertical planes, which prevented them from keeping the targets within the area centralis (the region of highest receptor density, spanning +/-3 degrees horizontally by +/-1.5 degrees vertically, analogous to the fovea). Some untreated dogs also had small-amplitude (0.5-1 degrees), high-frequency (6-9 Hz) oscillations. Under the same conditions, successfully treated canines no longer exhibited clinically detectable IN. Their IN was converted to waveforms with very low amplitudes that yielded higher NAFX values and allowed target images to remain well within the area centralis. Of note, uniocular treatment appeared to damp the IN in both eyes. Behaviorally, the treated dogs were able to successfully navigate through obstacles more easily without inadvertent contact, a task beyond the untreated dogs' ability. Gene therapy that successfully restored retinal function also reduced the accompanying IN to such a great extent that it was not clinically detectable approximately 90% of the time in many of the dogs. IN improvement, as quantified by the NAFX, is an objective motor indicator of visual improvement due to gene therapy.

Eye closure in darkness animates olfactory and gustatory cortical areas

In two previous fMRI studies, it was reported that eyes-open and eyes-closed conditions in darkness had differential effects on brain activity, and typical patterns of cortical activity were identified. Without external stimulation, ocular motor and attentional systems were activated when the eyes were open. On the contrary, the visual, somatosensory, vestibular, and auditory systems were activated when the eyes were closed. In this study, we investigated whether cortical areas related to the olfactory and gustatory system are also animated by eye closure without any other external stimulation. In a first fMRI experiment ( n = 22), we identified cortical areas including the piriform cortex activated by olfactory stimulation. In a second experiment ( n = 12) subjects lying in darkness in the MRI scanner alternately opened and closed their eyes. In accordance to previous studies, we found activation clusters bilaterally in visual, somatosensory, vestibular and auditory cortical areas for the contrast eyes-closed vs. eyes-open. In addition, we were able to show that cortical areas related to the olfactory and gustatory system were also animated by eye closure. These results support the hypothesis that there are two different states of mental activity: with the eyes closed, an “interoceptive” state characterized by imagination and multisensory activity and with the eyes open, an “exteroceptive” state characterized by attention and ocular motor activity. Our study also suggests that the chosen baseline condition may have a considerable impact on activation patterns and on the interpretation of brain activation studies. This needs to be considered for studies of the olfactory and gustatory system.

Effects of uncertainty and target displacement on the latency of express saccades in man

Saccadic eye movements generated in response to a gap paradigm in which the fixation light spot was extinguished 200 ms prior to presentation of the target light spot showed appreciably shorter latencies than for the overlap paradigm in which the target light spot was presented 200 ms prior to extinction of the fixation light spot. When there was unpredictability in the direction of target presentation, i.e., to the left or right of the fixation light spot, the gap paradigm evoked mainly fast regular saccades of peak latency of 155 ms with relatively few express saccades which were defined as having latencies of less than 120 ms. By contrast, when the target always appeared to the right, a substantial population of express saccades with peak latency 95 ms was now generated. There was also a change in the relationship between saccadic latency and target angular displacement which covered the range 5–35 °. With the overlap paradigm and unpredictability of target direction, the latencies of the slow regular saccades increased markedly with target angular displacement. This was not the case with the same target direction when the latency of slow regular, fast regular, and express saccades remained constant with increasing target angular displacement. This indicates for targets appearing in the same hemifield that the ocular motor system operates with shortest latency irrespective of target angular displacement.

Eye Movements of the Murine P/Q Calcium Channel Mutant Tottering, and the Impact of Aging

Mice carrying mutations of the gene encoding the ion pore of the P/Q calcium channel (Cacna1a) are an instance in which cerebellar dysfunction may be attributable to altered electrophysiology and thus provide an opportunity to study how neuronal intrinsic properties dictate signal processing in the ocular motor system. P/Q channel mutations can engender multiple effects at the single neuron, circuit, and behavioral levels; correlating physiological and behavioral abnormalities in multiple allelic strains will ultimately facilitate determining which alterations of physiology are responsible for specific behavioral aberrations. We used videooculography to quantify ocular motor behavior in tottering mutants aged 3 mo to 2 yr and compared their performance to data previously obtained in the allelic mutant rocker and C57BL/6 controls. Tottering mutants shared numerous abnormalities with rocker, including upward deviation of the eyes at rest, increased vestibuloocular reflex (VOR) phase lead at low stimulus frequencies, reduced VOR gain at high stimulus frequencies, reduced gain of the horizontal and vertical optokinetic reflex, reduced time constants of the neural integrator, and reduced plasticity of the VOR as assessed in a cross-axis training paradigm. Unlike rocker, young tottering mutants exhibited normal peak velocities of nystagmus fast phases, arguing against a role for neuromuscular transmission defects in the attenuation of compensatory eye movements. Tottering also differed by exhibiting directional asymmetries of the gains of optokinetic reflexes. The data suggest at least four pathophysiological mechanisms (two congenital and two acquired) are required to explain the ocular motor deficits in the two Cacna1a mutant strains.

Underdeveloped extraocular muscles in the naked mole rat (Heterocephalus glaber)

The extraocular muscles (EOM) are the final effector arm of the ocular motor system. These small muscles have a unique embryological origin and phenotype. Their diversity is highlighted by their resistance to some neuromuscular disorders (muscular dystrophy, ALS) and increased susceptibility to others (myasthenia gravis and mitochondrial myophathies). The naked mole rat (NMR) is a subterranean rodent with a reduced visual system; it is an ideal model to examine the potential codependence of full EOM and visual system phenotype development and evolution. Our goal was to compare the structural features of NMR EOMs to those of a similar sized rodent with a fully developed visual system. Whole orbits and EOMs were dissected from perfusion-fixed adult NMR and C57BL mice and examined by light and electron microscopy. NMR orbital anatomy showed smaller EOMs in roughly the same distribution around the eye as in mouse and surrounded by a very small Harderian gland. The NMR EOMs did not appear to have the two-layer fiber distribution (orbital and global) seen in mouse EOMs; fibers were also significantly smaller (118 vs. 551 sq um in mouse EOMs). Myofibrillar density was less in NMR EOMs, and triad and other membranous structures were rudimentary. Finally, mitochondrial volume density was significantly less in NMR EOMs than in mouse EOM (4.5% vs. 21.2% respectively). These results demonstrate that NMR EOMs are smaller and less well organized than those in a rodent with a fully developed visual system. It is likely that at least some aspects of EOM organization depend on visual experience.

You Too Can Perform Successful Surgery for Nystagmus

The purpose of this course is to summarize the instructor’s experience with, and provide concise recommendations and descriptions of, childhood and acquired forms of nystagmus. We will focus on the common indications and surgical treatment techniques in these patients and discuss expected ocular motor and visual system outcomes as a result of the surgery. We will use case examples to illustrate the diagnoses and surgical techniques as well as allow time for the audience to ask the instructors their opinion(s) regarding particular cases. At the conclusion of this course, the attendee will acquire knowledge they can immediately use to assist their patients with nystagmus.

Development of Saccadic Suppression in Children

We measured saccadic suppression in adolescent children and young adults using spatially curtailed low spatial frequency stimuli. For both groups, sensitivity for color-modulated stimuli was unchanged during saccades. Sensitivity for luminance-modulated stimuli was greatly reduced during saccades in both groups but far more for adolescents than for young adults. Adults' suppression was on average a factor of about 3, whereas that for the adolescent group was closer to a factor of 10. The specificity of the suppression to luminance-modulated stimuli excludes generic explanations such as task difficulty and attention. We suggest that the enhanced suppression in adolescents results from the immaturity of the ocular-motor system at that age.

Biologically Relevant Models of Infantile Nystagmus Syndrome: The Requirement for Behavioral Ocular Motor System Models

Infantile nystagmus syndrome (INS) is a combination of several types of nystagmus, each representing dysfunction in one subsystem of the ocular motor system (OMS) and having characteristic waveforms. Eye-movement recordings are the only certain way to identify IN and differentiate it from other types. The waveform classification scheme in use for 30 years is both accurate, inclusive, and suggests the underlying subsystem instabilities. In different individuals, they may appear at birth (hard wired) or in early infancy (developmental). The primary subsystem instability in IN is hypothesized to lie in the normally underdamped smooth pursuit system; vestibular dysfunction (imbalance) may also be present. Less often, the nucleus of the optic tract may be involved. Ocular motility studies over the past 40 years have demonstrated that saccades and gaze holding are normal in the INS and saccades contained within IN waveforms are always corrective; i.e., they cannot be the initiating movement responsible for IN. Because there are an infinite number of solutions to simulating specific waveforms, models that merely generate waveforms that resemble IN in isolation are of little use, either clinically or to increase our understanding of the underlying mechanisms of IN. A biologically relevant model of the INS should be part of, and operate within, a complete OMS model, capable of reproducing the normal ocular motor behavior of these individuals while still oscillating; i.e., the model, like the patient, must not have oscillopsia and be able to respond correctly to various target inputs.

THE CEREBELLUM AND EYE MOVEMENTS

Background and objectives: The central foveal area of the retina is designed for high definition vision. Hence we need to move our eyes so that images fall on the fovea. The cerebellum plays a crucial part in the visual guidance of movement by optimizing the output of the ocular motor system during eye movements. The objective is to discuss the role of the cerebellum in processing eye movements including saccades, smooth pursuit and saccadic adaptation, a form of motor learning that corrects the amplitude of saccades in response to saccadic amplitude errors.

“Staircase” Saccadic Intrusions plus Transient Yoking and Neural Integrator Failure Associated with Cerebellar Hypoplasia: A Model Simulation

We present hypothesized ocular motor mechanisms of unique “staircase-like” sequences of saccadic intrusions in one direction that we have named, “staircase saccadic intrusions (SSI),” square-wave jerks/oscillations (SWJ/SWO), and transient failures of yoking and neural integrators in a patient with severe hypotonia, ataxic speech, motor and language developmental delays, and torticollis (Joubert syndrome). Brain magnetic resonance imaging showed hypoplasia of the cerebellar vermis and inferior cerebellar peduncles, abnormal superior cerebellar peduncles with deepening of the interpeduncular fossa, and enlargement of the fourth ventricle. During far and near fixation and smooth pursuit (rightward markedly better than leftward), the subject exhibited conjugate SSI (rightward more than leftward, with intersaccadic intervals equivalent to the normal 250 msec visual latency), SWJ, SWO, and uniocular, convergent and divergent saccades (including double saccades). Simulations using a behavioral ocular motor system model identified hypothetical mechanisms for SWJ, SWO, and SSI and ruled out the loss of efference copy as the cause. SSI may result from simultaneous dysfunctions: 1) a transient loss of accurate retinal-error information and/or sampled, reconstructed error; plus 2) a constant sampled, reconstructed retinal error that drives saccades.

Task-switching with antisaccades versus no-go trials: a comparison of inter-trial effects

Antisaccades involve the suppression of a pre-potent prosaccade and a vector inversion to generate the novel ocular motor response of looking away from the target. Antisaccades have also been found to prolong the latencies of saccades in upcoming trials, an effect that we attribute to a form of immediate plasticity in the ocular motor system. Our goal was to determine whether the inter-trial effects of antisaccades were similar to that of no-go trials, where subjects must suppress making a saccade when the target appears without substituting a novel ocular motor response. We tested 12 subjects with two different blocks of saccadic trials. In one, prosaccades randomly alternated with antisaccades. In the other, prosaccades alternated with no-go trials. We analyzed the error rates and latencies of prosaccades that followed antisaccades versus no-go trials, compared to repeated prosaccades, to determine if inter-trial effects were present for both types of responses that required prosaccade suppression. No-go responses increased the error rates of prosaccades in the following trial less than antisaccades did. However, no-go trials had the same effect on the latencies of upcoming prosaccades as antisaccades. The inhibitory effect that prolongs the latencies of prosaccades after antisaccades likely stems from the need to inhibit a prosaccade, a function that is also required in no-go trials. The greater impairment of prosaccade accuracy after an antisaccade may reflect either additional control mechanisms involved in vector inversion or a different form of inhibitory control that operates during antisaccades and not during no-go responses.

Nystagmus congénital. Nystagmus manifeste/latent. Nystagmus acquis

The main characteristics of early (manifested/latent) and acquired nystagmus are presented. Congenital forms are concordant, pendular or jerky, with an accelerating-velocity slow phase, and frequent sensorial defects, compensated by an eccentric gaze with concordant torticollis and a convergence; surgery consists of conjugate shifts of the eyes, artificial divergence or 4 horizontal recti large recessions. Manifested/latent forms are jerky, with a decelerating-velocity slow phase, discordant, with an optokinetic nystagmus directional asymmetry, infantile eso- or exotropia, compensated by an adduction (discordant torticollis), or equilibrate binocular inputs; surgical management consists in an orthotropisation or an adduction brake. Acquired nystagmus has specific characteristics: oscillopsia and associated neurological disorders; compensation results from versions and surgery is the same as for congenital nystagmus, ocular motor system palsies and gaze palsies.

Cognitive Requirements for Vestibular and Ocular Motor Processing in Healthy Adults and Patients with Unilateral Vestibular Lesions

This study investigated the role of cognition in the vestibulo-ocular reflex (VOR) and ocular pursuit using a dual-task paradigm in patients with unilateral peripheral vestibular loss and healthy adults. We hypothesized that cognitive resources are involved in successful processing and integration of vestibular and ocular motor sensory information, and this requirement would be greater in patients with vestibular dysfunction. Sixteen well-compensated patients with surgically confirmed absent unilateral peripheral vestibular function and 16 healthy age- and sex-matched controls underwent seven combinations of vestibular-only, visual-only, and visual-vestibular stimuli while performing three different information processing tasks. Visual-vestibular stimuli included a semicircular canal and an otolith stimulus provided through seated chair rotations; fixation on a laser target and sinusoidal smooth pursuit while still; and fixation on a head-fixed laser target during chair rotations. The information processing tasks were three different auditory reaction time (RT) tasks: (1) simple RT, (2) disjunctive RT, and (3) choice RT. Our results showed increases in RTs in both patients and controls under all vestibular-only stimulation conditions and during ocular pursuit. Patients showed greater increases in RTs during vestibular stimulation and the more complex disjunctive and choice RT tasks. No differences between the groups were found during the visual-only or visual-vestibular interaction conditions. These results reveal interference between vestibulo-ocular processing and a concurrent RT task, suggesting that the VOR and the ocular motor system are dependent upon cognitive resources to some extent, and thus, are not fully automatic systems. We speculate that this interference with cognition occurs as a result of the sensory integration required for resolving inputs from multiple sensory streams. The particularly large decrement in information processing task performance of the patients compared with controls during vestibular stimulation suggests that compensation for unilateral vestibular loss requires continued cognitive resources.

Asymmetric modulation of human visual cortex activity during 10° lateral gaze (fMRI study)

We used BOLD fMRI to study the differential effects of the direction of gaze on the visual and the ocular motor systems. Fixation of a target straight ahead was compared to fixation of a target 10° to the right and 10° to the left from gaze straight ahead, and to eyes open in complete darkness in thirteen healthy volunteers. While retinotopic coordinates remained the same in all fixation conditions, the fixation target shifted with respect to a head-centered frame of reference. During lateral fixation, deactivations in higher-order visual areas (one ventral cluster in the lingual and fusiform gyri and one dorsal cluster in the postero-superior cuneus) and, as a trend, activations in early visual cortical areas were found predominantly in the hemisphere contralateral to the fixation target. We propose that visual processing is performed predominantly in the hemisphere contralateral to gaze direction, even during small gaze shifts into one visual hemifield. The excitability of visual neurons may be modulated depending on eye position to construct a head-centered frame of reference from a retinotopic input, thus allowing perceptual stability of space during eye movements. A further finding was that BOLD signal increases in fronto-parietal ocular motor and attentional structures were more pronounced during lateral than central fixation.

Proprioception and Palisade Endings in Extraocular Eye Muscles

Palisade endings occur only in extraocular muscles, and their function is unknown. They form a cuff of nerve terminals around the tips of muscle fibers. We describe here the advantages of using antibodies to a synaptosomal-associated protein (SNAP-25) to study properties of palisade endings in man, monkey, and rat. The stain can be combined readily with other immunofluorescence procedures, and results suggest that the synapses of palisade endings do not bind alpha-bungarotoxin (i.e., are not motor), nor do they contain substance P. These double-labeling data support the hypothesis that palisade endings are non-nociceptive sensory receptors, and could serve a proprioceptive function. With SNAP-25 immunolabeling, palisade endings were identified in the rat for the first time. Thus, palisade endings appear to be present in all vertebrate extraocular muscles studied to date. Their apparent universality, which contrasts with the more variable manifestation of extraocular muscle spindles and Golgi tendon organs, would be expected if proprioceptive feedback is necessary to the function of the ocular motor system, and if palisade endings are the critical proprioceptive structure.

The Saccadic system more readily co-processes orthogonal than co-linear saccades

Real-life visual tasks such as tracking jumping objects and scanning visual scenes often require a sequence of saccadic eye movements. The ability of the ocular motor system to parallel process saccades has been previously demonstrated. We recorded the monocular eye movements of five normal human subjects using the magnetic search coil technique in a double step paradigm. Initial target jumps were always purely horizontal or purely vertical. We were interested in the latency to onset of the second saccade as a function of direction in relation to the first saccade. When the inter stimulus interval (ISI) was 150 or 180 ms orthogonal second saccades were of significantly shorter latency than second co-linear saccades. When the ISI was 250 ms the latencies of orthogonal and co-linear second saccades were statistically indistinguishable. Based on these findings it is postulated that the ocular motor system can more readily co-process orthogonal than co-linear saccades.

Pediatric neuro-ophthalmology

This review will update the ophthalmologist on recent developments in pediatric neuro-ophthalmology. Research into the genetics of congenital strabismus syndromes has brought new insights into the development of the ocular motor system. There is also new literature on childhood ocular myasthenia gravis and childhood neurosarcoidosis. The results of three different surgical treatments for congenital nystagmus are described. Reviews on cortical visual impairment, dyslexia, Aicardi syndrome, and neuronal ceroid lipofuscinosis are presented. Pediatric neuro-ophthalmology is a diverse and challenging field. As we strive to provide excellent care to these patients, we will use the results of basic science, genetic, and neurobiological research.

Congenital nystagmus: hypotheses for its genesis and complex waveforms within a behavioral ocular motor system model.

Attempts to simulate dysfunction within ocular motor system (OMS) models capable of exhibiting known ocular motor behavior have provided valuable insight into the structure of the OMS required for normal visual function. The pendular waveforms of congenital nystagmus (CN) appear to be quite complex, composed of a sustained sinusoidal oscillation punctuated by braking saccades and foveating saccades followed by periods of extended foveation. Previously, we verified that these quick phases are generated by the same mechanism as voluntary saccades. We propose a computer model of the ocular motor system that simulates the responses of individuals with pendular CN (including its variable waveforms) based on the instability exhibited by the normal pursuit subsystem and its interaction with other components of the normal ocular motor control system. Fixation data from subjects with CN using both infrared and magnetic search coil oculography were used as templates for our simulations. Our OMS model simulates data from individuals with CN during fixation and in response to complex stimuli. The use of position and velocity efference copy to suppress oscillopsia is the key element in allowing for normal ocular motor behavior. The model's responses to target steps, pulse-steps, ramps, and step-ramps support the hypothetical explanation for the conditions that result in sustained pendular oscillation and the rules for the corrective saccadic responses that shape this underlying oscillation into the well-known family of pendular CN waveforms: pendular (P), pseudopendular (PP), pendular with foveating saccades (Pfs), and pseudopendular with foveating saccades (PPfs). Position error determined the saccadic amplitudes of foveating saccades, whereas stereotypical braking saccades were not dependent on visual information. Additionally, we propose a structure and method of operation for the fixation subsystem, and use it to prolong the low-velocity intervals immediately following foveating saccades. The model's robustness supports the hypothesis that the pendular nystagmus seen in CN is due to a loss of damping of the normal pursuit-system velocity oscillation (functionally, it is pursuit-system nystagmus--PSN).

Visual and eye movement problems in multiple sclerosis

INTRODUCTION Neuro-ophthalmological involvement in multiple sclerosis (MS) is common, and often the initial manifestation. Increased understanding of both visual and ocular motor system demyelination has contributed significantly to advances in our knowledge of the prognosis, treatment, and pathogenesis of MS. Moreover, advances in neuroradiological techniques have improved correlation of brain demyelinating lesion burden with clinical disease activity, and their application to both optic nerve and ocular motility disorders has contributed to improved lesion localization, and prediction of disease course. Approximately one-fifth of patients ultimately diagnosed with MS have initially presented with acute visual loss secondary to optic neuritis, and up to two-thirds of MS patients have an episode of acute optic neuritis at some stage during the course of their disease (Rodriguez et al . 1995). The propensity of MS to affect the optic nerves is further evidenced by the frequent occurrence of subclinical optic neuropathy, with eventual development of bilateral