The mechanism of oscillopsia and its suppression.

We studied the mechanisms of oscillopsia suppression in subjects with infantile nystagmus syndrome, fusion maldevelopment nystagmus syndrome, and acquired nystagmus (AN). Hypothetical possibilities for perceptual stability were the following: (1) epochs of clear and stable vision during foveation periods of nystagmus waveforms; (2) cancellation by efference copy of motor output; (3) a combination of the effects of both foveation-period stability and efference-copy cancellation; or (4) elevated motion-detection threshold and vision suppression. Observations, studies, and models of oscillopsia suppression allowed comparison of these possibilities. Data from individual subjects supported some of the putative hypotheses. However, only one hypothesis remained viable that could explain how all subjects maintained perceptual stability despite their different nystagmus types, waveforms, and variability. Robust suppression of oscillopsia was only possible using efference-copy feedback of the motor output containing these specific nystagmus signals to cancel that motion from the retinal error signals. In cases of AN, where oscillopsia could not be suppressed, the deficit was postulated to interfere with or lie outside of this efference-copy feedback loop.

Effects of acetazolamide on infantile nystagmus syndrome waveforms: comparisons to contact lenses and convergence in a well-studied subject.

AIM: To determine if acetazolamide, an effective treatment for certain inherited channelopathies, has therapeutic effects on infantile nystagmus syndrome (INS) in a well-studied subject, compare them to other therapies in the same subject and to tenotomy and reattachment (T&R) in other subjects. METHODS: Eye-movement data were taken using a high-speed digital video recording system. Nystagmus waveforms were analyzed by applying an eXpanded Nystagmus Acuity Function (NAFX) at different gaze angles and determining the Longest Foveation Domain (LFD). RESULTS: Acetazolamide improved foveation by both a 59.7% increase in the peak value of the NAFX function (from 0.395 to 0.580) and a 70% broadening of the NAFX vs Gaze Angle curve (the LFD increased from 20° to 34°). The resulting U-shaped improvement in the percent NAFX vs Gaze Angle curve, varied from ~60% near the NAFX peak to over 1000% laterally. The therapeutic improvements in NAFX from acetazolamide (similar to T&R) were intermediate between those of soft contact lenses and convergence, the latter was best; for LFD improvements, acetazolamide and contact lenses were equivalent and less effective than convergence. Computer simulations suggested that damping the central oscillation driving INS was insufficient to produce the foveation improvements and increased NAFX values. CONCLUSION: Acetazolamide resulted in improved-foveation INS waveforms over a broadened range of gaze angles, probably acting at more than one site. This raises the question of whether hereditary INS involves an inherited channelopathy, and whether other agents with known effects on ion channels should be investigated as therapy for this condition.

Extending the eXpanded Nystagmus Acuity Function for vertical and multiplanar data.

We updated and extended the functionality of the eXpanded Nystagmus Acuity Function (NAFX), for application under more diverse circumstances, improving its clinical predictive value. The original NAFX "tau-surface" of minimum-necessary-foveation times had been individually calculated for each combination of position and velocity limits. We have replaced it with an idealized mathematical function that repairs the irregularities in its surface due to idiosyncrasies in the subject data used for the initial calculations. To extend applicability to multiplanar data, we combine horizontal and vertical eye-movement data into a single waveform using vector summation. Torsional eye movements have little effect on visual acuity and are ignored. Age-related visual acuity relationships, derived from population data, more accurately relate the NAFX value to acuity for individual patients. Using the same patient fixation data that established the original NAF and NAFX functions, we verified that the updated NAFX yielded equivalent results for uniplanar data. For biplanar data, the results were also comparable to those of uniplanar data of the same magnitude. The updated NAFX yields greater accuracy in prediction of potential visual acuity for subjects of all ages, for uniplanar and multiplanar nystagmus, extending the objective, direct measure of post-therapy waveform improvement, allowing selection of the best therapy for a wider range of nystagmus patients.

Factors influencing pursuit ability in infantile nystagmus syndrome: Target timing and foveation capability.

We wished to determine the influential factors for Infantile Nystagmus Syndrome (INS) subjects' ability to acquire and pursue moving targets using predictions from the behavioral Ocular Motor System (OMS) model and data from INS subjects. Ocular motor simulations using a behavioral OMS model were performed in MATLAB Simulink. Eye-movement recordings were performed using a high-speed digital video system. We studied five INS subjects who pursued a 10 degrees /s ramp target to both left and right. We measured their target-acquisition times based on position criteria. The following parameters were studied: Lt (measured from the target-ramp initiation to the first on-target foveation period), target pursuit direction, and foveation-period pursuit gain. Analyses and simulations were performed in MATLAB environment using OMLAB software (OMtools, download from http://www.omlab.org). Ramp-target timing influenced target-acquisition time; the closer to the intrinsic saccades in the waveform the ramp stimuli started, the longer was Lt. However, arriving at the target position may not guarantee its foveation. Foveation-period pursuit gains vs. target or slow-phase direction had an idiosyncratic relationship for each subject. Adjustments to the model's Fixation subsystem reproduced the idiosyncratic foveation-period pursuit gains; the gain of the Smooth Pursuit subsystem was maintained at its normal value. The model output predicted a steady-state error when target initiation occurred during intrinsic saccades, consistent with human data. We conclude that INS subjects acquire ramp targets with longer latency for target initiations during or near the intrinsic saccades, consistent with the findings in our step-stimuli timing study. This effect might be due to the interaction between the saccadic and pursuit systems. The combined effects of target timing and Fixation-subsystem gain determined how fast and how well the INS subjects pursued ramp stimuli during their foveations periods (i.e., their foveation-period pursuit gain). The OMS model again demonstrated its behavioral characteristics and prediction capabilities (e.g., steady-state error) and revealed an important interaction between the Fixation and Smooth Pursuit subsystems.

Extraocular proprioception and new treatments for infantile nystagmus syndrome.

Our goal is to develop the proprioceptive hypothesis for nystagmus damping; and present the resulting therapies for the treatment of infantile nystagmus syndrome (INS) and acquired nystagmus. Contact lenses, cutaneous stimulation, and neck-muscle vibration damped INS. Four-muscle tenotomy and reattachment was hypothesized as a treatment for INS in 1979 and successfully demonstrated to improve foveation in a canine model of INS and seesaw nystagmus in 1998 and in humans with INS (masked-data, NEI Clinical Trial) in 2003. Subsequently, tenotomy successfully damped acquired pendular nystagmus and oscillopsia in two MS patients and downbeat nystagmus in another. Tenotomy, used in isolation or combination with existing nystagmus and strabismus surgeries, damps different types of nystagmus in their plane of action. Recent neuroanatomical and neurophysiological discoveries support the hypothesis that proprioception is the mechanism for INS damping and allow more realistic models of peripheral ocular motor pathways.

Tenotomy procedure alleviates the "slow to see" phenomenon in infantile nystagmus syndrome: model prediction and patient data.

Our purpose was to perform a systematic study of the post-four-muscle-tenotomy procedure changes in target acquisition time by comparing predictions from the behavioral ocular motor system (OMS) model and data from infantile nystagmus syndrome (INS) patients. We studied five INS patients who underwent only tenotomy at the enthesis and reattachment at the original insertion of each (previously unoperated) horizontal rectus muscle for their INS treatment. We measured their pre- and post-tenotomy target acquisition changes using data from infrared reflection and high-speed digital video. Three key aspects were calculated and analyzed: the saccadic latency (Ls), the time to target acquisition after the target jump (Lt) and the normalized stimulus time within the cycle. Analyses were performed in MATLAB environment (The MathWorks, Natick, MA) using OMLAB software (OMtools, available from http://www.omlab.org). Model simulations were performed in MATLAB Simulink environment. The model simulation suggested an Lt reduction due to an overall foveation-quality improvement. Consistent with that prediction, improvement in Lt, ranging from approximately 200 ms to approximately 500 ms (average approximately 280 ms), was documented in all five patients post-tenotomy. The Lt improvement was not a result of a reduced Ls. INS patients acquired step-target stimuli faster post-tenotomy. This target acquisition improvement may be due to the elevated foveation quality resulting in less inherent variation in the input to the OMS. A refined behavioral OMS model, with "fast" and "slow" motor neuron pathways and a more physiological plant, successfully predicted this improved visual behavior and again demonstrated its utility in guiding ocular motor research.

Being "slow to see" is a dynamic visual function consequence of infantile nystagmus syndrome: model predictions and patient data identify stimulus timing as its cause.

The objective of this study was to investigate the dynamic properties of infantile nystagmus syndrome (INS) that affect visual function; i.e., which factors influence latency of the initial reflexive saccade (Ls) and latency to target acquisition (Lt). We used our behavioral ocular motor system (OMS) model to simulate saccadic responses (in the presence of INS) to target jumps at different times within a single INS cycle and at random times during multiple cycles. We then studied the responses of 4 INS subjects with different waveforms to test the model's predictions. Infrared reflection was used for 1 INS subject, high-speed digital video for 3. We recorded and analyzed human responses to large and small target-step stimuli. We evaluated the following factors: stimulus time within the cycle (Tc), normalized Tc (Tc%), initial orbital position (Po), saccade amplitude, initial retinal error (e(i)), and final retinal error (e(f)). The ocular motor simulations were performed in MATLAB Simulink environment and the analysis was performed in MATLAB environment using OMLAB software. Both the OMS model and OMtools software are available from http://http:www.omlab.org. Our data analysis showed that for each subject, Ls was a fixed value that is typically higher than the normal saccadic latency. Although saccadic latency appears somewhat lengthened in INS, the amount is insufficient to cause the "slow-to-see" impression. For Lt, Tc% was the most influential factor for each waveform type. The main refixation strategies employed by INS subjects made use of slow and fast phases and catch-up saccades, or combinations of them. These strategies helped the subjects to foveate effectively after target movement, sometimes at the cost of increased target acquisition time. Foveating or braking saccades intrinsic to the nystagmus waveforms seemed to disrupt the OMS' ability to accurately calculate reflexive saccades' amplitude and refoveate. Our OMS model simulations demonstrated this emergent behavior and predicted the lengthy target acquisition times found in the patient data.

The sub-clinical see-saw nystagmus embedded in infantile nystagmus.

A transient, decompensated vertical phoria in an individual with infantile nystagmus syndrome (INS) resulted in two images that oscillated vertically-a diplopic oscillopsia. Ocular motor studies during the vertical oscillopsia recreated by vertical prisms, led to the identification of a sub-clinical see-saw nystagmus (SSN), present under the prism-induced diplopic condition. Retrospective analysis of ocular motor recordings made prior to the above episode of vertical diplopia revealed the presence of that same sub-clinical SSN. The SSN had not been detected previously despite extensive observations and recordings of this subject's pendular IN over a period of forty years. Three- dimensional search-coil data from fourteen additional INS subjects (with pendular and jerk waveforms) confirmed the existence of sub-clinical SSN embedded within the clinically detectable horizontal-torsional IN in seven of the fifteen and a sub-clinical, conjugate, vertical component in the remaining eight. Unlike the clinically visible SSN found in achiasma, the cause of this sub-clinical SSN is hypothesized to be due to a failure of the forces of the oblique muscles (responsible for the torsional component of the IN) to balance out the associated forces of the vertical recti; the net result is a small, sub-clinical SSN. Thus, so-called "horizontal" IN is actually a horizontal-torsional oscillation with a secondary, sub-clinical SSN or conjugate vertical component. The suppression of oscillopsia by efference copy in INS appears to be accomplished for each eye individually, even in a binocular individual. However, failure to fuse the two images results in oscillopsia of one of them.

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.

Tenotomy does not affect saccadic velocities: support for the "small-signal" gain hypothesis.

We investigated the effects of four-muscle tenotomy on saccadic characteristics in infantile nystagmus syndrome (INS) and acquired pendular nystagmus (APN). Eye movements of 10 subjects with INS and one with APN were recorded using infrared reflection, magnetic search coil, or high-speed digital video. The expanded nystagmus acuity function (NAFX) quantified tenotomy-induced foveation changes in the INS. Saccadic characteristics and peak-to-peak nystagmus amplitudes were measured. Novel statistical tests were performed on the saccadic data. Six out of the 10 INS subjects showed no changes in saccadic duration, peak velocity, acceleration, or trajectory. In the other four, the differences were less than in peak-to-peak amplitudes (from 14.6% to 39.5%) and NAFX (from 22.2% to 162.4%). The APN subject also showed no changes despite a 50% decrease in peak-to-peak amplitude and a 34% increase in NAFX. The "small-signal" changes (peak-to-peak nystagmus amplitude and NAFX) were found to far exceed any "large-signal" changes (saccadic). Tenotomy successfully reduced INS and APN, enabling higher visual acuity without adversely affecting saccadic characteristics. These findings support the peripheral, small-signal gain reduction (via proprioceptive tension control) hypothesis. Current linear plant models, limited to normal steady-state muscle tension levels, cannot explain the effects of the tenotomy.

Time-varying, slow-phase component interaction in congenital nystagmus.

We investigated the nystagmus of a 12-year-old boy with suspected X-linked congenital nystagmus (CN) and exophoria to determine the underlying mechanisms and component signals in the 'dual-velocity' and other slow phases of his Asymmetric (a)Periodic Alternating Nystagmus (APAN). Fast Fourier transforms (FFT) were performed on the waveforms and residual data after subtracting a sawtooth waveform whose amplitude and frequency matched those of the jerk nystagmus. The FFT analyses identified two frequency components (jerk--4 Hz and pendular--4 and 8 Hz, variable) that varied differently in intensity and frequency/phase over the time-course of the APAN. We synthesized each of the patient's slow phases using summation of sawtooth and sinusoidal waveforms. The resulting waveforms included jerk (with different slow-phase appearances), dual jerk, and pendular. We demonstrated that the pendular nystagmus seen during the neutral phase of APAN and the appearance of either decelerating (mimicking latent nystagmus), dual-velocity, or dual-jerk slow phases can be explained and produced by the summation of linear and pendular components of variable amplitudes and frequencies/phases. Thus, one mechanism may be responsible for all the variation seen in this patient's slow phases, rather than the less parsimonious hypothesis of a switched-tonic-imbalance mechanism that we had originally suggested to simulate the dual-velocity waveform.

An expanded nystagmus acuity function: intra- and intersubject prediction of best-corrected visual acuity.

The Nystagmus Acuity Function (NAF) provides an objective measurement of the foveation characteristics of nystagmus waveforms and an assessment of potential visual acuity for subjects with congenital (CN) or latent/manifest latent (LMLN) nystagmus. It is based on the subjects' ability to maintain fixation within a physiologically based 'foveation window' of +/- 0.5 degrees and +/- 4.0 degrees/s. However, some subjects are incapable of controlling fixation well enough to remain within this window with duration sufficient for good foveation. To obtain a measure of the CN waveforms of these individuals, we are proposing an eXpanded Nystagmus Acuity Function (NAFX) that relaxes either the position limit, the velocity limit, or both. Data used in this study comes from 11 human subjects with CN (10 idiopathic and 1 with achiasma) and a Belgian sheepdog with achiasma. Visual acuity was tested with a standard Snellen chart and eye movements recorded with infrared oculography or scleral search coil. For the NAFX to be useful, it must not only be applicable for subjects who cannot maintain fixation within the standard limits of the NAF, but also must yield results equivalent to those obtained with the NAF when testing subjects who are capable of maintaining good fixation control. For the latter subjects, the amount of time when position and velocity fell within the expanded limits was measured, the standard deviations of the position and velocity during these times were calculated, and a tau-surface for the exponential function was generated to guarantee the equivalence between the NAF and the NAFX. We developed an automated NAFX equivalent to the original NAF. We demonstrated that equivalence in 10 subjects and the use of the NAFX on two additional (1 human and 1 canine) subjects who were incapable of maintaining fixation within the standard position and velocity limits. We demonstrated the effects of surgery and related the results to visual acuity. We found the results to be comparable to those seen when applying the NAF to subjects who had good fixation control. The NAFX can be determined for CN and LMLN subjects with poor control of fixation by extending the standard NAF position and/or velocity limits for foveation. The resulting function can be used along with the longest foveation domain (derived from the NAFX to measure breadth of a high-NAFX region) to identify the gaze or convergence angles with the best waveform and to predict the best-possible visual acuity that could be achieved with the reduction of their nystagmus.

The torsional component of "horizontal" congenital nystagmus.

OBJECTIVES: To study the relationship between the major horizontal and minor torsional components of congenital nystagmus to elucidate the diagnostic importance, effects on vision, and pathogenetic implications of the torsional components. METHODS: We recorded the eye movements of 13 subjects with congenital nystagmus using a three-dimensional magnetic search coil technique over a 15-year period. The subjects fixated on stationary targets straight ahead and along the horizontal and vertical meridians. Six of the 10 subjects with horizontal congenital nystagmus were asymptomatic; the remaining 4 (plus two with a vertical component to their congenital nystagmus) had adult-onset symptoms. An additional subject without symptoms had a vertical congenital nystagmus component plus seesaw nystagmus; one of the symptomatic subjects also had seesaw nystagmus. RESULTS: In all 13 subjects, the horizontal and torsional cycles were phase-locked, and positive horizontal (rightward), vertical (upward, if any), and torsional (clockwise) motion coincided in 10 subjects. That is, rightward horizontal eye rotation coincided with clockwise curvilinear motion (rightward and downward) of the upper pole of each eye. During the horizontal foveation periods, torsional motion was also of low velocity. In 2 of 13 subjects, the torsional waveforms differed from those in the horizontal plane; in others, the direction or the variation with gaze angle differed from that predicted by Listing. In each of the 13 subjects, the torsional components ranged from 8.16% to 94.42% (median, 32.94%) of the peak-to-peak magnitudes of the congenital nystagmus. In most cases, the measured torsion was far greater than that predicted by Listing's law for a worst-case analysis (range, 0.69-11.83%; median, 4.91%). The torsional components of the two subjects with seesaw nystagmus were 60.48% and 264.02%. CONCLUSIONS: The manner in which the horizontal and torsional components of "horizontal" congenital nystagmus were phase-locked made clinical detection of the torsional component difficult. Most "horizontal" congenital nystagmus is actually horizontal-torsional congenital nystagmus. Visual acuity during horizontal foveation periods is not significantly diminished by torsional motion. In only one subject did the torsional component of the congenital nystagmus have an amplitude equivalent to Listing torsion; in the other 12 subjects, torsion exceeded our estimate of what Listing's law would predict. The torsional components of the seesaw nystagmus in two subjects also greatly exceeded the torsion predicted by Listing torsion. The most parsimonious explanation for our data is that the cyclic torsion in congenital nystagmus was generated centrally and not a result of Listing torsion, mechanical crosstalk, or normal or abnormal extraocular-muscle (plant) dynamics. Further measurements are needed to confirm this hypothesis.

A normal ocular motor system model that simulates the dual-mode fast phases of latent/manifest latent nystagmus.

The fast phases of latent/manifest latent nystagmus (LMLN) may either cause the target image to fall within (foveating) or outside (defoveating) the foveal area. We previously verified that both types are generated by the same mechanism as voluntary saccades and propose a hypothetical, dual-mode mechanism (computer model) for LMLN that utilizes normal ocular-motor control functions. Fixation data recorded during the past 30 years from 97 subjects with LMLN using both infrared and magnetic search coil oculography were used as a basis for our simulations. The MATLAB/Simulink software was used to construct a robust, modular, ocular motor system model, capable of simulating LMLN. Fast-phase amplitude versus both peak velocity and duration of simulated saccades were equivalent to those of saccades in normal subjects. Based on our LMLN studies, we constructed a hypothetical model in which the slow-phase velocity acted to trigger the change between foveating and defoveating LMLN fast phases. Foveating fast phases were generated during lower slow-phase velocities whereas defoveating fast phases occurred during higher slow-phase velocities. The bidirectional model simulated Alexander's law behavior under all viewing and fixation conditions. Our ocular-motor model accurately simulates LMLN patient ocular motility data and provides a hypothetical explanation for the conditions that result in both foveating and defoveating fast phases. As is the case for normal physiological saccades, the position error determined the saccadic amplitudes for foveating fast phases. However, the final slow-phase velocity determined the amplitudes of defoveating fast phases. In addition, we suggest that individuals with LMLN use their fixation subsystem to further decrease the slow-phase velocity as the target image approaches the foveal center.

Saccades to sounds: effects of tracking illusory visual stimuli.

In 10 normal human subjects, we studied the accuracy of memory-guided saccades made to the remembered locations of visual targets and sounds. During the time of stimulus presentation, subjects were smoothly tracking a projected laser spot that was moving horizontally across a tangent screen, sinusoidally +/-15 degrees at 0.25 Hz. In one set of experiments, the laser spot moved across a 40 degrees x 28 degrees random dot display that moved synchronously in the vertical plane; this induced a strong illusion that the trajectory of the laser spot was diagonal (variant of Duncker illusion). In control experiments, the laser spot moved across the same display, which was stationary. The visual targets and speakers were at six locations (range +/-15 degrees ) in the horizontal plane. Saccades made to the remembered locations of targets presented during background motion (illusion) were significantly (P < 0.05) more inaccurate than with the background stationary (control) in 9 of 10 subjects for lights and in 6 of 10 subjects for sounds. As a group, the median change in errors due to the Duncker illusion was approximately 2.5 times greater for visual compared with acoustic targets (P < 0.001). These findings are consistent with electrophysiological studies which have shown that neurons in the primate lateral intraparietal area (LIP) may respond to both visual and auditory targets and these neurons are also influenced by the Duncker illusion during programming of memory-guided saccades.