Ординатура / Офтальмология / Английские материалы / Advances in Understanding Mechanisms and Treatment of Infantile Forms of Nystagmus_Leigh, Devereaux_2008

Farther Nearer

Location of the comparison target with respect to the standard target (cm)

Figure 1.1 Mean proportion of “near” responses for each comparison target location (at 0, both targets were presented at the same location). In the “JM first” condition, participants performed the contraction when the standard target was shown. In the “JM second” condition, the contraction was performed when the comparison target was shown. Bars show ±1 standard errors. JM, Jendrassik maneuver. Source: NiechwiejSzwedo E, Gonzalez E, Bega S, et al. Proprioceptive role for palisade endings in extraocular muscles: evidence from the Jendrassik Maneuver. Vis Res. 2006; 46(14):2268–2279.

after the contraction has been released). In accordance with our hypothesis, results showed that participants systematically overshot the target when pointing in the third condition (p < 0.01), and no significant difference was found between the other two conditions. Furthermore, there was no significant difference in the vergence angle of the eyes between any of the conditions. Results from this experiment provided preliminary support for the hypothesis that the JM affected registered eye position, but there was a major caveat: since the JM has a general effect on the γ system, the localization errors might have been due to altered feedback from the arm muscles and not the EOM. Our next experiment was designed to address this limitation by using a perceptual localization task that did not require pointing.

Participants (n = 21) were tested on a two-alternative forced-choice (2AFC) procedure, which involved looking at a target and, when the target was removed, deciding whether a second target appeared closer or farther away than the first one. JM was randomly performed when either the first or the second target was presented. The point of subjective equality (PSE) and the y-intercept were both significantly different between the conditions (p < 0.0001) (Fig. 1.1). Specifically, when the afferent feedback was altered

Figure 1.2 Summary and interpretation of results from experiment 2. Participants perceive target location as “farther,” while feedback from the EOM is perturbed by the JM. EOM, extraocular muscles; JM, Jendrassik maneuver. Source: Niechwiej-Szwedo E, Gonzalez E, Bega S, et al. Proprioceptive role for palisade endings in extraocular muscles: evidence from the Jendrassik Maneuver. Vis Res. 2006;46(14):2268–2279.

during the presentation of the first target, participants perceived the second target as nearer. In contrast, the second target was perceived as farther when the JM was performed during presentation of the second target. In other words, in the case when both targets (standard and comparison) were shown at the same location and the JM was performed when the standard target was presented, participants reported that the comparison target was nearer more frequently. This result suggests that participants perceived the location of the standard target as farther with the JM. In contrast, when the JM was performed while the comparison target was presented, it was reported more frequently as farther, which again suggests that during JM the locationofthecomparisontargetwasperceivedasfarther (Fig. 1.2). In summary, results from the second experiment provided strong evidence that eye position is registered as more divergent when feedback from the EOM is perturbed by the JM.

The third study was conducted to examine the effect of JM on target localization in patients with strabismus who have had surgeries that most likely compromised the EOM afferent feedback loops. It was hypothesized that patients’ responses would not be affected by the JM perturbation because activity of the PE could not be altered via the γ system. To date we have tested 3 patients, all of whom underwent different surgeries involving resection and/or recession of the EOM for congenital esotropia or fourth nerve palsy. Following the surgery, all patients had binocular vision: two patients had stereoacuity of 40 seconds of arc and the other patient had stereoacuity of 140 seconds of arc as tested by the Titmus test. Patients were tested on a 2AFC task using the methodology used in the second experiment. In accordance with our

hypothesis, preliminary data showed that the order of the JM did not significantly affect patients’ localization responses. These data provide additional support that the JM alters registered eye position through an EOM proprioceptive feedback loop that has been compromised in patients whose myotendinous region was damaged by the surgery.

Effect of JM on Higher-Order

Perceptual Judgments

Overall, results from the three studies provided evidence that the JM alters the proprioceptive gain of the vergence system. Thus, we hypothesized that the JM would also affect higher-order perceptual judgments that rely on accurate registration of absolute depth. This was examined in the three experiments. Since the vergence angle of the eyes is an important source of extraretinal information contributing to size constancy, we expected that participants would perceive the size of a constant retinal stimulus as larger when the feedback from the eye muscles was altered via the JM. Participants (n = 20) were seated in the dark and were tested on a 2AFC procedure. The JM was performed while viewing the first stimulus (standard square) or the second stimulus (comparison square). In contrast to the hypothesis, data showed no significant differences between the two experimental conditions (when the JM was performed and the control condition).

In the next two experiments, we examined whether the perceptual phenomenon of depth constancy was affected by the JM perturbation. First, we examined stereoscopic depth constancy. Horizontal disparities must be scaled by viewing distance in order for depth constancy to be preserved, and the vergence angle of the eyes can be used to calibrate horizontal disparities for different viewing distances. If the JM affected the registered eye position as shown in the previous experiments, we hypothesized that for the same disparity the perceived depth would be greater when the JM was performed compared to the condition without the JM. Results from the study (n = 6) showed no significant differences between the two conditions. Since the stimulus was presented stereoscopically it is possible that the negative result was partly due to a conflict between the ocular motor cues of convergence and accommodation. Therefore, we examined depth constancy using a different paradigm: the Pulfrich illusion.

The Pulfrich effect is based on a cortical time delay that is interpreted by the CNS as a disparity. The cortical time delay is induced when a horizontally moving pendulum is seen with one eye viewing it through a neutral density filter, in which case the pendulum appears to move in an elliptical orbit. Previous work

has shown that the perceived depth (i.e., the short axis of the ellipse) is scaled with viewing distance and presumably is dependent on the vergence angle of the eyes.46-48 Therefore, we examined whether the perceived depth during the Pulfrich illusion is also affected by the JM. Participants (n = 5) viewed a moving vertical bar through an apparatus containing a variable filter, which could be adjusted, over one eye and a constant, nonadjustable filter over the other eye. The task was to move the variable filter to match the constant filter, which would null the illusion. The task was performed with and without the JM. Again, in contrast to the hypothesis, no significant effect between the two conditions was found.

In summary, the results clearly showed that altering feedback from the EOM via the JM did not affect the perceptual judgments of size or depth.49 The lack of a significant effect would not be surprising, given that the JM manipulation affects the registered vergence eye postions, but vergence itself is not a perfect cue to distance. In addition, the relative contribution of EOM afference to registered eye position has been estimated to be approximately 30%,10,11 and it might be even less significant for higher order perceptual judgments. In short, the perceptual phenomena of size and depth constancy depend on the perceived distance, which is an internally generated estimate of the viewing distance. In the real world, the neural estimate of viewing distance is based on multiple visual and ocular motor cues. In the present experiments, visual cues were removed, and ocular motor cues provided the only input for distance estimation. Nevertheless, the perturbed vergence signal was not taken into account by the CNS.

Effect of JM on the Saccadic System

In the next set of studies, we examined whether the JM affects the saccadic system and localization responses in the median plane.50 Based on the results from our vergence study, we hypothesized that participants would overshoot the target while the JM was performed. Participants (n = 10) were seated in the dark and were tested on a 2AFC procedure. The task was to make a saccadic eye movement to the peripheral target as fast as possible. The JM was performed during the programming and execution of the saccade or during the perceptual judgment task. In the control condition, the JM was not performed. All three conditions were fully randomized.

In contrast to the hypothesis, the JM did not affect the localization responses, as shown by the lack of differences between the conditions across examined variables: PSE, slope, and y-intercept values. In addition, the mean amplitude and velocity of saccadic eye

movements were not significantly different between the conditions. Overall, the study showed that the JM perturbation did not affect the saccadic system, which is in contrast to what we had found for the vergence system. The lack of difference can be explained by considering that the input to the non-twitch motoneurons that innervate the MIF comes from areas that are involved with programming of vergence eye movements, the ocular following response, and gaze-holding mechanisms, but which are not associated with the saccadic system.38

SUMMARY

Our behavioral studies with binocularly normal observers and people who have undergone strabismus surgery provide preliminary support for the hypothesis that the JM affects the registered eye position, but only for the vergence system, and only when the task requires localization in depth. Higher-order perceptual judgments that require accurate registration of absolute depth are not affected by the perturbation. The fact that the saccadic system was not affected is analogous to the findings of Guthrie and colleagues,51 who reported that cutting monkeys’ ophthalmic branch of the trigeminal nerve (i.e., deafferentation) altered their vergence responses but had no effect on conjugate eye movements. Our results reinforce the importance of the EOM proprioceptive feedback loop for binocular function.

A critical finding from our studies is the fact that neither vergence nor saccadic eye movements were affected by the JM. Since the non-twitch motoneurons do not add to the force that is used to move the eyes,52 the eye movement data from our study yield further support for our hypothesis that the JM most likely affects the activity of the non-twitch (γ) motoneurons, not the twitch (α) motoneurons. In summary, using a proxy method to alter the activity of the γ system (i.e., the JM manipulation), we have provided behavioral evidence to support Robinson’s original claim that the PE and MIF might be part of an “inverted muscle spindle.”

FUTURE DIRECTIONS FOR RESEARCH

Although our research provides novel insights into the mechanism of EOM feedback, it also raises questions. For instance, we have found that the JM affects the vergence system but not the saccadic system, which we believe can be explained by the premotor input to the non-twitch motoneurons. Since the premotor regions identified by Wasicky and colleagues38 also

include areas involved in gaze-holding mechanisms and ocular following response, the next step will be to examine how these responses are affected by the JM perturbation.

An important question that remains is, what is the role of the γ system and proprioception in general in ocular motor control and visuomotor behavior? The unique structure of the EOM and the fact that the cell body and the afferent pathway of the putative proprio- ceptors—the PE—have not been traced makes it more difficult to study the question. The role of EOM proprioception in the control and execution of different types of eye movements has been reviewed extensively by Donaldson,6 but the possibility that the γ system might modulate the gain of sensory feedback was only briefly mentioned by that researcher.

It has been suggested that in the skeletal system, “the fusimotor system allows state dependent parametric adjustment of proprioceptive feedback.”53 The implication of this hypothesis is that the γ loop is important for parametric adjustment of the feedback loops to match the demands of different tasks, and this might also be relevant for the ocular motor system. For example, many studies have shown that the relationship between the eye position and the firing frequency of the ocular motoneurons is highly correlated.54 However, a study by Mays and Porter reported that the relationship between eye position and firing rate is also dependent on the type of eye movement.55 In that study, recordings were made from the abducens nucleus during conjugate adduction and during convergence. Data showed that for a given eye position the firing rate increased during convergence compared to conjugate adduction. Extending these results, Miller and colleagues56 measured the oculorotary forces in the horizontal recti muscles to test whether the force developed in the lateral rectus is in fact higher in the converged state. Paradoxically and in contrast to the hypothesis, they found decreased forces in both the lateral and medial recti muscles during convergence. These results clearly show that the innervation of the EOM is much more complex than previously acknowledged, and it is possible that motor commands to the eye muscles differ during convergence and adduction. In light of our results, it should also be acknowledged that the gain of the proprioceptive system might be set differently for different types of eye movements.

In conclusion, after years of neglect, EOM proprioception has recently received its due attention. It is now indisputable that both afferent and efferent signals play a role in ocular motor control and visuomotor behavior and must be taken into account when developing models of ocular motor control. Furthermore, the efferent signals that have to be considered must include the α and γ systems.

ACKNOWLEDGMENTS Funding for the authors’ experiments came from the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, the Krembil Family Foundation, the Sir Jules Thorn Trust, and the Vision Science Research Program of the University of Toronto and the University Health Network. We thank our collaborators and those who have helped with this research in direct and indirect ways: B. Bahl, S. Bega, E. Gonzalez, S. Kraft, L. Lillakas, H. Ono, D. Smith, J. Trotter, R. Steinbach, L. Tarita-Nistor, M. Verrier, and A. Wong.

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ABSTRACT

The involuntary eye movements in patients with infantile nystagmus (IN) generate rapid to-and-fro motion of the retinal image, which has the potential to produce oscillopsia and the perception of motion smear. In normal subjects, extraretinal signals can neurally “cancel” the retinal image motion that occurs during eye movements and can reduce the extent of perceived motion smear. Previous studies indicate that extraretinal signals also contribute to perceived stability in subjects with IN. In addition to “canceling” the to-and-fro motion of the retinal image, extraretinal signals also partly compensate for changes in retinal-image orientation that occur during the torsional component of IN. We show that extraretinal signals reduce perceived motion smear in subjects with IN, preferentially for relative target motion in the opposite direction of slow-phase eye movements. A possible mechanism for the reduction of perceived motion smear is a decrease in the duration of the temporal impulse response function during eye movements. Temporal contrast sensitivities measured in normal observers, and subjects with IN are consistent with this possibility. Although extraretinal eye movement signals have similar influences on perceived stability and clarity in normal observers and subjects with IN, the characteristics of the operative neural mechanisms may not be identical.

The involuntary eye movements of patients with infantile nystagmus (IN) generate rapid to-and-fro motion

of the retinal image, which has the potential to degrade a number of visual functions. The beneficial influence of the low-velocity foveation periods of the IN waveform for visual functions such as visual acuity, contrast sensitivity, and stereopsis has previously been documented.1-8 However, in addition to its influence on visual function, the retinal image motion produced by IN also has the potential to produce oscillopsia and the perception of motion smear. In normal observers, the introduction of simulated foveation periods into rhythmic motion of the retinal image does little to protect against the perception of either oscillopsia or motion smear.2,9 Our hypothesis is that similar, but not necessarily identical, neural mechanisms facilitate the perception of a stable and relatively clear visual scene during normal eye movements and in IN. The purpose of this chapter is to present arguments and recent evidence that bear upon this hypothesis.

PERCEPTUAL STABILITY DURING IN

As proposed initially by von Helmholtz10 and elaborated on subsequently by von Holst and Mittelstädt,11 perceptual stability can be maintained during eye movements if the resulting displacement and motion of the retinal image are compared to (and “canceled” by) information about changes in the eye position. During normal eye movements, efference copy information and ocular muscle proprioception are two types of extraretinal signals that inform the brain about changes in eye position.12,13 Several studies

demonstrated that extraretinal signals also accompany the involuntary eye movements of subjects with IN and contribute to the perception of a stable visual world.14-17 For example, we showed that subjects with IN point relatively accurately to visual stimuli that are flashed briefly at various times, and therefore are imaged at different retinal locations, during the IN waveform.16 Because these stimuli were presented in an otherwise dark visual field, veridical pointing required accurate information of the eye position at the instant that the flashed stimulus was presented. Subsequently, Abadi et al.17 showed that patients with IN perceive oscillopsia if the magnitude of retinal image motion is either substantially larger or smaller than the amplitude of the nystagmus eye movements. These results also are consistent with the proposition that, as in normal observers, the perception of motion or stability in subjects with IN derives from the comparison of sensory information about the ongoing motion of the retinal image to extraretinal eye position signals.

Averbuch-Heller et al.18 reported that, in addition to rhythmic horizontal eye movements, most patients with horizontal IN manifest a torsional component of nystagmus. In 10 of the 13 subjects in this study, clockwise torsion (from the subjects’ point of view) was associated with the rightward horizontal component of IN. More recently, Dell’Osso et al.19 reported that approximately half of their subjects with horizontal IN also had rhythmic torsional and vertical eye movement components, consistent with a small seesaw nystagmus. We recorded horizontal, vertical, and torsional eye movements in a sample of 7 patients with IN using the magnetic search-coil technique as they fixated successively in the straight-ahead direction and at eight additional locations in horizontal, vertical, and oblique gaze. The results demonstrated the existence of a torsional nystagmus component in each subject.20 Across subjects, the mean amplitude of the torsional

component of IN in straight-ahead gaze ranged from 0.3° to 3.7°, which was larger than the amplitude of the vertical eye movements during nystagmus in all

7 subjects (t[6 df] = 7.58; p = 2.7 × 10 −4) (Table 2.1). In all of the subjects, clockwise torsional rotation accompa-

nied rightward fast phases of IN, and counterclockwise torsional rotation accompanied leftward fast phases of IN (Fig. 2.1), consistent with the results reported by Averbuch-Heller et al.18 for the majority of their subjects. In 5 of our 7 subjects, the directions of the torsional and horizontal slow phases of IN also consistently obeyed the same relationship.

Based primarily on recordings made in straightahead gaze, Averbuch-Heller et al.18 suggested that the torsional component of their subjects’ IN did not appear to conform to the torsional variations predicted from Listing’s law.10 In 3 of the 7 subjects with IN that we tested, neither the amplitude nor the direction of the torsional component of IN varied systematically with the direction of gaze (evaluated at ±12º from the straight-ahead direction, horizontally and vertically). In the other 4 subjects with IN, the amplitude, but not the direction, of the torsional component of IN varied according to the direction of gaze. In contrast to the subjects with IN, both the amplitude and the direction of the torsional eye movements that accompanied rightward and leftward optokinetic nystagmus (OKN) in normal observers varied with gaze position, as expected from Listing’s law. Figure 2.2 compares the amplitudes of horizontal and torsional eye movements in 3 subjects with IN and during OKN in 1 normal observer for two directions of vertical gaze, that is, 12º up and down from straight ahead at eye level. Straight lines are fit to the data obtained for each subject, separately for the two vertical gaze directions. If the torsional components of IN and OKN vary with the direction of gaze as predicted by Listing’s law, then the slope of the best fitting line is expected to

change between 12º down and 12º up gaze by approximately +0.21. This value follows from the formula that Helmholtz10 provided to calculate the torsion expected from Listing’s law:

Tan(T/2) = Tan(V/2) × Tan(H/2)

where T is the angle of torsion and H and V are the horizontal and vertical gaze directions. For small angles, the tangents of the half-angles can be replaced by the half-angles themselves, from which one can deduce that the expected change in slope between down and up gaze in Figure 2.2 does not depend on the location of the primary gaze position. For 3 normal observers, the observed change in slope between down and up gaze during OKN was 0.20 ± 0.003, in excellent agreement with the prediction from Listing’s law. In contrast, the change in slope for the subjects with IN averaged 0.15 ± 0.08, and 4 of the 7 subjects exhibited changes in slope that were less than half of the value predicted from Listing’s law. Even in the 3 subjects with IN whose torsional components changed

in amplitude with vertical gaze direction by amounts that are consistent with Listing’s law, the constant direction of the torsional component of IN for vertical (and horizontal) gaze changes of ±12º suggests substantial deviations of the primary position from the straight-ahead direction.

The torsional component of IN is relevant to perceived stability because torsional eye movements alter the orientation on the retina of the images produced by objects in the environment. Psychophysical evidence indicates that extraretinal signals are available to observers with normal eye movement control to compensate partly for the changes in torsional eye position that occur in eccentric positions of gaze.21-23 Less evidence is found for extraretinal compensation when the change in torsional eye position results from natural vestibular stimulation.24,25 We evaluated whether extraretinal signals compensate for the torsional component of IN by assessing orientation-discrimina- tion thresholds for horizontal and vertical lines that were flashed briefly in darkness. Thresholds were obtained for 6 of the 7 subjects with idiopathic IN.

In these 6 subjects, the standard deviation (SD) of torsional eye positions during 10 seconds of recording ranged from 0.53º to 2.0º (Table 2.1). The same subjects’ optimal orientation discrimination thresholds, assessed using 5.6° flashed horizontal lines, ranged from 0.58º to 1.5º.20 These results are in contrast to those of normal subjects, whose orientation-discrimi- nation thresholds are uniformly larger than the SDs of torsional eye position during fixation. Because orientation-discrimination thresholds in 3 of the subjects with IN are reliably smaller than the variability of their torsional eye position, we conclude that extraretinal signals compensate partially for the changes in retinal-image orientation that result from the torsional component of IN.

THEORETICAL CONSIDERATIONS CONCERNING EXTRARETINAL EYE MOVEMENT SIGNALS IN IN

An important potential limitation on the usefulness of extraretinal eye movement signals for maintaining perceptual stability in normal observers may be their limited temporal fidelity. A number of observations made by normal observers suggest that extraretinal eye movement signals are temporally low-pass filtered when compared to the time course of the eye movements themselves. For example, Purkinje (as cited by Grüsser et al.26) noted a perceptual lag between the time that he initiated a saccade and the time that he perceived an afterimage to move. Grüsser et al. found that when normal observers make back-and- forth saccades in the dark, the perceived amplitude of afterimage displacement decreases systematically with the temporal frequency of the eye movements. Because the afterimage is stabilized on the retina, perceived movement must be attributed to a change in the extraretinal eye movement signal. The observers in this study reported little or no perceived displacement of the afterimage when the frequency of back-and-forth saccades reached approximately 1.75 to 2 Hz, which is substantially lower than the median frequency of IN (ca. 3 to 3.5 Hz27,28). A similar result was reported for an electronically stabilized retinal image during smooth pursuit.29 Finally, normal observers report oscillopsia during high-frequency voluntary nystagmus30 as well as during sequences of uninterrupted eye movements at lower rates.31 If extraretinal eye movement signals are temporally low-pass filtered by as much as these studies suggest, then after filtering they should be much too attenuated to “cancel” the motion of the retinal image that occurs in subjects with IN.

Further evidence for temporal low-pass filtering of normal extraretinal eye movement signals comes from

reports that a target flashed briefly near the time of a saccade is systematically mislocalized. This mislocalization usually starts substantially before the onset of the saccade and continues for at least 100 milliseconds after the saccade is completed.32-34 The time course of these location errors is consistent with an extraretinal signal for saccades that changes much more slowly than the observer’s eye position. Recently, Pola35 presented modeling results to show that the protracted and non-monotonic time course of visual-location errors around the time of a saccade can be accounted for by the combination of an extraretinal eye position signal that faithfully represents the time course of the saccade and a persisting retinal signal from the flash, which he described using a temporal impulse response function (TIRf) with a duration of approximately 200 milliseconds. Although we agree that the retinal signal from a flash should be filtered temporally in accordance with the TIRf, Pola’s suggestion that the extraretinal signal accurately reflects the time course of a saccade is not easily reconciled with the observations of stabilized images by normal subjects, which were summarized earlier. A stabilized image that is viewed in darkness should produce a temporally unvarying retinal signal which, according to our understanding of Pola’s model, should undergo perceived displacements that mirror the movements of the eyes.

One way for extraretinal eye movement signals to contribute usefully to perceptual stability is for these signals to undergo less low-pass filtering in persons with IN than in normal observers. This suggested difference between the temporal filtering characteristic of the extraretinal signals in IN and normal observers is presumed to be an adaptive consequence of the early abnormal visual experience in IN. The absence of early abnormal experience and the associated adaptive changes would account for why oscillopsia occurs commonly in patients who acquire nystagmus as adults.36,37 However, an obvious question is why the extraretinal signals that accompany normal eye movements should be temporally low-pass filtered in the first place. An important benefit of low-pass filtering is that, after filtering, extraretinal and retinal signals should stay in reasonable temporal alignment regardless of modest relative timing differences that existed beforehand. To clarify, assume that extraretinal eye movement signals are generated, on average, at a fixed time with respect to the movement of the eyes. However, the latency of the information from the retina varies with stimulus characteristics, such as luminance and contrast.38-40 Studies of the Pulfrich, Hess, and flash-lag effects concur that a 2-log unit reduction in target luminance produces about a 40-millisecond increase in visual latency.41,42 If both retinal and extraretinal signals had high temporal fidelity, then