Neural Plasticity Following Surgical Correction of Strabismus in Monkeys.

Purpose: Although widely practiced, surgical treatment of strabismus has varying levels of success and permanence. In this study we investigated adaptive responses within the brain and the extraocular muscles (EOM) that occur following surgery and therefore determine long-term success of the treatment. Methods: Single cell responses were collected from cells in the oculomotor and abducens nuclei before and after two monkeys (M1, M2) with exotropia (divergent strabismus) underwent a strabismus correction surgery that involved weakening of the lateral rectus (LR) and strengthening of the medial rectus (MR) muscle of one eye. Eye movement and neuronal data were collected for up to 10 months after surgery during a monocular viewing smooth-pursuit task. These data were fit with a first-order equation and resulting coefficients were used to estimate the population neuronal drive (ND) to each EOM of both eyes. Results: Surgery resulted in a ∼70% reduction in strabismus angle in both animals that reverted toward presurgical misalignment by approximately 6 months after treatment. In the first month after surgery, the ND to the treated MR reduced in one animal and ND to the LR increased in the other animal, both indicating active neural plasticity that reduced the effectiveness of the treatment. Adaptive changes in ND to the untreated eye were also identified. Conclusions: Active neural and muscle plasticity corresponding to both the treated and the untreated eye determines longitudinal success following surgical correction of strabismus. Outcome of surgical treatment could be improved by identifying ways to enhance "positive" adaptation and limit "negative" adaptation.

Fixational Saccades and Their Relation to Fixation Instability in Strabismic Monkeys.

Purpose: To evaluate the contribution of fixational saccades toward fixation instability in strabismic monkeys. Methods: Binocular eye movements were measured as six experimental monkeys (five strabismic monkeys and one monkey with downbeat nystagmus) and one normal monkey fixated targets of two shapes (Optotype, Disk) and two sizes (0.5°, 2°) during monocular and binocular viewing. Fixational saccades were detected using an unsupervised clustering algorithm. Results: When compared with the normal monkey, amplitude and frequency of fixational saccades in both the viewing and nonviewing eye were greater in 3 of 5 strabismic monkeys (1-way ANOVA on ranks P < 0.001; median amplitude in the normal monkey viewing eye: 0.33°; experimental animals: median amplitude range 0.20-0.82°; median frequency in the normal monkey: 1.35/s; experimental animals: median frequency range 1.3-3.7/s). Increase in frequency of fixational saccades was largely due to quick phases of ongoing nystagmus. Fixational saccade amplitude was increased significantly (3-way ANOVA; P < 0.001) but by small magnitude depending on target shape and size (mean difference between disk and optotype targets = 0.02°; mean difference between 2° and 0.5° targets = 0.1°). Relationship between saccade amplitude and the Bivariate Contour Ellipse Area (BCEA) was nonlinear, showing saturation of saccade amplitude. Fixation instability in depth was significantly greater in strabismic monkeys (vergence BCEA: 0.63 deg2-2.15 deg2) compared with the normal animal (vergence BCEA: 0.15 deg2; P < 0.001). Conclusions: Increased fixational instability in strabismic monkeys is only partially due to increased amplitude and more frequent fixational saccades. Target parameter effects on fixational saccades are similar to previous findings of target effects on BCEA.

Comparison of Naso-temporal Asymmetry During Monocular Smooth Pursuit, Optokinetic Nystagmus, and Ocular Following Response in Strabismic Monkeys.

PURPOSE: Under monocular viewing conditions, humans and monkeys with infantile strabismus exhibit asymmetric naso-temporal (N-T) responses to motion stimuli. The goal of this study was to compare and contrast these N-T asymmetries during 3 visually mediated eye tracking tasks-optokinetic nystagmus (OKN), smooth pursuit (SP) response, and ocular following responses (OFR). METHODS: Two adult strabismic monkeys were tested under monocular viewing conditions during OKN, SP, or OFR stimulation. OKN stimulus was unidirectional motion of a 30°x30° random dot pattern at 20°, 40°, or 80°/s for 1 minute. OFR stimulus was brief (200 ms) unidirectional motion of a 38°x28°whitenoise at 20°, 40°, or 80°/s. SP stimulus consisted of foveal step-ramp target motion at 10°, 20°, or 40°/s. RESULTS: Mean nasalward steady state gain (0.87±0.16) was larger than temporalward gain (0.67±0.19) during monocular OKN (P<0.001). In monocular OFR, the asymmetry is manifested as a difference in OFR velocity gain (nasalward: 0.33±0.19, temporalward: 0.22±0.12; P=0.007). During monocular SP, mean nasal gain (0.97±0.2) was larger than temporal gain (0.66±0.14; P<0.001) and the mean nasalward acceleration during pursuit initiation (156±61°/s2) was larger than temporalward acceleration (118±77°/s2; P=0.04). Comparison of N-T asymmetry ratio across the 3 conditions using ANOVA showed no significant difference. CONCLUSIONS: N-T asymmetries are identified in all 3 visual tracking paradigms in both monkeys with either eye viewing. Our data are consistent with the current hypothesis for the mechanism for N-T asymmetry that invokes an imbalance in cortical drive to brainstem circuits.

Spatial patterns of fixation-switch behavior in strabismic monkeys.

PURPOSE: Patients with strabismus perceptually suppress information from one eye to avoid double vision. Mechanisms of visual suppression likely lead to fixation-switch behavior wherein the subject acquires targets with a specific eye depending on target location in space. The purpose of this study was to investigate spatial patterns of fixation-switch behavior in strabismic monkeys. METHODS: Eye movements were acquired in three exotropic and one esotropic monkey in a binocular viewing saccade task. Spatial patterns of fixation were analyzed by calculating incidence of using either eye to fixate targets presented at various gaze locations. RESULTS: Broadly, spatial fixation patterns and fixation-switch behavior followed expectations if a portion of the temporal retina was suppressed in exotropia and a portion of the nasal retina was suppressed in esotropia. Fixation-switch occurred for horizontal target locations that were approximately greater than halfway between the lines of sight of the foveating and strabismic eyes. Surprisingly, the border between right eye and left eye fixation zones was not sharply defined and there was a significant extent (>10°) over which the monkeys could acquire a target with either eye. CONCLUSIONS: We propose that spatial fixation patterns in strabismus can be accounted for in a decision framework wherein the oculomotor system has access to retinal error information from each eye and the brain chooses between them to prepare a saccade. For target locations approximately midway between the two foveae, strength of retinal error representations from each eye is almost equal, leading to trial-to-trial variability in choice of fixating eye.

Muscimol inactivation of caudal fastigial nucleus and posterior interposed nucleus in monkeys with strabismus.

Previously, we showed that neurons in the supraoculomotor area (SOA), known to encode vergence angle in normal monkeys, encode the horizontal eye misalignment in strabismic monkeys. The SOA receives afferent projections from the caudal fastigial nucleus (cFN) and the posterior interposed nucleus (PIN) in the cerebellum. The objectives of the present study were to investigate the potential roles of the cFN and PIN in 1) conjugate eye movements and 2) binocular eye alignment in strabismic monkeys. We used unilateral injections of the GABAA agonist muscimol to reversibly inactivate the cFN (4 injections in exotropic monkey S1 with ≈ 4° of exotropia; 5 injections in esotropic monkey S2 with ≈ 34° of esotropia) and the PIN (3 injections in monkey S1). cFN inactivation induced horizontal saccade dysmetria in all experiments (mean 39% increase in ipsilesional saccade gain and 26% decrease in contralesional gain). Also, mean contralesional smooth-pursuit gain was decreased by 31%. cFN inactivation induced a divergent change in eye alignment in both monkeys, with exotropia increasing by an average of 9.8° in monkey S1 and esotropia decreasing by an average of 11.2° in monkey S2 (P < 0.001). Unilateral PIN inactivation in monkey S1 resulted in a mean increase in the gain of upward saccades by 13% and also induced a convergent change in eye alignment, reducing exotropia by an average of 2.7° (P < 0.001). We conclude that cFN/PIN influences on conjugate eye movements in strabismic monkeys are similar to those postulated in normal monkeys and cFN/PIN play important and complementary roles in maintaining the steady-state misalignment in strabismus.

Three-dimensional kinematics of saccadic and pursuit eye movements in humans: relationship between Donders' and Listing's laws.

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.

Three-dimensional kinematics of saccadic eye movements in humans: is the "half-angle rule" obeyed?

The "half-angle rule" must be satisfied for Listing's law to be obeyed during saccades: 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 saccades. Horizontal and vertical saccades were recorded using the search coil technique, at different elevations and azimuths, in five normal humans. In all, eye positions were located on a twisted rather than planar surface. The mean tilt-angle coefficients (TACs; ratio of angle of eye velocity axis tilt to angle of eye position eccentricity) were 0.57 and 0.34 for horizontal and vertical saccades, respectively. TACs were significantly lower for vertical saccades. Thus, Listing's law is not perfectly obeyed during saccades. We suggest that the discrepancy in horizontal and vertical TACs causes eye positions to lie on a twisted rather than planar surface in three-dimensional space.

Responses of medial rectus motoneurons in monkeys with strabismus.

PURPOSE: Monkeys reared under conditions of alternating monocular occlusion during their first few months of life show large horizontal strabismus, "A" patterns, and dissociated vertical deviation. "A" patterns manifest as an inappropriate horizontal component in the deviated eye during vertical eye movements (cross-axis movement). The objective of this study was to investigate response properties of medial rectus motoneurons (MRMNs) in relation to strabismus properties. METHODS: Burst-tonic activity of 21 MRMNs in the oculomotor nucleus were recorded from two monkeys with exotropia as they performed horizontal and vertical smooth pursuit (0.2 Hz, ±10°) under monocular viewing conditions. Neuronal responses and horizontal component of eye movements were used to identify regression coefficients in a first-order model for each tracking condition. RESULTS: Comparison of position, velocity, and constant parameter coefficients, estimated from horizontal tracking data with either eye viewing, showed no significant differences (P > 0.07), indicating that neuronal activity could account for the horizontal misalignment. Comparison of the position, velocity, and constant parameter coefficients estimated from horizontal tracking and the cross-axis condition showed no significant differences (P > 0.07), suggesting that motoneuron activity could account for most of the inappropriate horizontal cross-axis movement observed in the covered eye during vertical smooth pursuit. CONCLUSIONS: These data suggest that, in animals with sensory-induced strabismus, central innervation to extraocular muscles is responsible for setting the state of strabismus. Mechanical factors such as muscle length adaptation (for horizontal misalignment) and pulley heterotopy or static torsion (for "A" patterns) likely do not play a major role in determining properties in a sensory-induced strabismus.

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.

Crossover trial of gabapentin and memantine as treatment for acquired nystagmus.

We conducted a masked, crossover, therapeutic trial of gabapentin (1,200mg/day) versus memantine (40 mg/day) for acquired nystagmus in 10 patients (aged 28-61 years; 7 female; 3 multiple sclerosis [MS]; 6 post-stroke; 1 post-traumatic). Nystagmus was pendular in 6 patients (4 oculopalatal tremor; 2 MS) and jerk upbeat, hemi-seesaw, torsional, or upbeat-diagonal in each of the others. For the group, both drugs reduced median eye speed (p < 0.001), gabapentin by 32.8% and memantine by 27.8%, and improved visual acuity (p < 0.05). Each patient improved with 1 or both drugs. Side effects included unsteadiness with gabapentin and lethargy with memantine. Both drugs should be considered as treatment for acquired forms of nystagmus.

Selective defects of visual tracking in progressive supranuclear palsy (PSP): implications for mechanisms of motion vision.

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/degree. 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/degree grating moving sinusoidally through several cycles at frequencies between 0.1 and 2.5 Hz. We found that OFR amplitude, and its dependence on spatial frequency, was similar in PSP patients (group mean 0.10 degree) and control subjects (0.11 degree), 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.

The linear vestibulo-ocular reflex, locomotion and falls in neurological disorders.

PURPOSE: During locomotion, head perturbations, consisting of rotations and translations (linear movements), occur with predominant frequencies of 0.5-5.0 Hz. The vestibular reflexes act at short latency to safeguard clear vision and stable posture during locomotion. Much is known about the angular vestibulo-ocular reflex (aVOR) in response to head rotations, which depend on the semicircular canals of the vestibular labyrinth. However, the means to test reliably the linear or translational vestibulo-ocular reflex (tVOR), which depends on the otolithic organs, has only become available more recently. METHODS: We used a moving platform to translate normal human subjects vertically at frequencies similar to those occurring during locomotion, under ambient illumination. RESULTS: Our findings suggested that, whereas aVOR is concerned with stabilizing images of visual targets on the retina to optimize visual acuity, tVOR seems best suited to minimize retinal image motion between objects lying in different depth planes, in order to optimize motion parallax information. We then asked whether the tVOR functioned abnormally in patients with two neurological disorders that often cause falls: progressive supranuclear palsy (PSP) and cerebellar ataxia. We found that patients with PSP cannot adjust tVOR responses appropriately during viewing of near objects, nor converge their eyes. Vestibular-evoked myogenic potentials (VEMPs), an otolith-spinal reflex, are also impaired in PSP patients. Patients with cerebellar ataxia also lack the ability to adjust tVOR for near viewing, even though they may be able to converge. CONCLUSIONS: Taken together, our studies suggest that abnormal otolithic vestibular reflexes contribute to postural instability in PSP and cerebellar ataxia, and deserve further investigation.

Effect of vergence on human ocular following response (OFR).

The human ocular following response (OFR) is a preattentive, short-latency visual-field-holding mechanism, which is enhanced if the moving stimulus is applied in the wake of a saccade. Since most natural gaze shifts incorporate both saccadic and vergence components, we asked whether the OFR was also enhanced during vergence. Ten subjects viewed vertically moving sine-wave gratings on a video monitor at 45 cm that had a temporal frequency of 16.7 Hz, contrast of 32%, and spatial frequency of 0.17, 0.27, or 0.44 cycle/deg. In Fixation/OFR experiments, subjects fixed on a white central dot on the video monitor, which disappeared at the beginning of each trial, just as the sinusoidal grating started moving up or down. We measured the change in eye position in the 70- to 150-ms open-loop interval following stimulus onset. Group mean downward responses were larger (0.14 degrees) and made at shorter latency (85 ms) than upward responses (0.10 degrees and 96 ms). The direction of eye drifts during control trials, when gratings remained stationary, was unrelated to the prior response. During vergence/OFR experiments, subjects switched their fixation point between the white dot at 45 cm and a red spot at 15 cm, cued by the disappearance of one target and appearance of the other. When horizontal vergence velocity exceeded 15 degrees/s, motion of sinusoidal gratings commenced and elicited the vertical OFR. Subjects showed significantly (P<0.001) larger OFR when the moving stimulus was presented during convergence (group mean increase of 46%) or divergence (group mean increase of 36%) compared with following fixation. Since gaze shifts between near and far are common during natural activities, we postulate that the increase of OFR during vergence movements reflects enhancement of early cortical motion processing, which serves to stabilize the visual field as the eyes approach their new fixation point.