Anand C. Joshi

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.

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.

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.

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

ABSTRACT 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.