Investigating the Role of the Superior Colliculus in Strabismus

Purpose: Strabismus is a global problem with prevalence of 3-5% in infants around the world. Besides eye misalignment, which leads to difficulty in perception of depth, other associated problems include fixation instability, unequal saccades in two eyes and nystagmus. Traditionally, extraocular muscles were thought to be responsible for ocular misalignment. However, recent data suggests that disrupted vergence circuits in the brain contributes towards strabismus. Before improving treatment modalities, a better understanding of basic neural mechanism and structures involved in strabismus is necessary. Superior Colliculus (SC) is an important visual-oculomotor structure that has been implicated in control of vergence in cats, monkeys, and humans. The goal of this dissertation was to understand the role of the SC in strabismus. Methods: Prism-reared adult strabismic monkeys (n=6) were used. Scleral search coils were used to measure eye movements. Behavioral-study: Fixational data from five strabismic and one normal monkeys were collected to determine the relationship between fixational saccade amplitude and fixational stability. Electrical stimulation-study: Electrical stimulation (10-40µamp, 400Hz, 500msec) was applied to the SC of three strabismic monkeys to investigate the effect of SC activation on strabismus angle. Neurophysiology-study: Single-cell recording within the rostral SC of two strabismic monkeys was used to localize cells related to eye misalignment. Firing properties of these cells were also studied during 5° and 15° ipsilateral and contralateral saccades and during brief periods of target extinction (300-400ms). Muscimol inactivation-study: Muscimol, a GABA-a agonist inhibitory neurotransmitter, was used to pharmacologically inactivate the SC in two strabismic monkeys to determine a causal role between SC activity and eye misalignment as well as fixation instability of strabismic animals. Results: Behavioral-study: Amplitude of fixational saccades was larger in strabismic monkeys than that of normal monkeys (p<0.001; one-way-ANOVA). There was a nonlinear relationship between amplitude of fixational saccades and fixation instability such that fixational saccade amplitude saturates for larger fixation instability. Vergence BCEA (instability in depth) was poor in strabismic monkeys. Electrical stimulation-study: Electrical stimulation of SC produced significant changes in the horizontal misalignment that could be either convergent or divergent. Amplitude of electrically-evoked saccades was similar in the two eyes (p>0.05; paired t-test), but directions were different. Approximately 50% of the change in strabismic angle was due to saccade disconjugacy and the other 50% was due to disconjugate post-saccadic drift. Neurophysiological-study: Cells related to eye misalignment were found within the rSC. Some cells showed increased responses for small angles of exotropia (Convergence or near-response cells - NRC) while others showed increased response for larger angles of exotropia (Divergence or far-response cells - FRC). Neural sensitivity of these cells was similar to that of normal monkeys for both NRC (M1=3.2±1.6 spks/sec/°; M2= 3.0±2.6 spks/sec/°) and FRC (M1= -3.3±1.8 spks/sec/°; M2= -2.2±1.2 spks/sec/°), but firing thresholds were significantly shifted towards the habitual strabismus angle. These cells decrease their discharge during saccades and were not affected by the presence of a visual stimulus. A subset of cells also encoded the quick phases of nystagmus. Muscimol inactivation-study: We performed a total of 13 injections (11 muscimol; 2 saline control) within the right (n=6) or left (n=7) SC of two strabismic monkeys. There was significant convergent (1.7°±1.3°) or divergent (-4.7°±3.2°) change due to inactivation of SC (p<0.01). The change in fixation instability was not significant. Conclusion: This series of experiment shows that the SC is part of a disrupted vergence circuit that contributes to the development and maintenance of strabismus. Anatomical connections from the SC to the abducens nucleus and the lateral rectus muscle or from the SC to the supraoculomotor area and then to the oculomotor nucleus and medial rectus muscle are potential circuits by which the SC might influence strabismus angle.