Daniel L. Adams

People with strabismus acquired during childhood do not experience diplopia (double vision). To investigate how perception of the duplicate image is suppressed, we raised two male monkeys with alternating exotropia by disinserting the medial rectus muscle in each eye at age four weeks. Once the animals were mature, they were brought to the laboratory and trained to fixate a small spot while recordings were made in primary visual cortex (V1). Drifting gratings were presented to the receptive fields of 500 single neurons for eight interleaved conditions: (1) right eye monocular; (2) left eye monocular; (3) right eye's field, right eye fixating; (4) right eye's field, left eye fixating; (5) left eye's field, right eye fixating; (6) left eye's field, left eye fixating; (7) both eyes' fields, right eye fixating; (8) both eyes' fields, left eye fixating. As expected, ocular dominance histograms showed a monocular bias compared with normal animals, but many cells could still be driven via both eyes. Overall, neuronal responses were not affected by switches in ocular fixation. Individual neurons exhibited binocular interactions, but mean population indices indicated no net interocular suppression or facilitation. Even neurons located in cortex with reduced cytochrome oxidase (CO) activity, representing portions of the nasal visual field where perception is suppressed during binocular viewing, showed no net inhibition. These data indicate that V1 neurons do not appear to reflect strabismic suppression and therefore the elimination of diplopia is likely to be mediated at a higher cortical level.SIGNIFICANCE STATEMENTIn patients with strabismus, images fall on non-corresponding points in the two retinas. Only one image is perceived, because signals emanating from the other eye that convey the duplicate image are suppressed. The benefit is that diplopia is prevented, but the penalty is that the visual feedback required to adjust eye muscle tone to realign the globes is eliminated. Here, we report the first electrophysiological recordings from the primary visual cortex (V1) in awake monkeys raised with strabismus. The experiments were designed to reveal how perception of double images is avoided.

The cerebral cortex is supplied by vascular microlobules, each comprised of a half dozen penetrating arterioles that surround a central draining venule. The surface arterioles that feed the penetrating arterioles are interconnected via an extensively anastomotic plexus. Embolic occlusion of a small surface arteriole rarely produces a local infarct, because collateral blood flow is available through the vascular reticulum. Collateral flow also protects against infarct after occlusion of a single penetrating arteriole. Cortical infarction requires blockage of a major arterial trunk, with arrest of blood flow to a relatively large vascular territory. For striate cortex, the major vessels compromised by emboli are the inferior calcarine and superior calcarine arteries, as well as the distal branches of the middle cerebral artery. Their vascular territories have a fairly consistent relationship with the retinotopic map. Consequently, occlusion by emboli results in stereotypical visual field defects. The organization of the arterial supply to the occipital lobe provides an anatomical explanation for a phenomenon that has long puzzled neuro-ophthalmologists, namely, that of the myriad potential patterns of cortical visual field loss, only a few are encountered commonly from embolic cortical stroke.

In subjects with alternating strabismus, either eye can be used to saccade to visual targets. The brain must calculate the correct vector for each saccade, which will depend on the eye chosen to make it. The superior colliculus, a major midbrain center for saccade generation, was examined to determine whether the maps serving each eye were shifted to compensate for strabismus. Alternating exotropia was induced in two male macaques at age 1 month by sectioning the tendons of the medial recti. Once the animals grew to maturity, they were trained to fixate targets with either eye. Receptive fields were mapped in the superior colliculus using a sparse noise stimulus while the monkeys alternated fixation. For some neurons, sparse noise was presented dichoptically to probe for anomalous retinal correspondence. After recordings, microstimulation was applied to compare sensory and motor maps. The data showed that receptive fields were offset in position by the ocular deviation, but otherwise remained aligned. In one animal, the left eye's coordinates were rotated ∼20° clockwise with respect to those of the right eye. This was explained by a corresponding cyclorotation of the ocular fundi, which produced an A-pattern deviation. Microstimulation drove the eyes accurately to the site of receptive fields, as in normal animals. Single-cell recordings uncovered no evidence for anomalous retinal correspondence. Despite strabismus, neurons remained responsive to stimulation of either eye. Misalignment of the eyes early in life does not alter the organization of topographic maps or disrupt binocular convergence in the superior colliculus.SIGNIFICANCE STATEMENTPatients with strabismus are able to make rapid eye movements, known as saccades, toward visual targets almost as gracefully as subjects with normal binocular alignment. They can even exercise the option of using the right eye or the left eye. It is unknown how the brain measures the degree of ocular misalignment and uses it to compute the appropriate saccade for either eye. The obvious place to investigate is the superior colliculus, a midbrain oculomotor center responsible for the generation of saccades. Here, we report the first experiments in the superior colliculus of awake primates with strabismus using a combination of single-cell recordings and microstimulation to explore the organization of its topographic maps.

Purpose: To determine if the deviation angle changes in subjects with intermittent exotropia as they alternate fixation between the right and left eye in primary gaze. Methods: In this prospective observational cohort study, 37 subjects with intermittent exotropia were tested for evidence of incomitance. The position of each eye was recorded with a video tracker during fixation on a small central target. A cover–uncover test was performed by occluding one eye with a shutter that passed infrared light, allowing continuous tracking of both eyes. The deviation angle was measured during periods of right eye and left eye fixation. Incomitance was assessed as a function of eye preference, fixation stability, and exotropia variability. Results: The mean exotropia was 18.2° ± 8.1°. A difference between right exotropia and left exotropia was detectable in 16/37 subjects. Allowing for potential tracking error, the incomitance had a mean amplitude of 1.7°. It was not related to a difference in accommodative effort, eye preference, fixation stability, or variability in deviation. Conclusions: Comitance is regarded as a feature that distinguishes strabismus from paralytic or restrictive processes. Unexpectedly, eye tracking during the cover–uncover test showed that incomitance is present in approximately 40% of subjects with intermittent exotropia. It averages 10% of the exotropia, and can equal up to 5°. When substantial, it may be worth considering when planning surgical correction.

The superior colliculus is a major brain stem structure for the production of saccadic eye movements. Electrical stimulation at any given point in the motor map generates saccades of defined amplitude and direction. It is unknown how this saccade map is affected by strabismus. Three macaques were raised with exotropia, an outwards ocular deviation, by detaching the medial rectus tendon in each eye at age 1 mo. The animals were able to make saccades to targets with either eye and appeared to alternate fixation freely. To probe the organization of the superior colliculus, microstimulation was applied at multiple sites, with the animals either free-viewing or fixating a target. On average, microstimulation drove nearly conjugate saccades, similar in both amplitude and direction but separated by the ocular deviation. Two monkeys showed a pattern deviation, characterized by a systematic change in the relative position of the two eyes with certain changes in gaze angle. These animals' saccades were slightly different for the right eye and left eye in their amplitude or direction. The differences were consistent with the animals' underlying pattern deviation, measured during static fixation and smooth pursuit. The tectal map for saccade generation appears to be normal in strabismus, but saccades may be affected by changes in the strabismic deviation that occur with different gaze angles.

In individuals with normal binocular function, visual feedback ensures accurate fixation on targets, so that the eyes maintain a state of nearly perfect alignment.^1,2 In strabismus, the inability to fuse images means that one eye is not directed at a target. Without a target, the deviated eye is more unstable in position than the fixating eye.³ Numerous studies have documented the variability of ocular misalignment in strabismus.^4-12 Reported values depend on observer skill, the method used to measure the deviation angle, the characteristics of the patient population, and the true variability in deviation angle. The Hirschberg, Krimsky, and prism alternate cover tests are relied on for clinical purposes but potentially error prone.^13-15 When repeated assessment of a patient’s strabismus angle yields variable results, it would be helpful to know whether the variability is likely to represent simple measurement error or real biological fluctuation in the magnitude of the ocular deviation.

The patches in primary visual cortex constitute hot spots of metabolic activity, manifested by enhanced levels of cytochrome oxidase (CO) activity. They are also labeled preferentially by immunostaining for glutamic acid decarboxylase (GAD), γ-aminobutyric acid (GABA), and parvalbumin. However, calbindin shows stronger immunoreactivity outside patches. In light of this discrepancy, the distribution of the vesicular GABA transporter (VGAT) was examined in striate cortex of two normal macaques. VGAT immunoreactivity was strongest in layers 4B, 4Cα, and 5. In tangential sections, the distribution of CO, GAD, and VGAT was compared in layer 2/3. There was a close match between all three labels. This finding indicates that GABA synthesis is enriched in patches, and that inhibitory synapses are more active in patches than interpatches.

To probe the mechanism of visual suppression, we have raised macaques with strabismus by disinserting the medial rectus muscle in each eye at 1 mo of age. Typically, this operation produces a comitant, alternating exotropia with normal acuity in each eye. Here we describe an unusual occurrence: the development of severe amblyopia in one eye of a monkey after induction of exotropia. Shortly after surgery, the animal demonstrated a strong fixation preference for the left eye, with apparent suppression of the right eye. Later, behavioral testing showed inability to track or to saccade to targets with the right eye. With the left eye occluded, the animal demonstrated no visually guided behavior. Optokinetic nystagmus was absent in the right eye. Metabolic activity in striate cortex was assessed by processing the tissue for cytochrome oxidase (CO). Amblyopia caused loss of CO in one eye's rows of patches, presumably those serving the blind eye. Layers 4A and 4B showed columns of reduced CO, in register with pale rows of patches in layer 2/3. Layers 4C, 5, and 6 also showed columns of CO activity, but remarkably, comparison with more superficial layers showed a reversal in contrast. In other words, pale CO staining in layers 2/3, 4A, and 4B was aligned with dark CO staining in layers 4C, 5, and 6. No experimental intervention or deprivation paradigm has been reported previously to produce opposite effects on metabolic activity in layers 2/3, 4A, and 4B vs. layers 4C, 5, and 6 within a given eye's columns.