5

Ocular Dominance Columns

of V1 (Striate Cortex)

LGN

2/3

4B

4C

R L R L

Periventricular

White Matter

Projections

Fig. 5.1 Neuroanatomic basis for binocular vision. Monocular retinogeniculate projections from left eye (temporal retina-nasal visual hemifiled) and right eye (nasal retina-temporal hemifield) remain segregated up to and within the input layer of ocular dominance columns (ODCs) in V1, layer 4C (striate visual cortex). Binocular vision is made possible by horizontal connections between ODCs of opposite ocularity in upper layers 4B and 2/3 (as well as lower layers 5/6, not shown). RE inputs red;

LE inputs blue

R LR L

Correlated

Activity

b

Stereo-blindness

Esotropia and

Gaze Asymmetries

R LR L

De-Correlated

Activity

Fig. 5.2 Horizontal connections for binocular vision in V1 of normal (correlated activity) vs. strabismic (decorrelated) primate, layer 2–4B. (a) V1 of normal primates is characterized by equal numbers of monocular and binocular connections. (b) In strabismic primates, the connections are predominantly monocular (i.e., a paucity of binocular connections). RE inputs red;

LE blue; binocular violet

5.1.11Too Few Cortical Binocular Connections in Strabismic Primate

Maturation of binocular connections in V1 requires correlated (synchronous) activity between right and left eye inputs (Fig. 5.2a) [66]. Decorrelation of inputs, by natural strabismus [68, 70], or as a consequence of experimental manipulations that produce retinal image noncorrespondence [66, 67], causes loss of binocular horizontal connections (Fig. 5.2b). Monocular connections between ODCs of the same ocularity are maintained. The loss is due to excessive pruning of connections, beyond the normal process of axon retraction and refinement that takes place within and between ODCs in the first weeks of life. (Captured in the neuroscience dictum: “Cells that fire together, wire together. Cells that fire apart, depart.”) The paucity of binocular connections is accompanied by loss of binocular responsiveness and disparity sensitivity, measured electrophysiologically, in V1 neurons [55, 63, 64]. The companion behavioral deficits are stereoblindness and absence of fusional vergence [47, 65].

5.1.12Projections from Striate Cortex (Area V1) to Extrastriate Cortex (Areas MT/MST)

Projections from V1 layer 4B feed forward to regions of extrastriate visual cortex, in particular the middle temporal and middle superior temporal area (MT/MST) [75]. MT and MST mediate pursuit/OKN and a closely related type of tracking movement, ocular following [73, 74]. MT/MST neurons are directionally selective and sensitive to binocular disparity, guiding both conjugate and disconjugate (near-far) tracking [80–82]. In normal primates, greater than 90% of MT/MST neurons exhibit balanced, binocular responses. In strabismic primates, the responses are predominantly monocular, indicating that the loss of binocularity found in V1 is passed on in the projections to MT/MST.

5.1.13Inter-Ocular Suppression Rather than Cooperation in Strabismic Cortex

When the eyes are misaligned, suppression is necessary to avoid diplopia or visual confusion. Suppression is a major sensorial abnormality in humans and monkeys

with infantile strabismus.Visual inputs may be suppressed from one eye continuously (causing unilateral amblyopia), or commonly in infantile strabismus, from each eye alternately ~50% of the time (alternate fixation) [83, 84]. In normal animals, horizontal connections between ODCs can mediate suppression when conflicting stimuli activate neurons in neighboring ODCs [85, 86].

The mitochondrial enzyme cytochrome oxidase (CO) is used to reveal neuronal activity within ODCs [87–89]. In normal primates, the input layer of area V1, layer 4C, shows a uniform pattern of CO activity in right eye and left eye columns (Fig. 5.3a), reflecting equal activity (absence of inter-ocular suppression). Unequal CO activity is a general finding in area V1 of primates who have strabismus [78, 90], amblyopia [91], or both [92]. The unequal activity is seen as reduced CO activity (metabolic suppression) in the ODCs driven by one eye in each cerebral hemisphere (Fig. 5.3b). When strabismus is combined with amblyopia, metabolic suppression is more pronounced.

The CO abnormality in monkey cortex correlates with clinical observations in strabismic humans. Binocularity is impaired to a greater degree, and suppression tends to be more pronounced, in patients who have combined

R LR L

Normal

b

Inter-ocular

Metabolic

Suppression

R LR L

Strabismic

Fig. 5.3 Metabolic activity in neighboring ODCs within V1 of normal vs. strabismic primate. (a) In normal, Layer 4C stains uniformly for the metabolic enzyme cytochrome oxidase (CO) (shown as brown), indicating equal activity in right-eye vs. left-eye columns. (b) In strabismic, a narrow monocular zone within the dominant ODCs (shown here as left-eye) shows normal metabolic activity (brown), but ODCs belonging to the suppressed eye (shown as right-eye) and binocular border zones between ODCs are pale, connoting abnormally low – i.e., suppressed – activity

strabismus and amblyopia, as compared with strabismus alone (that is, alternating fixation). The metabolic abnormalities are found throughout V1 when suppression is widespread; alternatively, suppression is confined to zones of V1 that match retinotopically the location of a suppression scotoma. The metabolic suppression is not found in the LGN, which is composed of neurons driven monocularly from each eye without binocular interaction. These findings imply that abnormal binocular interaction in V1 leads to heightened competition between ODCs of opposite ocularity, with suppression of metabolic activity in opposite-eye ODCs. The abnormalitis add to our knowledge of the brain damage caused by unrepaired strabismus. As noted in the preceding sections, the e ects include an ~50% reduction in longrange, excitatory binocular horizontal connections joining ODCs of opposite ocularity [70, 93]. In the presence of strabismus, the remaining 50% of binocular connections (long-range, short-range or a combination) may be predominantly inhibitory.

5.1.14Naso-Temporal Inequalities of Cortical Suppression

Psychophysical studies of the development of the visual hemifields in normal human infants indicate that temporal retina sensitivity matures slower than nasal retina sensitivity [94,95].The nasotemporal asymmetry in sensitivity diminishes if the infant develops normal vision, but lower temporal sensitivity remains permanently if early binocular development is disrupted by strabismus or amblyopia [96–98] (for review, see [78]).

In strabismic animals, metabolic suppression tends to be most apparent in ODCs driven by the ipsilateral eye in V1 of both the right and left hemispheres. Ipsilateral inputs originate from the temporal hemi-retinae of each eye, implying that inputs to V1 from the temporal hemiretinae are at a developmental disadvantage [78, 92, 99]. The human psychophysical findings, together with the monkey anatomic findings, reinforce the conclusion that abnormal binocular experience in early infancy unfairly punishes visual neurons that are slow to develop and fewer in number, that is, those driven by the temporal hemiretina [78].

5.1.15Persistent Nasalward Visuomotor Biases in Strabismic Primate

If normal maturation of binocularity is impeded by eye misalignment, the innate nasalward biases of eye tracking

phase) gaze drift. In newborns, the outputs from V1 to each area MST appear to favor innately the contralateral eye (i.e., inputs from the right eye make stronger connection – through area V1 of both hemispheres – to area MST of the left hemisphere) [13, 76]. The contralateral-

eye-to-MST connectivity advantage is consistent with an innate, contralateral-eye-to-V1 connectivity advantage. (Captured in twin dictums: “first come, first served ”and “majority rules.”) V1 neurons in each hemisphere, driven by the nasal hemiretinae (contralateral eye), develop earlier and outnumber (by a ratio of ~53:47 in primate) neurons from the temporal hemiretinae (ipsilateral eye).Area MST on the side ipsilateral to the viewing eye can only be accessed through binocular V1/MT connections.

The contralateral eye-to-MST connectivity bias provides a mechanism for the nasalward tracking bias, evident before onset of binocularity (Fig. 5.4). Right eye viewing activates right eye ODCs in each area V1. Right eye ODCs connect preferentially to the left area MST. The left area MST mediates ipsiversive/leftward tracking, which is nasalward tracking with respect to the viewing (right) eye. When binocular connections mature, right

eye ODCs gain equal access to neurons within areas MST of the right and left hemisphere, and the nasalward bias disappears. (Captured in the dictum: “Tracking from ear to nose will balance as binocularity grows.”) If binocular connections are lost, the nasalward bias persists and is exaggerated. The bias is evident clinically (Fig. 5.5) as a pathologic naso-temporal asymmetry of pursuit/OKN and a nasalward (slow phase) drift of gaze-holding (latent nystagmus) [103, 104].

Area MST neurons are sensitive to binocular disparity and also drive fusional vergence eye movements [80, 82]. Eye movement recordings in a primate with infantile esotropia showed inappropriate activation of convergence whenever nasalward monocular OKN was evoked [105]. Neuroanatomic analysis of V1 in this monkey showed a paucity of binocular connections and metabolic evidence of heightened interocular suppression. The

Fig. 5.5 Nasalward vergence and gaze asymmetries in strabismic humans and monkeys. Fusional vergence: esodeviation of the nonfixating eye, evident as alternating esotropia. Tracking pursuit/OKN: horizontal smooth pursuit is asymmetric during monocular viewing. Pursuit is smooth (normal) when target motion is nasalward in the visual field. Pursuit is cogwheel (low gain-abnor- mal) when the target moves temporalward. The movements of the two eyes are conjugate, and the direction of the asymmetry reverses instantaneously with a change of fixating eye, so that the direction of robust pursuit is always for nasalward motion in the visual field. Gaze holdinglatent nystagmus: viewing with the right-eye, both eyes have a nasalward slow-phase drift, followed by temporalward refoveating fast-phase microsaccades. The direction of the nystagmus reverses instantaneously when the left eye is fixating, so that the slow phase is nasalward with respect to the fixating eye

Fusional Vergence (esotropia)

Tracking (pursuit/OKN)

Gaze Holding (latent nystagmus)