Childhood Onset Strabismus: A Neurotrophic Factor Hypothesis.

Strabismus is a genetically heterogeneous disorder with complex molecular and neurophysiological causes. Evidence in the literature suggests a strong role for motor innervation in the etiology of strabismus, which connects central neural processes to the peripheral extraocular muscles. Current treatments of strabismus through surgery show that an inherent sensorimotor plasticity in the ocular motor system decreases the effectiveness of treatment, often driving eye alignment back toward its misaligned pre-surgical state by altering extraocular muscle tonus. There is recent interest in capitalizing on existing biological processes in extraocular muscles to overcome these compensatory mechanisms. Neurotrophins are trophic factors that regulate survival and development in neurons and muscle, including extraocular muscles. Local administration of neurotrophins to extraocular muscles partially reversed strabismus in an animal model of strabismus. The hypothesis is that sustained release of neurotrophins gives more time for the ocular motor system to adapt to a slow change in alignment in the desired direction. The effect of neurotrophins on extraocular muscles is complex, as different neurotrophic factors have diverse effects on extraocular muscle contraction profiles, patterns of innervation, and density of extraocular muscle precursor cells. Neurotrophic factors show promise as a therapeutic option for strabismus, which may help to improve treatment outcomes and offset devastating amblyopia and psychosocial effects of disease in strabismus patients.

Eye alignment changes caused by sustained GDNF treatment of an extraocular muscle in infant non-human primates.

The ability of sustained treatment of a single extraocular muscle with glial cell line-derived neurotrophic factor (GDNF) to produce a strabismus in infant non-human primates was tested. Six infant non-human primates received a pellet containing GDNF, releasing 2 µg/day for 90 days, on one medial rectus muscle. Eye alignment was assessed up to 6 months. Five of the six animals showed a slow decrease in eye misalignment from the significant exotropia present at birth, ending with approximately 10° of exotropia. Controls became orthotropic. Misalignment averaged 8° three months after treatment ended. After sustained GDNF treatment, few changes were seen in mean myofiber cross-sectional areas compared to age-matched naïve controls. Neuromuscular junction number was unaltered in the medial rectus muscles, but were significantly reduced in the untreated lateral recti. Neuromuscular junctions on slow fibers became multiply innervated after this sustained GDNF treatment. Pitx2-positive cells significantly decreased in treated and contralateral medial rectus muscles. Our study suggests that balanced GDNF signaling plays a role in normal development and maintenance of orthotropia. Sustained GDNF treatment of one medial rectus muscle resulted in a measurable misalignment largely maintained 3 months after treatment ended. Structural changes suggest mechanisms for producing an imbalance in muscle function.

Response of supraoculomotor area neurons during combined saccade-vergence movements.

Combined saccade-vergence movements allow humans and other primates to align their eyes with objects of interest in three-dimensions. In the absence of saccades, vergence movements are typically slow, symmetrical movements of the two eyes in opposite directions. However, combined saccade-vergence movements produce vergence velocities that exceed values observed during vergence alone. This phenomenon is often called "vergence enhancement", or "saccade-facilitated vergence," though it is important to consider that rapid vergence changes, known as "vergence transients," are also observed during conjugate saccades. We developed a visual target array that allows monkeys to make saccades in all directions between targets spaced at distances that correspond to ~1° intervals of vergence angle relative to the monkey. We recorded the activity of vergence-sensitive neurons in the supra-oculomotor area (SOA), located dorsal and lateral to the oculomotor nucleus while monkeys made saccades with vergence amplitudes ranging from 0 to 10°. The primary focus of this study was to test the hypothesis that neurons in the SOA fire a high frequency burst of spikes during saccades that could generate the enhanced vergence. We found that individual neurons encode vergence velocity during both saccadic and non-saccadic vergence, yet firing rates were insufficient to produce the observed enhancement of vergence velocity. Our results are consistent with the hypothesis that slow vergence changes are encoded by the SOA while fast vergence movements require an additional contribution from the saccadic system. NEW & NOTEWORTHY Research into combined saccade-vergence movements has so far focused on exploring the saccadic neural circuitry, leading to diverging hypotheses regarding the role of the vergence system in this behavior. In this study, we report the first quantitative analysis of the discharge of individual neurons that encode vergence velocity in the monkey brain stem during combined saccade-vergence movements.

Comparison of three models of saccade disconjugacy in strabismus.

In pattern strabismus the horizontal and vertical misalignments vary with eye position along the orthogonal axis. The disorder is typically described in terms of overaction or underaction of oblique muscles. Recent behavioral studies in humans and monkeys, however, have reported that such actions are insufficient to fully explain the patterns of directional and amplitude disconjugacy of saccades. There is mounting evidence that the oculomotor abnormalities associated with strabismus are at least partially attributable to neurophysiological abnormalities. A number of control systems models have been developed to simulate the kinematic characteristics of saccades in normal primates. In the present study we sought to determine whether these models could simulate the abnormalities of saccades in strabismus by making two assumptions: 1) in strabismus the burst generator gains differ for the two eyes and 2) abnormal crosstalk exists between the horizontal and vertical saccadic circuits in the brain stem. We tested three models, distinguished by the location of the horizontal-vertical crosstalk. All three models were able to simulate amplitude and directional saccade disconjugacy, postsaccadic drift, and a pattern strabismus for static fixation, but they made different predictions about the dynamics of saccades. By assuming that crosstalk occurs at multiple nodes, the Distributed Crosstalk Model correctly predicted the dynamics of saccades. These new models make additional predictions that can be tested with future neurophysiological experiments.NEW & NOTEWORTHY Over the past several decades, numerous control systems models have been devised to simulate the known kinematic features of saccades in normal primates. These models have proven valuable to neurophysiology, as a means of generating testable predictions. The present manuscript, as far as we are aware, is the first to present control systems models to simulate the known abnormalities of saccades in strabismus.

Nonhuman Primate Studies to Advance Vision Science and Prevent Blindness.

Most primate behavior is dependent on high acuity vision. Optimal visual performance in primates depends heavily upon frontally placed eyes, retinal specializations, and binocular vision. To see an object clearly its image must be placed on or near the fovea of each eye. The oculomotor system is responsible for maintaining precise eye alignment during fixation and generating eye movements to track moving targets. The visual system of nonhuman primates has a similar anatomical organization and functional capability to that of humans. This allows results obtained in nonhuman primates to be applied to humans. The visual and oculomotor systems of primates are immature at birth and sensitive to the quality of binocular visual and eye movement experience during the first months of life. Disruption of postnatal experience can lead to problems in eye alignment (strabismus), amblyopia, unsteady gaze (nystagmus), and defective eye movements. Recent studies in nonhuman primates have begun to discover the neural mechanisms associated with these conditions. In addition, genetic defects that target the retina can lead to blindness. A variety of approaches including gene therapy, stem cell treatment, neuroprosthetics, and optogenetics are currently being used to restore function associated with retinal diseases. Nonhuman primates often provide the best animal model for advancing fundamental knowledge and developing new treatments and cures for blinding diseases.

FEFsem neuronal response during combined volitional and reflexive pursuit.

Although much is known about volitional and reflexive smooth eye movements individually, much less is known about how they are coordinated. It is hypothesized that separate cortico-ponto-cerebellar loops subserve these different types of smooth eye movements. Specifically, the MT-MST-DLPN pathway is thought to be critical for ocular following eye movements, whereas the FEF-NRTP pathway is understood to be vital for volitional smooth pursuit. However, the role that these loops play in combined volitional and reflexive behavior is unknown. We used a large, textured background moving in conjunction with a small target spot to investigate the eye movements evoked by a combined volitional and reflexive pursuit task. We also assessed the activity of neurons in the smooth eye movement subregion of the frontal eye field (FEFsem). We hypothesized that the pursuit system would show less contribution from the volitional pathway in this task, owing to the increased involvement of the reflexive pathway. In accordance with this hypothesis, a majority of FEFsem neurons (63%) were less active during pursuit maintenance in a combined volitional and reflexive pursuit task than during purely volitional pursuit. Interestingly and surprisingly, the neuronal response to the addition of the large-field motion was highly correlated with the neuronal response to a target blink. This suggests that FEFsem neuronal responses to these different perturbations-whether the addition or subtraction of retinal input-may be related. We conjecture that these findings are due to changing weights of both the volitional and reflexive pathways, as well as retinal and extraretinal signals.

Neural mechanisms of oculomotor abnormalities in the infantile strabismus syndrome.

Infantile strabismus is characterized by numerous visual and oculomotor abnormalities. Recently nonhuman primate models of infantile strabismus have been established, with characteristics that closely match those observed in human patients. This has made it possible to study the neural basis for visual and oculomotor symptoms in infantile strabismus. In this review, we consider the available evidence for neural abnormalities in structures related to oculomotor pathways ranging from visual cortex to oculomotor nuclei. These studies provide compelling evidence that a disturbance of binocular vision during a sensitive period early in life, whatever the cause, results in a cascade of abnormalities through numerous brain areas involved in visual functions and eye movements.

Temporal dynamics of retinal and extraretinal signals in the FEFsem during smooth pursuit eye movements.

Neurons in the smooth eye movement subregion of the frontal eye field (FEFsem) are known to play an important role in voluntary smooth pursuit eye movements. Underlying this function are projections to parietal and prefrontal visual association areas and subcortical structures, all known to play vital but differing roles in the execution of smooth pursuit. Additionally, the FEFsem has been shown to carry a diverse array of signals (e.g., eye velocity, acceleration, gain control). We hypothesized that distinct subpopulations of FEFsem neurons subserve these diverse functions and projections, and that the relative weights of retinal and extraretinal signals could form the basis for categorization of units. To investigate this, we used a step-ramp tracking task with a target blink to determine the relative contributions of retinal and extraretinal signals in individual FEFsem neurons throughout pursuit. We found that the contributions of retinal and extraretinal signals to neuronal activity and behavior change throughout the time course of pursuit. A clustering algorithm revealed three distinct neuronal subpopulations: cluster 1 was defined by a higher sensitivity to eye velocity, acceleration, and retinal image motion; cluster 2 had greater activity during blinks; and cluster 3 had significantly greater eye position sensitivity. We also performed a comparison with a sample of medial superior temporal neurons to assess similarities and differences between the two areas. Our results indicate the utility of simple tests such as the target blink for parsing the complex and multifaceted roles of cortical areas in behavior.NEW & NOTEWORTHY The frontal eye field (FEF) is known to play a critical role in volitional smooth pursuit, carrying a variety of signals that are distributed throughout the brain. This study used a novel application of a target blink task during step ramp tracking to determine, in combination with a clustering algorithm, the relative contributions of retinal and extraretinal signals to FEF activity and the extent to which these contributions could form the basis for a categorization of neurons.

Examination of feline extraocular motoneuron pools as a function of muscle fiber innervation type and muscle layer.

This study explores two points related to the pattern of innervation of the extraocular muscles. First, species differences exist in the location of the motoneurons supplying multiply innervated fibers (MIFs) and singly innervated fibers (SIFs) in eye muscles. MIF motoneurons are located outside the extraocular nuclei in primates, but are intermixed with SIF motoneurons within rat extraocular nuclei. To test whether this difference is related to visual capacity and frontal placement of eyes, we injected retrograde tracers into the medial rectus muscle of the cat, a highly visual nonprimate with frontally placed eyes. Distal injections labeled smaller MIF motoneurons located ventrolaterally and rostrally within the oculomotor nucleus (III). More central injections also labeled a separate population of larger cells located dorsally in III. Thus, the cat shares with the nocturnal rat the feature of having MIF motoneurons located within the bounds of III. On the other hand, just as with monkeys, cats show segregation of the MIF and SIF medial rectus motoneuron pools, albeit in a different pattern. Second, extraocular muscles are divided into two layers; the inner, global layer inserts into the sclera, and the outer, orbital layer inserts into the connective tissue pulley. To test whether these layers are supplied by anatomically discrete motoneuron pools, we injected tracer into the orbital layer of the cat lateral rectus muscle. No evidence of either morphological or distributional differences was found, suggesting that the functional differences in these layers may be due mainly to their orbital anatomy, not their innervation. J. Comp. Neurol. 525:919-935, 2017. © 2016 Wiley Periodicals, Inc.

Improvement of Eye Alignment in Adult Strabismic Monkeys by Sustained IGF-1 Treatment.

PURPOSE: The goal of this study was to determine if continuous application of insulin-like growth factor-1 (IGF-1) could improve eye alignment of adult strabismic nonhuman primates and to assess possible mechanisms of effect. METHODS: A continuous release pellet of IGF-1 was placed on one medial rectus muscle in two adult nonhuman primates (M1, M2) rendered exotropic by the alternating monocular occlusion method during the first months of life. Eye alignment and eye movements were recorded for 3 months, after which M1 was euthanized, and the lateral and medial rectus muscles were removed for morphometric analysis of fiber size, nerve, and neuromuscular density. RESULTS: Monkey 1 showed a 40% reduction in strabismus angle, a reduction of exotropia of approximately 11° to 14° after 3 months. Monkey 2 showed a 15% improvement, with a reduction of its exotropia by approximately 3°. The treated medial rectus muscle of M1 showed increased mean myofiber cross-sectional areas. Increases in myofiber size also were seen in the contralateral medial rectus and lateral rectus muscles. Similarly, nerve density increased in the contralateral medial rectus and yoked lateral rectus. CONCLUSIONS: This study demonstrates that in adult nonhuman primates with a sensory-induced exotropia in infancy, continuous IGF-1 treatment improves eye alignment, resulting in muscle fiber enlargement and altered innervational density that includes the untreated muscles. This supports the view that there is sufficient plasticity in the adult ocular motor system to allow continuous IGF-1 treatment over months to produce improvement in eye alignment in early-onset strabismus.

Electrical Microstimulation of the Superior Colliculus in Strabismic Monkeys.

PURPOSE: Visually guided saccades are disconjugate in human and nonhuman strabismic primates. The superior colliculus (SC) is a region of the brain topographically organized in visual and motor maps where the saccade goal is spatially coded. The present study was designed to investigate if a site of stimulation on the topographic motor map was evoking similar or different saccade vectors for each eye. METHODS: We used microelectrical stimulation (MS) of the SC in two strabismic (one esotrope and one exotrope) and two control macaques under binocular and monocular viewing conditions. We compared the saccade amplitudes and directions for each SC site and each condition independently of the fixating eye and then between each fixating eye. A comparison with disconjugacies of visually guided saccades was also performed. RESULTS: We observed different saccade vectors for the two eyes in strabismic monkeys, but conjugate saccades in normal monkeys. Evoked saccade vectors for the left eye when that eye was fixating the target were different from those of the right eye when it was fixating. The disconjugacies evoked by the MS were not identical but similar to those observed for visually guided saccades especially for the dominant eye. CONCLUSIONS: Our results suggest that, in strabismus, the saccade generator does not interpret activation of a single location of the SC as the same desired displacement for each eye. This finding is important for advancing understanding of the development of neural circuits in strabismus. French Abstract.

Response properties of MST parafoveal neurons during smooth pursuit adaptation.

Visual motion neurons in the posterior parietal cortex play a critical role in the guidance of smooth pursuit eye movements. Initial pursuit (open-loop period) is driven, in part, by visual motion signals from cortical areas, such as the medial superior temporal area (MST). The purpose of this study was to determine whether adaptation of initial pursuit gain arises because of altered visual sensitivity of neurons at the cortical level. It is well known that the visual motion response in MST is suppressed after exposure to a large-field visual motion stimulus, showing visual motion adaptation. One hypothesis is that foveal motion responses in MST are associated with smooth pursuit adaptation using a small target spot. We used a step-ramp tracking task with two steps of target velocity (double-step paradigm), which induces gain-down or gain-up adaptation. We found that after gain-down adaptation 58% of our MST visual neurons showed a significant decrease in firing rate. This was the case even though visual motion input (before the pursuit onset) from target motion was constant. Therefore, repetitive visual stimulation during the gain-down paradigm could lead to adaptive changes in the visual response. However, the time course of adaptation did not show a correlation between the visual response and pursuit behavior. These results indicate that the visual response in MST may not directly contribute to the adaptive change in pursuit initiation.

Saccade-induced image motion cannot account for post-saccadic enhancement of visual processing in primate MST.

Primates use saccadic eye movements to make gaze changes. In many visual areas, including the dorsal medial superior temporal area (MSTd) of macaques, neural responses to visual stimuli are reduced during saccades but enhanced afterwards. How does this enhancement arise-from an internal mechanism associated with saccade generation or through visual mechanisms activated by the saccade sweeping the image of the visual scene across the retina? Spontaneous activity in MSTd is elevated even after saccades made in darkness, suggesting a central mechanism for post-saccadic enhancement. However, based on the timing of this effect, it may arise from a different mechanism than occurs in normal vision. Like neural responses in MSTd, initial ocular following eye speed is enhanced after saccades, with evidence suggesting both internal and visually mediated mechanisms. Here we recorded from visual neurons in MSTd and measured responses to motion stimuli presented soon after saccades and soon after simulated saccades-saccade-like displacements of the background image during fixation. We found that neural responses in MSTd were enhanced when preceded by real saccades but not when preceded by simulated saccades. Furthermore, we also observed enhancement following real saccades made across a blank screen that generated no motion signal within the recorded neurons' receptive fields. We conclude that in MSTd the mechanism leading to post-saccadic enhancement has internal origins.

Transmitter inputs to different motoneuron subgroups in the oculomotor and trochlear nucleus in monkey.

In all vertebrates the eyes are moved by six pairs of extraocular muscles enabling horizontal, vertical and rotatory movements. Recent work showed that each extraocular muscle is controlled by two motoneuronal groups: (1) Motoneurons of singly-innervated muscle fibers (SIF) that lie within the boundaries of motonuclei mediating a fast muscle contraction; and (2) motoneurons of multiply-innervated muscle fibers (MIF) in the periphery of motonuclei mediating a tonic muscle contraction. Currently only limited data about the transmitter inputs to the SIF and MIF motoneurons are available. Here we performed a quantitative study on the transmitter inputs to SIF and MIF motoneurons of individual muscles in the oculomotor and trochlear nucleus in monkey. Pre-labeled motoneurons were immunostained for GABA, glutamate decarboxylase, GABA-A receptor, glycine transporter 2, glycine receptor 1, and vesicular glutamate transporters 1 and 2. The main findings were: (1) the inhibitory control of SIF motoneurons for horizontal and vertical eye movements differs. Unlike in previous primate studies a considerable GABAergic input was found to all SIF motoneuronal groups, whereas a glycinergic input was confined to motoneurons of the medial rectus (MR) muscle mediating horizontal eye movements and to those of the levator palpebrae (LP) muscle elevating the upper eyelid. Whereas SIF and MIF motoneurons of individual eye muscles do not differ numerically in their GABAergic, glycinergic and vGlut2 input, vGlut1 containing terminals densely covered the supraoculomotor area (SOA) targeting MR MIF motoneurons. It is reasonable to assume that the vGlut1 input affects the near response system in the SOA, which houses the preganglionic neurons mediating pupillary constriction and accommodation and the MR MIF motoneurones involved in vergence.

Adaptation of slow myofibers: the effect of sustained BDNF treatment of extraocular muscles in infant nonhuman primates.

PURPOSE: We evaluated promising new treatment options for strabismus. Neurotrophic factors have emerged as a potential treatment for oculomotor disorders because of diverse roles in signaling to muscles and motor neurons. Unilateral treatment with sustained release brain-derived neurotrophic factor (BDNF) to a single lateral rectus muscle in infant monkeys was performed to test the hypothesis that strabismus would develop in correlation with extraocular muscle (EOM) changes during the critical period for development of binocularity. METHODS: The lateral rectus muscles of one eye in two infant macaques were treated with sustained delivery of BDNF for 3 months. Eye alignment was assessed using standard photographic methods. Muscle specimens were analyzed to examine the effects of BDNF on the density, morphology, and size of neuromuscular junctions, as well as myofiber size. Counts were compared to age-matched controls. RESULTS: No change in eye alignment occurred with BDNF treatment. Compared to control muscle, neuromuscular junctions on myofibers expressing slow myosins had a larger area. Myofibers expressing slow myosin had larger diameters, and the percentage of myofibers expressing slow myosins increased in the proximal end of the muscle. Expression of BDNF was examined in control EOM, and observed to have strongest immunoreactivity outside the endplate zone. CONCLUSIONS: We hypothesize that the oculomotor system adapted to sustained BDNF treatment to preserve normal alignment. Our results suggest that BDNF treatment preferentially altered myofibers expressing slow myosins. This implicates BDNF signaling as influencing the slow twitch properties of EOM.

Adaptability of the Immature Ocular Motor Control System: Unilateral IGF-1 Medial Rectus Treatment.

PURPOSE: Unilateral treatment with sustained release IGF-1 to one medial rectus muscle in infant monkeys was performed to test the hypothesis that strabismus would develop as a result of changes in extraocular muscles during the critical period of development of binocularity. METHODS: Sustained release IGF-1 pellets were implanted unilaterally on one medial rectus muscle in normal infant monkeys during the first 2 weeks of life. Eye position was monitored using standard photographic methods. After 3 months of treatment, myofiber and neuromuscular size, myosin composition, and innervation density were quantified in all rectus muscles and compared to those in age-matched controls. RESULTS: Sustained unilateral IGF-1 treatments resulted in strabismus for all treated subjects; 3 of the 4 subjects had a clinically significant strabismus of more than 10°. Both the treated medial rectus and the untreated ipsilateral antagonist lateral rectus muscles had significantly larger myofibers. No adaptation in myofiber size occurred in the contralateral functionally yoked lateral rectus or in myosin composition, neuromuscular junction size, or nerve density. CONCLUSIONS: Sustained unilateral IGF-1 treatment to extraocular muscles during the sensitive period of development of orthotropic eye alignment and binocularity was sufficient to disturb ocular motor development, resulting in strabismus in infant monkeys. This could be due to altering fusion of gaze during the early sensitive period. Serial measurements of eye alignment suggested the IGF-1-treated infants received insufficient coordinated binocular experience, preventing the establishment of normal eye alignment. Our results uniquely suggest that abnormal signaling by the extraocular muscles may be a cause of strabismus.

Abnormal tuning of saccade-related cells in pontine reticular formation of strabismic monkeys.

Strabismus is a common disorder, characterized by a chronic misalignment of the eyes and numerous visual and oculomotor abnormalities. For example, saccades are often highly disconjugate. For humans with pattern strabismus, the horizontal and vertical disconjugacies vary with eye position. In monkeys, manipulations that disturb binocular vision during the first several weeks of life result in a chronic strabismus with characteristics that closely match those in human patients. Early onset strabismus is associated with altered binocular sensitivity of neurons in visual cortex. Here we test the hypothesis that brain stem circuits specific to saccadic eye movements are abnormal. We targeted the pontine paramedian reticular formation, a structure that directly projects to the ipsilateral abducens nucleus. In normal animals, neurons in this structure are characterized by a high-frequency burst of spikes associated with ipsiversive saccades. We recorded single-unit activity from 84 neurons from four monkeys (two normal, one exotrope, and one esotrope), while they made saccades to a visual target on a tangent screen. All 24 neurons recorded from the normal animals had preferred directions within 30° of pure horizontal. For the strabismic animals, the distribution of preferred directions was normal on one side of the brain, but highly variable on the other. In fact, 12/60 neurons recorded from the strabismic animals preferred vertical saccades. Many also had unusually weak or strong bursts. These data suggest that the loss of corresponding binocular vision during infancy impairs the development of normal tuning characteristics for saccade-related neurons in brain stem.

Internal organization of medial rectus and inferior rectus muscle neurons in the C group of the oculomotor nucleus in monkey.

Mammalian extraocular muscles contain singly innervated twitch muscle fibers (SIF) and multiply innervated nontwitch muscle fibers (MIF). In monkey, MIF motoneurons lie around the periphery of oculomotor nuclei and have premotor inputs different from those of the motoneurons inside the nuclei. The most prominent MIF motoneuron group is the C group, which innervates the medial rectus (MR) and inferior rectus (IR) muscle. To explore the organization of both cell groups within the C group, we performed small injections of choleratoxin subunit B into the myotendinous junction of MR or IR in monkeys. In three animals the IR and MR myotendinous junction of one eye was injected simultaneously with different tracers (choleratoxin subunit B and wheat germ agglutinin). This revealed that both muscles were supplied by two different, nonoverlapping populations in the C group. The IR neurons lie adjacent to the dorsomedial border of the oculomotor nucleus, whereas MR neurons are located farther medially. A striking feature was the differing pattern of dendrite distribution of both cell groups. Whereas the dendrites of IR neurons spread into the supraoculomotor area bilaterally, those of the MR neurons were restricted to the ipsilateral side and sent a focused bundle dorsally to the preganglionic neurons of the Edinger-Westphal nucleus, which are involved in the "near response." In conclusion, MR and IR are innervated by independent neuron populations from the C group. Their dendritic branching pattern within the supraoculomotor area indicates a participation in the near response providing vergence but also reflects their differing functional roles.

Eye Velocity Gain Fields in MSTd During Optokinetic Stimulation.

Lesion studies argue for an involvement of cortical area dorsal medial superior temporal area (MSTd) in the control of optokinetic response (OKR) eye movements to planar visual stimulation. Neural recordings during OKR suggested that MSTd neurons directly encode stimulus velocity. On the other hand, studies using radial visual flow together with voluntary smooth pursuit eye movements showed that visual motion responses were modulated by eye movement-related signals. Here, we investigated neural responses in MSTd during continuous optokinetic stimulation using an information-theoretic approach for characterizing neural tuning with high resolution. We show that the majority of MSTd neurons exhibit gain-field-like tuning functions rather than directly encoding one variable. Neural responses showed a large diversity of tuning to combinations of retinal and extraretinal input. Eye velocity-related activity was observed prior to the actual eye movements, reflecting an efference copy. The observed tuning functions resembled those emerging in a network model trained to perform summation of 2 population-coded signals. Together, our findings support the hypothesis that MSTd implements the visuomotor transformation from retinal to head-centered stimulus velocity signals for the control of OKR.

Abnormal activity of neurons in abducens nucleus of strabismic monkeys.

PURPOSE: Infantile strabismus is characterized by persistent misalignment of the eyes. Mounting evidence suggests that the disorder is associated with abnormalities at the neural level, but few details are known. This study investigated the signals carried by abducens neurons in monkeys with experimentally induced strabismus. We wanted to know whether the firing rates of individual neurons are exclusively related to the position and velocity of one eye and whether the overall level of activity of the abducens nucleus was in the normal range. METHODS: We recorded 58 neurons in right and left abducens nuclei while strabismic monkeys (one esotrope and one exotrope) performed a saccade task. We analyzed the firing rates associated with static horizontal eye position and saccades by fitting the data with a dynamic equation that included position and velocity terms for each eye. Results were compared to previously published data in normal monkeys. RESULTS: For both strabismic monkeys the overall tonic activity was 50 to 100 spikes/s lower, for every suprathreshold eye position, than what has previously been reported for normal monkeys. This was mostly the result of lower baseline activity; the slopes of rate-position curves were similar to those in previous reports in normal monkeys. The saccade velocity sensitivities were similar to those of normal monkeys, 0.35 for the esotrope and 0.40 for the exotrope. For most neurons the firing rate was more closely related to the position and velocity of the ipsilateral eye. CONCLUSIONS: These data suggest that strabismus can be associated with reduced neural activity in the abducens nucleus.