Vergence neurons identified in the rostral superior colliculus code smooth eye movements in 3D space.

The rostral superior colliculus (rSC) encodes position errors for multiple types of eye movements, including microsaccades, small saccades, smooth pursuit, and fixation. Here we address whether the rSC contributes to the development of neural signals that are suitable for controlling vergence eye movements. We use both single-unit recording and microstimulation techniques in monkey to answer this question. We found that vergence eye movements can be evoked using microstimulation in the rSC. Moreover, among the previously described neurons in rSC, we recorded a novel population of neurons that either increased (i.e., convergence neurons) or decreased (i.e., divergence neurons) their activity during vergence eye movements. In particular, these neurons dynamically encoded changes in vergence angle during vergence tracking, fixation in 3D space and the slow binocular realignment that occurs after disconjugate saccades, but were completely unresponsive during conjugate or the rapid component of disconjugate saccades (i.e., fast vergence) and conjugate smooth pursuit. Together, our microstimulation and single-neuron results suggest that the SC plays a role in the generation of signals required to precisely align the eyes toward targets in 3D space. We propose that accurate maintenance of 3D eye position, critical for the perception of stereopsis, may be mediated via the rSC.

Neuronal evidence for individual eye control in the primate cMRF.

Previous single unit recordings and electrical stimulation have suggested that separate regions of the MRF participate in the control of vergence and conjugate eye movements. Neurons in the supraoculomotor area (SOA) have been found to encode symmetric vergence [Zhang, Y. et al. (1992). J. Neurophysiol., 67: 944-960] while neurons in the central MRF, the cMRF, located ventral to the SOA and lateral to the oculomotor nucleus are associated with conjugate eye movements [Waitzman, D.M. et al. (1996). J. Neurophysiol., 75(4): 1546-1572]. However, it remains unknown if cMRF neurons are strictly associated with conjugate movements since eye movements were recorded with a single eye coil in monkeys viewing visual stimuli at a distance of at least 50 cm. In the current study we addressed whether neurons in the cMRF might also encode vergence-related information. Interestingly, electrical stimulation elicited disconjugate saccades (contralateral eye moved more than the ipsilateral eye) from locations previously thought to elicit only conjugate saccades. Single unit recordings in this same area made in two rhesus monkeys trained to follow visual stimuli moved rapidly in depth along the axis of sight of an individual eye demonstrate that cMRF neurons do not simply encode conjugate information during disconjugate saccades; in fact our findings provide evidence that cMRF neurons are most closely associated with the movement of an individual eye. These results support the hypothesis that the midbrain shapes the activity of the pre-motor saccadic neurons by encoding integrated conjugate and vergence commands.

Anatomical evidence for interconnections between the central mesencephalic reticular formation and cervical spinal cord in the cat and macaque.

A gaze-related region in the caudal midbrain tegementum, termed the central mesencephalic reticular formation (cMRF), has been designated on electrophysiological grounds in monkeys. In macaques, the cMRF correlates with an area in which reticulotectal neurons overlap with tectoreticular terminals. We examined whether a region with the same anatomical characteristics exists in cats by injecting biotinylated dextran amine into their superior colliculi. These injections showed that a cat cMRF is present. Not only do labeled tectoreticular axons overlap the distribution of labeled reticulotectal neurons, these elements also show numerous close boutonal associations, suggestive of synaptic contact. Thus, the presence of a cMRF that supplies gaze-related feedback to the superior colliculus may be a common vertebrate feature. We then investigated whether cMRF connections indicate a role in the head movement component of gaze changes. Cervical spinal cord injections in both the cat and monkey retrogradely labeled neurons in the ipsilateral, medial cMRF. In addition, they provided evidence for a spinoreticular projection that terminates in this same portion of the cMRF, and in some cases contributes boutons that are closely associated with reticulospinal neurons. Injection of the physiologically defined, macaque cMRF demonstrated that this spinoreticular projection originates in the cervical ventral horn, indicating it may provide the cMRF with an efference copy signal. Thus, the cat and monkey cMRFs have a subregion that is reciprocally connected with the ipsilateral spinal cord. This pattern suggests the medial cMRF may play a role in modulating the activity of antagonist neck muscles during horizontal gaze changes.

Comparison of saccade-associated neuronal activity in the primate central mesencephalic and paramedian pontine reticular formations.

The oculomotor system must convert signals representing the target of an intended eye movement into appropriate input to drive the individual extraocular muscles. Neural models propose that this transformation may involve either a decomposition of the intended eye displacement signal into horizontal and vertical components or an implicit process whereby component signals do not predominate until the level of the motor neurons. Thus decomposition models predict that premotor neurons should primarily encode component signals while implicit models predict encoding of off-cardinal optimal directions by premotor neurons. The central mesencephalic reticular formation (cMRF) and paramedian pontine reticular formation (PPRF) are two brain stem regions that likely participate in the development of motor activity since both structures are anatomically connected to nuclei that encode movement goal (superior colliculus) and generate horizontal eye movements (abducens nucleus). We compared cMRF and PPRF neurons and found they had similar relationships to saccade dynamics, latencies, and movement fields. Typically, the direction preference of these premotor neurons was horizontal, suggesting they were related to saccade components. To confirm this supposition, we studied the neurons during a series of oblique saccades that caused "component stretching" and thus allowed the vectorial (overall) saccade velocity to be dissociated from horizontal component velocity. The majority of cMRF and PPRF neurons encoded component velocity across all saccades, supporting decomposition models that suggest horizontal and vertical signals are generated before the level of the motoneurons. However, we also found novel vectorial eye velocity encoding neurons that may have important implications for saccade control.

Neurones associated with saccade metrics in the monkey central mesencephalic reticular formation.

Neurones in the central mesencephalic reticular formation (cMRF) begin to discharge prior to saccades. These long lead burst neurones interact with major oculomotor centres including the superior colliculus (SC) and the paramedian pontine reticular formation (PPRF). Three different functions have been proposed for neurones in the cMRF: (1) to carry eye velocity signals that provide efference copy information to the SC (feedback), (2) to provide duration signals from the omnipause neurones to the SC (feedback), or (3) to participate in the transformation from the spatial encoding of a target selection signal in the SC into the temporal pattern of discharge used to drive the excitatory burst neurones in the pons (feed-forward). According to each respective proposal, specific predictions about cMRF neuronal discharge have been formulated. Individual neurones should: (1) encode instantaneous eye velocity, (2) burst specifically in relation to saccade duration but not to other saccade metrics, or (3) have a spectrum of weak to strong correlations to saccade dynamics. To determine if cMRF neurones could subserve these multiple oculomotor roles, we examined neuronal activity in relation to a variety of saccade metrics including amplitude, velocity and duration. We found separate groups of cMRF neurones that have the characteristics predicted by each of the proposed models. We also identified a number of subgroups for which no specific model prediction had previously been established. We found that we could accurately predict the neuronal firing pattern during one type of saccade behaviour (visually guided) using the activity during an alternative behaviour with different saccade metrics (memory guided saccades). We suggest that this evidence of a close relationship of cMRF neuronal discharge to individual saccade metrics supports the hypothesis that the cMRF participates in multiple saccade control pathways carrying saccade amplitude, velocity and duration information within the brainstem.

Temporal characteristics of neurons in the central mesencephalic reticular formation of head unrestrained monkeys.

The accompanying paper demonstrated two distinct types of central mesencephalic reticular formation (cMRF) neuron that discharged before or after the gaze movement: pre-saccadic or post-saccadic. The movement fields of pre-saccadic neurons were most closely associated with gaze displacement. The movement fields of post-saccadic neurons were most closely associated with head displacement. Here we examine the relationships of the discharge patterns of these cMRF neurons with the temporal aspects of gaze or head movement. For pre-saccadic cMRF neurons with monotonically open movement fields, we demonstrate that burst duration correlated closely with gaze duration. In addition, the peak discharge of the majority of pre-saccadic neurons was closely correlated with peak gaze velocity. In contrast, discharge parameters of post-saccadic neurons were best correlated with the time of peak head velocity. However, the duration and peak discharge of post-saccadic discharge was only weakly related to the duration and peak velocity of head movement. As a result, for the majority of post-saccadic neurons the discharge waveform poorly correlated with the dynamics of head movement. We suggest that the discharge characteristics of pre-saccadic cMRF neurons with monotonically open movement fields are similar to that of direction long-lead burst neurons found previously in the paramedian portion of the pontine reticular formation (PPRF; Hepp and Henn 1983). In light of their anatomic connections with the PPRF, these pre-saccadic neurons could form a parallel pathway that participates in the transformation from the spatial coding of gaze in the superior colliculus (SC) to the temporal coding displayed by excitatory burst neurons of the PPRF. In contrast, closed and non-monotonically open movement field pre-saccadic neurons could play a critical role in feedback to the SC. The current data do not support a role for post-saccadic cMRF neurons in the direct control of head movements, but suggest that they may serve a feedback or reafference function, providing a signal of current head amplitude to upstream regions involved in head control.

Spatial characteristics of neurons in the central mesencephalic reticular formation (cMRF) of head-unrestrained monkeys.

Prior studies of the central portion of the mesencephalic reticular formation (cMRF) have shown that in head-restrained monkeys, neurons discharge prior to saccades. Here, we provide a systematic analysis of the patterns of activity in cMRF neurons during head unrestrained gaze shifts. Two types of cMRF neurons were found: presaccadic neurons began to discharge before the onset of gaze movements, while postsaccadic neurons began to discharge after gaze shift onset and typically after the end of the gaze shift. Presaccadic neuronal responses were well correlated with gaze movements, while the discharge of postsaccadic neurons was more closely associated with head movements. The activity of presaccadic neurons was organized into gaze movement fields, while the activity of postsaccadic neurons was better organized into movement fields associated with head displacement. We found that cMRF neurons displayed both open and closed movement field responses. Neurons with closed movement fields discharged before a specific set of gaze (presaccadic) or head (postsaccadic) movement amplitudes and directions and had a clear distal boundary. Neurons with open movement fields discharged for gaze or head movements of a specific direction and also for movement amplitudes up to the limit of measurement (70 degrees). A subset of open movement field neurons displayed an increased discharge with increased gaze shift amplitudes, similar to pontine burst neurons, and were called monotonically increasing open movement field neurons. In contrast, neurons with non-monotonically open movement fields demonstrated activity for all gaze shift amplitudes, but their activity reached a plateau or declined gradually for gaze shifts beyond specific amplitudes. We suggest that presaccadic neurons with open movement fields participate in a descending pathway providing gaze signals to medium-lead burst neurons in the paramedian pontine reticular formation, while presaccadic closed movement field neurons may participate in feedback to the superior colliculus. The previously unrecognized group of postsaccadic cMRF neurons may provide signals of head position or velocity to the thalamus, cerebellum, or spinal cord.

Molecular cloning and expression profiling of optineurin in the rhesus monkey.

PURPOSE: It has been shown that mutations in the optineurin (OPTN) gene are involved in the etiology of adult-onset primary open-angle glaucoma (POAG). In view of close similarities between human and nonhuman primate ocular development and function, the rhesus monkey is considered a suitable model for human visual system research. Therefore, this study was conducted to clone the orthologue of the human OPTN gene in the rhesus monkey (Rh-OPTN) and to determine its genomic organization. A further purpose was to establish Rh-OPTN protein expression profiles and tissue distribution in the rhesus anterior segment, retina, and optic nerve. METHODS: The Rh-OPTN gene was cloned and its genomic structure determined. The mRNA expression pattern was examined by Northern blot analysis. The protein's cellular localization, ocular expression, and tissue distribution were established by immunolabeling. RESULTS: The Rh-OPTN gene has 13 exons and encodes for a 571-amino-acid protein. Both cDNA and amino acid sequences are 96% identical with the human OPTN. Northern blot analysis revealed prominent expression of two different transcripts in heart, brain, kidney, lung, spleen, skeletal muscle, and small intestine. Cellular and tissue distribution of Rh-OPTN protein were highly similar to its human and mouse homologous proteins. CONCLUSIONS: The optineurin gene and protein are evolutionary conserved between humans and the rhesus monkey. High similarity of ocular expression and tissue distribution between the two optineurin proteins suggests that this nonhuman primate is a suitable model for the pathophysiology and treatment of human glaucomatous optic neuropathy.

Treatment of recalcitrant idiopathic orbital inflammation (chronic orbital myositis) with infliximab.

PURPOSE: To report results of treatment with a monoclonal antibody (infliximab) directed against tumor necrosis factor alpha in seven patients with chronic and difficult-to-control idiopathic orbital inflammation (orbital myositis). DESIGN: Observational case series. METHODS: Retrospective data were collected from seven patients who had idiopathic orbital inflammation and who were evaluated at three medical centers. All patients were treated with infliximab after the failure of traditional therapy, which included corticosteroids, radiotherapy, or anti-inflammatory chemotherapeutic agents. RESULTS: All seven patients had a favorable response to treatment with infliximab. One patient with Behcet disease required supplemental oral corticosteroids. Pain, swelling, and need for concomitant corticosteroids were the primary measures of treatment success. Symptoms of comorbid disease in four patients also improved (Crohn disease in two, Behcet disease in one, and psoriasis in one). There were no untoward effects of treatment after a mean follow-up of 15.7 months (range, 4 to 31 months). CONCLUSIONS: Treatment with infliximab appears to offer another therapeutic option in cases of recalcitrant or recurrent idiopathic orbital inflammation in which conventional treatment fails.

Contribution of the superior colliculus and the mesencephalic reticular formation to gaze control.

Converging lines of evidence support a role for the intermediate and deep layers of the superior colliculus (SC) and the mesencephalic reticular formation (MRF) in the control of combined head and eye movements (i.e., gaze). Recent microstimulation, single-cell recording, and lesion experiments are reviewed in which monkeys are free to move their heads. Cells in the SC discharge in advance of combined head and eye movements and most likely provide a gaze error signal to downstream structures. In contrast, the neurons in the MRF are of at least two types. Eye cells have features that are similar to neurons in the rostral portion of the SC, but fire before the onset of horizontal eye movments. A second group of MRF neurons begin to fire after the onset of the gaze shift and are most closely associated with movements of the head. The peak discharge of these late-onset MRF neurons occurs near the peak head velocity. Stimulation in the rostral SC generates eye movements with fixed amplitude and direction. A similar response is noted after stimulation of the more dorsal portion of the caudal MRF. Stimulation in the caudal portion of the SC produces combined head and eye movements of fixed amplitude. Electrical activation of the more ventral portions of the caudal MRF generates goal-directed and centering eye movements. Temporary inactivation of the SC with the GABA agonist muscimol generated hypometria and curved trajectories of contralateral eye movements. Inactivation of the caudal MRF produced contralateral hypermetria and ipsilateral hypometria of saccades. Release of the monkey's head demonstrated a profound contralateral head tilt. Taken together, these data suggest that the gaze signal generated in the SC is filtered by neurons in the MRF to generate a feedback signal of eye motor error. The head signal found in the MRF could cancel a portion of the gaze signal coming from the SC in the form of head velocity feedback.