PARAMEDIAN PONTINE RETICULAR FORMATION

The paramedian pontine reticular formation (PPRF)is the primary center responsible for generatinghorizontal conjugate gaze. The PPRF is positionedventral to the medial longitudinal fasciculus (MLF). It extends from the level of the trochlear nerve nucleus to the abducens nerve nucleus. Its major efferent projections are to the ipsilateral abducens nucleus (Fig. 1). Secondary efferent projections are to the rostral interstitial nucleus of the MLF (riMLF), which controls vertical gaze. Most afferent connections to the PPRF are from the vestibular nuclei, but there also is input from the cerebellum, superior colliculus, and frontal eye fields (FEF).

Three types of cells have been identified in the PPRF: excitatory burst cells, inhibitory burst cells, and pause cells. The excitatory burst cells generate ipsilateral horizontal saccades by way of projections to the ipsilateral abducens nucleus. The axons from these cells synapse in the abducens nucleus onmotor neurons that innervate the ipsilateral lateral rectus and on interneurons that innervate the contralateral medial rectus subnucleus by way of the contralateral MLF (see Fig. 1). Burst cells discharge only when there is need for a fast eye movement and do not discharge during fixation, pursuit, or vergence eye movements.

Inhibitory burst cell axons have their synapse in the contralateral abducens nucleus. Stimulation of these neurons decreases the firing rate of those motor neurons and interneurons, thereby inhibiting the antagonist muscles of the intended eye movement. Their firing rate is inversely proportional to the burst cells.

Pause cells tonically discharge except when a saccade is being generated. These cells inhibit the burst cells within the ipsilateral PPRF. These cells are important during fixation and smooth pursuit. Abnormalities of these cells lead to opsoclonus and ocular flutter.

Lesions of the abducens nucleus cause an ipsilateral gaze palsy. In the rare instance in which there is an isolated lesion of the PPRF, there is an inability to make ipsilateral saccades. However, the response to vestibular stimuli (e.g., oculocephalic testing, caloric) and pursuit will be preserved. This is because there is a direct connection from the contralateral medial vestibular nuclei directly to the abducens nucleus, bypassing the PPRF (Fig. 2). These fibers synapse on abducens motor neurons and interneurons to the contralateral medial rectus muscle. Thus, labyrinthine reflex and pursuit eye movements may continue to be generated.

MEDIAL LONGITUDINAL FASCICULUS

The medial longitudinal fasciculus (MLF) is a fiber tract that extends from the spinal cord to the oculomotor nerve nucleus. It contains primarily ascending fibers, the majority of which arise in the superior and medial vestibular nuclei. The MLF is in close proximity to the ocular motor nuclei and influences both ipsilateral and contralateral nuclei. An abnormality of the MLF causes problems with horizontal and vertical gaze coordination of the two eyes. The clinically most important connection passing through the MLF links the contralateral abducens nucleus with the ipsilateral medial rectus subnucleus. Abnormalities of this tract produce an internuclear ophthalmoplegia. Such a lesion produces slowed or complete loss of adduction of the ipsilateral eye and abducting nystagmus of the fellow eye.

ROSTRAL INTERSTITIAL NUCLEUS OF THE MEDIAL LONGITUDINAL FASCICULUS

The rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) is located in the mesencephalon at the rostral termination of the MLF. This nucleus includes cells from the interstitial nucleus of Cajal. The riMLF has connections to motor neurons in the oculomotor and trochlear nuclei, as well as to the PPRF. On the basis of experimental and pathologic studies, this group of cells appears to be the immediate premotor area for vertical eye movements, both upward and downward. Its function is thus analogous to the PPRF for vertical eye movements. Damage to this area generally causes more difficulty with downward movement than with upward movement.

POSTERIOR COMMISSURE

Dorsal and rostral to the riMLF is the posterior commissure, a fiber tract that contains some scattered neuronal cell bodies. Lesions in this region produce abnormalities of upward gaze. It is likely that the fibers for upward gaze leave the riMLF and pass through this region before reaching the oculomotor and trochlear nuclei. Involvement of the posterior commissure may be part of the dorsal midbrain syndrome (Parinaud Syndrome). In this syndrome, there is impairment of upwardly directed saccades or, in extreme cases, loss of all vertical movement. Other signs include pupillary mydriasis and light-near pupillary dissociation, corectopia, and convergence-retraction nystagmus.

SUPERIOR COLLICULUS

These structures in the dorsal midbrain play a role in both ocular motor and sensory function. The superior colliculus receives visual input directly from branches of retinal ganglion cell axons. Visual input also comes indirectly from the visual cortex, the parietal and frontal lobes, and the substantia nigra. There are efferent projections to the brain-stem premotor areas. The superior colliculus can generate visually directed saccades independently and may play a role in the control of pursuit eye movements. In primates, ablation of both FEFs and both superior colliculi is necessary to produce permanent saccadic defects.

CEREBELLUM

The cerebellum appears to be involved in the immediate modulation of ongoing eye movements, as well as in the long-term adaptive processes that compensate for ocular motor dysmetria. The cerebellum controls and adjusts the size of saccades. The latter ability is essential for maintaining accurate ocular motor performance during growth and aging, during and after ocular motor disease, or even while using spectacles. For instance, the use of anisometropic spectacles produces a varying anisophoria in different directions of gaze, which must be compensated in each direction of gaze.

Hemicerebellectomy produces ipsilateral saccadic and contralateral pursuit defects, while total cerebellectomy creates persistent saccadic dysmetria and abolishes smooth pursuit. The cerebellum has numerous connections to nuclear and supranuclear ocular motor centers.

VESTIBULAR SYSTEM

The vestibular system consists of the semicircular canals, otolith organs, and vestibular nuclei. The first two structures form the peripheral vestibular system (labyrinth). There are three semicircular canals: horizontal (lateral), anterior (superior), and posterior (vertical). All are filled with perilymph, a fluid that communicates with the subarachnoidspace. The semicircular canals respond to angular acceleration produced during head rotation. The otoliths (the saccule and the utricle) respond to linear acceleration of the head and are especially important in maintaining eccentric eye position in response to a sustained head tilt. The neurosensory elements of the labyrinth are connected to sensory cells. The sensory cell bodies are located in the vestibular ganglion close to the peripheral vestibular apparatus. The vestibular nerve courses through the internal auditory meatus to enter the subarachnoid space. The nerve enters the brain stem in the superior portion of the medulla to reach the vestibular nuclei.

The vestibular nuclear complex is located in the medulla beneath the floor of the fourth ventricle. These nuclei are widely connected with nuclei in the brain stem, cerebral cortex, cerebellum, and reticular formation. Labyrinthine-stimulated eye movements are modulated by connections with the reticular formation and the cerebellum.

In addition to the labyrinthine inputs to the vestibular nuclei, visual and proprioceptive information reaches these nuclei. It is believed that opto-kinetic inputs from the striate cortex reach thevestibular nuclei by an accessory optic pathway. Proprioceptor input comes from the neck, providing the basis for cervico-ocular reflex. Each reflex acts to stabilize the orientation of the eyes in response to movements of the body and therefore opposes shifts of the line of sight caused by changes in position of the head or body.

Vertical gaze is produced by fibers carrying excitatory impulses from the ipsilateral vestibular nuclei. These pass to the contralateral side and ascend in the MLF to form a synapse in the appropriate ocular motor subnuclei. In addition, inhibitory projections from the same canals ascend ipsilaterally to mediate relaxation of the antagonist muscle or muscles (see Fig. 2; right inset).

Horizontal gaze produced by the vestibular system is by a direct excitatory projection to the contralateral abducens nucleus (see Fig. 2; left inset). The ipsilateral medial rectus muscle is innervated by way of an intercalated abducens neuron, as well as by some direct fibers to the medial rectus subnucleus. Each labyrinth exerts a continuous tonic innervation attempting to turn and rotate the eye to the opposite side. For example, the right labyrinth produces levoversion and levocycloversion. Removal of one labyrinth results in the eyes being turned conjugately toward that side because of the unopposed, intact labyrinth. Although the tonus from the labyrinth is constantly present, it may be superseded by other sources of ocular control. In particular, the visual ocular reflex often overrides thevestibular reflex. The visual ocular reflex attempts to ensure continued stimulus stabilization on the fovea.

Movements initiated by the otolith apparatus tend to keep the eyes fixed in position after a change in the position of the head. The otolith system generally attempts to keep the eyes aligned with the horizontal meridian. They do not appear to be involved in horizontal eye movements. The magnitude of the cyclovertical response is considered to be one-tenth of the head tilt. For every 10 degrees of head tilt, the eyes cyclovert 1 degree in the opposite direction. The maximal torsional response is produced by approximately 60 degrees of head tilt.

An important vestibular response in humans is the dynamic eye response produced by the semicircular canals. This system repositions the eyes during acceleration and deceleration of the head. The endolymph within the semicircular canals is displaced when the head is moved. This results in a change in pressure on the ciliated cells of the crista ampullaris, resulting in a stimulus to the brain. Once the head movement reaches a stable unchanging velocity, the pressure gradient disappears, and the peripheral vestibular signal disappears 30 to 45 seconds later. Thus, the semicircular canals make no contribution to the maintenance of static ocular position.

The semicircular canals function in a reciprocal fashion so that when an anterior canal is stimulated, the posterior canal is inhibited. Each canal primarily drives two extraocular muscles, one in each eye, that rotate the globe in the same plane as that in which semicircular canal is oriented. The horizontal canal excites the ipsilateral medial rectus muscle and the contralateral lateral rectus muscle. The anterior canal excites the ipsilateral superior rectus muscle and the contralateral inferior oblique muscle. The posterior canal excites the ipsilateral superior oblique muscle and the contralateral inferior rectus muscle.

A simple method for assessing the vestibulo-ocular reflex uses a direct ophthalmoscope. While the physician views one optic nerve, the patient's face is moved gently from side to side. If the vestibulo-ocular reflex is normal, the optic disk remains stationary. The vestibulo-ocular system also may be tested by active rotation of the head, called the doll's head maneuver. Such rotation stimulates a vestibular compensatory eye movement, allowing the clinician to evaluate the integrity of brain-stem extraocular muscle control. Disorders of the vestibulo-ocular reflex are nearly always manifest by oscillopsia.

CEREBRAL CORTEX

The most important centers for visually directed control of eye movements in humans are in the cerebral cortex. These include the FEFs and the cortex at the parieto-occipital-temporal (POT) junction.

FRONTAL EYE FIELDS

The frontal eye fields (FEF) are located at Brodman's area 8, the posterior end of the second frontal convolution. The FEFs are important for the generation of vertical and horizontal saccades. There are at least three different pathways from the FEF to the brain stem (see Fig. 2). First, the ventral pathway projects by way of the posterior portion of the anterior limb of the internal capsule and the medial part of cerebral peduncle to reach the pons, where there is a partial decussation and termination in the PPRF. Second, the dorsal pathway passes from the FEF through the thalamus, the pulvinar, the pretectal nuclei, and the superior colliculus to reach the brain stem. Third, the intermediate pathway extends from the FEF to the rostral ocular motor nuclei and the interstitial nucleus of Cajal. Although there are ipsilateral and contralateral projections, the predominant projections from the FEF to both the PPRF and the riMLF appear to be contralateral.

MIDDLE TEMPORAL AREA

The cerebral cortex in the region of the POT junction is important in the control of smooth pursuit eye movements and object tracking in space. This area is known as the middle temporal (MT) area in nonhuman primates. The area of the human brain that is the equivalent of the MT cortex of the nonhuman primate is Flechsig's area 10. The MT receives visual information from the striate and prestriate cortex. It projects to the brain stem, cerebellum, superior colliculi, and the FEF. The latter projections modulate visually directed saccadic eye movements. The POT junction cortex plays the key supranuclear role in the visual ocular reflex by way of projections to the PPRF and riMLF. This reflex keeps a moving image projecting on the fovea. There are specific efferent fibers for horizontal, vertical, and torsional movements.

Damage to only one side of the MT cortex slows ipsilateral slow pursuit, requiring catch-up saccades. Such lesions also temporarily impair pursuit responses to fast targets in moving in either direction.

SACCADES

Saccades are fast eye movements. They may be voluntary or involuntary. A voluntary saccade would be a visually directed refixation. An example of an involuntary saccade would be the fast phase of either optokinetic or caloric nystagmus.

Visually directed fast eye movements may be generated by either the FEF or the superior colliculus. Both structures project to the same premotor areas, the PPRF and the riMLF. Horizontal saccades may be triggered by either the contralateral FEF or the contralateral superior colliculus. Vertical eye movements require simultaneous activity of either both FEFs or both superior colliculi. Clinical evidence suggests that the FEFs are primarily concerned with voluntarily redirecting gaze, while the superior colliculi are concerned with reorienting gaze to novel visual stimuli.

Electrical stimulation or epileptic discharge of one FEF produces movement of the eyes to the opposite side. Sudden loss of one FEF leads to the temporary inability to deviate the eyes to the opposite side. Simultaneously, the continuing tone from the intact FEF drives the eyes toward the side of the damaged FEF. Within a few weeks, horizontal eye movements revert to normal. Similar findings in monkeys have been observed for experimental lesions of the superior colliculi. Damage to both the FEF and the superior colliculi is necessary to produce a permanent saccadic paralysis.

The pathways for optokinetic fast phases remain unknown. There must be a large striate cortical component. This likely shares the smooth pursuit pathways to reach the brain-stem premotor areas.

PURSUIT AND RELATED SLOW EYE MOVEMENTS

Smooth pursuit is a slow conjugate eye movement intended to permit continuous orientation of the fovea toward a moving target. Its earliest manifestation is the fixation reflex. The fixation reflex develops by 6 weeks of life. The ability to follow a target rapidly ensues.

The cortex at the POT junction may be the most important structure in the control of smooth pursuit. Lesions in this region produce ipsilateral pursuit defects. This may be shown at the bedside with the use of an optokinetic tape, which tests smooth pursuit in the direction the tape or target is being moved.

There are projections from the POT to brain-stem premotor nuclei, which, in turn, project to the ipsilateral cerebellum. The FEF and the superior colliculi play a modulating role in the production of pursuit eye movements by the POT cerebral cortex.

VERGENCE EYE MOVEMENTS

Vergence eye movements prevent diplopia as an object moves toward or away from the observer. Vergence eye movements may be triggered by retinal disparity or by retinal blur. Retinal disparity produces fusional vergence as the brain attempts to keep the two eyes aligned. Vergence triggered by retinal blur is called accommodative vergence. Both types of vergence are typically slow. Voluntary convergence is produced by the patient who voluntarily increases the basal level of accommodation. Associated with accommodation is increased convergence. There is no demonstrated ability for voluntary divergence.

The cortical pathways for vergence eye movements remain unknown. There appear to be specific neurons in the mesencephalon associated with the oculomotor complex that control convergence and divergence. These centers must bypass the ascending inputs from the abducens interneurons, because convergence is rarely affected by lesions of the MLF.

The inability to initiate voluntary saccades is known as ocular motor apraxia. The patient with the congenital onset of this disorder is unable to initiate voluntary horizontal saccades, but can make normal vertical saccades. Acquired ocular motor apraxia usually occurs with bilateral cerebral hemisphere disease. Patients with Parkinson's disease show difficulty in initiating multiple repetitive saccades.

Another saccadic abnormality is the generation of inappropriate saccades. Square wave jerks are small, unwanted saccades that move the eye off the target. Ocular flutter and opsoclonus are caused by brain-stem or cerebellar dysfunction. The onset of opsoclonus or ocular flutter in childhood may be caused by encephalitis or toxic etiologies, but could be the presenting sign of a neuroblastoma. The latter eye movements are caused by an immune response that damages the pause cells of the PPRF.

An imbalance of pursuit tone occurs when there is unilateral cerebral hemisphere disease. This produces a constant drift of both eyes toward the intact hemisphere. Such a patient has difficulty following a target moving toward the diseased hemisphere. An imbalance of pursuit also occurs during monocular viewing by a patient with latent nystagmus. The pursuit imbalance drives the uncovered eye nasally, with fast phases directed temporally.

Ping-pong gaze is a spontaneously alternating smooth eye movement seen in patients in coma with bilateral cerebral hemisphere disease. Rarely do the eye movements appear to be saccadic.

The sensory organ systems modify the tonus of the ocular muscles through unknown connections. For instance, loud noise causes the eyes to reflex and turn to the side from which the noise seems to come. A painful stimulus applied to the side of the face causes the eyes to turn involuntarily toward the origin of the pain.

The vestibulo-colic reflex produces slow and quick phases of head nystagmus in response tolabyrinth stimulation. Although more prominent in lower animals, head nystagmus still can be demonstrated in monkeys and in humans.

Breinin⁴ has electromyographically demonstrated a basal level of firing in the medial and lateral rectus muscles while the eye is in primary position. The firing diminishes when the muscles are severed from the globe. Stretching the muscle increases the firing to the base level found in the primary position. The firing can never be increased beyond this level, no matter how great the tension applied to the muscle. Normally, on right and left gaze, there is simultaneous, exact augmentation and diminution of firing in agonist and antagonists. This is lost when the medial and lateral rectus muscles are disinserted from the globe before right and left gaze are attempted.When abduction is attempted, a sudden violent burstof firing occurs in the lateral rectus; this abruptly ceases when adduction is tried next. This is followed by a sudden, violent burst of medial rectus firing, but this occurs only after there is an interval during which neither muscle fires. Therefore, disinsertion releases the tension normally experienced by attached antagonistic muscles; this seems to account for the loss of finely graded augmentation and diminution characterizing Sherrington's law of reciprocity for antagonist muscle groups.

This basic stretch reflex of the extraocular muscles probably is the substitute for proprioception. Such a feedback mechanism permits constantly accurate adjustments to be made in optomotor responses to visual stimuli. This is extremely important because constant corrections have to be made to ensure continued projection of the image onto the fovea. This is because the eye is never still while fixating, but it makes small movements about fixation.

Humans are devoid of a sense of ocular position. If vision is destroyed, a person is unaware of any passive eye movement. Furthermore, when asked to move the eyes while one eye is occluded and immobilized with forceps, the patient believes the covered, unmoving eye has made the same large angle of movement as the uncovered, unrestrained eye. This lack of a sense of ocular position also can be shown with after-images. The after-image is perceived as moving, although the eye movement was forceably restrained. A person with extraocular muscle palsy has the impression that the eye moved according to the degree it was willed to move, when actually no movement has occurred. There is no sense of ocular position to inform that person otherwise.

1. Leichnetz GR: The prefrontal cortico-oculomotor trajectories in the monkey: A possible explanation for the effects of stimulation/lesion experiments on eye movement. J Neurol Sci 1981:49:387–396

2. Allman JM, Baker JF, Newsome WT et al: The cortical visual areas of the owl monkey: Topographic organization and functional correlates. In Wollsey CN (ed): Cortical Sensory Organization. Englewood Cliffs, NJ: Humana Press, 1981:171–186

3. Cooper S, Daniel P, Whitteridge D: Muscle spindles and other sensory endings in the extrinsic eye muscles: The physiology and anatomy of these receptors and their connection with the brainstem. Brain 1955:78:564

4. Breinin GM: Electromyographic evidence for ocular muscle proprioception in man. Arch Ophthalmol 1957:57:176