Overview of Oculomotor System

In this section we'll review human eye movements and outline the behavior of the eyes for each movement type, along with providing some context for the subsequent sections where we'll discuss targeting and attention.

Human eye movements include:

• Fixation
• Ocular Following Response (OFR)
• Vestibulo-Ocular Reflex (VOR)
• Optokinetic Reflex (OKR)
• Smooth Pursuit
• Quick Nystagmus
• Vergence
• Saccades

To begin with, let's get the mile-high view of the oculomotor system, to help put things in context. The overall organization of the oculomotor system in humans is shown below. In addition to the cortical areas shown below there is also an eye field in the anterior cingulate cortex, that communicates with the frontal and supplementary eye fields. The second figure shows two different sets of pathways through the pontine nuclei, which are part of the cerebellar circuitry. We'll look at the anatomy more closely on subsequent pages.

Here is the corroboration of these pathways from the standpoint of functional MRI. The images start at the top left in the brainstem, and proceed to the rostral surface of the brain. On the top left you can see the abducens nucleus, one of the most important oculomotor nuclei in the brainstem that directly drives the lateral rectus muscle. On the top right is the superior colliculus, an important structure for target selection. On the bottom row are the parietal and frontal eye fields, and the supplementary eye fields in the premotor area. The cingulate eye field is shown in light blue in the middle row on the right.

To understand this architecture, we'll work bottom up. We'll start with the eyes and the eye muscles, and work our way up to the cerebral cortex. The organization of the oculomotor system is most logical when understood this way.

Eyes and Eye Muscles

There are six main muscles that move the eye in its socket, and several others related to the eyelid, pupil, and lens. Eye movements along the horizontal and vertical axes are organized by the rectus muscles, which are arranged into push-pull pairs. Each muscle maintains a low level of tonic activity even during fixation, to keep the eye stable and avoid drift. The figure below shows the organization of the muscles in the right and left eyes.

Each eye muscle consists of an orbital layer and a global layer. The global layer inserts at the sclera via a tendon. The classic muscle spindles associated with skeletal muscles are poorly developed in the eye muscles of most species, and Golgi tendon organs are sparse or entirely missing. Instead there are specialized endings called "palisade endings" that wrap themselves around the tip of smooth muscle fibers and contact both the tendon and the muscle fiber directly. These are thought to provide proprioceptive signals that eventually arrive in the cerebellum, but the pathways for these signals are not known.

The eyes can move together, conjugate from side to side, or they can move disjunctively, for example when focusing in depth. These systems are mostly separate in the brain, for example there is a separate system for vergence (disjunctive) movements. However they come together at the level of the oculomotor neurons. As you can see from the figures at the top of the page, the circuitry of the oculomotor system is somewhat complex, and the insertions of the eye muscles are not necessarily conveniently aligned along Cartesian axes. However the overall architecture can be organized functionally, into subsystems and pathways that make sense.

Horizontal eye movements are the best studied. They are programmed by circuitry involving the lateral rectus muscle, which is driven by the abducens nucleus motor neurons (via cranial nerve 6). The lateral rectus abducts the eye, that is, pulls it outward, away from the midline. The figure shows the eye movements for a horizontal saccade. The range of horizontal saccades in human is about 90 degrees, 45 degrees in each direction away from the midline. Saccades larger than about 20 degrees tend to also invoke head movements, which can be voluntarily inhibited. The peak velocity of the eyes can reach beyond 700 degrees/sec during a saccade, which is approximately equivalent to the fastest commercially available servo motors.

The range of eye movements is approximately aligned with the "immediate field of view", as shown in the figure. Targets outside of this range tend to evoke more complicated orienting movements involving the head and body. Some of these movements are organized by the superior colliculus, and transmitted through descending fibers that target the cervical and spinal motor pathways.

Overview of Eye Muscle Control

Anatomically, much of the eye movement circuitry is organized at the level of the midbrain, in the pons and neighboring areas, close to the vestibular systems and close to the cerebellum. The pontine reticular formation is an intricate tangle of tiny nuclei and fibers going in all directions. It has taken many years of study, and the invention of some clever technology, to map this area of the brain. The basic circuitry around the abducens nucleus is shown in the figure. You can see the pathway that cross the midline and activates the oculomotor nucleus on the contralateral side, which contracts the contralateral medial rectus muscle and keeps the eyes in alignment.

The eyes have "focus", both horizontally and vertically, and in depth. The horizontal and vertical foci are often conceived in terms of "gaze centers". When organized this way, the horizontal gaze center is in the paramedian pontine reticular formation (PPRF), and the vertical gaze center is in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). As you can see in the figure, horizontal saccades are primarily driven by the lateral rectus muscle on the abducting side, and its accompanying neural circuitry.

Vertical saccades use a separate set of pathways that control the superior and inferior rectus muscles via the oculomotor nucleus, whose axons travel through cranial nerve 3. Because of the way the eyes are arranged in the orbit, vertical eye movements also generate small amounts of torsion, and to correct this the superior and inferior oblique muscles get involved too. The superior oblique has its own pathway through the trochlear nucleus and the trochlear nerve (cranial nerve 4), whereas the inferior oblique uses the oculomotor nucleus and CN-3.

When the eyes are focused together on a target (moving or not), the angle between the eyes is calculated in relation to depth perception. Movements in depth are vergence eye movements, and they are regulated by a separate system in the brain. In general, each axis of motion is regulated by separate systems. The vergence system issues "corrections" that enter at the level of the oculomotor nuclei. These affect the oculomotor nucleus specifically, and not the abducens. Thus, human vergence movements often involve both eyes moving together towards the midline.

Horizontal Saccades

Horizontal eye movements involve the lateral and medial rectus muscles. The primary driver for the saccade is the lateral rectus muscle on the ipsilateral side (the one moving away from the midline). The oculomotor nucleus plays a somewhat secondary role in horizontal saccades, as it is driven contralaterally from the abducens motoneurons. This arrangement is shown in the figure. Both abducens and oculomotor nucleus neurons are eventually driven from the superior colliculus, but along the way the signals are processed by small brainstem nuclei that translate the desired eye position into actual muscle contractions. In humans there are about 6500 neurons in the abducens nucleus.

Types of horizontal saccades include:

• Spontaneous
  
• Voluntary
  
• Memory Guided
  
• Antisaccades
  
• Reflexive
  
• Microsaccades
  

Neither the amplitude nor the velocity of saccades is under voluntary control. This is primarily because the eye movements are too fast, by the time a control system could kick in the eye movement would already be over. In some cases the cerebellum may activate towards the end of a saccade, to tell the eye movement when to stop and to fine tune the ultimate destination.

Abducens motor neurons are driven by excitatory bursting neurons (EBN) in the ipsilateral paramedian pontine reticular formation (PPRF), and are inhibited by pause neurons in the nucleus raphe interpositus (NRI). (We'll understand these areas in more detail when we discuss the superior colliculus shortly). There are several other direct inputs, including most importantly the medial vestibular nuclei (for the vestibulo-ocular reflex), the nucleus prepositus hypoglossi (related to the neural integrator for horizontal eye movements), the interstitial nucleus of Cajal (related to vertical and torsional eye movements), the supraoculomotor area (related to vergence movements), and the pretectal area surrounding the superior colliculus (Buttner-Ennever 2006). The schematic below shows excitatory bursting neurons (EBN) from the PPRF driving the abducens motor neurons.

There are four sets of outputs from the abducens nucleus, from four different kinds of neurons. Two of them drive the twitchy and non-twitchy lateral rectus muscle fibers directly, the third crosses the midline to drive the contralateral medial rectus muscle, and the fourth sends axons into the paramedian tract to connect with the flocculus of the cerebellum. Each of these neurons receives a different kind of input. The twitchy motorneurons (related to saccades) get most of their inputs from the EBN's in the PPRF, while the non-twitchy motorneurons (related to gaze holding) are driven primarily from the NPH (Horn et al 2018). Incoming fibers from the medial vestibular nucleus (transmitting velocity signals for the VOR) cross the midline and excite both the contralateral twitch neurons and the contralateral internuclear neurons.

The twitchy muscle fibers are mostly singly innervated and respond with a twitch to electrical stimulation, whereas the slower muscle fibers are typically multiply innervated and respond with tonic contractions to stimulation. Both sets of motor neurons are cholinergic, they use acetylcholine (ACh) as an excitatory neurotransmitter. In contrast, the interneurons driving the contralateral medial rectus muscle and those feeding the cerebellum are non-cholinergic (Horn et al 2018).

Driving the abducens motoneurons are two other sets of neurons, the burst neurons and the pause neurons. The pause neurons (not shown in the schematic above, but shown in the diagram below) inhibit the oculomotor neurons when there are no eye movements going on, like during fixation. (These pause neurons do not disable the head-related reflexes like the vestibulo-ocular reflex). The burst neurons encode the extent and velocity of the saccade. They are released by input from the superior colliculus (which we'll discuss shortly). When the eyes are still, there is a small amount of tonic activity to keep some minimal tension on the eye muscles. And, there is an active control system to keep the eyes in place during fixation. Saccades are released only on command, either from sensory systems through reflexes, or voluntarily from cerebral input.

There are excitatory and inhibitory burst neurons driving saccades. The excitatory burst neurons excite the abducens motor neurons on the same side (ipsilateral), and the oculomotor neurons driving the medial rectus muscle on the opposite side (contralaterally). At the same time, they connect with inhibitory burst neurons on the opposite side, which inhibit the abducens motor neurons contralaterally, and the medial rectus ipsilaterally. These connections are shown in the diagram below. The burst neurons are located in the paramedian pontine reticular formation (PPRF), and the pause neurons are nearby in the nucleus raphe interpositus. EBNs from the PPRF project to the contralateral IBN's located in the area of the nucleus paragigantocellularis. The neurons labeled INT are the non-cholinergic abducens interneurons that cross the midline to feed the contralateral medial rectus motor neurons. Not shown are the connections with the cerebellum.

The firing pattern of an abducens motor neuron and an excitatory burst neuron relative to a saccade is shown in the figure below. Note that the burst occurs slightly before the saccade, and note that the abducens motoneuron retains a new tonic firing level after the saccade.

Between the burst neurons and the oculomotor neurons is a neural integrator (appropriately labeled in the previous two diagrams), that performs two essential functions. First, it converts the spike train representing a saccade into an eye position, which is a level of muscle contraction. And second, it maintains the eye position in the face of noise and small changes in muscle activity. In humans this integrator is located at least in part in the nucleus prepositus hypoglossi, which was shown in an earlier cross section of the pons (above). The NPH works in conjunction with the medial vestibular nucleus, which receives head velocity signals from the semicircular canals. The oculomotor integrator performs a crucial function for saccades, in that it translates the eye velocity information into eye position information. We'll see how it works in context on the next two pages, when we discuss the burst and pause neurons in the brainstem and the targeting system in the superior colliculus.

There is something missing in the above diagram. There are muscle spindles in the eye muscles, for both fast and slow (twitchy and non-twitchy) muscle fibers. However, the spindles look a little different than they do in ordinary skeletal muscles, and they enter the brain through the trigeminal nerve (CN-5) instead of the oculomotor nerves. The fast twitchy muscles have spindles that resemble the classic en plaque endings, while the non-twitchy muscles have en grappe spindles along the entire muscle length (Spencer & Porter 2006). The motor neurons for the slower non-twitchy fibers are located in the periphery of the abducens nucleus, while the twitchy motor neurons are clustered in the middle (Eberhorn et al 2005).

In humans and primates, there are specialized structures called "palisade endings" that make up the majority of proprioceptive input from the eye muscles. The palisade endings are about halfway between ordinary muscle spindles and Golgi tendon organs. They connect mostly with the smoother slower non-twitchy muscles, and as such they primarily provide information related to eye position. Recent data indicate that the cell bodies giving rise to palisade endings are located in the oculomotor nuclei, interspersed with the motoneurons feeding the slower non-twitchy eye muscles. The motor neurons are cholinergic whereas the PE cells are round and calretinin positive (Leinbacher 2012).

There is some evidence of specificity in the connections from the upstream areas (PPRF, NPH, MVN) into the abducens motoneurons. The faster twitchy neurons get burst input from the PPRF and vestibular nuclei, that generates eye movements. The slower non-twitchy neurons get eye position information from the neural integrator in the NPH. This specificity is currently the subject of active research.

The PMT neurons in the abducens nuclus feeding the cerebellar flocculus are important for gaze holding. Lesions in the PMT can result in nystagmus along both vertical and horizontal axes (Nakamagoe et al 2000).

It is vital to understand the role of the integrator in the brainstem oculomotor system (Goldman et al 2009). Many signals related to the eyes arrive in the form of velocities, for example the vestibular systems issues velocity information rather than position information. These velocities somehow need to be converted into eye positions, because gaze is usually target-centric. Even the saccade-generating burst neurons in the PPRF encode velocity, some of them encode saccade amplitude with the duration of the signal and saccade velocity with the spike rate within the signal.

The time constant of the oculomotor integrators is on the order of 25 seconds.

The cellular mechanisms of integration may include ion channels with particular time constants. In some cases these time constants are modifiable under synaptic control, but in most cases they end up becoming fixed after development.

Vertical Saccades

The range of vertical eye motion in humans is slightly smaller than the range of horizontal motion. Vertical eye movements involve the superior and inferior rectus muscles, in cooperation with small adjustments from the oblique muscles.

For the most part, the circuitry involved in horizontal movements is duplicated for vertical movements. The oculomotor neurons themselves are in the oculomotor nucleus and feed cranial nerve 3 (CN-3, oculomotor nerve), except for the trochlear neurons feeding the superior oblique that exit via cranial nerve 4 (CN-4, trochlear nerve).

In the vertical eye movement system, the rostral interstitial nucleus of the medial longitudinal fasciculus takes the place of the PPRF burst neurons, and the interstitial nucleus of Cajal takes the place of the neural integrator.

It is important to understand that the separation of horizontal and vertical axes begins all the way out in the semicircular canals. We'll take a moment to review the organization of the vestibular system, because it helps us to better understand the oculomotor design.

The semicircular canals operate much like the cochlea. There are hair cells embedded in a gelatinous cupula, and as the head rotates the cupula bends, deflecting the hair cells which in turn causes changes in the membrane potential. The canals detect rotational movements of the head, in the horizontal, vertical, and angular axes. The otolith organs (utricle and saccule) detect linear acceleration of the head, they help maintain balance during head movements.

The horizontal semicircular canal is approximately aligned with the horizontal axis of the head and therefore the horizontal axis of the eyes. The superior and inferior canals detect rotation of the head in the sagittal and frontal planes, and they're not "perfectly" vertical, such a motion would engage both of these canals. The primary sensory neurons for the semicircular canals are in Scarpa's ganglion, which is in the internal auditory canal where the superior and inferior divisions of the vestibular nerve converge. These are bipolar neurons, the sensory side (dendrite) travels through the vestibular nerve to connect with the hair cells in the labyrinths, and the motor side (axon) connects with the one of the four subdivisions of the vestibular nucleus.

The vestibular nerve (cranial nerve CN-8) has three terminal branches (superior, inferior, and posterior) which innervate the utricle, saccule, and semicircular canals respectively. Moving centrally, they converge in the superior (Scarpa's) and inferior vestibular ganglia. From there they target the vestibular nucleus. There are a few vestibular fibers that target the cerebellum directly, especially the nodulus and uvula of the vermis. These are related to balance and do not primarily affect the oculomotor circuitry.

The organization of the vestibular nucleus is shown in the figure. There are four sub-nuclei, called inferior, medial, lateral, and superior. (The lateral subdivision is also called Deiter's nucleus, and the superior subdivision is also called the nucleus of Bechterew, while the inferior subdivision is sometimes referred to as the descending vestibular nucleus or the nucleus of Roller). The main projections of these areas are to the spinal cord (mostly reflexes), to the oculomotor nuclei (for eye movements), to the thalamus (VPi) for perception, and to the cerebellum (for coordination of posture).

Afferents to the oculomotor system arise from the medial and superior vestibular nuclei. These coordinate eye movements in relation to head movements. The fibers from the superior vestibular nucleus primarily target the thalamus, but they send collaterals into the oculomotor system. The fibers from the medial vestibular nucleus primarily target the oculomotor nuclei. The figure below shows how the fibers from the semicircular canals enter the medial vestibular nucleus, and from there the MVN connects with all of the oculomotor nuclei.

From the medial vestibular nucleus, outgoing fibers innervate the NPH, and the oculomotor nuclei directly. The abducens, trochlear, and oculomotor nucleus are all innervated directly by the MVN (the MVN is also known as the nucleus of Schwalbe). The MVN is divided into three parts, a parvocellular region most medially consisting of densely packed small neurons, a ventral magnocellular area providing the main output, and a caudal region with heterogeneous cytoarchitectonics. In primates, inputs to the MVN originate from the ipsilateral semicircular canals and otolith organs and the ipsilateral interstitial nucleus of Cajal, and contralaterally from the spinal cord. Bilateral inputs originate from other vestibular nuclei, the NPH, pontine and medullary reticular formation, the cerebellum, and the cerebral cortex. Commissural fibers interconnect the MVN's bilaterally.

Neurons in the MVN show two types of behavior called A and B. Type A neurons have a rectifying membrane potential and generate a single deep after-hyperpolarization. Type B neurons are non-rectifying and show two distinct after-hyperpolarizations, an initial fast one followed by a slower delayed one. Both types have resting potentials around -60 mV. Type A issues a tonic discharge with low frequency dynamics, while type B issues a phasic-tonic pattern with high frequency dynamics. Neurochemically there are glutamate synapses in the MVN containing both NMDA and AMPA receptors (suggesting plasticity), as well as acetylcholine (in both muscarinic and nicotinic forms), GABA, glycine, opioid peptides, somatostatin, substance P, and others.

The MVN controls the abducens nucleus for horizontal eye movements, and the trochlear nucleus for vertical eye movements. MVN neurons involved in the VOR are subdivided by their axonal pathways, and it is currently unknown whether there is any additional topographic organization in these areas. The vestibular system sends information in the form of velocity signals, and the disposition of these signals is not fully known. Velocity signals can become position signals through path integration, and whether and how this occurs is not fully known. This level of integration would be different than the oculomotor integration that keeps the eyes in place following a saccade, its purpose would be to layer pursuit movements over fixation, to enable the VOR to continue functioning while interspersed with saccades.

Vergence Movements

In a vergence movement, both eyes move towards the midline, or away from the midline. Vergence movements integrate with both saccades and smooth pursuit movements. The vergence pathways integrate with the horizontal controls at the level of the supraoptic nucleus and the oculomotor nuclei.

During saccades, vergence movements typically appear in the middle of the saccade, they don't "interrupt" the saccade per se, but they layer on top of it. The gaze center for vergence is in the supraoculomotor area (SOA). Neurons in the SOA increase their firing rates for near viewing. There are vergence burst neurons that encode peak vergence velocity, vergence tonic neurons encoding vergence angle, and burst-tonic neurons that encode both angle and velocity. Most SOA neurons project monosynaptically to the medial rectus subdivision of the oculomotor nucleus, and some project to the accessory oculomotor nucleus, also called the nucleus of Edinger-Westphal. A small subset of SOA neurons respond only to accommodation or only to vergence, generally the input to the SOA encodes both.

Stereopsis requires sensory fusion, and only occurs over a limited range around the horopter (called Panum's fusional area - please reference the earlier diagram showing the range of human binocular vision). The primary driver is retinal disparity, that is to say, a slight misalignment in the position of an object on one retina versus another. If the target is already within Panum's area, the eyes may adjust smoothly, however if the target is outside Panum's area the horizontal saccade will begin before any vergence movements. The initial saccade is thus entirely ballistic and does not require binocular correspondence. Vergence must first bring the eyes into rough alignment within Panum's area, and then achieve sensory fusion with a more precise alignment.

Vergence debatably has its own neural integrator, although there are some reports that neurons in the rostral superior colliculus may perform at least a portion of the integrative function. The figure shows a proposed model handling both slow and fast aspects of vergence (Quinet et al 2025).

There are generally two hypotheses for organizing vergence, championed by Ewald Hering and Hermann von Helmholtz respectively. In the Hering model, target position is encoded by a saccade channel controlling the abducens motoneurons, and then "corrected by" a vergence channel that affects only the motoneurons in the oculomotor nucleus controlling the medial rectus muscle. In the Helmholtz model, each eye is controlled independently. Current evidence favors a mixed model, where vergence position and velocity commands are derived from a 3-dimensional superior colliculus and then decoded into the relevant oculomotor components. There is definitely complexity in this issue and it remains a subject of intensive research.

The evidence against a purely Hering architecture is amplified by the observation that vergence eye movements made alone reach peak velocities of around 60 degrees/sec, while vergence velocities during saccades can reach peaks in excess of 200 degrees/sec. Apparently, the saccadic pathways encode the movement of an individual eye, rather than conjugate and vergence locations. EBN's that drive the oculomotor neurons are monocular, that is to say, there is no "conjugate burst". The monocular EBN's are controlled from each hemilateral superior colliculus individually.

Pursuit Movements

(Smooth) Pursuit is a visual reflex involving the cerebral cortex. It keeps the eyes foveated on a moving target. If the smooth pursuit system can't keep up with the target, saccades are engaged.

While the eyes will move to a spot of bright light on the retina (a reflex mediated in and by the superior colliculus), pursuing moving prey requires more sophisticated visual input. This input is provided by cortical fibers that descend from many areas of the visual cortex. Most important are a portion of the frontal lobe known as the "frontal pursuit area", and area MT of the temporal cortex (V5), which processes visual motion. Axons from V5 travel to the dorsolateral pontine nucleus, and axons from the frontal and supplementary eye fields target both the DLPN and the nucleus reticularis tegmenti pontis (NRTP). This anatomy is shown in the figure.

The NRTP then sends fibers to the fastigial nucleus of the cerebellum, whereas the DLPN targets the vermis which connects with the flocculus and paraflocculus. Both systems then converge onto the medial vestibular nucleus. The cerebellar systems are needed for the prediction phase of the smooth pursuit movement. The predictive systems engage rapidly after initiation.

Within a smooth pursuit movement there are stop and go signals, and there is target selection. Movement initiation is separable from movement maintenance. Initiation is more closely linked to the frontal pathway (shown in green in the figure above), whereas maintenance is more closely linked with the purple pathway. Target selection occurs in the frontal cortex, and is precisely guided by the cerebellum. Termination also involves the cerebellum.

Smooth pursuit movements have three phases: an initial ballistic phase that lasts about 100 msec and is open-loop (that is, the cerebellar systems have not yet had time to correct velocity or direction). Then a closed loop error-correcting pathway through the cerebellum engages for the remainder of the movement, and finally it is turned off with the help of the pause neurons in the nucleus raphe interpositus.

Humans find it difficult to engage in smooth eye movements without a target. An effort along these lines typically results in a series of small saccades.

Vestibulo-Ocular Reflex

The vestibulo-ocular reflex keeps the eyes aligned on target when the head moves. Its organization is shown in the figure.

There is a vertical VOR, tested by moving the head up and down at an amplitude of about 20 degrees around 3 Hz. In such tests the eyes can sometimes remain fixed on target even while the subject experiences sensations of dizziness, nausea, or headache.

Activity At Rest

The eyes move even at rest. During fixation there is "fixation tremor", and there are "micro-saccades", and there is drift (which is sometimes corrected by a subsequent micro-saccade). The frequency of fixation tremor is fast, usually in the range of 30 to 120 Hz, and the amplitude is small, usually just a few seconds of arc. In Parkinson's and other conditions, there may be abnormal forms of fixation tremor at lower frequencies, in the 4-12 Hz range, indicating involvement of the substantia nigra, and indeed there is a direct projection from the superior colliculus to the pars reticulata of the substantia nigra (more on this later, when we discuss the superior colliculus in detail). The frequency of micro-saccades is normally in the 1-3 Hz range, with the amplitude varying from 2 to 120 arc-minutes. These numbers can be contrasted with neural spike rates during saccades, which may reach 700 Hz or more.