Overview Of Oculomotor System

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 cerebral cortex, 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.

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.

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.

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.

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.

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.