The goal of the efferent visual system is to direct and maintain the angle of gaze on an object of regard, thereby guaranteeing the best possible visual acuity and clarity. Several mechanisms are crucial in attaining this goal: (A) saccades, which direct the eyes to the object of regard; (B) fixation and pursuit tracking, which detects (and corrects for) retinal image drift, and suppresses unwanted saccades; (C) the vestibulo-ocular reflex (VOR) that compensates for head perturbations at short latency to preserve visual acuity during locomotion; and (D) the gaze-holding system, which counteracts the elastic forces of orbital tissue (1–3). In species with frontally directed eyes with central foveas, the vergence system enables bifoveal fixation of a single object of regard by correctly aligning the visual axes (1). The cerebellum plays a vital role in ensuring the precision and accuracy of ocular movements regardless of changes in head or body positions and is intimately involved in controlling gaze-shifting and gaze-stabilizing reflexes, both in their real-time, immediate modulation, and in their long-term calibration (1).
Three cerebellar regions are especially important for ocular motor control (Fig. 1):
- ocular motor vermis (OMV) and caudal fastigial nuclei (CFN);
- ventral uvula and nodulus; and
- flocculus and paraflocculus
To maintain visuomotor precision, the cerebellum continuously monitors and adapts the network's performance. The cell groups of the paramedian tract (PMT) receive collaterals from all ocular motor neurons and in turn convey efference copy signals to the flocculus, paraflocculus, and vermis (1). In addition, retinal slip signals are conveyed from the inferior olivary nucleus (ION) to the contralateral flocculus via climbing fibers (1,4).
The main afferents to the flocculus and paraflocculus are mossy fibers from the medial vestibular nucleus (MVN), superior vestibular nucleus (SVN), nucleus prepositus hypoglossi (NPH), nucleus reticularis tegmenti pontis (NRTP), and cell groups of the PMT, as well as climbing fibers from the ION (1,4). The main efferents from the flocculus and paraflocculus travel to the ipsilateral SVN, MVN, and Y-group (1).
Major inputs to the nodulus and ventral uvula are mossy fibers arising from the ipsilateral vestibular nerve (with preferential input from the semicircular canals to the nodulus, and the sacculus to the ventral uvula), SVN, MVN, and NPH, as well as ION climbing fibers (1,4). Important efferents project to the SVN, MVN, and the Y-group (1).
The OMV receives mossy fiber afferents from the pontine paramedian reticular formation (PPRF), NRTP, vestibular nuclei, NPH, and dorsolateral and dorsomedial pontine nuclei, as well as ION climbing fibers (1,4,5). Efferent projections from the OMV Purkinje cells are directed to the ipsilateral CFN (1). The CFN also receive climbing fiber afferents from the ION and mossy fibers from pontine nuclei (particularly the NRTP) (1,6). CFN efferents project primarily to the contralateral CFN, before travelling via the uncinate fasciculus in the superior cerebellar peduncle to the omnipause neurons in the pontine raphe, contralateral brainstem burst neurons (rostral medulla, PPRF, and rostral interstitial nucleus of the medial longitudinal fasciculus [riMLF]), NRTP, central mesencephalic reticular formation, periaqueductal gray, nucleus of the posterior commissure, vestibular nuclei, thalamus, and bilateral rostral poles of the superior colliculi (1,4–6).
Clinical observations indicate an important role for the cerebellum in vergence eye movements. A range of disorders in cerebellar disease has been reported including convergence insufficiency and esodeviation during distance viewing (1).
The OMV, CFN, and posterior interposed nuclei (PIN) are involved in vergence (7–10). Neurons controlling vergence project to the NRTP from the medial superior temporal area (MST), supplementary eye field (SEF), frontal eye field (FEF), superior colliculi, and mesencephalic pretectum. The NRTP subsequently projects to the OMV and deep cerebellar nuclei (5,11–13).
Esodeviation at distance has been recognized in cerebellar disease (1,7). To understand how cerebellar lesions affect vergence, it is important to note that neural pathways for convergence and divergence are separately organized; divergence-related neurons in the PIN receive input from the ventral paraflocculus and OMV, while the convergence is controlled by the OMV-CFN pathway (1,9,10,12–16). Further, since divergence-related neurons in the OMV may be more susceptible to injury, and convergence may be better compensated for (7), vermal lesions are more often associated with incomitant esodeviation (5,17).
Skew deviation is a vertical misalignment of the eyes resulting from lesions disrupting otolithic input to the interstitial nucleus of Cajal (1). When skew deviation is associated with ocular torsion (with the upper poles of the eyes rotated toward the lower ear) and a head tilt (toward the lower eye), this combination is called the ocular tilt reaction (OTR) and is often associated with deviation of the subjective visual vertical (1). The OTR is believed to arise from an imbalance in the otolith-colic reflexes, part of the phylogenetically ancient righting response to a lateral head tilt (1).
Skew deviations have been long recognized as a feature of cerebellar disease (1,17). Sometimes, the vertical misalignment may change with horizontal position, with the abducting eye being higher (the alternating skew deviation) (17–23). The cerebellum (specifically, the uvula, nodulus, biventer lobe, and dentate nucleus) is involved in otolithic signal processing, ensuring the accuracy of the internal representation of the earth-vertical (24,25). Lesions affecting these structures may cause a skew deviation or OTR, presumably by disrupting the symmetry of the otolithic pathways (24,26). Generally, uvulonodular and dentate nuclear lesions result in a contraversive OTR, while lesions affecting the biventral or inferior semilunar lobule cause an ipsiversive OTR (1,24).
Saccades are rapid eye movements that redirect the fovea from one object of interest to another and must be fast and accurate to ensure visual clarity. Human saccades jump to a target within ∼250 milliseconds are fast (∼600°/s), brief (∼30–100 milliseconds), accurate, and stop abruptly (with little subsequent ocular drift) (27). Saccades are generated by a pulse-step command. To ensure accuracy, the pulse command must be of the correct magnitude; to keep the eye still following the saccade, the step command must match that of the pulse and be sustained for the duration of the fixation (17).
Cortical eye fields (frontal, parietal, and supplementary) predominantly project to the superior colliculi, the vital nodal point that integrates and relays commands from the cortical eye fields and basal ganglia to the brainstem saccade-generator, as well as to the OMV and CFN by way of the NRTP and the dorsolateral pontine nuclei (1,5,6,22,27–31). The cerebellum also receives input from the cortical eye fields, NPH, and premotor burst-neurons in the brainstem reticular formation (1). The cerebellum in turn projects efferents back to these structures, including projections to the cortical eye fields (via the thalamus) and superior colliculi (1).
The cerebellum is essential to saccadic sensorimotor adaptation and accuracy. Its immediate responsibility is propelling and accelerating the eyes to a target of interest, monitoring the progress of the saccade, and ensuring that the saccade lands on target by choking the pulse drive off at the precise time; its long-term role is to assure accuracy by adapting for persistent end-point errors (4,32). Total cerebellectomy abolishes saccadic adaptation for both pulse-size and pulse-step match (33). The OMV and CFN play a crucial role in saccadic adaptation and accuracy. Stimulation studies show that OMV stimulation produces ipsiversive saccades, and that it is organized topographically; lobule V produces upward and horizontal saccades, while lobules VI and VII elicit horizontal and downward saccades (1). The CFN and OMV show significant changes in electrical activity related to saccadic adaptation; furthermore, brainstem structures (especially the NRTP) that are intimately linked by afferent and efferent projections with the CFN and OMV also demonstrate changes in neuronal activity during adaptation (34). Inactivation of the CFN abrogates saccadic adaptation (34–36); however, there is evidence that saccadic adaptation can occur during the period of CFN inactivation but cannot be expressed until this output pathway regains function, suggesting that the OMV is the critical cerebellar structure required for saccadic adaptation, rather than the CFN (34,35). Lesion studies suggest that while OMV-CFN lesions impair the pulse-size adaptation (resulting in pulse-size dysmetria), pulse-step match is controlled by the flocculus-paraflocculus (1,37). Apart from these structures, there is evidence that the lateral cerebellar hemispheres also participate in saccade adaptation (38).
Conjugate saccade pulse dysmetria is a classic sign of cerebellar disease (1,17,18,39). Bilateral OMV lesions that spare the CFN cause hypometric saccades; on the other hand, unilateral CFN lesions result in hypometric contraversive and hypermetric ipsiversive saccades (35,40–49). Total cerebellectomy and bilateral CFN inactivation causes saccadic hypermetria (33,48,50). As such, we can infer that the CFN overcomes the inherent hypermetric tendency of the brainstem saccade pulse-generator (41), presumably by balancing the activity between omnipanuse neurons and excitatory and inhibitory burst-neurons (51–55).
To guarantee the eyes land on target, the OMV monitors saccade performance and adjusts its inhibition of the CFN (4) to ensure that saccade-related CFN neurons fire just before the onset of contraversive saccades and toward the end of ipsiversive saccades (36,51,56–58); this discharge pattern suggests that the CFN provides the “push” for contraversive saccades to propel the eyes toward a target and applies the “brakes” for ipsiversive saccades to stop on target. Therefore, in unilateral CFN lesions, contralesional saccades are hypometric due to insufficient “push,” and ipsilesional saccades are hypermetric as a result of damaged “brakes.” On the other hand, unilateral OMV lesions cause hypermetric contraversive and hypometric ipsiversive saccades, and bilateral OMV damage results in bilateral hypometric saccades because their inhibitory effect on the CFN is lost (thereby “disinhibiting the inhibitors”) (59).
Ocular lateropulsion refers to horizontal conjugate gaze deviation during eye closure, either toward (ipsipulsion) or away from (contrapulsion) the side of the lesion, that is, corrected by a saccade when the eyes are opened. Ocular lateropulsion is typically accompanied by saccadic lateropulsion and horizontal misdirection of vertical saccades. In ipsipulsion, damage to the inhibitory climbing fibers from the contralateral ION (travelling in the inferior cerebellar peduncle) to OMV Purkinje cells leads to increased inhibition of the ipsilateral CFN (mimicking the effects of an ipsilateral CFN lesion) (60,61). This results in hypometric contraversive and hypermetric ipsiversive saccades. On the other hand, contrapulsion results from damage to fibers traveling in the uncinate fasciculus from the contralateral CFN to the ipsilateral PPRF (62,63), leading to hypometric ipsilesional and hypermetric contralesional saccades (Fig. 2).
CFN damage also affects vertical saccades and gaze position, since both CFNs are active during vertical saccades (36,55,56). In unilateral lesions, the unopposed “push” from the unaffected CFN results in ipsilesional horizontal deviation of vertical saccades. Additionally, the eyes are often slightly deviated ipsilesionally during fixation (48,55). In saccadic lateropulsion, vertical saccades exhibit a curved trajectory due to cross-coupling of horizontal bias into vertical eye movements. The horizontal bias is directed contralesionally in contrapulsion and vice versa (1,63,64). Further, the amplitude of horizontal misdirection may be greater in upward compared to downward saccades (65).
The posterior inposed nuclei (PIN) fire for every saccade (66) and receive projections from saccade-related pontine nuclei via the paraflocculus (67,68). Each PIN, in turn, conveys efferent projections to the contralateral superior colliculi and interstitial nucleus of Cajal (69). In primates, PIN inactivation results in hypermetric upward saccades and hypometric downward saccades, as well as upward deviation of horizontally directed saccades (70). The cross-coupling of inappropriate vertical components into horizontal saccades has also been observed with pontine lesions (71), perhaps reflecting damage to the brainstem-PIN circuitry.
Saccadic intrusions are a feature of certain disorders that affect the cerebellum and/or brainstem. Square-wave jerks are prominent sign in certain cerebellar disorders (e.g., Friedreich ataxia, spinocerebellar ataxia 8); while the precise etiopathological basis is unclear, some have suggested that a dysfunctional inhibitory system (which includes the cerebellum) is to blame (1,72). Macrosaccadic oscillations (thought to be an extreme form of saccadic hypermetria) have been recognized in midline cerebellar lesions affecting the CFN and are hypothesized to be due to CFN output dysfunction (72). Ocular flutter and opsoclonus are believed to arise in cerebellar disorders that impair Purkinje cell inhibition of the CFN, resulting in premotor burst neuron oscillations (1,72).
The cerebellum plays a crucial role in the smooth eye tracking of a moving target, either when the head is still (i.e., smooth pursuit), or when the head is passively moving with the target (i.e., VOR cancelation). Complete cerebellectomy abolishes smooth pursuit in humans and monkeys (19,73,74). The main cerebellar structures involved in pursuit eye movements are the flocculus-paraflocculus, OMV, CFN, and ansiform lobule (hemisphere lobule VII). The nodulus, uvula, and lateral cerebellar hemispheres also contribute to pursuit (7,75–83).
In monkeys, bilateral flocculus and paraflocculus ablation completely impairs smooth pursuit (75,80), while unilateral inactivation impairs ipsilateral pursuit (84). In humans, the paraflocculus plays a greater role in smooth pursuit compared to the flocculus, which is predominantly concerned with the VOR (16, 80). As part of the network that controls smooth pursuit, the paraflocculus receives afferents from the dorsolateral pontine nuclei and mossy fiber input from the vestibular nuclei, NPH, PMT, as well as climbing fibers from the contralateral ION (16,67,85).
The OMV (which receives pursuit input from the NRTP) is also important in pursuit tracking. In addition to encoding gaze velocity during pursuit tracking, the OMV Purkinje cells also respond to retinal slip velocity and hence encode target velocity in space (1,76,86). OMV lesions affect the initiation of smooth pursuit (reducing initial acceleration by over 50%) and affect pursuit adaptation to novel stimuli (87). In contradistinction, uvulonodular lesions impair sustained pursuit without affecting pursuit initiation (81).
CFN neurons fire most vigorously during contraversive pursuit and just before the end of ipsiversive pursuit (88,89). As such, their role in pursuit is similar to their role in saccades—to accelerate contraversive pursuit and to slow down ipsiversive pursuit so that the eyes accurately match the target's velocity (89). Unilateral CFN lesions impair contralateral pursuit, while unilateral OMV damage affects ipsilateral pursuit (87,89). Interestingly, while bilateral OMV lesions cause bilateral pursuit deficits (87), bilateral CFN damage leaves pursuit relatively intact (89), suggesting that pursuit deficits from CFN lesions are the result of asymmetry between the 2 CFN (4). In vertical pursuit, the CFN, nodulus, and ventral uvula are more active during downward pursuit and as such, lesions of these structures may cause decreased downward pursuit gain (87–89).
The ansiform lobule receives input from the frontal cortical areas (via the pontine nuclei) and from the nucleus of the optic tract (via climbing fibers from the ION); it is hypothesized that the ansiform lobule may help suppress background motion induced by smooth pursuit of a small target on the foreground (1,90,91).
An unusual, but highly conspicuous manifestation of cavernous angiomas of the middle cerebellar peduncle (MCP) is cross-coupling of torsional into vertical eye movements, resulting in direction-changing torsional nystagmus during vertical pursuit (64). It is hypothesized that the smooth pursuit neural network is based on a vestibular labyrinthine coordinate system; vertical VOR and pursuit signals encoded in “anterior canal coordinates” are conveyed to the vestibulocerebellum via the MCP (92–94). Therefore, unilateral MCP lesions would cause an imbalance in the torsional components during vertical pursuit, resulting in a contralesional-beating torsional nystagmus during upward tracking (due to the unopposed anterior canal signals) and a ipsilesional-beating torsional component during downward tracking (due to the unopposed posterior canal signals) (64).
The neural integrator is inherently “leaky” and the eye position signal is a decaying exponential resulting in slow centripetal drifting of the eyes until corrective saccadic quick-phases move the eye back to target. This is the basis for gaze-evoked nystagmus (GEN) (1).
The flocculus-paraflocculus is tasked with improving the performance of this inherently leaky neural integrator (75,95). Positive feedback loops between the cerebellum and brainstem, via connections from the NPH and MVN, to the vestibulocerebellum and PMT, optimize the performance of the neural integrator to maintain eccentric gaze stability (1,96). Floccular-parafloccular lesions result in GEN (since the output of the neural integrator cannot be maintained) and postsaccadic drifts (because the step is not correctly matched to the pulse command) (1). Furthermore, since the flocculus is crucial for adaptive control of the time constant of the neural integrator, the GEN from cerebellar disease is often persistent (1,97). Postsaccadic drifts are another manifestation of the pulse-step mismatch arising from flocculus-paraflocculus lesions (1,75).
Downbeat nystagmus (DBN) is a prominent and common manifestation of floccular-parafloccular lesions (75,98–102). Less frequently, DBN is caused by lesions affecting the uvula/nodulus (103), OMV (104), or PMT (105).
Hypothetically, the upward drift consists of 2 components—a gaze-evoked drift and an upward bias (106). The gaze-evoked drift results from a leaky gaze-holding neural integrator (106,107). The upward bias is hypothesized to consist of gravity-dependent and gravity-independent components (98,99,106). The gravity-dependent component may be the consequence of otolith-ocular reflex hyperactivity (98) and explain the effect of position on DBN. The pathophysiologic basis of the gravity-independent component is less clear; the most-favored hypothesis (108) is that the geometric configuration of the canals predisposes to an upward ocular drift (due to relative predominance of the anterior canal pathways), that is, normally suppressed by the flocculus-paraflocculus. Cerebellar disease unmasks this upward vestibular bias, resulting in DBN (108–113).
Others have proposed that neural integrator dysfunction results in an upward shift of Listing's plane for static eye positions (104,106). Alternately, based on the observation that downward pursuit is more impaired than upward pursuit in cerebellar disease, it is possible that floccular damage causes an asymmetry of vertical smooth-pursuit signals, where a preponderance of upward velocity results in spontaneous upward drifts (1,99,102,114,115).
By detecting head motion and position and generating compensatory eye movements, the VOR ensures that the angle of gaze remains on target during head motion (1,116). The 3-neuron VOR reflex path consists of vestibular ganglion cells, inhibitory and excitatory oculomotor relay neurons in the medial and superior vestibular nuclei and Y-group, and the motor neurons of the ocular motor nuclei (85). The angular VOR (AVOR) stabilizes the eyes in space during angular head acceleration (1,117). On the other hand, the translational VOR (TVOR), which relies on the otolithic organs to transform linear head acceleration into angular eye rotation, stabilizes eye position to compensate for translational head movements (118–121).
VOR performance needs to be continuously adjusted and optimized to correct for any change in visual circumstance (e.g., changes in spectacle lenses, disease states that affect balance) (1). VOR adaptation (changes in gain, direction, and phase) is driven by error signals from retinal slip. While vestibulocerebellar lesions do not abolish the VOR, such lesions impair VOR adaptation (80,97,116,117,122–128).
The flocculus is essential to VOR adaptation. It receives bilateral mossy fiber input primarily from the vestibular nuclei, PMT, NPH, and NRTP, as well as climbing fibers from the contralateral ION (1). The flocculus, in turn, projects to the ipsilateral SVN, MVN, Y-group, and basal interstitial nucleus of the cerebellum (1,129,130). Floccular Purkinje cells transform vestibular and nonvestibular (efference copies, head velocity, and retinal image slip) input into compensatory ocular motor signals that ultimately produce accurate and precise VOR responses (1,96,121,122,125,131–136). Additionally, the flocculus modifies VOR gain, inhibiting the horizontal VOR during low-frequency stimulation, but facilitating it at high-frequency stimulation (137). Following floccular damage, VOR gain exceeds 1 with low frequency stimulation (75,116,117,123,138), but is diminished at high frequencies (75,123,137,139). Furthermore, floccular lesions may cause VOR misdirection, as evidenced by cross-coupling of upward bias into horizontal VOR, most likely due to disinhibition of anterior canal pathways (116,117,140).
The nodulus and ventral uvula receive afferent signals from the canals and otolith organs, secondary projections from the vestibular nuclei, and tertiary input from the ION (141–163). Uvulonodular efferent fibers project in a topographic fashion back to the Y-group and the magnocellular layer of the MVN (1,164). The nodulus and ventral uvula are responsible for generating the TVOR (by integrating linear head acceleration signals from otolithic organs to head velocity) and controlling the velocity-storage mechanism (which enhances the low frequency performance of the AVOR) (1,162). Nodular lesions in monkeys impair the sustained component of TVOR, impair downward pursuit, and cause DBN when fixation is eliminated (80,162). Clinically, uvulonodular lesions cause DBN in the dark, positional horizontal nystagmus, abnormal ocular counter-roll, and variants of the skew deviation (1). In some cerebellar diseases, the TVOR can be severely impaired despite relative preservation of AVOR (93,165), suggesting that preferential uvulonodular damage occurs in certain pathologies.
The velocity-storage mechanism maintains the spatial orientation of the AVOR by realigning the eye velocity-vector toward the gravito-inertial acceleration vector. Since movement in a terrestrial environment activates the canals and otolith organs, these signals are processed in a head-based canal-coordinate frame (rotated relative to the cardinal axes of the head). On the other hand, velocity storage processes information in a spatially linked coordinate frame, the yaw axis of which is a combination of the head-vertical and gravito-inertial acceleration vector. In other words, the velocity-storage mechanism transforms sensory signals from a head-fixed reference frame into a spatially linked reference frame (1,166–174). The nodulus and ventral uvula (with their GABAergic Purkinje projections to the ipsilateral vestibular nuclei) are critical components of the velocity-storage mechanism (171,175–179). Stimulation of the nodulus reduces the VOR time-constant, while stimulation of the uvula produces nystagmus without altering the VOR time-constant (180). Lesions of these structures prolong the velocity-storage effect for horizontal AVOR and negate the effect of maneuvers that typically shorten the duration of postrotational nystagmus (e.g., pitching the head forwards—“tilt-suppression nystagmus”) (1,138,175,181–184). Velocity-storage dysfunction from uvulonodular damage may also account for the cross-coupling of upward bias into horizontal eye movements with low-frequency head rotation around an earth-vertical axis, with sustained optokinetic stimulation with the head upright, and following horizontal head-shaking (4,116,174).
PERIODIC ALTERNATING NYSTAGMUS
Acquired periodic alternating nystagmus (PAN) is a spontaneous horizontal nystagmus that reverses direction at predictable intervals (approximately 90–120 seconds); during the brief transition period, vertical nystagmus or square-wave jerks may occur (1). Some patients learn to use Alexander law to partially or completely null the nystagmus by using periodic head turns in the direction of the quick phases (185,186). Smooth pursuit and optokinetic responses are usually impaired in PAN; convergence is typically spared and may sometimes suppress PAN (187,188). Uvulonodular lesions have been shown to result in PAN in both experimental studies and in humans (173,175). Since the nodulus and uvula normally inhibits velocity storage, uvulonodular damage results in excessive prolongation of rotationally induced nystagmus; normal vestibular adaptive mechanisms are activated to correct this abnormality but instead produce the alternating oscillations that characterize PAN (1,187,189). Visual fixation usually suppresses these oscillations; however, diseases that cause PAN often affect the flocculus and paraflocculus and impair this process (1). The ability of baclofen to successfully abolish PAN provides pharmacological evidence that the nodulus and uvula maintain inhibitory control over the velocity-storage mechanism using gamma-aminobutyric acid (GABA) (1,190).
The cerebellum ensures the precision of ocular movements and occupies a central role in all classes of eye movements, both in real-time control and in long-term calibration and learning (i.e., adaptation). The flocculus-paraflocculus are crucial to VOR gain and direction, pulse-step matching for saccades, pursuit gain, and gaze-holding. The OMV-CFN are essential in saccadic accuracy and pursuit gain. The nodulus and ventral uvula are involved in the low-frequency VOR responses (Table 1). The most important, intriguing, and impressive role of the cerebellum in eye movement control is its ability to constantly monitor the brain's performance, detect errors, readjust, and recalibrate its responses to guarantee optimal visual acuity.
STATEMENT OF AUTHORSHIP
Category 1: a. Conception and design: S. C. Beh, T. C. Frohman, E. M. Frohman; b. Acquisition of data: S. C. Beh; c. Analysis and interpretation of data: S. C. Beh. Category 2: a. Drafting the manuscript: S. C. Beh; b. Revising it for intellectual content: S. C. Beh, T. C. Frohman, E. M. Frohman. Category 3: a. Final approval of the completed manuscript: S. C. Beh, T. C. Frohman, E. M. Frohman.
The authors thank Jason Thean Kit Ooi for his help in preparing the figures herein.
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