The control and coordination of extraocular muscles both rely on a complex interaction between pre-motor neurons located in the cerebral cortex and cerebellum. The pathway from these supranuclear structures leads to the neural network in the brainstem and ends in three cranial nerve nuclei (III, IV, and VI) involved in ocular rotation. The dichotomy in size, which can be observed among the pool of motor neurons in all of the nuclei, is also present among the efferent nerve fibers and the muscle fibers that they innervate. This neuromuscular organization suggests that there is a division of labor in the oculomotor system in which the firing of small motor neurons initiates signals with a low velocity and slow muscular contractions, whereas the firing of larger neurons initiates signals with a high velocity and forceful muscular contractions.
When combined, these neuromuscular features form the basis for the gaze-shifting mechanism, which performs distinctive types of eye movements. Slow, fine-tuned eye movements help to stabilize the image of an object on the fovea when pursuing a slow-moving object or retain the eye in a stable position during fixation. Rapid eye movements (700 degrees/second) help to keep the minimum temporal disruption of the visual image while transferring the eye from one object to another.1 The same combination of eye movements serves as the basis for the system's gaze-stabilizing mechanism, which aims to counteract potential movements of the head and torso while the eye is fixating on an object. Eye movement reflexes (the vestibulo-ocular and opto-kinetic reflexes) suggest that the oculomotor system receives detailed information from the vestibular apparatus and proprioceptors in the somatic muscles in the neck and torso.
The oculomotor system receives information on the eye's position in relation to the head and orbit and shifting gaze can require both head and eye rotations. This information, which may be effectively provided by proprioceptors in the extraocular muscles, facilitates the calculation of the final efferent signal that is required to move and re-stabilize the eye.
To move and hold the eye in an eccentric position, the extraocular muscles must overcome the viscoelastic forces imposed by the supporting tissue and mechanical constraints from the lengthening antagonistic muscles. There are six pairs of antagonistic muscles responsible for the rotation of the eye and each of these muscles is tonically active to maintain the required stability of the eyes. The muscles rotate the eye around three principal virtual axes, rising to adduction and abduction, elevation and depression, and intortion and extortion. These movements must be joined to maintain binocularity and prevent diplopia.
The unique speed and high precision of eye movements suggest a particularly elaborate muscle control system, preferably with the capability of monitoring active contraction and passive stretching of the extrinsic muscles involved in the rotation of the eye. This enables the brain centers to confidently locate the direction of the eye's target. Even in the absence of vision or with the eyes closed, there seems to be a degree of eye position sense that suggests the retrieval of extraretinal information by the oculomotor system. It is a common belief that such non-visual information may arise from the sensory organs (proprioceptors) located in the extraocular muscles.2
Increasing evidence from recent morphological, behavioral, and physiological studies on animals and humans supports this opinion and suggests that proprioception from extraocular muscles and/or efferent signals deriving from other ocular structures play a vital role in retaining cortical binocular integration, oculomotor control, and spatial localization.3–7
The aim of the current study was to review and critically discuss the role of ocular proprioception in oculomotor control and the development of eye motility disorders.
The term proprioception was coined by Sir Charles Sherrington8 in 1906, when it was defined as a reflex system for maintaining body position and movement coordination. The sensory signal was believed to arise from receptors associated with muscles, tendons, and joints in the periphery of the body and conveyed through afferent neural pathways to the brain, resulting in the perception of movement and spatial orientation. Sherrington observed that proprioceptive inflow from the periphery to the brain (inflow theory) played a vital role in the control and coordination of all somatic muscles in the body.9 However, in contrast to conventional cross-striated muscles, the extraocular muscles are not influenced by variable external loads or gravitational forces. Therefore, Sherrington suggested that the oculomotor system did not need to elaborate the reflex system.9 The fact that a stretch reflex has not been demonstrated in these muscles seems to support this view.
This unique neuromuscular arrangement gave reason to question Sherrington's inflow theory and many scholars began to favor the outflow theory previously promoted by Helmholtz (1867). According to this theory, also described as the “efference copy” or “corollary discharge” theory, the brain relies on information derived from the final efferent signals sent to the extraocular muscles during eye movements.10 Based on this information, the brain can accurately estimate the subsequent eye positions if the respective muscles contract according to the initial motor command. It was broadly accepted that this type of central monitoring of the outflow innervation was the only extraretinal source of eye position information.11,12 Proprioception from the extraocular muscles was considered unnecessary due to the presence of the highly efficient exteroceptor in the retina.10
Recently, evidence of a non-visual afferent feedback system, assumed to arise from extraocular muscle proprioceptors, has proved the inflow theory.10,11,13 Data from animal studies suggest that this type of feedback influences both gaze holding and shifting systems.10 There are large interspecies variations and individual variations within the same species in the morphology of the receptors in extraocular muscles.11 Comparative studies on the oculomotor system of animals cannot serve as a fully reliable model for understanding the role of ocular proprioception in humans. However, clinical observations have served to identify some common physiological properties. Observation on individuals who were monocularly blind and showed conjugate eye movements as adults supports the notion of proprioception taking a part in ocular position sense.14 These observations are apparent in the work of Steinbach and Smith,15 in which they underline that the postoperative angle of deviation will vary according to the complement of receptors that are jeopardized during the surgical procedure.
Further testing of the role of proprioception in oculomotor control has been undertaken using behavioral and psychophysical experiments such as the Jendrassik maneuver, in which the participant is asked to perform an isometric voluntary contraction of a given muscle group. This will alter the reflex response to such an extent that it will affect the proprioceptive feedback from the eye muscles and lead to eye position misinterpretation and localization of the target. Accordingly, alterations in the eye position signal are due to the effect of the Jendrassik maneuver, which changes the gain of the sensory feedback from the eye muscles, possibly due to the activity of small non-twitch motoneurons.16
Despite many hypotheses, there seems to be some consensus in the experimental evidence accumulated over the past century. Based on results from the beginning of the 21st century, it is believed that the receptors in extraocular muscles are capable of producing proprioception, meaning that the signals sent by the receptors in extraocular muscles to the brain are used to provide information about the position and movement of the eye within the orbit, which is important to control some types of eye movements. The same information may also support the brain's capacity to determine the desired direction of gaze and position of the body in relation to the environment. Additionally, signals from these receptors may be necessary for the development of normal mechanisms of visual analysis in the mammalian visual cortex and both the development and maintenance of normal visuomotor behavior.10 Much uncertainty remains and further research is required to advance our current understanding of the oculomotor system. It is argued that detailed knowledge of eye muscle proprioception is necessary for understanding the physiology and pathophysiology of eye movement control. Furthermore, this knowledge is also essential in understanding how complex biological organisms, including humans, build and maintain knowledge of their relationship to the external visual world.10
Results from previous studies suggest that visual localization may rely on more than one system. Rather than being mutually exclusive, systems might collaborate during normal eye movements.17 After supplementary studies, Bridgeman and Stark4 concluded that, although proprioception provides a significant supplement to the registration of eye position in unstructured visual fields, it functions as a back-up system for the principal influence of efferent copy signals. Similar results have also been obtained in other studies.5,18,19 In another study, Balslev et al.3 concluded that the efference copy of the motor command may be the primary signal that is used under normal circumstances, whereas eye proprioception, although continuously monitored, is used only under conditions in which these two sources of information do not match.
Recent studies on sensory information from extraocular muscles have suggested that proprioception participates in space localization and that individuals with strabismus may have deficits in this particular function.7,20–23
Structure and Proprioceptors of Eye Muscles
Our knowledge of somatic proprioceptors is not applicable to the understanding of the role of proprioception in the development of binocular vision, ocular alignment, and adaptive processes. Each extraocular muscle exhibits two distinct layers: an outer orbital layer adjacent to the periorbita and orbital bone and an inner global layer adjacent to the eye and optic nerve. There are also studies that identify a third layer outside of the orbital layer, called the marginal layer.24
Extraocular muscles are composed of a variable number of fibers. For a healthy adult, the muscle volume is approximately 500 mm3 for all rectus muscles combined, 270 mm3 for the superior oblique muscle, and 170 mm3 for the inferior oblique muscle.22 Regarding extraocular muscles, the mean number of fibers in the global layer is 10,000 to 13,000 in all rectus muscles from childhood to adulthood. In the orbital layer, the number is higher in the medial rectus muscle (approximately 11,000) than in other rectus muscles (7,000 to 9,000).25
In the early studies, Goldberg et al.26 identified only three types of motor units: twitch, multiply innervated twitch, and multiply innervated slow. Later, Goldberg and Shall27 used a more elaborate technique and were able to identify five types of motor units. They based their classification on the assumption that all muscle fibers innervated by the same motor neuron (ie, motor unit) had the same functional and morphological characteristics. Spencer and Porter28 identified six types of fibers in the extraocular muscles based on their microscopic appearance and distinct gene expressions. However, most muscle fibers seem to fall into two main categories when the classification criteria are based exclusively on the organization of efferent nerve terminals: non-twitch multiply innervated muscle fibers and twitch singly innervated muscle fibers.29,30
Singly Innervated Muscle Fibers
In the orbital layer, the singly innervated muscle fibers are the more numerous of the two and constitute approximately 80% of the fiber population, whereas the multiply innervated muscle fibers constitute the remaining 20%. In the global layer, there are three types of singly innervated muscle fibers: red (33%), intermediate (25%), and white (32%). Additionally, there is one type of multiply innervated muscle fiber (10%).23 Singly innervated muscle fibers are innervated by large myelinated nerve fibers that end in prominent motor endplates, which tend to make indentations on the post-synaptic surface on the associated muscle fiber. Sole plate nuclei can be observed accumulated in the terminal area along with other characteristics similar to those found in conventional somatic motor endplates. Singly innervated muscle fibers commonly display well-developed sarcoplasmic reticulum, a high content of mitochondria, and oxidative enzymes and have fast-twitch capacities.31,32
Mulptiply Innervated Muscle Fibers
Multiply innervated muscle fibers, which are unique to extraocular muscles, are found at the distal end of small unmyelinated and some myelinated nerve fibers. Clusters of small terminal buttons are distributed along the entire length of the muscle fiber, which has a modest diameter and contains little sarcoplasmic reticulum when compared to singly innervated muscle fibers. There is a seemingly unequal distribution of multiply inner-vated muscle fibers in horizontal human extraocular muscles. Although the number of slow fibers is the same as in the global layers of the two muscles, the orbital layer in the medial rectus muscle contains 20% more multiply innervated muscle fibers when compared to the orbital layer of its antagonist, the lateral rectus muscle.25 The small efferent nerve fibers and morphological features of their associated multiply innervated muscle fibers suggest that they perform slow contractions and primarily participate in pursuit eye movements and fixation stability. The presence of a large number of multiply innervated muscle fibers in the medial rectus muscle would arguably serve as further support of these functions, especially when observing objects at close range.33 Büttner-Ennever et al.29 demonstrated that extraocular muscle fibers receive dual motor innervation from two groups of ocular motoneurons: large motoneurons within the abducens, trochlear, and oculomotor nuclei that innervate twitch singly innervated muscle fibers and smaller motoneurons around the periphery of these nuclei that innervate non-twitch multiply innervated fibers.
Although it was demonstrated through the use of intraoperative electromyography that all muscle fiber types participate in all types of eye movements,32 the distinct morphological differences of the muscle fiber types suggest that their functional contribution will vary depending on the type of eye movement that is being performed. Further studies have also shown that the twitch and non-twitch motoneurons receive different pre-motor inputs, which highlight the dissimilar roles played by these fibers in oculomotor control.24 Currently, there is a consensus in the literature suggesting that twitch motoneurons receive projections from areas within the brainstem that are involved in the programming of fast eye movements, such as saccades and the vestibulo-ocular reflex. A similar consensus suggests that non-twitch motoneurons receive pre-motor input from areas that are known to be involved in gaze-holding mechanisms, vergence eye movements, and smooth pursuit.16,24
Although the motor innervation of extraocular muscles is well understood, their sensory innervation continues to be a subject of considerable debate and controversy. Thus far, the two principal types of sensory receptors that have been identified within the extraocular muscles of humans are muscle spindles and palisade endings.
Muscle spindles in the extraocular muscles of humans have a specific structure that differs from spindles in their somatic counterparts or from that of other species.34,35 Muscle spindles are found within the proximal and distal thirds regions of infant and adult extraocular muscles and are located at the junction of the orbital and global layers. They consist of thin intrafusal fibers enveloped by a thin capsule of connective tissue and lie parallel to the extrafusal fibers.36,37 The modification of the sensory region of the intrafusal fibers is inconsistent with a variable number of nuclei. The most common type of fiber in these spindles is the nuclear chain fiber and the least common type is the nuclear bag fiber.36 The third type of intrafusal fiber, the anomalous fiber, is also present. This term was introduced by Ruskell38 to describe the presence of large unmodified fibers with extrafusal features that lack a sensory nerve ending at the equatorial region.
The two types of sensory endings that are normally present in somatic muscle spindles, group I and II afferent fibers that arise from primary annulo-spiral endings and secondary “flower spray” endings, respectively, have not been clearly identified in the spindles in human extraocular muscles.13 The functional basis for modulation of sensitivity in these spindles has not been solved. It has been argued that spindles in human extraocular muscles play a role in the fine control of eye movements.13,38 However, structural peculiarities such as the presence of anomalous fibers, lack of nuclear modification in the sensory region, and fragmentation have been identified in these spindles. If these structural anomalies could be attributed to degeneration due to redundancy, then the developmental role of muscle spindles could still be retained, but further studies have shown that these anomalies are also present in infants.34,36,37,39 Such anomalous spindle features, which are present in both adult and infant extraocular muscles, have generated questions about their ability to function as proprioceptors.34,36
Golgi tendon organs, which are reputed providers of proprioception in skeletal muscles, have not been thus far observed in the extraocular muscles of humans, but they have been identified in other species.13,40,41 This has added to the enigma of ocular proprioception because these receptors are present and seemingly fully functional in the extraocular muscles of a variety of other mammals.33,41–43
Another possible origin of proprioception to the central nervous system is the palisade ending, a nerve-end organ that is unique to extraocular muscles. According to Ruskell's38 terminology, palisade endings with a surrounding fibroblast-like cell capsule are called myotendinous cylinders. In the recent literature, the terms palisade ending and myotendinous cylinder tend to be used interchangeably. Dogiel44 was one of the first scientists to describe palisade endings in the extraocular muscles of several mammals. Thus far, palisade endings have been found in the extraocular muscles of almost all species investigated, including monkeys and humans.33,43,45–48
Anatomical studies show that palisade endings are exclusively found in the global inner layer of extraocular muscles and are enclosed in a capsule at the distal end of the multiply innervated muscle fibers, with several motor contacts along their length.49–51 In humans, they have been observed at both the proximal and distal muscle insertions of infants and mature individuals.52 It was reported that this tendon nerve ending in extraocular muscles is composed of myelinated nerve fibers that penetrate the tendon and then turn back 180 degrees to divide into several approximately parallel running branches exclusively on the tip of multiply innervated muscle fibers.49 Greater numbers of myotendinous cylinders are found within the horizontal rectus muscle when compared with the vertical rectus or oblique muscles.28 Myotendious cylinders seem to be less numerous in muscle samples from infants, indicating that they progressively increase in number through postnatal development.33
Although direct physiologic evidence is still lacking, the recent literature suggests that palisade endings are sensory organs that provide important information about the eye's position.11,49,51,53,54 Sas and Scháb55 and others46,47,51,56,57 have promoted that these structures are cholinergic and that their origin lies in the oculomotor nuclei. Alternatively, the location of innervated myotendinous cylinders at the myotendinous junctions and their remote location in relation to the contractile elements of the muscle fiber indicate a sensory function, thereby questioning the assumption of a pure motor function.51,58
The most compelling argument that palisade endings are sensory structures has come from Billig et al.,59 who injected neuronal tracers into the trigeminal ganglion, which is presumed to exclusively contain cell bodies of afferent nerve fibers. In cats, Billig et al.59 found three kinds of labeled nerve endings, one of which resembled palisade endings. Recently, Wang et al.60 provided further evidence that palisade endings are sensory by recording eye position signals from the contralateral side in the primary somatosensory cortex in rhesus monkeys. Because muscle spindles and Golgi tendon organs are rare or absent in the extraocular muscles of monkeys whereas palisade endings are numerous, the authors concluded that the signals came from the palisades. Alternatively, Lukas et al.50 claimed that such structures may receive dual sensorimotor innervation similar to that found in muscle spindles.
Based on the general organization of the sensory innervation of orbital structures, the primary afferent neurons carrying non-visual inflow information from mammalian extraocular muscles are located in the trigeminal ganglion.61–63 Projections from palisade endings are then divided in the central nervous system (the cerebellum, superior colliculus, vestibular nuclei, pontine nuclei, central gray matter dorsal to the third nerve nucleus, and the frontal and visual cortex). Due to this, it is reasonable to conclude that proprioception may be involved with visuomotor and oculomotor processing at different levels.58,64 However, as with many other aspects of extraocular muscle proprioception, this issue is still debated and the precise pathway in humans has not been identified.
The morphology of extraocular muscles in humans differs from skeletal muscles in many ways. One of the most striking differences is the complement and potential function of proprioceptors. Human extraocular muscles have spindles with peculiar features and they seem to completely lack Golgi tendon organs, although both of these receptors are present and seem to play an important developmental role in the extraocular muscles of many other species. Palisade endings, which are unique to eye muscles, have been found in all mammalian species and may be the most important provider of ocular proprioception. Another difference is that eye muscles have an inner global layer and an outer orbital layer, both containing different types of muscle fiber. Finally, eye muscles contain not only twitch muscle fibers with a single endplate zone (singly innervated muscle fibers), but also non-twitch muscle fibers with multiple endplate zones (multiply inner-vated muscle fibers), both of which are otherwise absent from mammalian muscles.64,65
Studies of patients with strabismus in the course of their surgical or pharmacological treatment have yielded interesting evidence regarding the functional implications of changes in the proprioceptive signals from the extraocular muscles. These observations are relevant to clinical practice because they suggest that abnormalities of the eye muscle proprioceptors and their signals may play a part in the genesis of certain types of strabismus.21,66 Anomalies in the proprioceptive feedback from one eye may also have clinical implications for the eye on the contralateral side. Studies on adults with strabismus have indicated that the proprioceptive input from one eye may be suppressed by the neuromuscular activity in the other eye in a similar manner to visual suppression in concomitant strabismus.23 Although botulinum toxin type A is often used as an alternative to eye muscle surgery for the treatment of strabismus, some morphological studies on extraocular muscles suggest that botulinum toxins induce ultrastructural changes in the myotendinous nerve endings and that these changes might diminish the proprioceptive abilities of the extraocular muscle.67,68
Corsi et al.69 and Li and Shen70 noted alterations in the receptor morphology while analyzing resected rectus muscle specimens from patients who had undergone surgery for concomitant strabismus. They suggested that deranged proprioceptive function contributed to the cause of the strabismus. However, Corsi et al.69 acknowledged that such changes could also have occurred as a result of the strabismus. Domenici-Lombardo et al.71 reported similar morphological changes in the sensory nerve endings at the myotendinous junction of patients with congenital esotropia in which the myofilaments and mitochondria were among the implicated structures.
In addition to structural changes, the proprioceptive signal may also be influenced by the complement and distribution of proprioceptors. Extraocular muscles of adults and infants with strabismus and individuals with nystagmus were compared to the numbers and structural characteristics of receptors found in extraocular muscles obtained from normal cadaver eyes.21 There seem to be fewer proprioceptors in the extraocular muscles of infants with strabismus and individuals with nystagmus when compared to the numbers found in the extraocular muscles of normal cadaver eyes and adults with strabismus. Furthermore, structural changes were noted in the extraocular muscles of infants with strabismus and individuals with nystagmus. This is consistent with other studies in which these alterations of the distal myotendinous junction have been confirmed in infants with concomitant strabismus, but not in adults with concomitant strabismus.72
Kim et al.21 also observed that most nerve endings at the myotendinous junction in muscles obtained from patients with acquired strabismus had normal features, including cases such as constant exotropia, intermittent exotropia, paralytic strabismus, sensory strabismus, and secondary esotropia after retinal reattachment. Furthermore, they noted that some innervated myotendinous cylinders in non-infantile strabismus exhibited morphological alterations, which were interpreted as acquired abnormalities from strabismus rather than the causes of oculomotor disorders. These findings support the hypothesis that the disturbance of innervated myotendinous cylinders may play an important role in the pathogenesis of oculomotor disorders and that this is not a direct consequence of strabismus. Additionally, disturbances in the proprioceptive feedback network, such as degeneration and/or dysgenesis of innervated myotendinous cylinders, could result in oculomotor disorders. This is arguably of clinical significance in view of the fact that the distal myotendinous region where most innervated myotendinous cylinders are located is frequently manipulated during strabismus surgery.
Hertle et al.73 reported their findings from a cohort of 10 adult patients with different subtypes of congenital nystagmus who underwent tenotomies of all four horizontal rectus muscles. This procedure involved detaching all four horizontal rectus muscles and reattaching them at their original insertion sites. Hertle et al.73 argued that such a surgical procedure could lead to the interruption of the afferent proprioceptive loop involved in maintaining resting muscle tension. However, some authors questioned this interpretation because follow-up studies suggested that the four-muscle tenotomy procedure had no significant effect on the waveform structure or the underlying mechanism of the congenital nystagmus.12 Retinal detachment surgery, which involves the manipulation of the extraocular muscles when an encircling band is placed beneath the muscles, has been shown to affect spatial localization. The findings from Weir's13 study have been interpreted as being a part of an alteration in extraocular muscle proprioception derived from the operated eye as a consequence of the surgical procedure.
Proprioception is also assumed to be involved in the “magician's forceps phenomenon,” described by Tamura and Mitsui.74 By using forceps to passively adduct the dominant eye of patients with strabismus while they are under general anesthesia, the deviating eye retakes the normal position. This phenomenon is attributed to disequilibrium in the proprioceptive input from the two eyes.74
Ocular proprioception also seems to have implications for postural control because all sensory modalities are included in the process of neural integration. Legrand et al.75 studied the postural control in nine children with strabismus between the ages of 4 and 8 years before and after eye surgery. After surgery, they found that when the angle of deviation was reduced in all children, the childrens' postural stability improved. Based on these observations, Le-grand et al.75 suggested that eye surgery influenced somatosensory properties of extraocular muscles and led to the improvement of postural control.
Based on these observations, it is legitimate to argue that the proprioceptive input from human extraocular muscles most likely plays a role in the control of ocular alignment. Steinbach et al.76 first reported differences in spatial location after strabismus surgery and suggested that recession produces effects to a lesser extent than myectomies because the recession procedure is less damaging to the palisade endings than the myectomy procedure. Stein-bach et al.76 demonstrated that patients undergoing strabismus surgery for a second time showed more errors in perceiving shifts of eye position when compared with those undergoing their first surgery. The group also suggested that some sensory nerve terminals may be important for eye position proprioception. Jaggi et al.77 promoted similar views and claimed that the resection of muscle tissue containing proprioceptive elements may be more “deafferenting” than a recession of the same muscle tissue. The basis for their argument was that the medial and lateral rectus muscles have shorter myotendinous transition zones than were previously assumed and therefore insert directly onto the sclera.
In clinical practice, strabismus surgery may engage areas of the extraocular muscles that are richly supplied with proprioceptors. Greater attention should be given to better understand the visuomotor sequelae of muscle surgery and the role of proprioception in binocular vision development and oculomotor control.
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