Ординатура / Офтальмология / Английские материалы / Advances in Understanding Mechanisms and Treatment of Infantile Forms of Nystagmus_Leigh, Devereaux_2008

ABSTRACT

To stay informed about the position of the eyes in the orbits, the brain has available two extraretinal signals: a copy of the efferent signal (outflow) to the extraocular muscles (EOM) and proprioception (inflow) from the EOM. Palisade endings, associated with the multiply innervated fibers of the global layer of EOM, are the putative receptors supplying the inflow eye position signal. Büttner-Ennever’s proprioceptive hypothesis for the control of eye movements is based on neuroanatomical tracing studies that identified a distinct set of non-twitch (NT) motoneurons whose activity does not add to the force used to move the eyes. It has been suggested that NT motoneurons could be involved in modulating the gain of sensory feedback from the eye muscles analogous to the gamma-efferent fibers that control the sensitivity of muscle spindles in skeletal muscles. We tested this in a series of studies where the activity of NT motoneurons was altered using the Jendrassik maneuver (JM). JM facilitates the amplitude of all tendon reflexes, most likely due to the general up-regulation of the gamma system. We found that the JM perturbation altered registered vergence eye position when observers localized targets in depth. Surprisingly, the JM did not affect higher-order perceptual judgments (size constancies), nor did it affect the saccadic system. Overall, our studies provide insight into the putative mechanism involved in the control of sensory feedback from the EOM.

HOW DOES THE BRAIN KNOW WHERE THE EYE IS? OUTFLOW VERSUS INFLOW

The visual direction of an object can only be obtained by taking into account the position of the eyes in the orbit. Thus, knowledge of eye position is essential for accurate visuomotor behavior, such as reaching and grasping. The central nervous system (CNS) can obtain eye position information from two extraretinal sources: efference copy (i.e., a copy of the motor command sent to the eye muscles or outflow) and afferent feedback (inflow).

The debate between outflow and inflow as the source of the signal is longstanding, going back to Helmholtz and Sherrington.1 There are two major arguments against ocular proprioception. First, unlike skeletal muscles, eye muscles act against a constant load. Consequently, a copy of the motor command should theoretically provide sufficient information about the state of the oculomotor plant. There are some data that suggest that the “constant load” hypothesis may not be true. Steinbach and Lerman showed that the center of mass and the center of rotation of the human eye may not be in the same place.2 This means that the load on the eye muscles will differ as the orientation of the head changes with respect to the gravity vector.

Second, an important function of proprioceptors in the skeletal muscles is regulation of muscle length in response to stretch; however, the presence of stretch reflexes in extraocular muscles (EOM) is controversial. A classic experiment by Robinson and Keller3 in awake rhesus monkeys found no change in the activity of the

abducens motoneurons in response to muscle stretch. Similar results were also obtained in the oculomotor motor nucleus of cats by Tomlinson and Schwarz.4 In contrast, Dancause and colleagues5 have recently recorded electromyographic activity in the horizontal recti muscles in anesthesized rats and squirrel monkeys in response to passive eye rotation. This is the first study to suggest that stretch reflexes might be present in the EOM, and more studies are needed to confirm these findings.

Although the presence of monosynaptic stretch reflexes in the EOM has been questioned, there is substantial evidence to support the inflow theory. First, neural activity in response to passive stretch of the EOM has been recorded in several CNS structures: the cerebellum, superior colliculus, lateral geniculate nucleus, and primary visual cortex (for a review see Donaldson).6 Second, highly trained observers whose eyes were moved passively were able to report the correct direction of their eye movements in 70% of the trials.7 Previous studies have also shown that proprioceptive signals from eye muscles have a significant role in programming of eye movements8,9 during egocentric localization tasks10-13 and adaptation of smooth pursuit.14 In addition, registered eye position has been affected in patients whose proprioceptive feedback has been disrupted by surgical treatment15,16 or due to pathology involving the trigeminal nerve.17,18 In summary, proprioceptive signals from the EOM are clearly important for accurate visuomotor behavior.

Feedback is an integral part of sensorimotor control of movement. Since the properties of the oculomotor plant can change over time due to growth, aging, or disease, feedback ensures that accuracy is maintained over time. In other words, feedback is necessary to confirm that the motor command that was sent to the muscles to execute a particular movement actually achieved the desired motor output. The “hybrid model” of ocular motor control was first proposed by Ludvigh,19 who advocated that for optimal motor performance both the efferent and afferent signals must be used by the CNS. In brief, Ludvigh suggested that parametric control of eye movements is important to maintain accurate visuomotor control.

ANATOMY AND PHYSIOLOGY

OF EOM AFFERENCE

Although the afferent pathway and the location of the cell body of the EOM proprioceptors have not yet been determined, an elegant study by Wang and colleagues20 has provided evidence that eye position is represented in the somatosensory area 3a. The study involves recordings from neurons in the depth of the central sulcus in behaving rhesus monkeys. The signal

was clearly dependent on the orbital eye position and not gaze-in-space position, and it was not modulated by visual stimuli. In addition, a retrobulbar block of the contralateral eye abolished the eye position signal, which subsequently returned when eye movements returned to normal.

Results from the study by Wang et al. also illuminate the reason for apparently conflicting reports of the effect of surgical treatment for strabismus. Steinbach and Smith15 reported that patients who had a single surgery on their EOM were able to point accurately to targets as soon as the operated eye was uncovered, which was attributed to the afferent signal that informed the CNS about the change in the eye position. However, Bock and Kommerell21 failed to replicate these findings. The critical difference between the two studies was the type of anesthetic used: patients tested by Steinbach and Smith were under general anesthesia, whereas Bock and Kommerell used a retrobulbar block (described by Steinbach).22 As shown by Wang and colleagues, retrobulbar block abolishes the proprioceptive signal, which accounts for the discrepancy between the earlier studies.

There are two potential receptors in the EOM that could serve a proprioceptive function: muscle spindles and palisade endings. Muscle spindles, which are the primary proprioceptors in the skeletal muscles, are found in the orbital layer of some species, such as humans, sheep, and some primates, but not in other species, such as cats, rats, rabbits, or horses.23 Spindles found in the EOM have been described as “atypical.” For instance, Ruskell24 reported that more than 50% of EOM spindles were indistinguishable from extrafusal fibers, as they were not enclosed in a capsule and did not have a defined equatorial region. He also observed that nuclear bag fibers were virtually absent, a finding that was subsequently confirmed by others.25,26 It is currently unknown to what extent muscle spindles play a proprioceptive role in the human EOM.

Palisade endings (PE), which are associated with the multiply innervated fibers (MIF) of the global layer, are receptors that are unique to the EOM. They are sometimes referred to as innervated myotendinous cylinders and have been found in the EOM of all species tested to date, such as cats, monkeys, sheep, rats, and humans.27-30 Anatomical studies show that the PE are enclosed in a capsule at the distal end of the global MIF. A thinly myelinated axon runs along the muscle fiber and then loops back to enter the capsule as it bifurcates into several branches.27,28 Several studies have proposed a sensory function for PE based on structural properties and tracing studies—for example, the presence of a capsule and clear vesicles in the PE, which are also found in other sensory endings such as Golgi tendon organs and muscle spindles.27 Billig and

colleagues31 also reported that PE were labeled when anterograde tracers were injected into the Gasser’s (trigeminal) ganglion, which contains only sensory neurons. In contrast, a recent histochemical examination of the musculotendinous junction in the human EOM showed that the myoneuronal region might also contain motor endings. These motor endings were identified based on staining of the myoneuronal junction with α-bungarotoxin, which labels acetylcholinergic receptors. Upon microscopic examination, the authors also found basal lamina, which is indicative of motor terminals. Based on these results the authors suggested that PE might have a sensory and motor function.32 Additional examination of the musculotendinous junction in the cat and monkey has revealed that the region containing the PE is immunoreactive to histochemical markers for cholinergic nerve fibers and nerve terminals, which have been traditionally associated with motoneurons.33,34

DUAL INNERVATION OF THE EOM: PROPRIOCEPTIVE HYPOTHESIS

Although the question of whether PE have a sensory or motor function has not yet been resolved, several authors have proposed that PE, along with the MIF, might have a proprioceptive role in the control of eye movements. Robinson3 was the first to use the term inverted muscle spindle to suggest that the non-twitch MIF and the PE might be comparable to the γ-spindle system found in the skeletal muscles.5 This hypothesis has been further extended by Büttner-Ennever and colleagues36,37 based on their neuroanatomical tracing studies, which demonstrated that the singly innervated fiber (SIF) and MIF receive innervation from separate groups of ocular motoneurons. The two groups of neurons were identified when injections of tracer were made at different sites of the EOM. Large motoneurons were labeled when the midregion of the muscle fiber close to the endplate was injected (i.e., injection targeting the SIF), whereas smaller motoneurons in a distinct region around the periphery of the large motoneurons were labeled when the distal musculotendinous region of the muscle was injected (i.e., injection that targeted the MIF). These small motoneurons form a cap over the dorsal trochlear nucleus, and they are found in the medial half of the abducens nucleus, bilaterally around the midline of the oculomotor nucleus to the inferior oblique and the superior rectus, and at the dorsal medial border of the oculomotor nucleus to the medial rectus. A subsequent study has shown that the premotor input to the twitch and non-twitch motoneurons also comes from different premotor areas.38 The non-twitch motoneurons receive monosynaptic

input from the vestibular areas associated with gazeholding mechanisms, the central mesencephalic reticular formation, and the supraoculomotor area, which are involved in the programming of vergence eye movements and the ocular following response. In contrast, the twitch motoneurons receive input from classical premotor regions, such as the paramedian pontine reticular formation and the magnocellular vestibular nuclei. These results provide some support for Robinson’s claim that the non-twitch motoneurons of the global MIF might be equivalent to the γ motoneurons and control the baseline activity of PE, the putative EOM proprioceptors.

IS THE AFFERENT SIGNAL FROM EOM MODULATED BY GAMMA MOTONEURONS?

We have conducted a series of studies to examine the hypothesis that proprioceptive feedback from the EOM might be modulated by γ activity. We used behavioral and psychophysical approaches and a manipulation called the Jendrassik maneuver (JM) to examine the above hypothesis in healthy observers and patients who underwent surgeries for strabismus. The JM refers to a voluntary, forceful contraction of any muscle group, and it has been used extensively to alter the excitability of spinal reflexes39-42 and limb position information.43 Briefly, while the JM is performed, the amplitude of all skeletal reflexes is facilitated.44 One of the mechanisms proposed to explain the reflex reinforcement effect is that the muscle contraction has a general effect that results in up-regulation of the γ motoneuron activity, which increases the baseline activity of muscle spindles and, consequently, results in a larger efferent response when the muscle is stretched. We hypothesized that if the non-twitch motoneurons are analogous to the γ motoneurons the JM should also affect the activity of these neurons and alter the feedback from PE, which would result in misregistration of eye position and localization errors.

Effect of JM on the Vergence System

Since the non-twitch motoneurons receive direct premotor input from areas that are known to be involved in the control of vergence eye movements, we first examined the hypothesis in two studies in healthy observers while they localized targets in depth.45 In the first study, 10 healthy participants were tested on a task that required looking and pointing to targets in three conditions: (1) control (look and point to target);

(2) look and point during JM (while performing a muscle contraction with the lower limbs); and (3) look during JM and point after JM (point 2 to 3 seconds