Ординатура / Офтальмология / Английские материалы / The Neurology of Eye Movements_Leigh, Zee_2006

encode eye movement signals.The activity of any single neuron is represented by its frequency of spike discharges. Although differences exist between thephysiological properties of each member of the pool of ocular motoneurons,9'20'26'80 it is possible to make some general statements.The discharge frequency of neurons within the ocular motor nuclei varies quite linearly with eye position during fixation (Fig. 5-2A and B).33 In addition, during conjugate movements, these ocular motoneurons modulate their discharge in proportion to eye velocity (Fig. 5-2C and D). This combination of velocity and position information is necessary to compensate for the restrictions imposed upon eye movements by the mechanical properties of the orbital contents. The viscous drag of the orbital contents slows down eye movements; the elastic restoring forces tend to pull the eye

back towards its central position in the

orbit.

Consider the neural signal required to program a saccade (see Fig. 1-3, Chap. 1). A pulse of innervation (velocitycommand) causes a phasic contraction of the extraocular muscles, which overcomes the viscous drag of the orbit and moves the eye rapidly towards its destination. At the end of the saccade, a step of innervation (position command) causes a tonic contraction of the extraocular muscles, which resists the elastic restoring forces of the orbit and holds the eye steady at its new position. Hence ocular motoneurons carry information about both eye position and velocity. Although we have presented a scheme for saccades as our example here, ocular motoneurons encode velocity and position commands for all types of eye movements.

In contrast to the combined velocity and position commands encoded by ocular motoneurons, the raw sensory or premotor inputs, from which the final ocular motor command is assembled, primarily encode velocity signals. Thus, vestibular afferents24 and secondary vestibular neurons88 carry information on head velocity. Saccadic burst cells discharge at rates that reflect saccadic eye velocity.86 For the pursuit system, cells within cortical visual areas,46 brain stem nuclei,63 and cerebellum61 encode combinations of retinal er-

ror velocity and eye velocity signals. Moreover, during combined movements of the

head and eyes, it is gaze velocity (i.e., eye velocity in space) that is encoded, for example, by Purkinje cells of the cerebellum.61 Yet an eye position signal clearly is required in order to hold gaze steady. Therefore, a mathematical integration is necessary to convert velocity-coded information to position-coded signals. Theoretical and experimental evidence suggests a common neural network that integrates all conjugate eye movement commands;30'72 this is referred to as the neural integrator. A similar integration of vergence

signals also occurs, and is discussed in Chapter 8.

the end of the saccade (see Fig. 3-5, Chap. 3).64 For gaze to be held steady and vision to remain clear, the neural integrator must take these factors into account.

Also, certain neural signals need more integration than others. Thus, for the horizontal vestibulo-ocular reflex, more than one integration occurs between vestibular afferents and the ocular motoneurons.79 This further integration of the vestibular signal is called the velocity-storage mechanism69'70 and represents a perseveration or prolongation of the signal from the semicircular canals, which is important during sustained rotations of the head and body. Most evidence suggests that the neural integrator and the velocity-storage mechanism depend upon separate anatomical connections; the neural substrate for ve-

locity storage is reviewed in Chapter 2. When we view and follow the move-

ments of a near target, it becomes necessary to move the eyes by different amounts. Electrophysiological studies suggest that neurons contributing to the neural integrator network reflect these differences, and some cells may encode the position of a single eye.55 This aspect of interaction between conjugate and vergence eye movements is discussed in Saccade-Vergence Interactions in Chapter 8.

Special Demands on the

Neural Integrator

The concept of a velocity-position neural signal (such as the saccadic pulse-step shown in Fig. 1-3) that moves the eye

against the viscous and elastic forces of the orbit is valuable in interpreting gaze-

holding abnormalities at the bedside. In fact, the orbital mechanics are more complicated than this description. This is evident, for example, in the different centripetal drifts that occur after the eye is pulled to different eccentric positions and suddenly released (compare the curves in Fig. 5-1). The mechanical properties of the orbit are nonlinear, especially as the eye moves out toward the extremes of gaze. Furthermore, as discussed in Chapter 3, the brain must actually program a pulse-slide-step in order to avoid drift at

QUANTITATIVE ASPECTS OF NEURAL INTEGRATION

If the performance of the neural integrator is perfect, then eye velocity commands (e.g., a saccadic pulse) are converted into appropriate and sustained position commands (e.g., a step, shown in Fig. 5-3A). If the integrator does not function perfectly, the eye position signal decays with time and the integrator is said to be "leaky" (just as water might leak from a hole at the bottom of a bucket). The elastic restoring forces of the orbit pull the eye back toward the central position with a time course that approximates a negative (decreasing) exponential (Fig. 5-3B). The rate of this centripetal drift of the eyes indicates the time constant of the neural integrator (Fig. 5-3C). Specifically, 63% of the drift back to

the midline occurs during an interval equal to one time constant; so, for exam-

ple, if it takes 2 sec to drift back 63%, the time constant would be 2 sec. The time constant, therefore, is a quantitative measure of the fidelity of integration: the longer the time constant, the better the integration. When a leaky integrator causes centripetal drift of the eye, corrective saccades are required to carry the eye back to the desired eccentric position in the orbit. A convenient, approximate method to measure the time constant of the neural integrator is to measure the ratio of eye displacement from the midline immediately after an eccentrically directed sac-

cade to the initial velocity of the centripetal drift after that saccade (Fig. 5-3C).

Normal subjects do not have "perfect" neural integrators. In darkness, when vision cannot be used for ocular stabilization, healthy individuals show a drift of the eyes back from eccentric gaze to central position with a time constant of between 20 and 70 sec;5-39 the rate of this drift is influenced by the mental percept of the subject.74 If disease or drugs impair the process of neural integration, the time constant may become much smaller. In darkness, centripetal drifts due to deficient integration are corrected by quick phases of nystagmus;39 in the light, visual

fixation can also help to suppress any spontaneous drift (see Chap. 4).

The way in which the brain is able to hold the eyes still, the neural integrator function, has been conceptualized in a number of different ways.1'42'72'77'85 Recent attempts to model the neural integrator have simulated the behavior of networks of neurons.3 We will review these studies after discussing the anatomical pathways involved in gaze holding.

NEURAL SUBSTRATE FOR GAZEHOLDING

The neural integrator depends upon connections between a number of structures in the brain stem and cerebellum. Collectively, these circuits perform mathematical integration of vestibular, optokinetic, saccadic, and pursuit eye velocitycommands. For horizontal, conjugate eye movements, the nucleus prepositus hypoglossi and the adjacent medial vestibular nucleus are most important. The interstitial nucleus of Cajal plays an important role in vertical and torsional conjugate movements. The cerebellum also contributes to normal gaze holding, and for this purpose, it may receive important inputs from the cell groups of the paramedian tracts (PMT) (see Display 6-4, Chap. 6). The paramedian pontine reticular formation (PPRF) is no longer thought to contribute to neural integration because lesions there spare the ability to hold eccentric gaze.36

Contribution of the Nucleus Prepositus Hypoglossi and Medial Vestibular Nucleus to

Gaze Holding

The nucleus prepositus hypoglossi (NPH) is one member of the perihypoglossal complex of nuclei and lies just medial to the vestibular nuclei and caudal to the abducens nucleus (see Fig. 6-1). Other perihypoglossal nuclei are the nucleus intercalatus and the nucleus of Roller, which may also contribute to the control of eye move-

ments. The main afferent and efferent

connections of the NPH are summarized in Table 5-1.6,8,35,48,56 The NPH receives

projections from every structure that projects to the abducens nucleus.6 Both the NPH and adjacent medial vestibular nucleus (MVN) contain neurons that encode eye position.53'58 Acetylcholine appears to be a neurotransmitter in the projections of NPH to the abducens nucleus.57 Vestibular inputs to NPH may utilize nitric oxide, and inputs more concerned with eye position appear to utilize gamma-aminobutyric acid (GABA).62 The NPH sends a strong projection to the abducens nucleus via its rostrolateral "marginal" zone,48 where it abuts the medial vestibular nucleus.28

Studies in monkeys of the effects of lesions induced by excitotoxins have defined the crucial role of the NPH-MVN region in neural integration of ocular motor signals.13'16'31 At the beginning of the experimental session (Fig. 5-4A), the monkey holds steady horizontal gaze during fixation or in darkness. Following unilateral injection of excitotoxin, a unilateral lesion produces an acute, partial failure of both ipsilateral and contralateral gaze holding (Fig. 5-4B and C), and a shift of the null or neutral point (the eye position where eye velocity is zero) toward the side of the lesion. Bilateral excitotoxin lesions of NPH and MVN abolish neural integration for all horizontal, conjugate eye movements. Horizontal saccades are still possible and are of normal velocity, but the eye cannot be held at its new position and drifts rapidly back to central position with a time constant of about 200 msec, a value close to that determined by the mechanical properties of the orbital tissues (Fig. 5-4D). Besides saccades, horizontal vestibular, optokinetic, and smoothpursuit (Fig. 5-5) eye movements are also affected. Neurotoxic lesions confined to NPH and sparing MVN cause milder defects of neural integration.43 Pharmacological inactivation, achieved by discrete injections of muscimol, which increases normal GABA inhibition and thereby decreases neuronal activity, has largely confirmed that the NPH and adjacent central

portion of the MVN are key anatomical structures for the horizontal neural integrator.60'81 Local injection of NMDA agonists and antagonists into this region also cause partial integrator failure, but glycine and strychnine do not.59'73 Injections of either the GABA antagonist bicuculline81 or the GABA agonist muscimol73 into the more lateral parts of the medial vestibular nucleus may cause instabilityof gaze holding, in which the eye drifts away from the central position with increasing velocity. Electrolytic lesions in the midline of the pons, just caudal to the abducens nuclei, disable the horizontal neural inte-

grator; this effect may be due to interruption of commissural connections between the right and left NPH-MVN regions.3 Vertical gaze holding is also impaired following bilateral NPH-MVN lesions; following vertical saccades, centripetal drift has a time constant of about 2.5 sec.13 This result implies that other structures and pathways are important for vertical gaze holding, such as the interstitial nucleus of Cajal. A clinical lesion involving the nucleus intercalatus was reported to cause upbeat nystagmus, suggesting that this structure may relay vertical eye position signals to the cerebellum.40

The Interstitial Nucleus of Cajal and Vertical Gaze Holding

The anatomical connections of the interstitial nucleus of Cajal (INC) are summarized in Figure 6-5 and Display 6-6. The INC receives vertical and torsional saccadic inputs from the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and vestibular inputs via the medial longitudinal fasciculus (MLF) and other ascending pathways. It contains neurons that encode burst-tonic (velocity-position) sig- nals.19'27-29'44 Projections of the INC to ocular motoneurons may be exclusively via the posterior commissure.45 Pharmacological inactivation of the INC with muscimol produces failure of vertical and torsional gaze holding that is most evident after saccades that take the eye to a tertiary eye position

(combined horizontal and vertical displacement from primary position).18-19 The eye drifts toward a central position with a time constant of about 200 msec. The torsional drifts are clockwise with left INC inactivation and counterclockwise with right INC inactivation.19 Thus, the INC appears to play a crucial role for holding vertical and torsional gaze steady after saccades. The INC may contribute less to the integration of vertical vestibular signals, however.28'353 Torsional vestibular signals appear to be a special case in which little neural integration normally occurs. For example, when normal subjects rotate their head in roll to a new position, the eyes counterroll, but then drift back towards a central position with a time constant of 2 to 3 sec.76 Experimental inactivation or lesions of the posterior commissure,

which contains INC projections, disable the vertical neural integrator.66

Contribution of the Cerebellum to Gaze Holding

Lesions of the cerebellum,15'32'71'89 especially the flocculus and paraflocculus,82'87'93 make the neural integrator deficient. The centripetal drift following a saccade to an eccentric horizontal position typically has a time constant of 1.5 sec. It has been suggested that a function of the cerebellum is to improve the performance of an inherently leaky neural integrator in the brain stem.42'71'91 One way in which the cerebellum could perform this function is shown

Figure 5-6. A hypothesis of the cerebellar influence on the brain stem neural integrator. A positive feedback loop with a gain of K improves the time constant of an inherently leaky brain stem neural integrator. The effects of varying the value of K are shown below. If K is appropriate, neural integration is perfect and the eyes are held steady in their new position in the orbit after an eye movement. If K is too small, the integration becomes imperfect (leaky) and the eyes drift back, with a negative exponential time course, toward the central position; gazeevoked nystagmus results. If K is too large, the neural integrator becomes unstable and the eyes drift away from the central position with a positive exponential time course (increasing velocity) also causing nystagmus.91

If the value of K is appropriate, integration is nearly perfect. If the value of K falls, the integrator becomes leaky, with exponentially decaying drifts of the eyes back to the neutral position. This is the waveform of gaze-evoked nystagmus. If K rises above the appropriate value, then the integrator becomes unstable, with exponentially increasing drifts of the eyes away from the midline. This lastwaveform has been reported in patients with downbeating nystagmus (see VIDEO: "Downbeat nystagmus"),91 upbeating nystagmus (see Fig. 10-4, Chap. 10), and in monkeys with floccular lesions.93 The time constant of the neural integrator has been shown to be under adaptive control;47 the cerebellar flocculus may play a key role in this adaptation.

How a Network of NeuronsCould

Function as the Neural Integrator

The simple scheme shown in Figure 5-6

changes in the feedback loop gain, K, would cause the network to become leaky or unstable, but in reality, the gaze-holding network is quite stable. A second factor is that neurons that carry an eye-velocity signal to the neural integrator have a back-

gaze holding indicate that although the modulated signal is integrated, the background activity is not. Third, cells in the NPH-MVN region encode not just eye position but also, to varying extents, eye velocity, which the scheme in Figure 5-6 would not predict. Fourth, the integrator must be relatively robust to the effects of lesions; some integration must still be possible after loss of a proportion of its constituent neurons.12 Fifth, the properties of the neural integrator can be changed, such as during adaptation to novel vi- sual-vestibular demands.83 A neural network approach has been able to address some of these problems and also to repre-

sent the anatomical way that the neural integrator is distributed.

A network of neurons in which cells excite themselves through connections with other cells can sustain its activity after initial stimulation without further input. This integrating network is conceptually similar to Lorente de No's "system of reverberating collaterals."3'54'77 In practice, if each neuron inhibits its neighbors and is in turn inhibited by them, the overall effect is a positive feedback loop.12'14 Such a model, unlike the model shown in Figure 5-6, integrates velocity modulated signals, but not the background activity.14 Because the inhibition is distributed over many cells and synapses, the network is robust to the effect of lesions and also accounts for some of the subtle differences in waveforms of gaze-evoked nystagmus in patients with various neurologic diseases, such as an initial rapid centripetal drift (smaller time constant) followed by a slower drift (larger time constant).1'14 It has proved possible to "train" a network of neurons to simulate normal gaze-holding behavior using a Hebbian learning rule, in which correlated activity between preand postsynaptic neurons strengthens the synapse between them, whereas uncorrelated activity weakens the synapse.3 When such a network has been trained, each unit carries a weighted combination of eye position and velocity.The trained network is capable of simulating adaptation to new visual-vestibular demands. Furthermore, if the model is arranged into left and right sides, the synaptic development that occurs during training leads to the formation of an inhibitory commissure. "Lesioning" this commissure in the model disables the neural integrator in much the same way that a midline lesion in the pons, just caudal to the abducens nucleus, does.3

One unresolved aspect of neural integration of ocular motor signals concerns three-dimensional aspects of eye movements. When a sphere rotates first in one direction and then in another, the final eye position is not the same if the rotations were performed in the reverse order. This noncommutative property of the rotation of spheres also means that in a vectorial sense, eye position is not the exact integral

of eye velocity. This geometric property has led to the hypothesis that the brain uses a noncommutative operator to convert eye velocity to eye position.85 However, given the demonstration of pulleys (see Fig. 9-1, Chap. 9) that limit movement of the tendons of extraocular muscle,21 it has been proposed that for most eye movements (<40° amplitude), three simple integrators, one for each direction, will account for observed behavior.75 The issue remains unsettled65'68-84 and its clinical significance is unknown. However, if networks of neurons are accurate representations of how the brain integrates ocular motor signals, then three independent networks could be trained to carry out the necessary operation in which the transformation from an eye-velocitycommand to a change in eye position depends on eye position itself.3

CLINICAL EVALUATION OF GAZE HOLDING

The fidelity of the neural integrator is tested at the bedside by noting the patient's ability to hold the eyes in an eccentric position in the orbit (see Appendix A for a summary). When the integrator is leaky (i.e., has a low time constant) the eyes will drift back toward the central position; this necessitates corrective saccades, and gazeevoked nystagmus will result (see VIDEO: "Gaze-evoked, rebound and downbeat nystagmus"). (The term gaze-paretic nystagmus, although in common use, is probably best avoided because it implies a paresis of gaze, which may or may not accompany nystagmus with centripetal drifts.)

Before testing gaze stability in eccentric positions, examine the eyes during fixation in the central position and note any nystagmus. An ophthalmoscopic examination will often help to determine the presence and nature of any drift of the eyes, both with and without fixation (if the fixating eye is covered for a short period). Next, examine the eye movements as the patient fixates to the right, left, up, and down. Repeat this examination behind

Frenzel goggles to exclude the effects of visual fixation. If gaze-evoked nystagmus occurs, is it only present at extremes of gaze and is it symmetrical on looking right, left, up, and down? With sustained efforts at eccentric gaze, does the nystagmus diminish? On returning the eyes to central position, does transient nystagmus occur with slow phases toward the direction of prior gaze? (This phenomenon, called rebound nystagmus, is discussed below in the section Pathogenesis of Centripetal and Rebound Nystagmus.) The presence of gaze-evoked nystagmus in the light often implies more than just a leaky integrator: the visual fixation and stabilization reflexes are probably impaired, and hence smooth pursuit and cancellation of the vestibulo-ocular reflex may be abnormal. They require testing.

Recording of eye movements helps establish the nature of the slow-phase component during attempted eccentric fixation in both light and darkness. The time constant of drift (see Fig. 5-3), when measured in normal subjects in darkness, varies considerably but is typically 20 to 70 sec.5'23'39'74 Some normal subjects show a unidirectional drift.39 Centripetal drift caused by an inadequate (leaky) integrator due to disease typically has a time con-

nystagmus with an increasing-velocity slow-phase waveform that is evident clinically (see VIDEO: "Downbeat nystagmus").

The centripetal drifts of gaze-evoked nystagmus may appear to have a linear rather than a decaying exponential waveform (compare Fig. 10-1A and B, Chap. 10). This nystagmus may still be due to a deficient neural integrator; exponential decay may not be obvious if the integrator is only slightly leaky or if visual-following reflexes reduce the drift. In addition, lesions affecting the vestibular nuclei that impair gaze holding may also cause a vestibular imbalance leading to nystagmus with more linear slow-phases (see Alexander's law, below). In practice, the best way to show that slow phases of nystagmus have a negative exponential wave-

form is to record eye movements in darkness.

ABNORMALITIES OF THE NEURAL INTEGRATOR

Disease affecting the neural integrator causes an inadequately sustained eye position signal. This is manifest by drift of the eyes back from an eccentric position to the central position and corrective quick phases that produce gaze-evoked nystagmus. As noted previously, even normal subjects do not have a perfect neural integrator; most individuals will show some centripetal drift when in darkness. Some normal subjects show deficient gaze holding even when fixating a visual target. This physiological or end-point nystagmus usually occurs when such individuals are in extreme lateral gaze or upgaze.2'23'78 Certain normal subjects, however, develop gaze-evoked nystagmus even with modest eye deviations, such as at 20° eccentricity.2 End-point nystagmus usually comes on soon after turning the eyes to an eccentric position,78 and may damp after several seconds. It may be asymmetric (e.g., present on looking to the right but not to the left) and be of greater amplitude in the abducting eye.78 Important points in differentiatingphysi-

ological nystagmus from the effects of disease are low amplitude (slower drift) and the absence of other ocular motor abnormalities (see Display 10-8, Chap. 10).10 End-point nystagmus increases when the subject imagines a target location in darkness, rather than viewing it.23 Prolonged attempts to maintain extreme lateral gaze lead to fatigue nystagmus in some normal subjects,2-23 but this probably represents a different mechanism than the more common finding of nystagmus that develops soon after the eye reaches its eccentric position.

Although a leaky neural integrator produces gaze-evoked nystagmus, this does not produce great functional disability, since the eyes are used mostly near the central position. When the eyes are held in an eccentric position in the orbit, each quick phase (sac-

cade) resets the level of activity of the neural integrator so that the eye position is corrected before the eye drifts far off target. Only if the velocity of centripetal drifts is high will vision be noticeably degraded.

Pathogencsis of Deficient Neural Integration

In the clinic, the most common cause of gaze-evoked nystagmus is medication, including sedatives, tranquilizers, or anticonvulsants (see Table 10-21, Chap. 10). Such nystagmus may occur in the horizontal or vertical plane. Although the exact site of action of such agents is not always known, it seems likely that either the cerebellum or the vestibular nuclei may be affected.57

A variety of abnormalities affecting the cerebellum cause gaze-evoked nystagmus and usually reflect involvement of the vestibulocerebellum (flocculo-nodular lobe) or its connections (see Display 10-17,

sions affecting the NPH and MVN,which are essential for neural integration, impair gaze holding. Loss of neurons from the medial vestibular and prepositus hypoglossi nuclei has been reported in a patient who suffered from lithium intoxication.17 Prior to her death from respiratory failure, she lost voluntary and reflexive eye movements, except for what may have been saccades followed by a rapid centripetal drift.

When a vestibular imbalance occurs that is due to either a peripheral or central lesion, gaze-evoked nystagmus is often superimposed. Such interaction of vestibular nystagmus and gaze-evoked nystagmus is the basis for Alexander's law: nystagmus due to a vestibular lesion is more intense when the patient looks in the direction of the quick phases.38'74 In other words, slowphase velocity is greatest when the eye is turned away from the direction of drift. The effect of deficient gaze holding is small during natural behavior of the VOR, but is evident during sustained stimula-