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

Unilateral parietal lesions have also been thought to cause greater impairment of pursuit when the target moves towards the side of the lesion, but such deficits are probably due to involvement of other areas, such as MT and MST. A more specific defect for parietal lobe lesions, especially when Brodmann's area 40 is involved, is impaired smooth pursuit when the target moves across a structured background,

compared with pursuit across a dark background.171 This defect may be due to an

impaired ability to attend to the image of the moving target and "ignore" the smeared images of the stationary background consequent to the eye movement.

Bilateral posterior parietal lesions cause Balint's syndrome,253 features of which are disturbance of visual attention (simultanagnosia), inaccurate arm pointing (optic ataxia), and difficulty initiating voluntary saccades (ocular motor apraxia). These deficits, which are discussed further in Chapter 10, could be partly due to disruption of the normal mechanisms by which posterior parietal cortex encodes visual targets in spatial coordinates.

CONTRIBUTIONS OF THE

PARIETAL EYE FIELD TO GAZE CONTROL

In rhesus monkeys, the parietal eye field (PEF) lies adjacent to area 7a, in the caudal third of the lateral bank of the intraparietal sulcus, an area called the lateral interparietal area (LIP) (Display 6-17). The homologue of the PEF in humans may lie within or close to the horizontal portion of the intraparietal sulcus, corresponding to adjacent parts of the superior part of the angular gyrus and the supramarginal gyrus, bordering Brodmann areas 39 and 40.210 Area LIP receives inputs from secondary visual areas and projects strongly to the frontal eye field and the superior colliculus.5'22'183 Neurons here respond to visually salient stimuli112 and discharge prior to saccades,9'10'63 and they take into account the position of the target in threedimensional space.106 As in area 7a, the response of LIP neurons is influenced by eye position.6 These cells also show a shirt in their visual response field that antici-

pates the consequence of the upcoming gaze shift.80 Another important property of LIP neurons is their ability to remain active while the monkey is required to withhold eye movements and remember the desired target location.10'235 Thus, the activity of these neurons corresponds to the size and direction of the required eye movement—a memory of motor error— and is similar to that of certain quasivisual cells found in the superior colliculus and dorsolateral prefrontal cortex. Furthermore, LIP neurons appear not only to encode the intended saccade but also to reflectchanges in the planned movement26'191 and other cognitive factors,63'260 such as attention.272 Electrical stimulation of the lateral wall of the intraparietal sulcus produces saccades of similar direction irrespective of the starting position of the eye.322 However, stimulation in the floor of the intraparietal sulcus and underlying white matter produced saccades with a direction that depended on starting eye position, with a tendency for the end-points to be a goal zone. This finding has been interpreted as indicating that the summed output of the PEF is concerned with making saccades in craniotopic coordinates, rather than in a retinotopic mapping.322

Functional imaging of the PEF in humans has demonstrated activation during voluntary, visually guided saccades.210 Unilateral lesions of the PEF cause bilateral prolongation of latency to visually guided saccades if the fixation light is turned off before the target light is turned on ("gap" stimulus),256 and even more so if it is left on throughout the trial.257 These changes are more pronounced with rightsided lesions. A similar effect is seen in normal subjects if TMS is applied to the PEF region.84 Parietal lesions impair the ability to make two saccades to two targets flashed in quick succession. In response to this double-step stimulus, the brain must take into account not only the retinal location of the two targets but also the effect of the eye movements.82'119 Thus, patients with right parietal lesions show errors when the first target appears in the left hemifield and the second in the right; the first saccade may be accurate, but the second is not. Such a deficit may be present

even though there is no inattention or difficulty responding to the reverse order of presentation or of making single saccades to left-sided targets. It has been interpreted as being due to disruption of the ability to monitor the size of the first saccade using efference copy.82'119

Contributions of the Pulvinar to Gaze Control

The pulvinar is the posterior and largest portion of the thalamus (Display 6-18). It

has reciprocal connections with striate,

peristriate, parietal, and frontal cortex.56,70,144,244,273,274,276,331 The pulvinar re-

ceives inputs from the retina and superior colliculus, but inputs from the cortex seem most important.18'66'147 Indeed, the evolution of the pulvinar appears to have paralleled that of association cortex. Three regions of the pulvinar contain neurons that show visual responses: inferior, lateral, and dorsomedial. Neurons in the first two regions are retinotopically organized. They send a projection to visual area MT275 Neurophysiologic evidence suggests that these two regions may be impor-

tant in dealing with the visual effects of eye movements (for example, the visual blur produced by a saccade), because neurons here respond to moving visual stimuli, but they respond much less if the motion of images on the retina is caused by an eye movement.273 Visually responsive cells in the dorsomedial pulvinar are not retinotopically organized and have large receptive fields; some show sensitivity to visual features such as color.20-186 They respond vigorously if the visual stimulus is a cue for active behavior, such as a saccade. Like neurons in the inferior parietal lobe, to which they project, these pulvinar neurons seem more concerned with shifts of attention than with eye movements per se. Other neurons in the dorsomedial pulvinar discharge for saccades and quick phases, even in the dark, but these neurons do not encode the amplitude and direction of such movements and so are probably signaling that an eye movement has occurred, a form of efference copy. Pharmacological manipulation of cells in dorsomedial pulvinar, using microinjection of GABA-related drugs, has confirmed that this region is involved in shifts in spatial attention towards salient features.228'271'274 Functional imaging studies in humans support the notion that the pulvinar is important for directing visual attention.165 Pulvinar lesions in monkeys and in humans are reported to cause a characteristic prolongation of fixation, difficulties in shifting gaze into the contralateral hemifield,225'331'355 and perhaps loss of stereoacuity.320

Contributions of the Frontal Lobe to Gaze Control

The frontal lobes contain several areas important in the voluntary control of eye movements, especially saccades, but smooth pursuit and vergence as well. These areas include the frontal eye field (FEF), the supplementary eye field (SEF), and the dorsolateral prefrontal cortex (DLPC). In addition, cingulate cortex and the intralaminar thalamic nuclei, with which the frontal and supplementary eye fields have

reciprocal connections, may contribute to the control of gaze.

CONTRIBUTIONS OF THE

FRONTAL EYE FIELD TO GAZE CONTROL

Although the FEF is well known to contribute to the voluntary control of gaze,138 a clear definition of its role has required the application of modern electrophysiologic and anatomic studies, and novel test paradigms to demonstrate defects in patients (Display 6-19). In rhesus monkeys, the FEF has been precisely located by direct microstimulation and has been shown to lie in a circumscribed zone along the posterior portion of the arcuate sulcus (part of Brodmann area 8).33 In humans, localization of the FEF is based on studies of regional cerebral blood flow during saccadic tasks and the effects of electrical stimulation. Although there is some intersubject variability in the medial-lateral location, the FEF lies around the lateral part of the precentral sulcus,extending superiorly to its junction with the superior frontal sulcus, involving adjacent areas of the precentral gyrus, the middle frontal gyrus, and the superior frontal gyrus, and corresponding to confluent portions of Brodmann areas 6 and 4, but not

8.71,91,107,181,196,242,245-247,319 TllUS the FEF

lies about 2 cm lateral, 1 cm ventral, and 1 cm anterior to the area of motor cortex activated by hand movements.319 The FEF receives inputs from posterior visual cortical areas, inferior parietal cortex (PEF), contralateral FEF, supplementary eye field, prefrontal cortex, central thalamic nuclei, substantia nigra pars reticulata, su-

perior colliculus, and cerebellar dentate nucleus.145'308"310 The projections of the

FEF are discussed further in the section Descending Parallel Pathways that Control Saccades, below. Important targets include the caudate and putamen, superior colliculus, nucleus reticularis tegmenti

pontis (NRTP), and the omnipause neurons of the pontine raphe.144'174-310 The

FEF also projects to the claustrum and subthalamic nuclei, but the role of these structures in the control of eye movements is unknown.

Neurons in the FEF do not become active before every saccade, only those made purposively.32 A topographic motor map has been defined, with larger saccades being evoked from stimulation of the dorsomedial portion of the FEF and smaller saccades from stimulation of the ventrolateral part.33 Different subpopulations of FEF

neurons encode the visual stimulus, the planned saccadic movement, or both.109

Cells with visual responsiveness anticipate

the visual consequences of planned saccades.330 A second role for the FEF is a

contribution made by its inferior portion to smooth-pursuit eye movements.113'324'325 Neurons that discharge during pursuit project to the ipsilateral dorsolateral pontine nuclei (see Fig. 6-7). Some neurons also appear to be concerned with disengaging fixation prior to a saccade; their discharge increases when the fixation light is turned out, even before the new target becomes visible.75 Other neurons appear to promote fixation; if microstimulation of these neurons is timed to coincide with the visual stimulus for a saccade, the eye movement may be suppressed.35 In humans, functional imaging demonstrates activation of the FEF area during active

fixation of a stationary target.248 Finally, some FEF neurons show properties indicating that they contribute to selection of the target to which a saccade will be made284 and to the process of visual scanning of a complex visual scene.36 The FEF may also play a role in vergence.

Functional imaging studies in humans have demonstrated increased FEF activation during all visually guided saccades, be they reflex or voluntary,7'77'319 during repetitive saccades made in darkness,246-247 and during memory-guided saccades.233'319 In addition, activation of the right FEF is reported during antisaccades.224'319 Antisaccades are delayed by TMS over frontal cortex; the same effect can be achieved if the stimulus is delivered earlier over parietal cortex, suggesting flow of information from posterior to anterior during presaccadic processing.321a During smooth pur-

suit, the inferior lateral aspect of the FEF is activated.245

The influence of the FEF on eye movements has been demonstrated using the technique of pharmacological inactivation.76 Muscimol injection causes a contralateral ocular motor scotoma with abolition of all reflex visual and voluntary

saccades with sizes and directions corresponding to the injection site on the FEF map. In addition, during fixation, there is a gaze shift toward the side of the lesion. Acute destructive lesions of the FEF in monkeys produce an increase in latency for contralateral saccades and a decrease in latency for ipsilateral movements (that

is, an increase in express saccades ipsilateral to the side of the lesion).285 Re-

covery from acute FEF lesions is rapid

cially when directed contralaterally. In addition, ipsilateral smooth pursuit is im-

paired, but optokinetic responses may be preserved.120'151'153'201

CONTRIBUTIONS OF THE SUPPLEMENTARY EYE FIELD TO GAZECONTROL

The dorsomedial frontal lobe of monkeys contains neurons that discharge before contralateral saccades; this region has

been designated the supplementary eye field

(SEF) (Display 6-20).289 On the basis of functional imaging studies, the SEF in humans lies on the dorsomedial surface of the hemisphere in the posteromedial portion of the superior frontal gyrus, 7 mm anterior to the area of supplementary cortex activated by hand movements, cor-

responding to the medial portion of Brodmann area 6.246'247'319 The SEF has

reciprocal connections with the FEF, dorsolateral prefrontal cortex, cortex surrounding the cingulate, intraparietal and

superior temporal sulci, the thalamus, and the claustrum.15'299'301 Like the FEF, the

SEF projects to the caudate and putamen, superior colliculus, nucleus reticularis tegmenti pontis, and other pontine nuclei, including the pontine omnipause neurons in the nucleus raphe interpositus.143'299'300 Convergence of projections from the FEF and SEF occurs in the caudate nucleus.236 The SEF has more extensive connections with prefrontal and skeletomotor areas and fewer connections with vision-related structures than the FEE143

Saccade-related neurons in the monkey SEF have many properties similar to those

in FEF,279 but they also show certain differences, such as their function during learned eye movement tasks57 or during combined eye-arm movements.213 Like the FEF, some units in the SEF discharge in relation to smooth pursuit.121'324 Functional imaging studies in humans have demonstrated increased SEF activa-

tion during single memory-guided sac- cades7'233-319 or a series of them246 and dur-

ing antisaccades.224'319 Activation during visually guided saccades may occur if the task involves predictable behavior.91

Studies of patients with lesions involving the SEF suggest that left-sided lesions are more likely to impair the ability to make a sequence of saccades to an array of visible targets in the order that they were turned on.101'102 Single, memory-guided saccades are probably impaired only if the eye moves during the memory period.254 Taken together, the evidence suggests a role for the SEF in the planning of sac- cades—to both visual and nonvisual cues—as part of complex or learned behaviors. However, a deficit in the ability to remember a sequence of saccades has also been reported in patients with lesions affecting the hippocampus,211 and it seems likely that cerebral regions other than the SEF are important for normal performance on such tasks. Predictive aspects of smooth pursuit may also be impaired when lesions involve the SEE120

CONTRIBUTIONS OF THE DORSOLATERALPREFRONTAL CORTEX TO GAZE CONTROL

In monkeys, neurons in the posterior third of the principal sulcus (Fig. 6-8), which lies on the dorsolateral convexity of the frontal lobe, corresponding to Walker's area 46, show an ability to hold in memory the location of a visual target to which a saccade is to be made (Display 6-21).98'99 In humans, the homologue of the DLPC lies on the dorsolateral surface of the frontal lobe, anterior to the FEF,occupying approximately the middle third of the middle frontal gyrus and adjacent

cortex, corresponding to Brodmann's areas 46 and 9.264'265 The DLPC has recipro-

cal connections with the FEF, SEF, pos-

terior parietal cortex, and limbic cortex (including parahippocampal and cingulate cortex). It also receives inputs from the thalamus and medial pulvinar, and projects to the caudate, putamen, claus-

trum, thalamic nuclei, superior colliculus, and PPRF.55'297

Human subjects show activation of the DLPC when they make memory-guided saccades or antisaccades;209a'233>319 these results are consistent with properties of neurons in monkey DLPC." Pharmacological inactivation of DLPC with Dldopamine antagonists impairs the accu-

racy of monkeys in making contralateral memory-guided saccades.283 Patients with lesions affecting this area show defects of both memory-guided saccades and antisaccades.115'255 When TMS is applied over the DLPC in normal subjects during the memory period, memory-guided saccades become inaccurate.212

The DLPC receives inputs from the anterior cingulate cortex, which has been reported to show changes in regional cerebral blood flow during memory-guided saccades and antisaccades.7'319 This finding might reflect the cingulate's contribu-

tion to spatial information processing and suppressing reflexive saccades during the antisaccade task.15'319 Units located in the posterior cingulate cortex are reported to discharge during or after eye movements.229 In humans, small posterior lesions of the right cingulate cortex have been reported to impair memory-guided saccades, antisaccades, and sequences of memory-guided saccades.lola

CONTRIBUTIONS OF THE

INTRALAMINAR THALAMIC

NUCLEI TO GAZE CONTROL

The FEF, SEF, and PEF all have reciprocal connections with thalamic neurons lying near the upper wing of the internal medullary lamina (IML,the fiber pathway

that separates the medial from the lateral thalamic mass; see Display 6-22).288>290>291

These saccade-related neurons are scattered throughout adjacent portions of the central lateral, superior central lateral, and dorsomedial nuclei. In addition to frontal cortical areas, the intralaminar thalamic nuclei also receive inputs from the pontine reticular formation, cerebellum, tectum, and pretectum. However, the intralaminar nuclei do not project to brain stem structures concerned with eye movements.111'288'291 These thalamic neurons are variously active in relation to spontaneous and visually guided saccades and to fixation. Functional imaging has shown

that human thalamus shows activation when subjects make voluntary saccades.247 Because of their widespread projections and variety of properties, it has been suggested that these cells are concerned with controlling the onset and offset of saccadic and fixation behaviors and are an important source of efference copy to the cortical eye fields.291 In support of this hypothesis is the report that patients with lesions affecting the intralaminar nuclei show in-

accuracy of memory-guided saccades only if gaze is perturbed during the memory

period.103

Descending, Parallel Pathways that Control Voluntary Gaze

Here we will first describe the descending pathways from the several eye fields of cerebral cortex and then discuss the influence that each may have on the generation of saccades. No direct projection exists from cortical neurons to ocular motorkeurons;148 instead, several intermediate structures play important roles, including the caudate and putamen, substantia nigra pars reticulata, superior colliculus, and brain stem reticular formation. The descending pathway for smooth

pursuit is summarized in Figure 6-7. Refinement of the definition of the FEF

in monkeys, using microstimulation tech-

niques, has led to a revision of the projections of the FEE309-310 Each FEE projects

to its counterpart and also to other cortical areas concerned with visual processing, such as inferior parietal cortex.145 The descending projections of the FEF initially run in the anterior limb of the internal capsule; clinicallesions here and in the adjacent deep frontal region are reported to increase saccadic latency.258

Below the level of the internal capsule, several separate pathways can be discerned (Figure 6-9; Fig. 3-8, Chap.

3) 173,174 One projection, via the anterior limb of the internal capsule, goes to the caudate and adjacent putamen, which in turn project, via the pars reticulata of the substantia nigra (SNpr), to the superior colliculus. A transthalamic pathway starts in the anterior limb of the internal capsule and projects to the dorsomedial and intralaminar thalamic nuclei, to the ipsilateral superior colliculus and perhaps to certain midbrain reticular nuclei such as the riMLF.174 A pedunculopontine pathway runs from the internal capsule in the

most medial aspect of the cerebral peduncle.173 Its main projection is to the nucleus reticularis tegmenti pontis (NRTP) (Fig. 6-3), which in turn projects to the cerebellum. The PPRF and especially the midline pontine raphe nuclei that house saccadic omnipause cells also receive projections from the FEE174'293 A partial ocular motor decussation, first defined on the basis of stimulation studies,19'34 may occur between the levels of the trochlear and abducens nuclei.173

The SEE also projects to the caudate, putamen, superior colliculus, nucleus reticularis tegmenti pontis, and pontine omnipause neurons.143'300 The DLPC projects to parts of the caudate and

putamen the superior colliculus, and PPRF.8,173,297 Tne PEE projects to the su-

perior colliculus.5'183 How do these multiple projections from frontal and parietal cortex to the caudate nucleus, superior colliculus, and pontine nuclei (see Fig. 3-8) differ in the influence they exert on the voluntary control of saccades?

CONTRIBUTIONS OF THE STRIATAL-NIGRAL-COLLICULAR PATHWAY TO GAZE CONTROL

A pathway through the caudate and adjacent putamen seems to be important for execution of saccades, especially when made to remembered target locations.

The caudate and putamen receive inputs from the FEF,310 SEF,143 and DLPC.8 Most

neurons within the caudate nucleus that discharge for eye movements do so for memory-guided saccades,129 and the general properties of these cells suggests that they are concerned with complex aspects of ocular motor behavior that are neces-

sary, for example, in predicting environmental changes130'131 and the potential for

reward.1503 Functional imaging studies in humans have demonstrated activation of the putamen and substantia nigra during memory-guided saccades.233 Experimental lesions of the caudate and putamen produced ipsilateral gaze deviation and impairment of contralateral spontaneous, visually mediated, and memory-guided saccades.150'162 Patients with chronic lesions affecting the putamen (and globus

pallidus) show deficits in saccades made to remembered locations and in anticipation of predictable target motion; visually guided saccades are unaffected.336

The caudate and putamen send projections to the nondopaminergic substantia nigra pars reticulata (SNpr); these projections are probably GABAergic. Neurons in the SNpr have high tonic discharge rates that decrease before voluntary saccades that are either visually guided or made to remembered target locations.132"135 The SNpr, in turn, sends inhibitory projections to the superior colliculus; these projections are also GABAergic. A simplified view of this basal ganglia pathway is that it is composed of two serial, inhibitory links: a caudonigral inhibition, which is only phasically active, and a nigrocollicular inhibition, which is tonically active. If frontal cortex causes caudate neurons to fire, then the nigrocollicular inhibition is removed and the superior colliculus is able to activate a saccade. Studies of the effects of pharmacologically inactivating136-137 or chemically lesioning150'162 the nuclei in this pathway have supported this hypothesis. However, stimulation of caudate neurons produces suppression or facilitation of SNpr neurons; the facilitation may be due to a multisynaptic pathway.128 Thus, the means by which the frontal eye field influences the superior colliculus is complex and might produce difficulties in either initiating or suppressing saccades. Both deficits have been described in patients with disorders affecting the basal ganglia, such as Huntington's disease.170

DESCENDING PATHWAYS TO THE SUPERIOR COLLICULUS FOR GAZE CONTROL

The FEF, SEF, PEF, and DLPC all pro-

ject directly to the superior colliculus.143,183,295,297,310 In addition, the frontal

areas also project indirectly to the superior colliculus via the basal ganglia. The

superior colliculus has superficial, intermediate, and deep layers.203'204'303 The su-

perficial layers receive inputs from both the optic tract and visual cortical areas; these inputs are in register, so that a region receiving direct input from a specific

retinal area also receives indirect input from visual cortex that processes information about that same area of retina. The superficial layers of the superior colliculus contain neurons that enhance their activity when the visual stimulus to which they respond is to be the target for a saccadic eye movement.110 The more ventral layers of the superior colliculus contain neurons that, when stimulated, elicit saccadic eye movements. The direction and size of these elicited saccades is a function of the site of stimulation, indicating organization into a motor map.231'347 Neurons at the rostral pole of this motor map appear to be important for maintaining steady fixation and they project to omnipause neurons; more caudally located neurons project to burst neurons in the PPRF.46 Hypothetical schemes to account for how the superior colliculus might contribute to programing of saccades were reviewed in Chapter 3. An important point here is that the command by the superior colliculus to enact a saccade is influenced by several in- puts—directly from the FEF, SEF, and PEF, and indirectly via the basal ganglia.

CORTICOPONTINE PROJECTIONS FOR GAZE CONTROL

A direct pathway has been defined from the FEF to the PPRF, probably to longlead burst neurons and to the omnipause neurons that lie in the nucleus raphe interpositus (see Fig. 6-2).293'294>310 This pathway may explain why monkeys are still able to initiate saccades after ablation of the superior colliculus. However, this projection is small compared with that going via the nucleus reticularis tegmenti pontis (NRTP) to the cerebellum. Although this latter pathway is probably important in optimizing saccadic metrics, it is not essential for the initiation of saccades,

which persist even after total cerebellectomy.345

RELATIVE IMPORTANCEOF

DESCENDING PATHWAYSFOR GAZE CONTROL

Studies of the effects of restricted, experimental lesions have provided insights into

the relative roles of the descending pathways for saccades. In monkeys, pharmacological inactivation of the superior colliculus substantially impairs the ability to make saccades,172 but chronic lesions are associated with relatively minor deficits: an increase in saccadic latency, mild saccadic hypometria, reduced frequency of spontaneous saccades, and lessdistractibility on a fixation task.1 Collicular lesions also abolish short-latency or "express" saccades that occur if the fixation light is turned out prior to the appearance of a peripheral visual target.286 In normal circumstances, disappearance of the fixation light presumably releases the superior colliculus from inhibitory inputs so the appearance of the visual target can then elicit a short-latency saccade.89 If damage extends to the pretectum and adjacent posterior thalamus (possibly also affecting descending pathways for saccades), the deficit consists of an enduring hypometria without corrective saccades, suggesting that the correct motor error signal required to initiate a saccade no longer reaches the superior colliculus.2

Similarly, acute pharmacological inactivation of the FEF substantially impairs saccades, but chronic lesions cause minor deficits that affect visual search and saccades to remembered targets.72 In contrast, combined lesions of the FEFs and superior colliculi produce a severe and en-

marked hypometria of saccades and a restricted range of movement.152 Severe deficits of saccadic and pursuit eye movements also follow combined, bilateral lesions of parietal-occipital and frontal cortex in monkeys.182 With unilateral, combined parietofrontal lesions, saccades to visual targets in contralateral hemispace are impaired;184 with hemidecortication, the deficit is more enduring.329

In humans, the relative importance of the descending ocular motor pathways is less well defined. Functional imaging has not yet been able to document increased blood flow in the superior colliculi during saccadic tasks, but with increased resolu-